Reference Range
Adrenocorticotropin (ACTH) is a polypeptide hormone composed of 39 amino acids that is secreted by corticotroph cells in the anterior pituitary gland.
Each laboratory has its own reference range for ACTH depending on the assay used.
ACTH levels are higher in men and during pregnancy.
Normal findings
Adult/elderly [1]
Female (19 years or older): 6-58 pg/mL
Male (19 years or older): 7-69 pg/mL
Children [1]
Male and female (10-18 years): 6-55 pg/mL
Male and female (1 week-9 years): 5-46 pg/mL
Interpretation
Adrenocorticotropic hormone (ACTH) must be interpreted in context with the other components of the hypothalamic-pituitary-adrenal (HPA) axis, including hypothalamic corticotrophin-releasing hormone (CRH) and adrenal cortisol. Physiologic variations of plasma ACTH levels occur in response to physical stress (eg, hypoglycemia), diurnal variation (eg, highest in morning and lowest in late evening), and feedback inhibition from cortisol (see below).
Pathological plasma ACTH levels can be divided into clinic disorders resulting from either dysregulation (excess or deficiency) or compensatory responses (suppression or stimulation), or both (eg, Nelson syndrome), as described below. [2, 3, 4, 5, 6]
Increased plasma ACTH levels
Excess ACTH production may result from the following:
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ACTH-producing pituitary adenoma (Cushing disease)
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Ectopic ACTH-producing (nonpituitary) tumor
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Ectopic CRH-producing (nonpituitary) tumor
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Pseudo-Cushing disorders (depression, alcoholism, and anorexia nervosa)
Stimulated ACTH production may result from the following:
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Primary adrenal insufficiency (Addison disease)
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Congenital adrenal hyperplasia associated with impaired cortisol production
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11β-hydroxylase (CYP11B1)
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Cholesterol side-chain cleavage enzyme deficiency
Combined excess and stimulated ACTH production can result from Nelson syndrome (occurs in patients with Cushing disease treated with bilateral adrenalectomy)
Decreased ACTH levels
Insufficient ACTH production may result from the following:
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Hypothalamic CRH deficiency
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Craniopharyngioma and other structural lesions of the hypothalamus or pituitary stalk
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Infiltrative diseases of the hypothalamus (eg, sarcoid, histiocytosis X, tuberculosis, fungal infections)
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Traumatic brain injury (eg, basilar skull fracture)
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Pituitary corticotroph disease
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Congenital ACTH deficiency
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Autoimmune hypophysitis
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Drug-induced hypophysitis (eg, ipilimumab [Yervoy])
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Pituitary radiotherapy, infection, hemorrhage, or destructive sella turcica lesions
Suppressed ACTH production may result from the following:
Collection and Panels
Patient instruction: No need for fasting, preferred between 6 am and 9 am
Collection tube: Siliconized glass or plastic lavender top (EDTA)
Unacceptable conditions: Hemolyzed specimens
Specimen preparation: Separate serum from cells and transfer to transport tube
Storage/transport temperature: Frozen
Stability: 14 days frozen
Panels include the following:
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Part of the metyrapone stimulation test
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Part of the CRH stimulation test
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Part of the adrenocorticotropic hormone (ACTH) stimulation test
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Part of the insulin-induced hypoglycemia test
Background
Description
Adrenocorticotropic hormone (ACTH) is a polypeptide hormone composed of 39 amino acids that is secreted by corticotroph cells in the anterior pituitary gland; it derives from proopiomelanocortin (POMC), a preprohormone that undergoes several posttranslational modifications resulting in the production of many peptide fragments, including ACTH, melanotropin gamma (γ-MSH), lipotropin gamma (γ-LPH), and endorphin.
ACTH maintains the adrenal gland size, structure, and function and induces adrenal steroid production and secretion.
ACTH is secreted in two patterns. The circadian pattern start at 4 am, peaks before 7 am, and reaches its nadir between 11 pm and 3 am. The ultradian pulsatility pattern is characterized by secretory bursts that occur about 40 times per 24 hours. ACTH secretion is regulated by the hypothalamus through CRH and vasopressin, by some paracrine factor, and by negative feedback of the glucocorticoids. Under stressful conditions, the HPA axis is activated in order to produce glucocorticoid and to counteract the insult.
Indications/Applications
Because of the diurnal variability, episodic secretion, and wide reference range, random plasma ACTH levels have limited diagnostic value. Therefore, provocative testing with other components of the HPA axis is required for meaningful interpretation of plasma ACTH levels.
In general, suspected disorders of excessive ACTH production require testing for lack of suppressibility (usually with glucocorticoids). Conversely, for deficient ACTH production, stimulatory tests (usually CRH or metyrapone-induced hypocortisolism) are used.
Cushing disease due to excessive plasma ACTH levels caused by an ACTH-producing pituitary adenoma is often difficult to diagnose owing to the overlap with normal values. Dexamethasone suppression testing for this disease relies on serum cortisol measurement rather than plasma ACTH because cortisol is an easier assay with less variability. Ectopic CRH Cushing often mimics pituitary Cushing disease and cannot be differentiated with plasma ACTH. Nelson syndrome is associated with very high levels of plasma ACTH due to unrestrained ACTH-producing pituitary adenoma function following bilateral adrenalectomy and loss of cortisol feedback-inhibition. [5, 6]
Excessive plasma ACTH from ectopic ACTH-producing tumors characteristically have markedly elevated plasma ACTH (usually >200 pg/mL) levels and elevated serum cortisol levels. Measurement of ACTH by plasma extraction, which is used to detect ACTH precursors and POMC fragments, may be useful in distinguishing cancer-related syndromes or ACTH-secreting tumors from Cushing disease, as the former entities are more likely to produce these other forms of ACTH. ACTH-secreting neoplasm may be occult, creating diagnostic difficulties; in this instance, ACTH measurement using selective venous sampling has proven useful in localization of the lesion.
Low plasma ACTH levels are very useful in distinguishing endogenous Cushing syndrome caused by a cortisol-producing adrenal adenoma from pituitary and ectopic Cushing syndrome. Some adrenal adenomas produce just enough cortisol to suppress plasma ACTH levels, producing subclinical Cushing syndrome. After resection, significant adrenal insufficiency results from the HPA axis suppression, requiring short-term cortisol supplementation.
Plasma ACTH has also shown usefulness in monitoring the adequacy of cortisol replacement in congenital adrenal hyperplasia. [6] When replacement therapy is optimal, ACTH values are similar to those seen in a reference population, whereas excessive replacement suppresses plasma ACTH levels.
Perhaps the most useful application of plasma ACTH is to distinguish primary (adrenal) from secondary (pituitary) or tertiary (hypothalamic) adrenal insufficiency. Pharmacologic ACTH-stimulated cortisol levels are usually measured in patients suspected of having hypocortisolism. Pre-test ACTH levels are elevated in primary adrenal insufficiency, whereas low in secondary or tertiary adrenal insufficiency.
Provocative insulin-induced hypoglycemia testing
Hypoglycemia causes major stress and stimulates CRH and ACTH release, so it is helpful in evaluating the integrity of the HPA axis. It can be used in the diagnosis of adrenal insufficiency and growth hormone deficiency.
After an overnight fast, intravenous insulin at a dose of 0.1-0.3 unit/kg is injected in order to achieve symptomatic hypoglycemia and a blood glucose level of less than 40 mg/dL. Blood samples for glucose, ACTH, and cortisol levels are collected at 15 minutes before the injection; upon injection; and 15, 30, 45, 60, 90, and 120 minutes following the injection.
After the end of the test, glucose should be administered. Intravenous hydrocortisone should be available in case an adrenal crisis is precipitated by the hypoglycemia.
The test is contraindicated in pregnant patients and in patients known to have seizures, coronary artery disease, or stroke.
Provocative CRH stimulation testing
CRH (100 mcg or 1 mcg/kg) is administered intravenously, and cortisol and ACTH levels are measured at 5 minutes and one minute prior to injection; upon injection; and 15, 30, 60, 90, and 120 minutes following injection. This is used mainly in the diagnosis of Cushing syndrome.
The test can be combined with petrosal venous sampling to differentiate between Cushing disease and ectopic ACTH-secreting tumor. When combined with a 48-hour dexamethasone suppression test, it can help distinguish Cushing syndrome from a pseudo-Cushing disorder.
Considerations
ACTH production is under physiologic regulation from physical stress (eg, hypoglycemia), diurnal variation, and cortisol feedback-inhibition. Those factors should be considered when measurements of ACTH are obtained.
Altered molecular forms of ACTH with varying biologic and immunologic identity may be produced by ectopic ACTH-producing tumors. This may create discordance between measured ACTH levels and biologic activity .
