Background
The adrenocorticotropic hormone (ACTH) stimulation test is a relatively noninvasive laboratory assessment that involves the administration of a medication followed by the collection of blood samples. ACTH is a naturally occurring hormone released from the pituitary gland that stimulates the secretion of cortisol from the adrenal glands. Cortisol is a glucocorticoid that is responsible for the regulation of fat, carbohydrate, and protein metabolism. The test is extremely valuable, as it is safe and reliable in the diagnosis and assessment of adrenal insufficiency. Other names for this test include corticotropin or cosyntropin stimulation test, or short Synacthen test.
How to Use It
Adrenal insufficiency, either from a primary or secondary origin, is a condition in which the adrenal cortex of the adrenal gland does not produce adequate amounts of cortisol, aldosterone, and/or various androgens. In primary adrenal insufficiency (PAI), or Addison’s disease, the adrenal cortex is destroyed through various mechanisms, with the majority of cases (80%–90%) in developed countries due to autoimmune dysfunction. Other causes of PAI include medications that can either inhibit cortisol synthesis or increase cortisol metabolism. Secondary adrenal insufficiency (SAI) results in low concentrations of cortisol and ACTH, and it is commonly associated with long-term and/or high-dose exogenous glucocorticoid use. Chronic use of glucocorticoids may potentially result in atrophy of the anterior pituitary and hypothalamus, consequently leading to impaired recovery and function of these organs and prolonging cortisol insufficiency. Other causes of SAI are tumors, surgery, or radiation in the hypothalamic-pituitary region. To distinguish between these causes, comprehensive patient history and laboratory work are required, including the ACTH stimulation test. The ACTH stimulation test is currently regarded as the diagnostic gold standard for diagnosis of PAI and may potentially be used in determining the presence or resolution of SAI.
How It Is Done
PAI is first suspected with a low morning cortisol concentration from a blood draw and then confirmed by the ACTH stimulation test. The ACTH stimulation test is generally performed in an outpatient setting under the expertise of an endocrinologist. Although ACTH is lowest around midnight, the test is performed without concern for a specific time of day. , The standard or “high-dose” test begins with intravenous administration of 250 mcg of synthetic ACTH (cosyntropin) for adults, 125 mcg for children <2 years of age, or 15 mcg/kg for infants. After administration, a rise in cortisol is expected in about 30 minutes, with plasma cortisol concentrations peaking between 45 and 60 minutes. Blood samples are obtained to measure serum cortisol concentrations at the time of cosyntropin administration, then again 30 and/or 60 minutes after the injection. Peak cortisol concentrations <18 mcg/dL (500 nmol/L) indicate PAI. , , , These results are diagnostic; however, a normal concentration (>18 mcg/dL) could still be present in patients with SAI. Therefore, other testing is required to determine the presence of SAI and could include a corticotropin-releasing hormone stimulation test or insulin-induced hypoglycemia test. Changes in stress response should be considered for the management of patients in the setting of critical illness, since these factors greatly affect the sensitivity of the ACTH stimulation test. ,
Medication Implications
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The ACTH stimulation test is only performed at the initial diagnosis of PAI, and only symptomatic monitoring is required following diagnosis. ,
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Cosyntropin is a synthetic derivative of ACTH that is used for evaluation and diagnosis of adrenocortical insufficiency. ,
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Cosyntropin stimulates adrenal activity to the same extent of natural ACTH and may be referred to as tetracosactide outside of the United States.
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Side effects are rare, since it is only used for diagnostic purposes, but may include anaphylactic reaction, bradycardia, tachycardia, hypertension, peripheral edema, and rash; it may also accentuate electrolyte loss associated with diuretic therapy.
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Since there is potential for anaphylactic reactions, healthcare professionals should be prepared to treat an acute reaction prior to administering cosyntropin injection.
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Cosyntropin is considered as Pregnancy Category C; administration to pregnant women should only be done if the benefits outweigh the risks, and caution should be used during breastfeeding.
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The reference limit ranges for serum cortisol in correspondence with diagnosis should be based on assay-specific normative data.
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The ACTH stimulation test results may be severely affected by conditions such as cortisol-binding globulin (CBG) deficiency, glucocorticoid resistance, and hypersensitivity.
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Factors that will affect interpretation of test results include:
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CBG and albumin concentrations: Plasma cortisol is 80%–90% protein bound to CBG and 6%–10% bound to albumin. Therefore, only about 4% of cortisol is considered unbound or free. Medications that increase CBG concentrations (e.g., estrogen-containing oral contraceptives, mitotane) or albumin concentrations need to be considered when interpreting cortisol concentrations. ,
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Conditions such as nephrotic syndrome, cirrhosis, hyperthyroidism, immediate postoperative period, and patients requiring intensive care may have lower CBG and albumin concentrations, therefore lowering initial cortisol measurements. ,
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Medications that should be held prior to testing on test day: cortisone, hydrocortisone, and spironolactone; estrogen-containing drugs should be held 4–6 weeks prior to testing.
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An accurate medication history is vital to determine a potential cause of adrenal insufficiency. Drug-induced PAI may be caused by the following: adrenal hemorrhage (e.g., anticoagulants), inhibiting cortisol synthesis (e.g., ketoconazole, aminoglutethimide, mitotane, metyrapone, or etomidate), activation of glucocorticoid metabolism by anticonvulsants (e.g., phenytoin or phenobarbital), increased cortisol metabolism (e.g., levothyroxine), or antibiotics (e.g., rifampin). ,
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Exogenous glucocorticoid administration via any route (e.g., oral, intravenous, inhaled) may lead to adrenal suppression in patients taking supraphysiological doses, which is >20–30 mg prednisolone or equivalent for >3 weeks (see Table 8.1 for glucocorticoid equivalency). Formulations with longer half-lives have a higher risk of inducing adrenal insufficiency and include prednisolone, dexamethasone, and methylprednisolone. Glucocorticoids administered at doses as low as 5 mg/day prednisolone or equivalent have been shown to result in inadequate cortisol concentrations when undergoing ACTH stimulation testing. Thus, screening for use of these medications before testing is of utmost importance. Prior to discontinuing glucocorticoid therapy, a slow taper is required so that the hypothalamic-pituitary-adrenal (HPA) axis can regain its ability to respond to appropriate stimulation. Slowly reducing the dose every 3–4 days over a few weeks allows recovery of the HPA axis. After approximately 2–3 months of being on the same reduced dose of glucocorticoid, the ACTH stimulation test may be used to assess function of the HPA axis. Full recovery of the axis could take a total of 9–12 months. Once there is an adequate response to the test, ultimately signifying return of adrenal function, glucocorticoids may be safely discontinued. , ,
