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ACTH Stimulation Test (Cosyntropin)

Purpose: Evaluation of possible primary or secondary adrenal insufficiency, as well as disorders of adrenal steroid biosynthesis, such as congenital adrenal hyperplasia (CAH).1,2

Rationale: Cosyntropin, (ACTH 1-24), consists of the first 24 amino acids of the N-terminal portion of the intact native ACTH molecule (ACTH 1-36). This portion comprises the biologically active region of intact ACTH and is less allergenic than other forms of ACTH. It acts rapidly when bound to the melanocortin-2 receptor (MC2R) of the adrenal cortex initiating synthesis and release of cortisol and its precursors by 30 minutes3 and a saturating pulse dose is believed to act for at least two hours.4The magnitude and duration of response as measured by serum steroid levels may depend on the prior stimulation or suppression of the hypothalamic-pituitary-adrenal axis and the adequacy of drug administration. Normative interpretive data (See Adrenal Steroid Response to ACTH: Pediatrics) are for serum levels drawn at 60 minutes post stimulation and assume supraphysiological drug levels, causing maximal cortical stimulation. The half-life of cosyntropin is about 15 minutes and, since the drug is not reported to have any direct toxicity, a dose of 15 μg/kg up to a full dose of 250 μg (for a patient weight of ≥37 pounds) will give reliable results with the high likelihood of maximal stimulation; that a maximal cortisol response occurs at 30 minutes post 1 μg of ACTH (1-36) has been reported, but in that report the response waned by 60 minutes.5 Testing strategies should be tailored to the patient's age and suspected diagnosis, as outlined below.

(1) ACTH deficiency is suspected. Atrophy of the adrenal cortex due to ACTH deficiency may result in the lack of a significant cortisol response to single-pulse ACTH administration; the aldosterone response usually remains normal due to its synthesis in the zona glomerulosa, which is orchestrated by the renin-angiotensin system, not ACTH. Repeated ACTH stimulation may be necessary to judge the latent potential for synthesis of cortisol by the adrenal zona fasciculate and zona reticularis. An unstimulated morning cortisol level of 15 μg/dL suggests an intact hypothalamic-pituitary-adrenal axis.6

Metyrapone and insulin tolerance tests (ITT) have been the standards for evaluation of the hypothalamic-pituitary-adrenal axis, although a low-dose (1 μg of cosyntropin) can be considered instead of the ITT.6-12

(2) Disorder of steroid biosynthesis (CAH) is suspected. A baseline and 60-minute poststimulation CAH Comprehensive Screen (androstenedione, 11-desoxycortisol [specific compound S], cortisol, DHEA, DOC, 17 OH-pregnenolone, progesterone,17 OH-progesterone, and testosterone) for initial diagnosis. Abnormally high or low individual results, along with the clinical assessment will guide diagnosis and treatment. Some genetic abnormalities, such as p450 oxidoreductase deficiency may be difficult to diagnose by these biochemical means.9

(3) Primary adrenal insufficiency is suspected. If in an adrenal insufficiency crisis stimulation testing can be delayed until patient stabilization although usually an ACTH level and cortisol measurement can be drawn before hydrocortisone administration.

(4) Cortical suppression by chronic corticosteroid administration is suspected. If corticosteroid had been recently administered a hypoadrenal crisis is unlikely and a routine ACTH stimulation test can often proceed at the physician’s discretion. Modulation of the synthetic response may be blunted even though a supraphysiological dose is administered.

In all testing scenarios a baseline ACTH should be drawn. Baseline expected values for adrenal steroids are indicated by age (See Adrenal Steroid Response to ACTH: Pediatrics).

Procedure:

  • The patient may have a fat-free meal prior to testing.
  • Although it may make more physiologic sense to perform the test during the nadir of endogenous ACTH production (around midnight) it is usually performed at 8:00-9:00 AM for ease of collection and comparison to normative data that was collected during that time-frame.
  • Blood is drawn for baseline studies and the ACTH (1-24) administered intramuscularly or intravenously.
    • If intramuscularly, 250 μg for patient weight of ≥37 pounds.
    • If intravenously, dilute the cosyntropin in 2 mL to 5 mL of normal saline and inject over two minutes.
  • Samples for analysis are collected 60 minutes after administration of the cosyntropin.

Orderable Profiles−Procedures that include baseline and stimulated tests:

Interpretation: A rise from the baseline of at least 7 μg/dL to 10 μg/dL of cortisol, reaching at least 18 μg/dL at 60 minutes post stimulation effectively rules out primary adrenal insufficiency and suggests that adrenal suppression is minimal. A blunted or absent response suggests some level of secondary adrenal insufficiency (cortical atrophy or significant suppression.) If a subnormal response is obtained with an elevated baseline ACTH level, the patient has primary adrenal insufficiency or a form of ACTH unresponsiveness. A subnormal response with a low baseline ACTH level suggests CRF (corticotrophin releasing factor) and/or ACTH deficiency of hypothalamic and/or pituitary origin. Prior administration of estrogens, spironolactone, cortisone, and hydrocortisone (cortisol) can all interfere with the ACTH stimulation test by causing abnormally high baseline cortisol levels.

In children with CAH, a specific enzyme deficiency is reflected in accumulation of steroid intermediates along the synthetic pathway of cortisol, prior to, or parallel to the blocked enzymatic step. The levels of intermediates between cholesterol and cortisol, and on the alternative pathways leading to testosterone and aldosterone production, are different in newborns than in older children and adults: normal levels at various ages are (See Adrenal Steroid Response to ACTH: Pediatrics) to aid in interpretation of the test results.

References

1. Miller WL, Achermann JC, Fluck CE. The adrenal cortex and its disorders. In Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, Pa: Elsevier; 2008:444-511.

2. Dekkers OM, Timmermans JM, Smit JW, et al. Comparison of the cortisol responses to testing with two doses of ACTH in patients with suspected adrenal insufficiency. Eur J Endocrinol. 2011; 164(1):83-87. PubMed 21036888

3. Spiga F, Liu Y, Aguilera G, et al. Temporal effect of adrenocorticotrophic hormone on adrenal glucocorticoid steroidogenesis: Involvement of the transducer of regulated cyclic AMP-response element-binding protein activity. J Neuroendocrinol. 2011; 23(2):136-142. PubMed 21083631

4. Personal communication with S. Melmed.

5. Dickstein G, Spigel D, Arad E, et al. One microgram is the lowest ACTH dose to cause a maximal cortisol response. There is no diurnal variation of cortisol response to submaximal ACTH stimulation. Eur J Endocrinol. 1997; 137(8):172-175. PubMed 9272106

6. Stewart P, Krone N. The adrenal cortex. In Melmed S, Polonsky KS, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, Pa: Elsevier; 2011:479-544.

7. Rasmuson S, Olsson T, Hagg E. A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf). 1996; 44(2):151-156. PubMed 8849568

8. Hurel SJ, Thompson CJ, Watson MJ, et al. The short synacthen and insulin stress tests in the assessment of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf). 1996; 44(2):141-146. PubMed 8849566

9. Talwar V, Lodha S, Dash RJ. Assessing the hypothalamo-pituitary-adrenocortical axis using physiological doses of adrenocorticotropic hormone. QJM. 1998; 91(4):285-290. PubMed 9666951

10. Nye EJ, Grice JE, Hockings GI, et al. Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: Low dose, standard high dose, and 8-hour ACTH (1-24) infusion tests. J Clin Endocrinol Metab. 1999; 84(10):3648-3655. PubMed 10523009

11. Nye EJ, Grice JE, Hockings GI, et al. Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: Low dose, standard high dose and 8-h infusion tests. Clin Endocrinol (Oxf). 2001; 55(5):625-633. PubMed 11894974

12. Soule S, Van Zyl Smit C, Parolis G, et al. The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism. Clin Endocrinol (Oxf).2000; 53(2):211-227. PubMed 10931104

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