Normal hypothalamic-pituitary-adrenal axis by high-dose cosyntropin testing in patients with abnormal response to low-dose cosyntropin stimulation: a retrospective review.

OBJECTIVE To analyze the interpretation of the 1-microg low-dose adrenocorticotropic hormone (ACTH) test (LDT) for assessment of the presence of adrenal insufficiency (AI) in comparison with the 250-microg or standard high-dose ACTH test (HDT), which uses the same cutoff cortisol value of 18 microg/dL (500 nmol/L) as the lower limit of normal. METHODS We present a retrospective review of 26 patients referred to the Pituitary Clinic who underwent both the LDT and the HDT for evaluation of the function of the hypothalamic-pituitary-adrenal axis. RESULTS Of the 26 study patients, 23 had discordant findings--abnormal LDT and normal HDT results with use of the empiric cortisol cutoff of 18 microg/dL at 30 minutes in response to the ACTH dose. Glucocorticoid replacement therapy was stopped or not started in these patients, and no clinical symptoms of AI developed during a follow-up period ranging from 19 to 24 months. CONCLUSION Our retrospective review of patients' discordant LDT and HDT results questions the reliability of the LDT as a screening test for AI, as currently interpreted. Our data suggest that abnormal results should be evaluated in the context of the clinical picture and that additional testing may be indicated to prevent unwarranted treatment with glucocorticoids. Further studies are needed to establish a safe, sensitive, and specific test for the diagnosis of AI.

[1]  M. Maghnie,et al.  Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. , 2008, The Journal of clinical endocrinology and metabolism.

[2]  L. Saiegh,et al.  Low-dose and high-dose adrenocorticotropin testing: indications and shortcomings , 2008, Current opinion in endocrinology, diabetes, and obesity.

[3]  E. Husebye,et al.  Replacement therapy for Addison's disease: recent developments , 2008, Expert opinion on investigational drugs.

[4]  M. Magnotti,et al.  Diagnosing Adrenal Insufficiency: Which Test is Best—The 1-μg or the 250-μg Cosyntropin Stimulation Test? , 2008 .

[5]  R. Bouillon.  Acute adrenal insufficiency. , 2006, Endocrinology and metabolism clinics of North America.

[6]  C. Villabona,et al.  Profile, mean residence time of ACTH and cortisol responses after low and standard ACTH tests in healthy volunteers , 2006, Clinical endocrinology.

[7]  M. Maghnie,et al.  Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. , 2005, European journal of endocrinology.

[8]  A. Atkinson,et al.  Low- and standard-dose corticotropin and insulin hypoglycemia testing in the assessment of hypothalamic-pituitary-adrenal function after pituitary surgery. , 2004, The Journal of clinical endocrinology and metabolism.

[9]  T. Mckenna,et al.  The low‐dose ACTH test does not provide a useful assessment of the hypothalamic–pituitary–adrenal axis in secondary adrenal insufficiency , 2002, Clinical endocrinology.

[10]  G. Dickstein.  Hypothalamo–pituitary–adrenal axis testing: nothing is sacred and caution in interpretation is needed , 2001, Clinical endocrinology.

[11]  F. Keleştimur,et al.  A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery. , 2000, The Journal of clinical endocrinology and metabolism.

[12]  O. Jolobe,et al.  The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism. , 2000, Clinical endocrinology.

[13]  Y. Greenman,et al.  Low‐dose (1 μg) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo–pituitary–adrenal axis function: sensitivity, specificity and accuracy in comparison with the high‐dose (250 μg) test , 2000 .

[14]  R. Dullaart,et al.  Evaluation of adrenal function in patients with hypothalamic and pituitary disorders: comparison of serum cortisol, urinary free cortisol and the human‐corticotrophin releasing hormone test with the insulin tolerance test , 1999, Clinical endocrinology.

[15]  D. Streeten.  Shortcomings in the low-dose (1 microg) ACTH test for the diagnosis of ACTH deficiency states. , 1999, The Journal of clinical endocrinology and metabolism.

[16]  R. Clayton,et al.  Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. , 1999, The Journal of clinical endocrinology and metabolism.

[17]  H. C. Hoeck,et al.  Reproducibility of Growth Hormone and Cortisol Responses to the Insulin Tolerance Test and the Short ACTH Test in Normal Adults , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[18]  L. Blevins.  Serum cortisol is not an accurate predictor of the integrity of the hypothalamic-pituitary-adrenocortical axis. , 1995, Clinical endocrinology.

[19]  T. Mckenna,et al.  The overnight single‐dose metyrapone test is a simple and reliable index of the hypothalamic‐pituitary‐adrenal axis , 1994, Clinical endocrinology.

[20]  P. Hindmarsh,et al.  Reproducibility of the cortisol response to stimulation with a low dose of ACTH(1-24): the effect of basal cortisol levels and comparison of low-dose with high-dose secretory dynamics. , 1993, The Journal of endocrinology.

[21]  M. Lahav,et al.  Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. , 1991, The Journal of clinical endocrinology and metabolism.

[22]  W. Oelkers,et al.  Dose-response relationships between plasma adrenocorticotropin (ACTH), cortisol, aldosterone, and 18-hydroxycorticosterone after injection of ACTH-(1-39) or human corticotropin-releasing hormone in man. , 1988, The Journal of clinical endocrinology and metabolism.

[23]  H. Kehlet,et al.  RE‐EVALUATION OF THE CLINICAL VALUE OF THE 30 MIN ACTH TEST IN ASSESSING THE HYPOTHALAMIC‐PITUITARY‐ADRENOCORTICAL FUNCTION , 1987, Clinical endocrinology.

[24]  H. Kehlet,et al.  Value of the 30-minute adrenocorticotropin (ACTH) test in demonstrating hypothalamic-pituitary-adrenocortical insufficiency after acute ACTH deprivation. , 1983, The Journal of clinical endocrinology and metabolism.

[25]  H. Kehlet,et al.  Short ACTH test in assessing hypothalamic-pituitary-adrenocortical function. , 1976, British medical journal.

[26]  F. Poynton.  Observations ON THE NATURE AND SYMPTOMS OF CARDIAC INFECTION IN CHILDHOOD , 1918, British medical journal.