The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency

Clin Endocrinol (Oxf). 2002 Apr;56(4):533-9. doi: 10.1046/j.1365-2265.2002.01509.x.


Objective: The 1 microg ACTH stimulation test has been introduced to improve the sensitivity of ACTH as a test of the integrity of hypothalamic-pituitary-adrenal axis (HPAA). This study aims to compare the sensitivity, specificity and diagnostic accuracy of the "low-dose" 1 microg ACTH (LDACTH) test and the "standard dose" 250 microg ACTH (SDACTH) test, with the overnight metyrapone test (OMT) which assesses the entire HPAA.

Design: A prospective evaluation of the performance of SDACTH and LDACTH screening tests in a diverse cohort of patients with possible adrenal insufficiency as routinely encountered in clinical practice using the OMT as the reference method.

Patients: A total of 51 patients (26 with asthma on inhaled glucocorticoid, nine with hypopituitarism, three with hypothyroidism, one with hyponatraemia, one with Crohn's disease, one with encephalitis and 10 with non-specific symptoms) each underwent SDACTH, LDACTH and OMT tests in random sequence at least 1 week apart.

Measurements: Blood was sampled for plasma cortisol levels at 0 and 30 min after intravenous administration of 1 microg and 250 microg of ACTH. Metyrapone 30 mg/kg body weight was taken orally at midnight, and plasma samples were taken for measurement of 11-deoxycortisol and cortisol next morning between 08.00 and 09.00 h. The OMT was deemed to be abnormal when both 11-deoxycortisol and cortisol levels were less than 200 nmol/l.

Results: The sensitivity and specificity at an empirical "normal" plasma cortisol threshold value of 500 nmol/l were 67% and 100% for the SDACTH test, and 73% and 81% for the LDACTH test, respectively. As the plasma cortisol cut-off value was increased to 550 nmol/l and 600 nmol/l, the sensitivity of the SDACTH test was 67% and 80% and specificity was 97% and 92%, respectively. The sensitivity of the LDACTH test increased from 93% at plasma cortisol cut-off value of 550 nmol/l to 100% at plasma cortisol cut-off value of 600 nmol/l. However, the specificity of the LDACTH test fell from 72% to 56% as the plasma cortisol cut-off value was increased from 550 nmol/l to 600 nmol/l. A receiver operating characteristic curve demonstrated that the specificity of the SDACTH test was higher than the specificity of the LDACTH test at any given level of sensitivity.

Conclusions: Both the LDACTH and SDACTH tests fail to achieve acceptable levels of sensitivity and specificity to be useful as screening tests for secondary adrenal insufficiency. In this context the OMT can be safely used to assess the integrity of the entire HPAA.

Publication types

  • Clinical Trial
  • Evaluation Study
  • Randomized Controlled Trial

MeSH terms

  • Adrenal Insufficiency / chemically induced
  • Adrenal Insufficiency / diagnosis*
  • Adrenocorticotropic Hormone*
  • Adult
  • Aged
  • Asthma / drug therapy
  • Dose-Response Relationship, Drug
  • Female
  • Glucocorticoids / adverse effects
  • Humans
  • Hydrocortisone / blood
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Male
  • Middle Aged
  • Pituitary-Adrenal System / physiopathology*
  • Prospective Studies
  • ROC Curve
  • Sensitivity and Specificity


  • Glucocorticoids
  • Adrenocorticotropic Hormone
  • Hydrocortisone