High-, Low-Dose ACTH Stimulation Tests Adequate for Ruling in Adrenal Insufficiency Diagnosis

Blood sample
Blood sample
Both high- and low-dose adrenocorticotropic hormone stimulation tests are adequate for including adrenal insufficiency as a diagnosis.

High- and low-dose adrenocorticotropic hormone (ACTH) stimulation tests appear to be similar in accuracy and are adequate for ruling in, but not ruling out, a diagnosis of primary or secondary adrenal insufficiency, according to data published in the Journal of Clinical Endocrinology & Metabolism.

“Prompt diagnosis [of adrenal insufficiency] is important since adequate hormonal replacement therapy is lifesaving,” the researchers wrote. “Even with early diagnosis and institution of therapy, patients with the diagnosis of adrenal insufficiency have higher mortality, decreased quality of life, and increased risk of adrenal crisis.”

However, the insulin-induced hypoglycemia test, which is considered the gold standard for diagnosis of secondary adrenal insufficiency, and the single-dose overnight metyrapone test, which has similar diagnostic accuracy, are “expensive, cumbersome, and have potential significant side effects compared to the ACTH stimulation tests,” the researchers noted.

To assess the accuracy of the high- and low-dose ACTH stimulation tests (250 mg and 1 mcg, respectively) for diagnosing primary or secondary adrenal insufficiency, the researchers conducted a systematic review and meta-analysis.

Thirty studies involving 1209 adults and 228 children were included for secondary adrenal insufficiency, and 5 studies involving 100 patients were included for primary adrenal insufficiency.

The studies evaluating diagnostic accuracy of high-dose ACTH stimulation for secondary adrenal insufficiency used different peak serum cortisol levels, ranging from 500 nmol/L at 30 minutes to 550 nmol/L.

Sensitivity was low and specificity was high for both high- and low-dose tests, yielding reasonable likelihood ratios for a positive test in adults (high-dose, 9.1; low-dose, 5.9) and children (high-dose, 43.5; low-dose, 7.7). Likelihood ratios for a negative test, however, were “fairly suboptimal” in both adults (high-dose, 0.39; low-dose, 0.19) and children (high-dose, 0.65; low-dose, 0.34).

For primary adrenal insufficiency, sensitivity of the high-dose ACTH stimulation test was 92% (95% CI, 81%-97%). The available data were insufficient to assess specificity, likelihood, and diagnostic ratios, according to the researchers.

“Both high- and low-dose ACTH stimulation tests have similar diagnostic accuracy,” the researchers wrote. “Both tests are adequate to rule in, but not rule out, primary and secondary adrenal insufficiency. Our confidence in these estimates is low-moderate due to the risk of bias of the included studies, heterogeneity, and imprecision.”


  1. Ospina NS, Nofal AA, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: Systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2015-1700.