Seractide/ACTH (1-39)

This is one of the few controlled human studies using full-length ACTH 1-39 (seractide) itself rather than the 1-24 fragment. Healthy men received IV bolus placebo, porcine ACTH 1-39 (1.5 U), or h-CRH, and cortical auditory evoked potentials were recorded. ACTH 1-39 produced central nervous system effects on evoked-potential components that differed from those of CRH, indicating that the intact 1-39 peptide exerts direct extra-adrenal (neuromodulatory) actions in humans independent of its classical adrenocortical cortisol-stimulating role.

Unlike most ACTH research, which uses a shortened synthetic fragment, this study gave people the complete natural ACTH molecule (the 1-39 form). Researchers measured brain electrical responses to sounds and found that full-length ACTH changed how the brain processed sound, separate from its familiar job of telling the adrenal glands to make cortisol. It shows the whole hormone can act directly on the brain, not just on the adrenal glands.

In healthy volunteers, graded intravenous ACTH doses were used to define the dose-response relationship for adrenal cortisol secretion. A dose as low as 1 microgram produced a maximal cortisol response essentially equal to that of the conventional 250 microgram dose, establishing 1 microgram as the threshold for maximal adrenocortical stimulation. The cortisol response to submaximal ACTH did not vary by time of day, indicating adrenal sensitivity to ACTH is stable across the diurnal cycle.

Doctors traditionally inject a large dose of ACTH to test whether the adrenal glands can make cortisol. This study showed that a tiny dose, one microgram, pushes the adrenal glands just as hard as the standard large dose. It also found the adrenal response is the same whether tested in the morning or later, which helped establish the modern 'low-dose' ACTH stimulation test.

This meta-analysis pooled 30 studies (1209 adults and 228 children for secondary adrenal insufficiency, ~100 patients for primary) evaluating high-dose (250 microgram) and low-dose (1 microgram) ACTH stimulation tests. High- and low-dose tests had similar diagnostic accuracy, with generally low sensitivity and high specificity; positive likelihood ratios were favorable (adults: high dose 9.1, low dose 5.9) but negative likelihood ratios were suboptimal. For primary adrenal insufficiency the high-dose test sensitivity was 92% (95% CI 81-97%), whereas both tests performed less reliably for excluding mild secondary (central) adrenal insufficiency.

This is a large review combining many studies of the ACTH stimulation test, the standard way to check if the adrenal glands are working. It found that both the high-dose and low-dose versions are good at confirming adrenal insufficiency when the test is abnormal, but a normal result does not fully rule out milder cases, especially when the problem originates in the pituitary. It gives clinicians a clear, evidence-based picture of what the test can and cannot tell them.