A GHRP-2 test can sort two forms of adrenal insufficiency

The research team reviewed records from 69 people who had both an insulin tolerance test and a CRH stimulation test between August 2015 and December 2024 ¹. An insulin tolerance test uses a controlled drop in blood sugar to see whether the adrenal glands answer with cortisol. CRH is a brain peptide that tells the pituitary to release ACTH, which then asks the adrenal glands for cortisol. A CRH test measures that chain. Secondary adrenal insufficiency means the adrenal glands themselves are normal, but the upstream pituitary or hypothalamus is not sending enough signal.

In this group, 43 people had insufficient cortisol on the insulin tolerance test, so they were diagnosed with secondary adrenal insufficiency ¹. The remaining 26 were classified as not adrenal insufficient. Among the 43 with insufficiency, the team used a cortisol cutoff of 18 micrograms per deciliter on the CRH test to split them further into hypothalamic and pituitary causes ¹. A lower CRH cortisol response pointed to a pituitary problem, and a response of 18 or above with still low insulin tolerance test cortisol pointed to a hypothalamic problem.

The CRH test was not enough on its own for people whose cortisol response looked normal. The team found that ACTH measurements during the CRH test could not cleanly separate hypothalamic adrenal insufficiency from non-adrenal insufficiency ¹. One pattern helped: a low basal ACTH level combined with a high ACTH peak after CRH suggested a hypothalamic cause. But the overlap was still wide. On the clinical side, the two groups looked different. Pituitary adrenal insufficiency was linked with tumors, immune-related side effects, glucocorticoid treatment, COVID-19, hypophysitis (inflammation of the pituitary gland), and empty sella (an imaging finding where the pituitary area appears flattened or empty). Hypothalamic adrenal insufficiency was linked mainly with tumors, opioids, and COVID-19 ¹. That difference helps doctors decide who needs more testing. It also explains why the CRH test alone can leave uncertainty.

GHRP-2 is a synthetic peptide that mimics the hunger hormone ghrelin and binds to its receptor in the pituitary. This causes the pituitary to release growth hormone ² and also nudges ACTH upward ⁴. In the new analysis, the team looked at peak cortisol after a GHRP-2 test. Among people whose CRH cortisol response was normal, a peak cortisol below 12 micrograms per deciliter on the GHRP-2 test was specific to hypothalamic adrenal insufficiency ¹. That means when the GHRP-2 test produced a weak cortisol response, the problem was more likely in the brain's control center than in the pituitary or adrenal gland itself.

The GHRP-2 test gives a different kind of challenge. It acts on the ghrelin receptor, not the CRH receptor, so it can expose a weak signal from the hypothalamus even when the pituitary answers a direct CRH order normally. In this study, the 12 microgram cutoff worked only among patients whose CRH cortisol response was already normal. For patients with a low CRH cortisol response, the pituitary cause was already clear ¹.

This is not the first evidence that GHRP-2 can probe the adrenal chain. A 2022 study in patients with hypothalamic-pituitary disorders found that GHRP-2 testing helped uncover secondary adrenal insufficiency that standard tests may have missed ⁵. A 2018 comparison also reported that GHRP-2 testing can evaluate the adrenal response when an insulin tolerance test is hard to perform ⁶. The new study goes one step further by using a specific cutoff to identify hypothalamic secondary adrenal insufficiency among people whose CRH cortisol response was normal ¹. Most of the existing data lean in the same direction: GHRP-2 acts on the pituitary to release ACTH, and a weak cortisol response can flag a problem in the brain-to-adrenal chain ⁴.

GHRP-2 already has a longer history as a growth hormone stimulation test in Japan and other settings ³. A peak growth hormone value after GHRP-2 helps identify severe adult growth hormone deficiency ³. The same test also produces an ACTH and cortisol rise, which is why researchers began looking at adrenal reserve ⁴. That dual response is uncommon among substances that trigger hormone release (secretagogues) and makes GHRP-2 useful in endocrine testing. In daily practice, the GHRP-2 test is less burdensome than an insulin tolerance test because it does not require a controlled drop in blood sugar ⁴. Still, the new work shows the GHRP-2 cortisol result is most useful as an add-on, not a replacement.

Adrenal insufficiency is not one condition. If the pituitary is damaged, the adrenal glands may shrink from lack of stimulation. If the hypothalamus is damaged, the pituitary still works but receives the wrong or absent signal. Treatments differ. A person with a pituitary tumor may need surgery or radiation, while a person with an opioid effect or a brain tumor may need a different plan. The new finding matters because a normal CRH test can hide the hypothalamic form. The GHRP-2 test adds a second angle: by asking the pituitary to respond through a different receptor, it can reveal whether the weak link sits above the pituitary ¹.

The limitation is that the new study looked back at records from one institution over about nine years. The participants were already selected for both tests, so the sample may not represent everyone with possible adrenal insufficiency. The result is a specific cutoff in a defined group, not a proven rule for all clinics. The authors also note that the insulin tolerance test remains necessary when the clinical picture suggests hypothalamic dysfunction ¹. The GHRP-2 cutoff is a supportive measurement when that test cannot be done or is unsafe.

Researchers have not tested whether the 12 microgram per deciliter GHRP-2 cortisol cutoff works in a large prospective group. It is not clear how well it separates hypothalamic from pituitary causes when people have mixed or mild disease. No multi-year safety or outcome data exist for repeated GHRP-2 testing outside short diagnostic use ². It also remains unknown how this test performs in children, in people using glucocorticoids, or in settings outside Japan where the test is not routine ¹.