GHRP-2 Directly Stimulates ACTH in Pituitary Disorders, Bypassing Hypothalamus

The hypothalamo-pituitary-adrenal (HPA) axis is crucial for stress response, with its function typically assessed by the insulin-induced hypoglycemia test (ITT) and the corticotropin-releasing hormone (CRH) test. While growth hormone-releasing peptide-2 (GHRP-2) is known as a potent growth hormone secretagogue, it also stimulates adrenocorticotropin (ACTH) secretion. This study aimed to evaluate GHRP-2's precise role in HPA axis assessment, particularly in patients with existing hypothalamo-pituitary disorders, to understand its mechanism of ACTH release.

The study revealed significant differences in HPA axis responses among the 6 patients with hypothalamo-pituitary disorders. None of the 6 patients demonstrated any significant ACTH or cortisol responses during the insulin-induced hypoglycemia test (ITT), indicating a severe impairment in their HPA axis's ability to respond to hypoglycemia. In stark contrast, all 6 patients exhibited significant ACTH release when administered corticotropin-releasing hormone (CRH), suggesting their pituitary glands retained some capacity to produce ACTH. Crucially, the administration of growth hormone-releasing peptide-2 (GHRP-2) also induced significant ACTH secretion in all 6 patients, mirroring the response seen with CRH. This pattern of response, where GHRP-2 elicited ACTH release despite ITT failure, strongly suggests a direct stimulatory effect. The study's most important finding is that GHRP-2 directly stimulates ACTH secretion from the pituitary gland, bypassing the hypothalamic control mechanisms that were dysfunctional in all 6 patients.