Endocrine responses to ghrelin in adult patients with isolated childhood-onset growth hormone deficiency

OBJECTIVE: Ghrelin, a 28 amino acid acylated peptide, is a natural ligand of the GH secretagogues (GHS) receptor (GHS-R), which is specific for synthetic GHS. Similar to synthetic GHS, ghrelin strongly stimulates GH secretion but also displays significant stimulatory effects on lactotroph and corticotroph secretion. It has been hypothesized that isolated GH deficiency (GHD) could reflect hypothalamic impairment that would theoretically involve defect in ghrelin activity. PATIENTS: In the present study, we verified the effects of ghrelin (1 μg/kg i.v.) on GH, PRL, ACTH and cortisol levels in adult patients with isolated severe GHD [five males and one female, age (mean ± SEM) 24.7 ± 2.6 years, BMI 25.7 ± 2.7 kg/m²]. In all patients, the GH response to insulin-induced hypoglycaemia (ITT, 0.1 IU regular insulin i.v.) and GH releasing hormone (GHRH) (1 μg/kg i.v.) + arginine (ARG, 0.5 g/kg i.v.) was also studied. The hormonal responses in GHD were compared with those in age-matched normal subjects (NS, seven males, age 28.6 ± 2.9 years, BMI 22.1 ± 0.8 kg/m²). RESULTS: IGF-I levels in GHD were markedly lower than in NS (69.8 ± 11.3 vs. 167.9 ± 19.2 μg/l, P < 0.003). Ghrelin administration induced significant increase in GH, PRL, ACTH and cortisol levels in all GHD. In GHD, the GH response to ghrelin was higher (P < 0.05) than that to GHRH + ARG, which, in turn, was higher (P < 0.05) than that to ITT (9.2 ± 4.1 vs. 5.3 ± 1.7 vs. 1.4 ± 0.4 μg/l). These GH (1 μg/l = 2 mU/l) responses in GHD were markedly lower (P < 0.0001) than those in NS (ghrelinvs. GHRH + ARG vs. ITT 92.1 ± 16.7 vs. 65.3 ± 8.9 vs. 17.7 ± 3.5 μg/l). In GHD, the highest individual peak GH response to ghrelin was markedly lower than the lowest peak GH response in NS (28.5 vs. 42.9 μg/l). GHD and NS showed overlapping PRL (1 μg/l = 32 mU/l) (10.0 ± 1.4 vs. 14.9 ± 2.2 μg/l), ACTH (22.3 ± 5.3 vs. 18.7 ± 4.6 pmol/l) and cortisol responses (598.1 ± 52.4 vs. 486.9 ± 38.9 nmol/l). CONCLUSIONS: This study shows that ghrelin is one of the most powerful provocative stimuli of GH secretion, even in those patients with isolated severe GHD. In this condition, however, the somatotroph response is markedly reduced while the lactotroph and corticotroph responsiveness to ghrelin is fully preserved, indicating that this endocrine activity is fully independent of mechanisms underlying the GH-releasing effect. These results do not support the hypothesis that ghrelin deficiency is a major cause of isolated GH deficiency but suggest that ghrelin might represent a reliable provocative test to evaluate the maximal GH secretory capacity provided that appropriate cut-off limits are assumed.