Effects of ghrelin, growth hormone-releasing peptide-6, and growth hormone-releasing hormone on growth hormone, adrenocorticotropic hormone, and cortisol release in type 1 diabetes mellitus.

In type 1 diabetes mellitus (T1DM), growth hormone (GH) responses to provocative stimuli are normal or exaggerated, whereas the hypothalamic-pituitary-adrenal axis has been less studied. Ghrelin is a GH secretagogue that also increases adrenocorticotropic hormone (ACTH) and cortisol levels, similarly to GH-releasing peptide-6 (GHRP-6). Ghrelin's effects in patients with T1DM have not been evaluated. We therefore studied GH, ACTH, and cortisol responses to ghrelin and GHRP-6 in 9 patients with T1DM and 9 control subjects. The GH-releasing hormone (GHRH)-induced GH release was also evaluated. Mean fasting GH levels (micrograms per liter) were higher in T1DM (3.5 ± 1.2) than in controls (0.6 ± 0.3). In both groups, ghrelin-induced GH release was higher than that after GHRP-6 and GHRH. When analyzing Δ area under the curve (ΔAUC) GH values after ghrelin, GHRP-6, and GHRH, no significant differences were observed in T1DM compared with controls. There was a trend (P = .055) to higher mean basal cortisol values (micrograms per deciliter) in T1DM (11.7 ± 1.5) compared with controls (8.2 ± 0.8). No significant differences were seen in ΔAUC cortisol values in both groups after ghrelin and GHRP-6. Mean fasting ACTH values were similar in T1DM and controls. No differences were seen in ΔAUC ACTH levels in both groups after ghrelin and GHRP-6. In summary, patients with T1DM have normal GH responsiveness to ghrelin, GHRP-6, and GHRH. The ACTH and cortisol release after ghrelin and GHRP-6 is also similar to controls. Our results suggest that chronic hyperglycemia of T1DM does not interfere with GH-, ACTH-, and cortisol-releasing mechanisms stimulated by these peptides.

Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing's disease: comparison with GH-releasing peptide-6 (GHRP-6) and GHRH.

GH responsiveness to GH secretagogues (GHS) is blunted in Cushing's disease (CD), while ACTH/cortisol responses are enhanced, by mechanisms still unclear. Ghrelin, the endogenous ligand for GHS-receptors (GHS-R), increases GH, ACTH, cortisol and glucose levels in humans. This study evaluated the GH, ACTH, cortisol and glucose-releasing effects of ghrelin in CD in comparison with GHRP-6. GHRH-induced GH release was also studied. Ten patients with CD (BMI 26.9+/-1.0 kg/m(2)) and ten controls (BMI 24.4+/-1.1 kg/m(2)) received ghrelin (1 microg/kg), GHRP-6 (1 microg/kg) and GHRH (100 microg) separately. GH, ACTH, cortisol and glucose levels were measured. In CD ghrelin-induced GH (microg/L; mean +/- SE) release (peak: 7.2+/-3.0) was higher than seen with GHRP-6 (2.7+/-1.0) and GHRH (0.7+/-0.2), but lower than in controls (ghrelin: 58.3+/-12.1; GHRP-6: 22.9+/-4.8; GHRH: 11.3+/-3.7). In controls ACTH (pg/mL) release after ghrelin (79.2+/-26.8) was higher than after GHRP-6 (23.6+/-5.7). In CD these responses (ghrelin: 192+/-43; GHRP-6: 185+/-56) were similar, and enhanced compared to controls. The same was observed with cortisol. Glucose levels failed to increase after ghrelin in CD, differently than in controls. Our data suggests that hypothalamic and pituitary pathways of GH release activated by ghrelin, GHRP-6 and GHRH are deranged in chronic hypercortisolism. The increased ACTH/cortisol responses to ghrelin and GHRP-6 in CD could be mediated by overexpression of GHS-R in ACTH-secreting adenomas. Hypercortisolism apparently impairs the ability of ghrelin to increase glucose levels.

Growth hormone measurements versus auxology in treatment decisions: the Australian experience.

Growth hormone (GH) therapy is regulated in Australia by an expert national government committee. A national database (OZGROW) enables regular audits and rational guideline revisions. In 1988 the guidelines were revised to allow eligibility on auxologic criteria alone because of difficulties in diagnosing GH deficiency (GHD) and GH responses in non-GH-deficient children. Initial entry criteria were height less than the 3rd percentile and growth velocity less than the 25th percentile of bone age. Growth hormone testing was continued in most children. More than 3100 children have been treated since 1988 (35 percent with GHD, 12.5% with Turner syndrome, and 52% with other non-GHDs). Five-year responses (change in height SD scores) were best in the group with complete GHD (+2) (which received the lowest dose of GH) and similar in other groups, including those with partial GHD (+1.5). The increase in final height is 4 to 6 cm in subjects with Turner syndrome. This data is not yet available for subjects with other non-GHDs. In 1994 the guidelines were revised to restrict use of GH therapy to subjects with height less than the 1st percentile, and cessation of GH therapy was brought forward to bone age 13.5 years for girls and 15 years for boys. Subjects with maturational delay were excluded because of the finding that in the presence of significant bone age delay height prognosis was good. New patient accruals have decreased since 1992, from 100/yr to less than 50/yr. Expenditures have also fallen, from $31 to $16 in 1994-1995, because of reduced patient numbers and GH pricing. Australian use of GH is 68.7% that of the United States and 42.2% that of Sweden and is in the midrange internationally. In conclusion, an auxology-based GH program coupled with a comprehensive national database enables rational and economic use of GH in short children.

Long-term therapy with a single daily subcutaneous dose of growth hormone releasing hormone (1-29) in prepubertal growth hormone deficient children. Venezuelan Collaborative Study Group.

As part of a multicenter study to evaluate the efficacy and safety of one daily subcutaneous dose of 30 micrograms/kg of GHRH, 16 prepubertal GH-deficient children with a mean chronological age of 9.0 +/- 2.3 years were treated for 12 to 24 months. After six months of therapy 11 children (68.7%) were considered good responders in that their growth velocity increased by greater than 2 cm/yr over baseline and were continued on GHRH, while five subjects (31.3%) were regarded as poor responders and switched to recombinant hGH for the following six months. Growth velocity increased significantly in responders from a baseline of 3.4 +/- 0.7 cm/yr (mean +/- SD) to 6.8 +/- 0.1 cm/yr, 6.2 +/- 0.9 cm/yr, 6.6 +/- 1.0 cm/yr and 6.5 +/- 0.7 cm/yr at 6, 12, 18 and 24 months respectively. Bone ages advanced by an amount equivalent to the months of treatment. GHRH antibodies were detected in 4/11 and 6/11 responders at six and 12 months of treatment and in 2/5 non-responders at six months, but seemed not to interfere with growth. No side effects or changes in glucose and lipid levels were noted during therapy. These results suggest that GHRH (1-29) at the dose and schedule used is generally effective in the treatment of GH deficiency.