From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion

A secreção de hormônio de crescimento (HC) é modulada pelo hormônio liberador de HC e pela somatostatina. Na ultima década foi descoberto um terceiro mecanismo de controle, envolvendo os secretagogos de HC. A ghrelina é um peptídeo acilado, descoberto recentemente, que é produzido no estômago, porém também é sintetizado no hipotálamo. Este peptídeo é capaz de liberar HC, além de aumentar a ingestão alimentar. A ghrelina endógena parece amplificar o padrão básico de secreção de HC, ampliando a resposta do somatotrófo ao hormônio liberador de HC. Este peptídeo estimula múltiplas vias intracelulares interdependentes no somatotrófo, envolvendo a proteína quinase C, proteína quinase A e sistemas moduladores de cálcio extracelular. Entretanto, como a liberação de HC induzida pela ghrelina in vivo é mais acentuada que in vitro, seu local de atuação predominante é no hipotálamo. Nesse artigo apresentamos uma revisão sobre a descoberta da ghrelina, os dados existentes sobre os mecanismos de ação e possível papel fisiológico dos secretagogos de HC e da ghrelina na secreção de HC e, finalmente, os efeitos da administração endovenosa destes peptídeos sobre a secreção de HC no homem.

Growth acceleration in children with chronic renal failure treated with growth-hormone-releasing hormone (GHRH)

Growth retardation is a prominent clinical manifestation in children with chronic renal failure (CRF). Nine children with CRF (3 on conservative treatment; 3 on dialysis and 3 after renal transplantation) aged 1.6 to 14.0 (x+ SE: 8.1 + 1.4) years, were treated with twice daily subcutaneous injections of 26 + 2.4 mug/Kg/day growth-hormone-releasing-hormone [GHRH (1-29) NH2 Serono (Geref)] during 3 to 6 months. Mean serum urea and creatinine remained stable, although 2 patients on conservative treatment showed a moderate increase in serum creatinine. At the start of the study, heigth SDS was - 2.2 + 0.2 (x + SE), growth velocity was 4.5 + 1.0 cm/year (-2.3 + 0.6 DS for chronological age) and growth hormone (GH) response to acute GHRH test (1 mug/Kg IV) was 62 + 17.5 ng/ml. Five patients increased height velocity from 3.8 + 0.7 to 8.0 + 1.2 cm/year (paired t test, p < 0.05). The peak GH response to GHRH was significantly higher in the group of growth non-responders than in the responders (p<0.05). In conclusion, 5 out of 9 short children with CRF, 3 on conservative treatment, 1 on dialysis and 1 post renal transplantation, showed improved growth in response to GHRH therapy. No consistent effect on renal function was detected. GHRH may be an alternative therapy to increase grwth velocity in patients with CRF.

Different effects of pyridostigmine on growth hormone (GH) response to GH-releasing hormone in endogenous and exogenous hypercortisolemic patients

1. Somatostatin may play a role in the inhibition of growth hormone (GH) response to GH-releasing hormone (GHRH) in hypercortisolism. To examine this hypothesis we studied the effect of pyridostigmine, a cholinergic agonist that decreases hypothalamic somatostatin, on the GH response to GHRH in 8 controls, in 6 patients with endogenous hypercortisolism (3 with Cushing's disease and 3 with adrenal adenomas) and in 8 patients with exogenous hypercortisolism (lupus erythematosus chronically treated with 20-60 mg/day of prednisone). Each subject received GHRH(1-29)NH2,100 micrograms iv twice, preceded by pyridostigmine (120 mg) or placebo, orally. 2. The GH response to GHRH was significantly blunted in all hypercortisolemic patients compared to controls both after placebo (GH peak, 5.8 +/- 1.6 vs 46.2 +/- 15.9 micrograms/l, mean +/- SEM) and after pyridostigmine (15.7 +/- 5.6 vs 77.2 +/- 19.8 micrograms/l). 3. The GH response was absent in endogenous hypercortisolemic patients compared to the exogenous group, both after placebo (2.2 +/- 0.3 vs 8.5 +/- 2.4 micrograms/l) and after pyridostigmine (4.9 +/- 2.5 vs 23.8 +/- 8.7 micrograms/l). The GH release after GHRH/pyridostigmine for the exogenous group was similar to the response of controls treated with GHRH/placebo. 4. These results confirm that the GH response to GHRH is blunted in hypercortisolism, although more pronounced in the endogenous group. Pyridostigmine partially reversed this inhibition in the exogenous group. Therefore, somatostatin may play a role in the inhibition of GHRH-induced GH release in exogenous hypercortisolemic states

Inhibitory effect of calcitonin on growth hormone response to growth hormone releasing hormone in acromegaly

1. A neuroendocrine role for calcitonin (CT) has been suggested by the finding of CT receptors in the hypothalamus. We have recently shown that salmon calcitonin (sCT) inhibits growth hormone releasing hormone (GHRH)-induced GH secretion in msn by a mechanism apparently independent of changes in peripheral cortisol, glucose, calcium or parathyroid levels. 2. We have further investigated the inhibitory action of sCT on GH secretion by studying the effects of sCT (100 MRC units, im) or placebo on basal and GHRH (1-29) NH2 (50µg, iv) stimulated GH secretion in 6 acromemgalic patients with active disease. 3. Basal GH lelvels were not altered by sCT administration (placebo: 136 ñ 99 µg/1 vs sCT: 99 ñ 53 µg/1). However, the GH response to GHRH was decreased by sCT. The area under the curve was signficantly smaller when patients were treated with sCT compared to placebo controls (placebo: 77202 ñ 57036 vs sCT: 64828 ñ 51909 µg min-1 1-1; P < 0.01). No changes in glucose or calcium levels were observed. 4 These results demonstrate that sCT decresases GHRH-induced GH secretion in acromegalic patients. Although the mechanism of action of sCT on GH secretion is unknown, our results indicate that the inhibitory effect of this peptide on GH secretion is also observed in patients harboring pituitary adenomas

El uso del factor liberador de hormona de crecimiento (GRF) como prueba de reserva hipofisiaria para hormona de crecimiento (hGH) / Growth hormone releasing factor (GRF) as a test of pituitary reserve of growth hormone (hGH)

Diferentes pruebas inespecíficas de estimulación se emplean para estudiar la capacidad de la hipófisis para secretar hormona del crecimiento, pero ninguno es totalmente confiable. Los autores emplearon factor liberador de hormona del crecimiento (1microng x kg de peso corporal endovenoso) en 6 niños de talla baja pero sin afecciones endocrinas y en 4 pacientes con deficiencia comprobada de hormona del crecimiento. La concentración plasmática máxima de la hormona en los niños normales, durante la prueba, fue de 47,4 + ou - 15,4 ng x ml. Tres de los cuatro pacientes no mostraron respuesta a la provocación y en el cuatro la concentración plasmática máxima alcanzada fue de 5,3 ng x ml sugiriendo un origen hipotalámico para su deficiencia hormonal. El empleo de factor liberador sería de utilidad en el futuro para el diagnóstico y tratamiento de la deficiencia de hormona del crecimiento