Novel mechanisms of growth hormone regulation: growth hormone-releasing peptides and ghrelin

Growth hormone secretion is classically modulated by two hypothalamic hormones, growth hormone-releasing hormone and somatostatin. A third pathway was proposed in the last decade, which involves the growth hormone secretagogues. Ghrelin is a novel acylated peptide which is produced mainly by the stomach. It is also synthesized in the hypothalamus and is present in several other tissues. This endogenous growth hormone secretagogue was discovered by reverse pharmacology when a group of synthetic growth hormone-releasing compounds was initially produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor to increase growth hormone release and food intake. It is still not known how hypothalamic and circulating ghrelin is involved in the control of growth hormone release. Endogenous ghrelin might act to amplify the basic pattern of growth hormone secretion, optimizing somatotroph responsiveness to growth hormone-releasing hormone. It may activate multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, since ghrelin has a greater ability to release growth hormone in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide, b) mechanisms of action of growth hormone secretagogues and ghrelin and possible physiological role on growth hormone modulation, and c) regulation of growth hormone release in man after intravenous administration of these peptides.

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

Prevalence and magnitude of osteopenia in patients with prolactinoma

1. The association between hypogonadism and osteoporosis has been reported. We conducted a study to establish the prevalence and magnitude of osteopenia in patients with prolactinoma and the relationship of bone loss with the duration of hypogonadism. 2. We measured the bone mineral density (BMD) of spine and femur (a site that has not been analyzed earlier) in 35 patients with prolactinoma using a dual-energy X-ray absorptiometer. The patients were classified as normal BMD and low BMD (osteopenics). 3. Seventeen patients (48 per cent ) showed osteopenia. The mean bone loss in the different regions was: spine, 13 per cent ; femoral neck, 15 per cent ; trochanter, 11 per cent ; Ward's, 22 per cent . This difference was only significant when the spine and Ward's region were compared. The duration of hypogonadism was significantly greater in the low-BMD group (11.3 vs 4.9 years) when compared to the normal BMD group. There was a positive relationship between the duration of hypogonadism and magnitude of bone loss in both spine and femur (P = 0.04; r = 0.6). 4. A high prevalence of osteopenia in both spine and femur was found in patients with prolactinoma, and was highly associated with the duration of hypogonadism. Early treatment of this condition seems important to prevent bone loss

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

Dose-dependent effects of vasoactive intestinal polypeptide on somatostatin release from hypothalamic fragments in vitro

Vasoactive intestinal polypeptide (VIP) is present in high concentrations in the hypothalamus and appears to be involved in the modulation of growth hormone (GH) secretion. The effects of VIP on huypothalamic somatostatin (SMS) release are, however, controversial. To further elucidate the mechanism of action of this peptide on GH secretion we studied the effects of VIP on SMS secretion from incubated rat hypothalamic fragments in vitro. At 10**6 M, VIP induced a significant increase in basal SMS release (P<0.01), whereas at 10**-10 M it had an inhibitory effect. We suggest that the increase in GH after in vivo administration of VIP may be modulated, at least in part, by a direct effect of this peptide on SMS neurons, while the stimulatory effect of high doses of VIP on SMS release may represent a pharmacological interaction of this peptide with growth hormone releasing hormone, peptide histidine isoleucine, or glucagon receptors

Desenvolvimento de um radioimunoensaio heterologico para a dosagem de prolactina humana no soro. / Development of a heterologous radioimmunassay for the determination of human prolactin in serun

Os autores descrevem o desenvolvimento de um radioimunoensaio heterologico para a dosagem de prolactina humana no soro. Anti-soros foram produzidos em coelhos pela injecao de prolactina ovina; o anti-soro escolhido propiciou o desenvolvimento de um metodo simples rapido e sensivel (2ng/ml) e nao apresenta reatividade cruzada significativa com hormonio de crescimento e com hormonio lactogenico placentario (inferior a 0,03%). A marcacao da prolactina humana foi feita pelo metodo da lactoperoxidade, obtendo-se, por cromatografia em coluna de Sephadex G-100, o monomero de prolactina-I125. A comparacao dos resultados obtidos na dosagem de 153 soros com o metodo descrito e com um radioimunoensaio homologo de referencias nao mostrou diferencas estatisticamente significativas