Partial restoration of GH responsiveness to ghrelin in Cushing's disease after 6 months of ketoconazole treatment: comparison with GHRP-6 and GHRH.

OBJECTIVE: In Cushing's disease (CD), GH responsiveness to several stimuli, including ghrelin, GHRP-6, and GHRH, is blunted. Recovery of GH secretion after remission of hypercortisolism after transsphenoidal surgery, radiotherapy, or adrenalectomy is controversial. There are no studies evaluating the effect of primary clinical treatment with ketoconazole on GH secretion in CD. The aim of this study is to compare ghrelin-, GHRP-6-, and GHRH-induced GH release before and after ketoconazole in CD. DESIGN: GH responses to ghrelin, GHRP-6, and GHRH of eight untreated patients with CD (mean age: 33.8+/-3.1 years; body mass index: 28.5+/-0.8 kg/m(2)) were evaluated before and after 3 and 6 months of ketoconazole treatment, and compared with 11 controls (32.1+/-2.5; 25.0+/-0.8). Methods Serum GH was measured by an immunofluorometric assay and urinary free cortisol (UFC) by liquid chromatography and tandem mass spectrometry. RESULTS: After ketoconazole use, mean UFC decreased significantly (before: 222.4+/-35.0 microg/24 h; third month: 61.6+/-10.1; sixth month: 39.1+/-10.9). Ghrelin-induced GH secretion increased significantly after 6 months (peak before: 6.8+/-2.3 microg/l; sixth month: 16.0+/-3.6), but remained lower than that of controls (54.1+/-11.2). GH release after GHRP-6 increased, although not significantly, while GH responsiveness to GHRH was unchanged. CONCLUSIONS: Ghrelin-induced GH release increases significantly after 6 months of ketoconazole treatment in CD. This could suggest that a decrease in cortisol levels during this time period can partially restore glucocorticoid-induced GH suppression in CD. GH-releasing mechanisms stimulated by ghrelin/GHS could be more sensitive, as no changes in GHRH-induced GH release were observed.

Avances en el diagnóstico de las alteraciones del eje somatotrófico que causan retardo del crecimiento / An update on the diagnosis of growth hormone axis disturbances that cause stunting

Human growth is a complex process regulated by several genes, most of which are unknown. Recently, our knowledge regarding the etiology of genetically determined causes of short stature has greatly increased, so molecular analysis is becoming essential for the diagnosis of growth retardation. The advances in our understanding of the molecular mechanisms involved in the function of the somatotrophic axis have resulted in a dramatic enhancement of our ability to diagnose and treat growth disorders. We hope that in the next few years improved methods for identifying specific abnormalities which cause short stature will expand our ability to diagnose other causes of growth retardation, and reduce the proportion of patients with "idiopathic" short stature.

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.

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.

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

Growth hormone (GH)-releasing hormone and somatostatin modulate GH secretion. A third mechanism has been discovered in the last decade, involving the action of GH secretagogues. Ghrelin is a new acylated peptide produced mainly by the stomach, but also synthesized in the hypothalamus. This compound increases both GH release and food intake. The relative roles of hypothalamic and circulating ghrelin on GH secretion are still unknown. Endogenous ghrelin might amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GH-releasing hormone. This peptide activates multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, as ghrelin induces a greater release of GH in vivo, its main site of action is the hypothalamus. In this paper we review the available data on the discovery of ghrelin, the mechanisms of action and possible physiological roles of GH secretagogues and ghrelin on GH secretion, and, finally, the regulation of GH release in man after intravenous administration of these peptides.

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.

Hormônio do crescimento ou somatotrófico: novas perspectivas na deficiência isolada de GH a partir da descrição da mutação no gene do receptor do GHRH nos indivíduos da cidade de Itabaianinha, Brasil / Growth or somatotrophic hormone: new perspectives in isolated GH deficiency after description of the mutation in the GHRH receptor gene in individuals of Itabaianinha county, Brazil

Além de influenciar o crescimento corpóreo, o hormônio do crescimento, ou somatotrófico, desempenha importante papel no metabolismo, composição corporal, perfil lipídico, estado cardiovascular e longevidade. Seu controle é multi-regulado por hormônios, metabólitos e peptídeos hipotalâmicos. Dados sobre a Deficiência Isolada de GH (DIGH) obtidos a partir da descrição da mutação IVS1+1G®A no gene do receptor do hormônio liberador do GH (GHRH-R) em indivíduos da cidade de Itabaianinha, SE, são revisados. São abordadas novas perspectivas sobre o modelo de resistência ao GHRH, a importância do GHRH no controle da secreção de GH, a freqüência das mutações do gene do GHRH-R, a relevância diagnóstica do IGF-I e os achados metabólicos, cardiovasculares e de qualidade de vida nestes indivíduos.

[Growth or somatotrophic hormone: new perspectives in isolated GH deficiency after description of the mutation in the GHRH receptor gene in individuals of Itabaianinha County, Brazil]. / Hormônio do crescimento ou somatotrófico: novas perspectivas na deficiência isolada de GH a partir da descrição da mutação no gene do receptor do GHRH nos indivíduos da cidade de Itabaianinha, Brasil.

In addition to stimulating body growth, growth or somatotrophic hormone plays an important role in metabolism, body composition, lipid profile, cardiovascular status and longevity. Its control is multiregulated by hormones, metabolites and hypothalamic peptides. Obtained data of the isolated growth hormone deficiency (IGHD) after the description of the IVS1+1G-->A GHRH receptor gene mutation in individuals of Itabaianinha County are reviewed. New perspectives about the growth hormone resistance model, the importance of GHRH in the control of GH secretion, the frequency of GHRH-R gene mutations, the diagnostic relevance of IGF-I and the metabolic, cardiovascular and quality of life findings are approached.

Lactogênese e reflexo ejecto-láctil / Lactogenesis and milk-ejection reflex

Apresenta-se uma revisäo näo exaustiva sobre os processos fisiológicos envolvidos com a produçäo e a ejeçäo de leite, bem como fatores que interferem em tais processos.

Physiology of growth hormone secretion during sleep.

The temporal relation between the first few hours of sleep and the secretion of growth hormone (GH), which is present in normal persons of both sexes from early childhood until late adulthood, is reviewed. In adults the most reproducible pulse of GH secretion occurs shortly after the onset of sleep in association with the first phase of slow-wave sleep (SWS) (stages III and IV). In men approximately 70% of the GH pulses during sleep coincide with SWS, and the amount of GH secreted during these pulses correlates with the concurrent amount of SWS. Sleep-related secretion of GH appears to be primarily dependent on the release of growth hormone-releasing-hormone. Rodent and human studies have shown that growth hormone-releasing hormone injections decrease wakefulness and increase SWS. During the fourth decade of life (ages 30 to 40 years) the total amount of GH secreted over a 24-hour span decreases by two- to threefold. Similarly, the amount of SWS decreases dramatically over the same narrow age range. Because the sleep-onset GH pulse is often the major secretory output in adults, age-related decrements in sleep-related GH secretion likely play a major role in the hyposomatotropism of senescence.

National Cooperative Growth Study substudy. II: Do growth hormone levels from serial sampling add important diagnostic information?

The National Cooperative Growth Study includes growth data on more the 24,000 children in the United States and Canada who have been treated with growth hormone (GH). To determine whether dysregulation of GH release causes growth failure in children, we initiated the National Cooperative Growth Study substudy II to evaluate the diagnostic utility of serially sampled GH levels and to determine whether those patterns were responsible for the low growth rates in certain subsets of short children and whether children in any of the diagnostic categories would respond to GH therapy. A total of 3744 subjects whose mean height standardized for their chronological age was -2.8 SD and whose pretreatment growth rate was 4.2 cm/yr had complete 12-hour data sets-- serial samples obtained in a 12-hour overnight period. Pulsatile characteristics of GH release were assessed with the cluster algorithm. There was a virtually complete overlap of the GH pulsatile characteristics between control subjects and short children, but the insulin-like growth factor I (IGF-I) levels were markedly lower in the short children, suggesting impairment in the GH-IGF-I axis. THe growth response to administered GH showed only very weak correlations with the various cluster-derived parameters. Our results indicate that one must look beyond the release of GH to find an explanation for the short statures and low IGF-I levels in the subsets of children with idiopathic short stature.

Efecto de la administración aguda de rilmenidina sobre la secreción de la hormona de crecimiento: estudio preliminar / Effect of rilmenidine of growth hormone secretion: preliminary study

En el presente estudio preliminar se analiza el efecto de la rilmenidina como estimulante de la secreción de hormona del crecimiento en un grupo de 8 niños pre-puberales con talla por debajo del promedio, pero dentro del rango normal (entre percentil 3 y el 25). Se encuentra que este agente en general es tan eficiente como la clonidina en este aspecto. De acuerdo con estos resultados se considera que la rilmenidina podría ser utilizada como prueba funcional en niños prepuberales con retraso del cresimiento y se plantea la posibilidad de utilizarla en el tratamiento de estos pacientes, en forma similar a la que se ha hecho con la clonidina