Growth hormone-releasing hormone-secreting pulmonary neuroendocrine tumor associated with pituitary hyperplasia and somatotropinoma

SUMMARY Acromegaly caused by ectopic growth hormone-releasing hormone (GHRH)-secreting tumor is exceedingly rare. We report a case of acromegaly secondary to GHRH secretion by an incidentally diagnosed pulmonary neuroendocrine tumor (NET) and review 47 similar cases in literature. A 22-year-old male patient presented with symptoms of pituitary apoplexy. Magnetic resonance imaging (MRI) showed apoplexy of a pituitary adenoma. Routinely prior to surgery, a chest radiography was performed which revealed a mass in the left lung. During investigation, the patient was diagnosed with metastatic GHRH-secreting pulmonary NET. In retrospect, it was noted that the patient had pituitary hyperplasia 20 months prior to the MRI which showed the presence of a pituitary adenoma. The histological findings confirmed somatotroph hyperplasia adjacent to somatotropinoma. This case suggests that GHRH secretion can be associated with pituitary hyperplasia, which may be followed by pituitary adenoma formation.

The treatment effect of novel hGHRH homodimer to male infertility hamster

Extra-hypothalamic growth hormone-releasing hormone (GHRH) plays an important role in reproduction. To study the treatment effect of Grin (a novel hGHRH homodimer), the infertility models of 85 male Chinese hamsters were established by intraperitoneally injecting 20 mg/kg of cyclophosphamide once in a week for 5 weeks and the treatment with Grin or human menopausal gonadotropin (hMG) as positive control was evaluated by performing a 3-week mating experiment. 2–8 mg/kg of Grin and 200 U/kg of hMG showed similar effect and different pathological characteristics. Compared to the single cyclophosphamide group (0%), the pregnancy rates (H-, M-, L-Grin 26.7, 30.8, 31.3%, and hMG 31.3%) showed significant difference, but there was no difference between the hMG and Grin groups. The single cyclophosphamide group presented loose tubules with pathologic vacuoles and significant TUNEL positive cells. Grin induced less weight of body or testis, compactly aligned tubules with little intra-lumens, whereas hMG caused more weight of body or testis, enlarging tubules with annular clearance. Grin presented a dose-dependent manner or cell differentiation-dependentincrease in testicular GHRH receptor, and did not impact the levels of blood and testicular GH, testosterone. Grin promotes fertility by proliferating and differentiating primitive cells through up-regulating testicular GHRH receptor without triggering GH secretion, which might solve the etiology of oligoasthenozoospermia.

Análise dos genes GHRH e GL12 em pacientes com deficiência de hormônio do crescimento congênita / GHRH and GLI2 genes analysis in patients with congenital growth hormone deficiency

Introdução: Alterações em genes relacionados com a secreção de GH ou a organogênese hipofisária foram identificadas em pacientes com deficiência de hormônio do crescimento (DGH) congênita. Entretanto, poucos casos de DGH têm sua etiologia esclarecida. O GHRH é um candidato óbvio para explicar a deficiência isolada de GH (DIGH). Na literatura, os estudos de análise do GHRH não conseguiram identificar mutações, porém são antigos e utilizaram uma metodologia com limitações. A maioria dos pacientes com deficiência hipotálamo-hipofisária múltipla (DHHM) apresenta neuroipófise ectópica sugerindo a importância do estudo de genes que atuam no início do desenvolvimento hipofisário, com expressão inclusive no infundíbulo. O GLI2 é um fator de transcrição na sinalização Sonic Hedgehog, envolvido com o início da embriogênese hipofisária, expresso na bolsa de Rathke primordial e no diencéfalo ventral. Previamente, mutações no GLI2 foram encontradas em pacientes com holoprosencefalia, e também alterações hipofisárias. Objetivos: Analisar o GHRH em 151 pacientes com DIGH (42 brasileiros e 109 encaminhados de centros internacionais) e analisar o GLI2 em 180 pacientes brasileiros com DIGH ou DHHM por PCR e sequenciamento automático dos genes; e descrever o fenótipo dos pacientes com mutações identificadas. Resultados: No GHRH foram identificadas seis variantes em heterozigose com previsão benigna pelas análises in silico. A análise do GLI2 identificou três mutações novas em heterozigose com códon de parada prematuro (p.L788fsX794, p.L694fsX722 e p.E380X), e geração de proteínas truncadas, com perda do domínio responsável pela ativação transcricional. A mutação p.L788fsX794 foi identificada numa paciente com baixa estatura, polidactilia, epilepsia e hipoglicemias. Apresentava deficiência de GH, TSH, ACTH, prolactina, LH e FSH. Na investigação familiar foi diagnosticada DIGH em dois tios e DHHM numa prima. Estes familiares, além de sua mãe e outros parentes maternos também...

Introduction: Alterations in genes related to GH secretion and pituitary organogenesis have been identified in patients with congenital GH deficiency (GHD). However, in only few cases of GHD the etiology has been established. GH-releasing hormone (GHRH) is an obvious candidate to explain isolated GH deficiency (IGHD). Previous reports in the literature did not identify mutations in GHRH, however, the methodology used was limited. Most patients with combined pituitary hormone deficiency (CPHD) have an ectopic posterior pituitary lobe (EPP) suggesting the study of genes involved in early pituitary development and also expressed in the infundibulum. GLI2 is a transcription factor in Sonic hedgehog signaling expressed in the primordial Rathkes pouch and ventral diencephalon during early pituitary development. Previously, GLI2 mutations were found in patients with holoprosencephaly and pituitary abnormalities. Aim: Analyse GHRH in 151 patients with IGHD (42 Brazilian and 101 from international centers) and GLI2 in 180 Brazilian patients with IGHD or CPHD by PCR and automatic sequencing, and describe the phenotype of patients with mutations. Results: In GHRH, six heterozygous variants that are benign according to in silico analysis were identified. GLI2 study revealed three novel heterozygous mutations leading to premature stop codons (p.L788fsX794, p.L694fsX722 e p.E380X) and truncated proteins, without the transcriptional activator domain. p.L788fsX794 was identified in a girl with short stature, polydactyly, epilepsy and hypoglycemia. She had GH, TSH, ACTH, prolactina, LH and FSH deficiencies. Two uncles had IGHD and one cousin CPHD. These relatives, the mother and other maternal relatives had polydactyly and carried the mutation. p.L694fsX722 was identified in a boy with short stature due to GHD who also had cleft lip and palate. His healthy father also carried the mutation. p.E380X was identified in an infant with delayed development, hypoglycemia, polyuria...

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.

Study on the Reciprocal Interactions between Growth Hormone and Ghrelin in the Rat / 대한소아내분비학회지

PURPOSE: The aim of this study was to determine whether there is a feedback relationship between pituitary growth hormone (GH) and gastric ghrelin. METHODS: We intravenously administered 10 microgram of either rat ghrelin or normal saline to adult male Sprague-Dawley rats and then measured the plasma GH levels and the mRNA expression levels of pituitary GH mRNA and hypothalamic GH-releasing hormone (GHRH) mRNA. Human GH (500 microgram/kg, twice a day) or normal saline was subcutaneously administered to rats with or without food for 3 days. Thereafter, the plasma ghrelin levels and the ghrelin mRNA levels in the stomach were measured. RESULTS: The plasma GH levels increased more significantly in rats that were administered ghrelin than in controls (P<0.05). The mRNA levels of pituitary GH and hypothalamic GHRH were similar in the 2 groups. The plasma ghrelin levels and the stomach ghrelin mRNA levels were not affected by GH administration. Fasting significantly increased plasma ghrelin levels (P<0.05) and stomach ghrelin mRNA levels (P<0.05). CONCLUSION: Exogenous ghrelin administration only stimulated GH secretion without stimulating the synthesis of GH and GHRH. The synthesis and secretion of ghrelin were not suppressed by exogenous GH administration. These findings indicate that there is no feedback relationship between pituitary GH and gastric ghrelin.

Conseqüências em longo prazo da deficiência do hormônio de crescimento / Long time consequences of the growth hormone deficiency

Este artigo descreve as conseqüências puras, em longo prazo, da deficiência isolada e vitalícia do hormônio de crescimento (GH) porque usa um modelo único de resistência ao hormônio liberador do GH (GHRH), em virtude da mutação homozigótica no gene do receptor do GHRH, em uma centena de indivíduos acometidos. Elas incluem baixa estatura grave com estatura final entre -9,6 a -5,2 desvios-padrão abaixo da média, com redução proporcional das dimensões ósseas, redução do volume da adenohipófise corrigido para o volume craniano e da tireóide, do útero, do baço e da massa ventricular esquerda, todos corrigidos para a superfície corporal, em contraste com o tamanho de pâncreas e fígado, maior que o de controles, quando igualmente corrigidos. As alterações características da composição corporal incluem redução acentuada da quantidade de massa magra (kg) e aumento do percentual de gordura com depósito predominante no abdome. Nos aspectos metabólicos são encontrados aumento de colesterol total e LDL, redução de insulina e do índice de resistência à insulina homeostasis model assessment, acompanhados de aumento da proteína C reativa de alta sensibilidade e da elevação da pressão arterial sistólica nos adultos, embora sem evidências de aterosclerose precoce. Outros achados incluem resistência óssea menor, embora acima do limiar de fraturas, puberdade atrasada, fertilidade normal, paridade diminuída, climatério antecipado e qualidade de vida normal.

This article describes the long time consequences of the isolated and lifetime growth hormone (GH) deficiency using a single model of GH releasing hormone resistance (GHRH) due to a homozygous mutation in the GHRH receptor gene, in a hundred of subjects. These consequences include severe short stature with final height between -9.6 and -5.2 standard deviations below of the mean, with proportional reductions of the bone dimensions; reduction of the anterior pituitary corrected to cranial volume and the thyroid, the uterus, the spleen and left ventricular mass volume, all corrected to body surface, in contrast of pancreas and liver size, bigger than in controls, when equally corrected. Body composition features included marked reduction in the amount of fat free mass (kg) and increase of fat mass percentage, with predominant abdominal deposit. In the metabolic aspects, we find increase in the total cholesterol and LDL cholesterol; reduction of the insulin and the insulin resistance assessed by Homeostasis model assessment; increase of ultra sensitive C reactive protein and systolic body pressure in adults, although without evidences of premature atherosclerosis. Other findings include smaller bone resistance, although above of the threshold of fractures, delayed puberty, normal fertility, small parity, anticipated climacteric and normal quality of life.

Ghrelina e secretagogos do hormônio de crescimento (GHS): modulação da secreção do hormônio de crescimento e perspectivas terapêuticas: [revisão] / Ghrelin and growth hormone secretagogues (GHS): modulation of growth hormone secretion and therapeutic applications: [review]

A secreção do hormônio de crescimento (GH) é modulada pelo hormônio liberador de hormônio de crescimento (GHRH) e pela somatostatina. Na última década foi descoberto um terceiro mecanismo de controle, envolvendo os secretagogos de GH (GHS). A ghrelina, o ligante endógeno do receptor dos GHS, é um peptídeo acilado produzido no estômago, que também é sintetizado no hipotálamo. Este peptídeo é capaz de liberar GH, além de aumentar a ingesta alimentar. A ghrelina endógena parece amplificar o padrão básico de secreção de GH, ampliando a resposta do somatotrofo ao GHRH, estimulando múltiplas vias intracelulares interdependentes. Entretanto, seu local de atuação predominante é o hipotálamo. Neste trabalho, será apresentada revisão sobre a descoberta da ghrelina, os mecanismos de ação e o possível papel fisiológico dos GHS e da ghrelina na secreção de GH e, finalmente, as possíveis aplicações terapêuticas destes compostos.

Growth hormone-releasing hormone (GHRH) and somatostatin modulate growth hormone (GH) secretion. A third mechanism was discovered in the last decade, involving the action of growth hormone secretagogues (GHS). Ghrelin, the endogenous ligand of the GHS-receptor, is an acylated peptide mainly produced by the stomach, but also synthesized in the hypothalamus. This compound increases both GH release and food intake. Endogenous ghrelin might amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GHRH, activating multiple interdependent intracellular pathways. However, its main site of action is the hypothalamus. In the current paper it is reviewed the available data on the discovery of this peptide, the mechanisms of action and possible physiological roles of the GHS and ghrelin on GH secretion, and finally, the possible therapeutic applications of these compounds.

Effect of one month ketoconazole treatment on GH, cortisol and ACTH release after ghrelin, GHRP-6 and GHRH administration in patients with cushing’s disease

GH responses to ghrelin, GHRP-6, and GHRH in Cushing’s disease (CD) are markedly blunted. There is no data about the effect of reduction of cortisol levels with steroidogenesis inhibitors, like ketoconazole, on GH secretion in CD. ACTH levels during ketoconazole treatment are controversial. The aims of this study were to compare the GH response to ghrelin, GHRP-6, and GHRH, and the ACTH and cortisol responses to ghrelin and GHRP-6 before and after one month of ketoconazole treatment in 6 untreated patients with CD. Before treatment peak GH (mg/L; mean ± SEM) after ghrelin, GHRP-6, and GHRH administration was 10.0 ± 4.5; 3.8 ± 1.6, and 0.6 ± 0.2, respectively. After one month of ketoconazole there was a significant decrease in urinary cortisol values (mean reduction: 75 percent), but GH responses did not change (7.0 ± 2.0; 3.1 ± 0.8; 0.9 ± 0.2, respectively). After treatment, there was a significant reduction in cortisol (mg/dL) responses to ghrelin (before: 30.6 ± 5.2; after: 24.2 ± 5.1). No significant changes in ACTH (pg/mL) responses before (ghrelin: 210.9 ± 69.9; GHRP-6: 199.8 ± 88.8) and after treatment (ghrelin: 159.7 ± 40.3; GHRP-6: 227 ± 127.2) were observed. In conclusion, after short-term ketoconazole treatment there are no changes in GH or ACTH responses, despite a major decrease of cortisol levels. A longer period of treatment might be necessary for the recovery of pituitary function.

Na doença de Cushing (DC), as respostas do GH à ghrelina, ao GHRP-6 e ao GHRH estão diminuídas. Não existem dados sobre o efeito da redução dos níveis de cortisol, após cetoconazol, na secreção de GH na DC. Nessa situação, os níveis de ACTH são variáveis. Os objetivos do estudo são comparar as respostas do GH à administração de ghrelina, GHRP-6 e GHRH, e de ACTH e cortisol à ghrelina e ao GHRP-6 antes e após um mês de tratamento com cetoconazol em 6 pacientes com DC não tratados. Antes do tratamento, o pico de GH (mg/L; média ± EPM) após a administração de ghrelina, GHRP-6 e GHRH foi de 10,0 ± 4,5; 3,8 ± 1,6 e 0,6 ± 0,2, respectivamente. Após um mês de cetoconazol, ocorreu diminuição significante do cortisol urinário (redução média: 75 por cento), mas as respostas de GH permaneceram inalteradas (7,0 ± 2,0; 3,1 ± 0,8; 0,9 ± 0,2, respectivamente). Após o tratamento, houve redução da resposta de cortisol (mg/dL) à ghrelina (antes: 30,6 ± 5,2; após: 24,2 ± 5,1), mas não ocorreram mudanças nas respostas de ACTH (pg/mL) (ghrelina antes: 210,9 ± 69,9; após: 159,7 ± 40,3; GHRP-6 antes: 199,8 ± 88,8; após: 227 ± 127,2). Assim, o tratamento a curto prazo com cetoconazol não modificou as respostas de GH ou ACTH, apesar da redução do cortisol. Para a recuperação da função hipofisária deve ser necessário um período de tratamento maior.

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

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.

Current Research on the Structure and Function of the Growth Hormone Releasing Hormone Receptor / 대한내분비학회지

Growth hormone releasing hormone receptor (GHRH-R) is a family B1 G-protein coupled receptor found predominantly on pituitary somatotrophs. In the adults it is required for the normal synthesis and release of growth hormone (GH) from the pituitary. During development it is required for the normal proliferation and maturation of somatotrophs within the pituitary. Mutations of this receptor in mouse and man are associated with GH deficiency, short stature and pituitary hypoplasia. This signaling system plays important roles in growth and development, metabolism of muscle and fat, and is implicated in the regulation of cardiac and immune function, wound healing, tumor growth and the aging process. Current areas of active research discussed here include: studiesof the structure of the receptor binding site and its interaction with GHRH, alternative splice variants of the GHRH-R which appear to promote tumor proliferation, truncated receptor isoforms that act as dominant negative inhibitors of wild type receptor, and the unclear physiologic role of the GHRH system in birds and fishes.

Growth of children with beta-thalassemia major.

Hypertransfusion and regular chelation therapy have allowed improved survival in patients with thalassemia major (TM). Despite medical advances, growth failure and hypogonadism remain significant clinical problems in these patients in adolescence. Disproportionate truncal shortening which is common especially among adolescents with thalassemia, is due to platyspondyly resulting from a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements. Although growth hormone (GH) deficiency and GH neurosecretory dysfunction have been described in TM patients, most short TM patients have normal GH reserve. The low serum IGF-1 and IGFBP-3 concentrations in TM patients despite having normal GH reserve and serum GH binding protein levels suggest that a state of secondary GH insensitivity exists. The pubertal growth spurt may be impaired in TM patients going through spontaneous or induced puberty and may have a negative effect on final adult height. GH therapy in dosages ranging from 0.5-1.0 IU/kg/wk has resulted in a significant improvement in growth velocity in short TM children without any adverse effects on skeletal maturation, blood pressure, glucose tolerance and serum lipids. There is limited evidence that GH treatment can result in an improved final adult height in short TM children. Careful and regular clinical and biochemical monitoring should be preformed on these patients while they are treated with GH.

Changes in Somatostatin Receptor mRNA Levels by G Protein Mutation in GH3 Cells Which Show Responsiveness to Growth Hormone-Releasing Hormone / 대한내분비학회지

BACKGROUNDS: GH3 cells lack growth hormone(GH)-releasing hormone(GHRH) receptors. In this study, GH3 cells permanently transfected with human GHRH receptor cDNA(GH3-GHRHR cells), were established in order to examine the effects of GHRH and G protein mutation(gsp oncogene) on the levels of somatostatin receptor mRNA. METHODS: GH3 cells were permanently transfected with a plasmid expressing human GHRH receptor cDNA. The GHRH receptor mRNA was detected by RT-PCR. The responsiveness to GHRH was evaluated using a GHRH binding assay, Western blot analysis, Northern blot analysis, and measurements of the intracellular cAMP levels and GH release. Cells were transiently transfected with the gsp oncogene, and then treated with GHRH or octreotide for 4h. The sst1 and sst2 mRNA levels were measured using real-time RT-PCR analyses. RESULTS: GHRH receptor mRNA was detected in the GH3 cells permanently transfected with human GHRH receptor cDNA. The GHRH binding assay showed that GHRH was bound to the GH3-GHRHR cells. The GHRH treatment increased the intracellular cAMP levels, GH release, GH mRNA levels, and MAPK activity, as well as the levels of sst1 and sst2 mRNA. Transient expression of the gsp oncogene for 48h increased the cAMP, GH release, and levels of sst1 and sst2 mRNA. In the gsp-transfected GH3-GHRHR cells, GHRH stimulation resulted in decreases in the magnitude of the increase in the levels of sst1 and sst2 mRNA compared to those transfected with a control vector. Octreotide treatment did not alter the levels of sst1 and sst2 mRNA in either the control or gsp-transfected cells. CONCLUSION: These results suggest that GH3 cells permanently transfected with the GHRH receptor are useful in the in vitro studies on the actions of GHRH. The gsp oncogene was shown to increases the levels of sst1 and sst2 mRNA in GH3 cells, but these findings are unlikely to be the major mechanism by which gsp-positive pituitary tumors show a greater response to somatostatin. The discrepancy between the in vivo and these in vitro results should be examined further.

The effect of chronic intermittent hypoxia to hypothalamus-pituitary-adrenal axis and growth hormone level in rats during sleep / 中国应用生理学杂志

<p><b>AIM</b>To research the effect of intermittent hypoxia during sleep on hypothalamus-pituitary-adrenal (HPA) axis and growth hormone (GH) level.</p><p><b>METHODS</b>Rats were respectively exposed to intermittent hypoxia, room air and continuous hypoxia, after 1 day, 3 days, 7 days and 30 days, mRNA levels of corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH) in hypothalamus of rats were detected using RT-PCR, and the levels of CRH, GHRH, corticotropin(ACTH), cortex ketone, and growth hormone in plasma were measured.</p><p><b>RESULTS</b>After 30 days, the CRH mRNA levels in rats hypothalamus which exposed to intermittent hypoxia were increased significantly than those exposed to continuous hypoxia as well as normal control but GHRH decreased, there was no difference between continuous hypoxia and normal control. After 1 day, 3 days, and 7 days, there was no difference between continuous hypoxia and intermittent hypoxia. After 30 days, the plasmic level of CRH,ACTH and cortex ketone increased, GHRH decreased and GH had no obvious change.</p><p><b>CONCLUSION</b>The rats' HPA axis level increases and GHRH restrained with chronic intermittent hypoxia during sleep, feedback regulation disorders.</p>

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.

The expression of growth hormone release factor gene carried with PLGA microspheres in muscle tissue and its effect on mouse growth / 生物工程学报

Injectable sustained-release pcDNA3-GRF (1-32) microspheres were prepared by double emulsion-in liquid evaporation process,using biodegrable poly lactic-co-glycolic acid as carrier. The enrapment efficiency, mean particle size, drug content thus prepared were 69%, 2.20 microm, 8% and 70% respectively. The result of transfection in vivo showed that after 30 days, accumulative increased body weights on the group injected with pcDNA3-GRF (1-32) microspheres was significantly higher than those group injected with naked plasmid (12.87%), plasmid-empty microspheres (19.72%) and saline (58.58%) respectively. PCR and RT-PCR showed that the expression level of GRF gene on the group injected with pcDNA3-GRF (1-32) microspheres was the highest. GRF gene released by microspheres was still detected after 30 days. In conclusion, pcDNA3-GRF (1-32) microspheres have a controlled release effect and GRF gene could be successfully transfected into muscle cells of mouse by microspheres with higher efficacy and stronger biological function.

Response to the Combined Pituitary Stimulation Test by CRH, GHRH, GnRH and TRH in Normal Human According to Age and Gender / 대한내분비학회지

BACKGROUND: It has been already known that each trophic hormone in combined pituitary responsiveness according to gender and age brings about variable response, but in Korea, there has been no actual data. In this study, in order to assess the pituitary responsiveness, a combined pituitary stimulation test was performed in Korean subjects with the variation in CRH, GHRH, GnRH, and TRH according to their age and gender. Were these the variables that were changed according to age and gender? Clarify that. Also, it might be good to write out the abbreviations.) METHOD: Fourteen physically and mentally healthy male subjects and fourteen female subjects, also physically and mentally healthy, underwent the combined anterior pituitary stimulation test by CRH, GHRH, LHRH, and TRH. Each gender group was divided further into young(meanSE; male: 231, female: 221) and old (mean; male: 513, female: 522) groups. RESULTS: There were significant differences between the gender and age groups. The Peak GH level and maximal GH increment were significantly increased in young men compared to old men. The Peak ACTH level and maximal ACTH increment were significantly increased in old men as opposed to young men. The Peak PRL level, maximal PRL increment, Peak TSH level, and maximal TSH increment were significantly increased in old women compared to old men. The Peak FSH level was significantly increased in the two old groups compared to the young groups, which showedindependence in gender, and the maximal FSH increment was significantly increased in old men when compared with the young men. CONCLUSION: These results show that in order to for accurate interpretation of the response from the combined pituitary stimulation test, it is necessary to consider age and gender of the subjects. We suggest response values of the combined pituitary stimulation test in terms of age and gender in healthy Korean subjects.

The One Year Effects of Growth Hormone Replacement on the Body Composition in the Normal Adults / 대한내분비학회지

BACKGROUND: The secretion of growth hormone [GH] declines by 14.4% every decade, leading to the suggestion that the elderly are functionally GH deficient, which may increase adipose tissue and decrease the bone mass and density, as well as other negative changes in body composition. Recently, many studies have shown that GH replacement therapy may restore the changes that occur in the body composition with aging. AIM: The GH and insulin like growth factor-I[IGF-I] profiles were identified during GH replacement therapy in the elderly and compared with those of GH deficient[GHD] patients. The metabolic effects of GH replacement on the body composition of the elderly was also investigated, especially the body fat, muscle and bone parameters. Subjects and METHODS: 98 healthy normal out-patients and 13 GHD patients, who had peak GH concentrations less than 5 ng/mL after an insulin tolerance test [ITT] or growth hormone releasing hormone [GHRH] stimulation test, were the subjects of this study. All were receiving appropriate thyroid, adrenal and gonadal hormone replacements. The dose of recombinant human GH [rhGH] was 0.02~0.04 mg [0.06~0.12 IU]/kg of body weight.per week, given nightly by a subcutaneous injection, six times a week, over a 52 week period. The GH was measures after the ITT and GHRH stimulation tests, and the IGF-1, lipid parameters [total cholesterol, triglyceride, HDL-, and LDL cholesterol], visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], VAT/SAT ratio, quadriceps muscle area, total body fat, total bone mineral density [BMD], alkaline phosphatase [ALP], osteocalcin and urine deoxypyridinoline [DYP], as well as anthropometry, were also assessed. RESULTS: All the anthropometry features between the normal and GHD subjects were very similar. The hormonal profiles were checked; the GH peaks of the ITT and GHRH stimulation tests were significantly higher in the normal compared to the GHD patients, but the GHRH test showed lower GH peaks in than those of the ITT test in the normal subjects. The IGF-I levels after GH replacement were constantly maintained in the normal and GHD groups after 3 week and until the 52nd week. According to the lipid profiles, the GHD group showed significantly decreased total cholesterol and LDL-cholesterol after 12 weeks of GH replacement. The normal male group revealed constantly increased triglyceride levels during the entire 52 weeks of GH replacement, but thr other lipid parameters remained completely unchanged. The normal female group showed no change in any of their lipid parameters. Although the amounts of VAT at the baseline were the same in all groups, only the normal males showed effective visceral fat removal, with significantly reduced VAT after 52 weeks of GH treatment. In the normal female and GHD groups the bone mineral density had a V shaped curve after GH replacement, and the ALP and osteocalcin levels were significantly increased after 26 weeks of GH therapy in the GHD group. CONCLUSION: The body compositions in the normal male, female and GHD groups were similar before the GH replacement therapy, and the serum IGF-I levels were well maintained in all these groups during GH replacement. Although the majority of aging symptoms were improved, the body compositions tended to return to their original stati in the normal groups. GH replacement is recommended in the elderly for better health and well-being

The One Year Effects of Growth Hormone Replacement on the Body Composition in the Normal Adults / 대한내분비학회지

BACKGROUND: The secretion of growth hormone [GH] declines by 14.4% every decade, leading to the suggestion that the elderly are functionally GH deficient, which may increase adipose tissue and decrease the bone mass and density, as well as other negative changes in body composition. Recently, many studies have shown that GH replacement therapy may restore the changes that occur in the body composition with aging. AIM: The GH and insulin like growth factor-I[IGF-I] profiles were identified during GH replacement therapy in the elderly and compared with those of GH deficient[GHD] patients. The metabolic effects of GH replacement on the body composition of the elderly was also investigated, especially the body fat, muscle and bone parameters. Subjects and METHODS: 98 healthy normal out-patients and 13 GHD patients, who had peak GH concentrations less than 5 ng/mL after an insulin tolerance test [ITT] or growth hormone releasing hormone [GHRH] stimulation test, were the subjects of this study. All were receiving appropriate thyroid, adrenal and gonadal hormone replacements. The dose of recombinant human GH [rhGH] was 0.02~0.04 mg [0.06~0.12 IU]/kg of body weight.per week, given nightly by a subcutaneous injection, six times a week, over a 52 week period. The GH was measures after the ITT and GHRH stimulation tests, and the IGF-1, lipid parameters [total cholesterol, triglyceride, HDL-, and LDL cholesterol], visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], VAT/SAT ratio, quadriceps muscle area, total body fat, total bone mineral density [BMD], alkaline phosphatase [ALP], osteocalcin and urine deoxypyridinoline [DYP], as well as anthropometry, were also assessed. RESULTS: All the anthropometry features between the normal and GHD subjects were very similar. The hormonal profiles were checked; the GH peaks of the ITT and GHRH stimulation tests were significantly higher in the normal compared to the GHD patients, but the GHRH test showed lower GH peaks in than those of the ITT test in the normal subjects. The IGF-I levels after GH replacement were constantly maintained in the normal and GHD groups after 3 week and until the 52nd week. According to the lipid profiles, the GHD group showed significantly decreased total cholesterol and LDL-cholesterol after 12 weeks of GH replacement. The normal male group revealed constantly increased triglyceride levels during the entire 52 weeks of GH replacement, but thr other lipid parameters remained completely unchanged. The normal female group showed no change in any of their lipid parameters. Although the amounts of VAT at the baseline were the same in all groups, only the normal males showed effective visceral fat removal, with significantly reduced VAT after 52 weeks of GH treatment. In the normal female and GHD groups the bone mineral density had a V shaped curve after GH replacement, and the ALP and osteocalcin levels were significantly increased after 26 weeks of GH therapy in the GHD group. CONCLUSION: The body compositions in the normal male, female and GHD groups were similar before the GH replacement therapy, and the serum IGF-I levels were well maintained in all these groups during GH replacement. Although the majority of aging symptoms were improved, the body compositions tended to return to their original stati in the normal groups. GH replacement is recommended in the elderly for better health and well-being

Influência dos glicocorticóides sobre o eixo somatotrófico / Influence of glucocorticoids on the somatotrophic axis

A secreçäo de hormônio de crescimento (growth hormone, GH) é modulada por uma interaçäo complexa entre dois fatores hipotalâmicos: o hormônio liberador do GH (GH-releasing hormone, GHRH) e a somatostatina (SRIF). Recentemente foi sugerida a existência de uma terceira via fisiológica de regulaçäo deste hormônio, mediada pelos GHS (growth hormone secretagogues) e provavelmente pelo peptídeo endógeno, ghrelina. Os glicocorticóides (GCs) influenciam a secreçäo de GH atuando em diversos níveis, apesar dos mecanismos envolvidos nessas múltiplas açöes näo estarem totalmente elucidados. Além disso, esses esteróides têm efeitos estimulatórios ou inibitórios na liberaçäo de GH, dependendo do modelo experimental, duraçäo da exposiçäo, dose, tipo e via de administraçäo, entre outros. Embora controvertida, a administraçäo aguda de GCs aumenta a secreçäo de GH em humanos. No entanto, quando presente em níveis suprafisiológicos por períodos mais longos (meses ou anos), os GCs inibem a liberaçäo de GH. O efeito desses esteróides na IGF-1 e IGFBPs säo bastante controvertidos