RESUMO
The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hormones, GH-releasing hormone and somatostatin. These hormones are subject to modulation by a host of neurotransmitters and are the final mediators of endocrine and neural influences for GH secretion. Interest in the possible role of γ-aminobutyric acid (GABA) in the control of GH secretion began decades ago. However, interest in its role as an ergogenic aid is only recent. It is well accepted that GABAergic neurons are found in the hypothalamus and recent evidence suggests its secretion within the pituitary itself. Inhibition of GABA degradation and blockade of GABA transmission as well as administration of GABA and GABA mimetic drugs have all been shown to affect GH secretion. However, there are many controversial findings. The effects may depend on the site of action within the hypothalamic-pituitary unit and the hormonal milieu. Experimental and clinical evidence support the presence of a dual action of GABA - one mediated centrally, the other exerted directly at the pituitary level. The two sites of action may be responsible for excitatory and inhibitory effects of GABA on GH secretion. This chapter will outline the anatomical basis for possible influences of GABA on GH secretion and present evidence for a role of GABA in the control of GH release by actions at either hypothalamic or pituitary sites. The potential ergogenic benefits of oral GABA supplementation will also be discussed.
Assuntos
Suplementos Nutricionais , GABAérgicos/uso terapêutico , Hormônio do Crescimento Humano/efeitos dos fármacos , Adeno-Hipófise/efeitos dos fármacos , Ácido gama-Aminobutírico/uso terapêutico , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Adeno-Hipófise/metabolismo , Receptores de GABA/efeitos dos fármacos , Receptores de GABA/metabolismoRESUMO
N(omega)-Nitro-L-arginine methyl ester (L-NAME) induces a pre-eclampsia-like syndrome in pregnant rats. We have previously reported the anti-hypertensive effects of several Japanese traditional (Kampo) medicines in this model, and one of these, Tokishakuyakusan (TS), also improved intrauterine growth retardation (IUGR). In the present study, we characterized the effect of TS on IUGR. TS administration reversed the decrease in fetal body weight and fetal blood glucose concentration induced by the infusion of L-NAME. Growth hormone (GH) levels in the fetal blood, which were decreased by L-NAME infusion, were also significantly elevated by TS; however, levels of GH releasing hormone (GHRH) and insulin-like growth factor I (IGF-I) were unchanged and only slightly changed, respectively. Treatment with L-NAME with or without TS had no apparent effect on GH, GHRH, and IGF-I levels of dams. In an immunocytochemical study, the number of GH-positive cells in the fetal pituitary gland was significantly increased in TS-treated rats. These data suggest that enhanced proliferation of somatotrope cells of the pituitary gland and the resultant increase in GH secretion in the fetus may be involved in the improvement of IUGR by TS.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Retardo do Crescimento Fetal/tratamento farmacológico , Pré-Eclâmpsia/tratamento farmacológico , Animais , Glicemia/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Peso Fetal/efeitos dos fármacos , Hormônio do Crescimento/efeitos dos fármacos , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster , Hipófise/citologia , Hipófise/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placentação , Plantas Medicinais/química , Pré-Eclâmpsia/induzido quimicamente , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
The effect of exogenous growth hormone (GH) and insulin-like growth factor I (IGF-I) on brain IGF-I binding sites (IGF-IR), and on the levels of growth hormone-releasing hormone (GHRH) and somatostatin was studied in hypophysectomized and intact juvenile male rats. Animals were injected subcutaneously twice daily (n = 5 each) with recombinant GH (rGH) (2.5 U/kg per day) or rIGF-I (500 microg/kg per day). In the hypophysectomized rats, serum GH and IGF-I levels were markedly suppressed and IGF-I levels were partially restored by GH treatment. There was a significant increase in IGF-IR binding capacity in the IGF-I-treated hypophysectomized rats compared to the saline-treated hypophysectomized animals (150.61 +/- 45.66 vs 41.32 +/- 12.42 fmol/mg, p < 0.05) but no significant difference in IGF-IR mRNA levels. GHRH levels in the saline-treated hypophysectomized group were significantly lower than in the saline-treated intact rats (31.2 +/- 11.2 vs 140.6 +/- 48.1 pg/mg tissue, respectively, p < 0.01); no effect was induced by GH or IGF-I (37.5 +/- 26.8 and 53.8 +/- 22.5 pg/mg tissue, respectively). However, in the intact rats, GH and IGF-I injection led to a decrease in GHRH content, which was significant in the GH-treated compared to the saline-treated animals (33.1 +/- 16.2 vs 140.6 +/- 48.1 pg/mg tissue, p < 0.01). No difference was found in somatostatin levels between intact and hypophysectomized rats (631.2 +/- 81.2 and 625.0 +/- 62.5 pg/mg tissue, respectively). However, in the hypophysectomized animals, GH and IGF-I treatment induced a significant increase in somatostatin levels (1300 +/- 193.7 pg/mg tissue, p < 0.01, and 912.5 +/- 81.2 pg/mg tissue, p < 0.05, respectively). Our findings suggest that the bioavailability of exogenous IGF-I is greater than that of GH-stimulated endogenous IGF-I. Because IGF-I is a potent neurotrophic agent, this effect may have important implications for states of neurodegenerative diseases.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/farmacologia , Hipotálamo/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Somatostatina/metabolismo , Fatores Etários , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Hormônio do Crescimento/sangue , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hipofisectomia , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Ratos , Ratos Wistar , Receptor IGF Tipo 1/efeitos dos fármacos , Receptor IGF Tipo 1/genética , Proteínas Recombinantes de Fusão/farmacologia , Somatostatina/efeitos dos fármacosRESUMO
Testosterone (T) is known to affect the growth hormone (GH) axis. However, the mechanisms underlying the activation of GH secretion by T still remain to be clarified. Available data in animals and humans have shown that withdrawal of somatostatin (SRIH) infusion induces a GH-releasing hormone (GHRH)-mediated rebound release of GH, and there is accumulating evidence that SRIH infusion withdrawal may be a useful test to probe the GHRH function in vivo. With the aim of investigating whether the stimulatory effect of androgens on GH release in man could be accounted for by activation of the hypothalamic GHRH tone, we evaluated the plasma GH response to SRIH withdrawal in 10 patients aged 29.6 +/- 2.4 years (mean +/- SEM), diagnosed with hypergonadotropic hypogonadism, before and after a 6-month replacement therapy with T enanthate (250 mg every 3 weeks, i.m.), and in 10 healthy men, aged 26.7 +/- 2.8 years. To verify whether the modulation of GH secretion by T could also be mediated through changes in SRIH tone and/or pituitary releasable pool, we examined GH secretory responses to combined GHRH and L-arginine (ARG) in the same individuals. Basal plasma concentrations of GH (0.48 +/- 0.11 microg/l) and IGF-I (23.79 +/- 1.83 nmol/l) were significantly lower in untreated hypogonadal patients than in healthy men, and significantly increased after T replacement therapy (GH 1.13 +/- 0.28 microg/l; IGF-I 28.71 +/- 1.46 nmol/l). The mean Delta GH peak after SRIH withdrawal recorded in untreated hypogonadal men (2.65 +/- 0.86 microg/l) was significantly (p < 0.05) lower than that observed in healthy men (6.53 +/- 1.33 microg/l) and significantly increased after T replacement therapy (5.52 +/- 1.25 microg/l). The GH responses to GHRH combined with ARG (a functional SRIH antagonist) were not significantly different between healthy men and untreated hypogonadal patients, and were not significantly affected by T treatment. Plasma T and estradiol (E(2)) levels significantly correlated with Delta GH peak after SRIH withdrawal in healthy men and in T-treated hypogonadal patients, whereas in untreated patients they did not. No significant correlation was found between GH areas under the curve after GHRH + ARG test and T and E(2) plasma levels in either healthy men or in hypogonadal patients (both before and after T replacement). These findings are consistent with the view that in humans the stimulatory action of T on the GH axis appears to be mediated at the hypothalamic level primarily by promoting GHRH function.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/metabolismo , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Hipófise/metabolismo , Testosterona/administração & dosagem , Testosterona/metabolismo , Adulto , Área Sob a Curva , Arginina/administração & dosagem , Arginina/metabolismo , Estudos de Casos e Controles , Estradiol/sangue , Hormônio do Crescimento/sangue , Hormônio do Crescimento/efeitos dos fármacos , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Heptanoatos/administração & dosagem , Heptanoatos/metabolismo , Humanos , Hipogonadismo/tratamento farmacológico , Hipotálamo/efeitos dos fármacos , Ensaio Imunorradiométrico , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Hipófise/efeitos dos fármacos , Radioimunoensaio , Somatostatina/metabolismoRESUMO
BACKGROUND: According to the existence in anorexia nervosa (AN) of peripheral growth hormone (GH) resistance, low circulating insulinlike growth factor I (IGF-I) levels may be coupled with GH hypersecretion; however, there is also evidence for alterations in the neural control of GH secretion. In fact, reportedly GH secretion is partially refractory to the inhibitory effect of muscarinic cholinergic antagonists as well as to the stimulatory effect of muscarinic cholinergic agonists, which act via opposite modulation of hypothalamic somatostatin (SS) release. Thus, somatostatinergic activity could be impaired in AN. This could be due to an impaired hypothalamic SS release or, alternatively, an altered somatotroph sensitivity to SS. METHODS: We studied in 10 women with AN in acute phase (AN, age, mean +/- SEM: 18.7 +/- 0.8 years) the effect of exogenous SS1-14 (25 and 75 micrograms/hour i.v., infused from +15 to +75 min), at doses that had previously been shown capable of increasing circulating SS levels within the physiological range, on the GH response to GH-releasing hormone (GHRH) (1 microgram/kg i.v. at 0 min). The same study protocol was performed in 8 normal age-matched women (NW, 22.9 +/- 1.0 years). RESULTS: In AN patients, IGF-I levels were lower (p < .01) than those in NW, while basal GH levels were similar in both groups. The GHRH-induced GH rise in AN was higher (p < .01) than that in NW. In AN, the exaggerated GH response to GHRH was inhibited to the same extent by both SS doses (p < .05) and became similar to that after GHRH alone in NW. In NW both 25 and 75 micrograms/hour SS decreased the GHRH-induced GH response; however, the inhibitory effect of the lower dose did not attain statistical significance, whereas the higher dose did (p < .02). During SS infusion, the GHRH-induced GH response in NW was persistently lower (p < .02) than that in AN. The percent inhibitory effect of SS on the somatotroph responsiveness to GHRH was similar in both groups at each dose. CONCLUSIONS: Our present findings demonstrate that the sensitivity of somatotroph cells to exogenous SS given at physiological doses is preserved in patients with AN. It is noteworthy that, during the infusion of physiological SS doses, the GH response to GHRH in AN overlaps on that to GHRH alone under physiological conditions. Thus, in AN, the sensitivity of somatotroph cells to SS apparently being preserved, an impairment of somatostatinergic neurons cannot be ruled out.
Assuntos
Anorexia Nervosa/fisiopatologia , Hormônio Liberador de Hormônio do Crescimento , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/análise , Somatostatina/farmacologia , Adolescente , Adulto , Análise de Variância , Anorexia Nervosa/sangue , Área Sob a Curva , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Interações Medicamentosas , Retroalimentação , Feminino , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Humanos , Hipotálamo/efeitos dos fármacos , Somatostatina/metabolismo , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Growth hormone-releasing peptides (GHRPs) are synthetic molecules with strong, dose-related and reproducible growth hormone (GH)-releasing activity in humans. GHRPs act at both the pituitary and the hypothalamic level, where specific receptors have been located. In adults, GHRPs release more GH than does GH-releasing hormone (GHRP), whilst their co-administration has a synergistic effect, indicating that they have, at least partially, different mechanisms of action. However, normal activity of GHRH-secreting neurones is needed to achieve the full GH-releasing effect of GHRPs. In contrast to GHRH, the GH-releasing activity of GHRPs is not further increased by substances acting via inhibition of hypothalamic somatostatin, and is only blunted by substances that stimulate hypothalamic somatostatin release. Even free fatty acids and exogenous somatostatin, which act directly on somatotrophs, do no more than blunt the effect of GHRPs. Thus, the GH-releasing activity of GHRPs is partially refractory to inhibitory influences, GHRPs act, at least in part, by antagonism of somatostatin activity, both at the pituitary and the hypothalamic level. The GH-releasing effect of GHRPs is not dependent on gender, but undergoes age-related variations. Gonadal steroids seem to influence the activity of GHRPs only in childhood. The reduced GH response to GHRPs in the elderly is probably due mainly to concomitant GHRH hypoactivity and somatostatinergic hyperactivity. A preserved GH-releasing effect of GHRPs has been reported in acromegaly, anorexia nervosa, hyperthyroidism and in critically ill patients. GHRPs have also been found to increase GH release in children with idiopathic short stature, in GH deficiency and in obese patients, in whom there is a well-known reduction of somatotroph function. The GH response to GHRPs is markedly reduced in hypothyroidism and Cushing's syndrome.
Assuntos
Envelhecimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/fisiologia , Substâncias de Crescimento/farmacologia , Hormônio do Crescimento Humano/metabolismo , Oligopeptídeos/farmacologia , Sinergismo Farmacológico , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/fisiologia , Humanos , Hipotálamo/efeitos dos fármacos , Hipófise/efeitos dos fármacosRESUMO
The individual role played by GH and IGF-I in the regulation of hypothalamic GHRH and SRIF gene expression is still object of debate. We have investigated the effect of exogenously administered recombinant hGH (rhGH) and recombinant hIGF-I (rhIGF-I) in ad libitum fed control and starved rats, the latter an animal model which is characterized by low circulating levels of endogenous GH and IGF-I. Adult male rats were fed ad libitum (C) or food-deprived (S) for 72 hours; rats in either C or S groups were treated with systemic administration of rhGH and rhIGF-I for 3 days. GHRH, SRIF and GH mRNA levels were evaluated by Northern and slot blot hybridization. Administration of rhGH (250 micrograms/kg/twice daily, sc) induced a significant inhibition of GHRH and a significant stimulation of SRIF mRNA levels in C rats; GH treatment was, however, ineffective on both neuropeptide mRNA levels in the S group. Continuous infusion of rhIGF-I (300 micrograms/kg/day, sc) induced a significant increase of SRIF levels in both C and S rats but did not modify GHRH mRNA levels in either group. In the pituitary, GH mRNA levels followed a pattern very similar to that of GHRH. These results provide evidence for a direct role of GH in the inhibition of GHRH mRNA levels; IGF-I appears more involved in the direct stimulation of SRIF mRNA levels.
Assuntos
Privação de Alimentos/fisiologia , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , RNA Mensageiro/efeitos dos fármacos , Somatostatina/efeitos dos fármacos , Animais , Ingestão de Alimentos , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/genética , Humanos , Hipotálamo/química , Hipotálamo/metabolismo , Injeções Intraventriculares , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/genética , Masculino , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Somatostatina/genética , Somatostatina/metabolismoRESUMO
This review systematically analyses recent knowledge of the biology of the growth hormone-releasing peptides. Many years before native GHRH had been isolated and sequenced, the synthesis of an enkephalin analog, devoid of any opioid activity but capable of specifically releasing GH from in vitro pituitaries, prompted the design of a number of structurally interrelated GHRPs with improved GH-releasing activity. Nowadays, GHRPs are the most effective GH-secretagogues known and could be used profitably in humans with GH hyposecretory disturbances to promote a pattern of GH secretion that mimics physiology in a better way than the exogenously administered GH.
Assuntos
Substâncias de Crescimento/farmacologia , Hormônio do Crescimento Humano/efeitos dos fármacos , Oligopeptídeos/farmacologia , Animais , Canais de Cálcio/metabolismo , Desenho de Fármacos , Encefalinas/farmacologia , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/biossíntese , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiologia , Adeno-Hipófise/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/metabolismo , Somatostatina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Glucocorticoids are known to inhibit GH secretion via somatostatin. The aim of our study was to elucidate the involvement of somatostatin in the GH-releasing action of the alpha 2 agonist clonidine and the cholinergic agent pyridostigmine in conscious, freely-moving rats chronically treated with dexamethasone. After seven days of chronic glucocorticoid treatment, animals received an i.v. injection of either saline (1 ml/kg) or clonidine (150 micrograms/kg) or pyridostigmine (100 micrograms/kg) at -15 min. Three blood samples were then drawn (-10 min, -5 min, and 0 min) to assess the GH response to either clonidine or pyridostigmine alone. After the 0 min sample, saline (1 ml/kg) or GNRH (500 ng/kg) was injected i.v. and additional blood samples were drawn from 5 to 30 min. The GH response to clonidine alone or combined with GNRH in rats treated with dexamethasone was significantly lower (p < 0.05) as compared to vehicle-treated rats. The GH response to pyridostigmine alone or combined with GNRH did not significantly differ between vehicle- and dexamethasone-treated rats. These data suggest that in the rat the mechanism of action of clonidine is mainly to stimulate endogenous GNRH secretion, while pyridostigmine appears to predominantly act by decreasing hypothalamic somatostatin.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Clonidina/farmacologia , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Hipotálamo/metabolismo , Parassimpatomiméticos/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Hormônio do Crescimento/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Masculino , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Effects of growth hormone (GH) hypersecretion on somatostatin-(SRIH) and GH-releasing hormone (GHRH) were studied by in situ hybridization and receptor autoradiography in rats bearing a GH-secreting tumor. 6 and 18 wk after tumor induction, animals displayed a sharp increase in body weight and GH plasma levels; pituitary GH content was reduced by 47 and 55%, while that of prolactin and thyrotropin was unchanged. At 18 wk, hypothalamic GHRH and SRIH levels had fallen by 84 and 52%, respectively. In parallel, the density of GHRH mRNA per arcuate neuron was reduced by 52 and 50% at 6 and 18 wk, while SRIH mRNA levels increased by 71 and 83% in the periventricular nucleus (with no alteration in the hilus of the dentate gyrus). The numbers of GHRH- and SRIH-synthetizing neurons in the hypothalamus were not altered in GH-hypersecreting rats. Resection of the tumor restored hypothalamic GHRH and SRIH mRNAs to control levels. GH hypersecretion did not modify 125I-SRIH binding sites on GHRH neurons. Thus, chronic GH hypersecretion affects the expression of the genes encoding for GHRH and SRIH. The effect is long lasting, not desensitizable and reversible.
Assuntos
Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Hipotálamo/química , Neurônios/química , RNA Mensageiro/análise , Somatostatina/análise , Animais , Peso Corporal , Retroalimentação , Feminino , Hormônio do Crescimento/sangue , Hormônio Liberador de Hormônio do Crescimento/análise , Hormônio Liberador de Hormônio do Crescimento/efeitos dos fármacos , Hibridização In Situ , Radioisótopos do Iodo , Hipófise/química , Neoplasias Hipofisárias/metabolismo , Prolactina/análise , Ligação Proteica , Ratos , Ratos Endogâmicos WF , Somatostatina/efeitos dos fármacos , Somatostatina/metabolismo , Tireotropina/análiseRESUMO
The mechanism underlying the sexually dimorphic pattern of growth hormone (GH) secretion in the rat has not been clearly elucidated. In the present study, we assayed the possible direct effect of gonadal steroids on both somatostatin (SS) and growth hormone-releasing factor (GRF) in fetal rat hypothalamic cells in culture. Hypothalamic cells, obtained by mechanical dispersion, were maintained as monolayer cultures in serum-supplemented medium. After 20 days in culture, cells were incubated with serum free medium containing testosterone (T, 10, 20, 40 ng/dl) or estradiol (E, 0.1, 1, 10 ng/dl) for 48 h. At the end of the experiments, immunoreactive SS (IR-SS) and immunoreactive GRF (IR-GRF) were measured by specific radioimmunoassays (RIAs) in media and cell extracts. After 48 h of incubation with testosterone, somatostatin in both media and cells was significantly reduced. On the contrary, this treatment lead to a dose-dependent increase in media and cell GRF content. When cells were incubated with estradiol for 48 h, a significant inhibition in medium SS release was observed, whereas intracellular SS slightly increased at the highest concentration of 10 ng/dl. Estradiol treatment resulted in an inconsistent decrease in media and cells IR-GRF. Our results indicate that both SS and GRF are under the influence of testosterone and estradiol acting at the hypothalamic level, and furthermore suggest that at this stage of brain development, gonadal steroids may regulate GH secretion through their ability to modulate hypothalamic SS and GRF.