生长激素释放多肽在体外对人分泌生长激素腺瘤和胎儿垂体分泌生长激素的影响

生长激素释放多肽(GHRP)是具有刺激各种动物垂体分泌GH的六肽。本研究应用自行合成的六肽,已发现在体外对胎儿垂体和分泌GH的垂体腺瘤同样具有刺激垂体细胞分泌GH的作用。对1例垂体瘤的实验证明这种刺激作用是一种剂量依赖关系。GHRP的这种功能可被低浓度生长激素释放抑制因子(10~(-7)M)所部分抑制。电镜观察显示1例垂体瘤受GHRP刺激后,细胞内高尔基器及未成熟分泌颗粒明显增加,提示GH合成增加的事实。     

生长素的心血管调节作用

生长素(Ghrelin)是1999年日本科学家Kojima等[1]在小鼠和人胃内分泌细胞及下丘脑弓状核中发现的含有28个氨基酸残基的多肽,是生长激素促分泌素受体(growth hormone secretatogue receptor,GHS-R)的内源性配体,能够刺激垂体前叶释放生长激素(growth hormone,GH).GHS-R不仅存在于下丘脑、垂体等部位,在心血管系统包括心脏、冠状动脉、主动脉等部位亦广泛存在,而且心脏本身也合成和分泌生长素,因此,生长素也可能作为一个旁/自分泌因子参与心血管稳态调节.     

生长介素对肢端肥大症患者垂体瘤生长激素分泌影响的体外研究

作者在8例肢端肥大症体外培养的垂体GH瘤细胞上探讨IGF-1对GH分泌的反馈调节作用。10~(-7)mol IGF-1使3例垂体GH瘤细胞GH基础分泌抑制到对照的44.6％～52.4％(P<0.05),1例GH分泌增加134.9％(P<0.05),4例GH基础分泌没有明显改变,表明体外培养的垂体GH瘤有一半以上对IGF-1 3小的·的急性作用失去正常的GH分泌抑制反应。3例对IGF-1失去GH分泌抑制反应的垂体GH瘤细胞同时伴有GH对GHRH_(1-44)及(或)生长抑素激动剂SMS_(201-995)反应消失,提示部分垂体GH瘤细胞的IGF-1和某些下丘脑激素受体或受体后有异常。     

生长素的心血管调节作用

生长素(Ghrelin)是1999年日本科学家Kojima等[1]在小鼠和人胃内分泌细胞及下丘脑弓状核中发现的含有28个氨基酸残基的多肽,是生长激素促分泌素受体(growthhormonesecretatoguereceptor,GHS R)的内源性配体,能够刺激垂体前叶释放生长激素(growthhormone,GH)。GHS R不仅存在于下丘脑、垂体等部位,在心血管系统包括心脏、冠状动脉、主动脉等部位亦广泛存在,而且心脏本身也合成和分泌生长素,因此,生长素也可能作为一个旁/自分泌因子参与心血管稳态调节。1生长素的结构及生化特性从小鼠及人胃中分离出的生长素氨基酸序列为G S S F L S P …     

肥胖病的内分泌

作者全面综述目前对肥胖病内分泌功能方面的认识,本文仅摘录部分有关垂体方面的主要内容。 垂体-生长激素 肥胖病患者生长激素(GH)的释放显著减少,基础血清GH及24小时总血清GH均明显下降,对各种生理刺激的GH分泌反应减低,且对各种药物刺激的GH增加受抑。许多证据表明,GH释放减少     

TRH试验及其临床应用

1969年 Guillemine 等和 Schalley 等几乎同时各自独立地从动物的下丘脑中提取出促甲状腺素释放激素(thyrotropin releasing hormone,TRH),并测定了其化学结构。以后人工合成了 TRH。TRH 是由下丘脑分泌,具有兴奋垂体前叶分泌促甲状腺素(thyrotropin-stimulatinghormone,TSH)细胞的作用,与 TSH 和甲状腺激素(thyroxine,T_4)一起构成了所谓下丘脑-垂体-甲状腺轴。以后尚发现,在某些情况下 TRH 有兴奋垂体分泌催乳素(PRL)和生长激素(GH)的作用。据此,目前已把 TRH 视为     

肢端肥大症

本文着重讨论肢端肥大症的病理生理学进展,并简单介绍诊断及治疗。 病理生理学 一、正常生长激素(GH)分泌的控制 下丘脑分泌的生长激素释放激素(GH-RH)能刺激垂体分泌和合成GH,还可诱导GH基因转录。生长抑素(SS)抑制GH分泌但不改变GH的mRNA水平。这两种下     

常见垂体腺瘤的临床诊断

垂体腺瘤是发生于腺垂体的良性肿瘤 ,占中枢神经系统肿瘤的 10 %～ 2 0 % ,是颅内最常见的肿瘤之一。根据免疫组织化学将垂体腺瘤按功能进行分类 ,主要有激素分泌活性腺瘤和非激素分泌活性腺瘤两大类。前者包括生长激素瘤 ( GH腺瘤 )、催乳素瘤 ( PRL 腺瘤 )、促肾上腺皮质素瘤 ( ACTH腺瘤 )、Nelson综合征、促甲状腺素瘤 ( TSH腺瘤 )、促性腺素瘤( FSH和 L H腺瘤 ) ;后者包括无功能细胞腺瘤。现将临床比较常见的垂体腺瘤的临床表现介绍如下。1　 GH腺瘤GH腺瘤系因腺垂体生长激素分泌细胞过度分泌 GH所致。成年人若发病在骨骺联合…     

成人生长激素缺乏症治疗的研究进展

生长激素(GH)是由垂体前叶生长激素细胞以脉冲方式分泌的促蛋白合成类蛋白。成人GH的主要亚型是一个191个氨基酸的蛋白质(分子量为22 kD),GH在维持肌肉力量、改善心脏功能、延缓衰老、防止骨质疏松、减肥以及促进伤口愈合等方面具有重要作用。GH的缺乏可对机体产生许多不利影响,替代治疗可逆转或减轻这些影响。成人生长激素缺乏症     

促皮质释放因子刺激试验帮助鉴别库兴氏综合征患者

促皮质释放因子(CRF)为一种首先从羊下丘脑分离得到的41~-氨基酸肽,当给予啮齿动物,类人灵长类和人时,刺激垂体ACTH和β内啡肽分泌。因CRF选择性地刺激垂体促肾上腺皮质细胞且比较完全,所以它提供了一种研究异常ACTH分泌的方法,本文旨在研究一组库兴氏病(CD),异位ACTH分泌综合征或肾上腺原性库兴综合征患者对CRF的激素反应的特点和探讨CRF对鉴别库兴综合征(CS)的可能效用。 作者对22例CS患者和10名对照者进行了研究。22例CS中13例(19—62岁)有ACTH分泌性垂体     

Complementary secretagogue pairs unmask prominent gender-related contrasts in mechanisms of growth hormone pulse renewal in young adults

The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) L-arginine/GHRH (to clamp low SS and high GHRH input); 2) L-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) L-arginine/GHRH and L-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to L-arginine/GHRP-2 (r2= 0.49, P = 0.005), whereas testosterone negatively predicted those to L-arginine/GHRH (r2= 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.     

The effects of PGE2, 2-DG and L-arginine on hypothalamic GHRH and SRIF releases in conscious rats, with respect to GH secretion

The effects of prostaglandin E2 (PGE2), 2-deoxy-D-glucose (2-DG) and L-arginine on hypothalamic GHRH and SRIF release with respect to GH secretion were studied in conscious male rats. Intracerebroventricular (icv) injection of 5 micrograms PGE2 and intravenous (iv) infusion of 1 g/kgBW L-arginine caused an increase in plasma GH levels, but icv (36 micrograms) or iv (400 mg/kgBW) injection of 2-DG suppressed spontaneous GH surge in conscious rats. The concentration of hypothalamic GHRH was decreased in all three groups of the animals, but the concentration of hypothalamic SRIF was decreased only in 2-DG-treated animals. In the perifusion system using rat hypothalamus, PGE2 (0.28 microM, 2.8 microM), 2-DG (22 mM) and L-arginine (3 mM) stimulated GHRH release from rat hypothalamus. 2-DG also stimulated SRIF release more predominantly than GHRH release. Passive immunization with anti-GHRH serum inhibited the GH secretion induced by icv injection of 5 micrograms PGE2 and by iv infusion of 1 g/kgBW L-arginine in conscious rats. In contrast, GH secretion induced by iv injection of 50 micrograms/kgBW PGE2 was not affected by the pretreatment with the antiserum. These results suggest that the central effect of PGE2 and peripheral effect of L-arginine to stimulate GH secretion are mediated by hypothalamic GHRH release, and that the inhibitory effect of 2-DG on GH secretion is predominantly mediated by hypothalamic SRIF release rather than GHRH release in rats.     

L-arginine-induced growth hormone secretion is not influenced by co-infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine in healthy men.

In animals, it has been demonstrated that nitric oxide (NO) is a potent neuroregulatory substance. By intravenous infusion, L-arginine is converted to NO and citrulline, but it is unknown whether NO is responsible for the GH stimulating effect of L-arginine in humans. We investigated whether intravenous infusion of the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) influenced L-arginine stimulated GH secretion. Ten healthy men, aged 28.6 +/- 1.9 (mean +/- SEM) years were examined twice. L-arginine was infused intravenously in a dose of 0.5 g/kg, max 35 g, from 0 to 30 min, accompanied by either: (1) L-NMMA from -5 to 0 min, in a dose of 3 mg/kg, max 250 mg, and in a dose of 3.5 mg/kg, max 250 mg from 0 to 60 min; or (2) a saline infusion. Heart rate increased (P = 0.032), and diastolic blood pressure decreased (P < 0.001) in the two situations. Plasma cGMP was unchanged and identical in the two situations (P = 0.679). Urine cGMP/creatinine ratio increased during both examinations (P = 0.041). Growth hormone secretion increased significantly during L-arginine infusion (P = < 0.001) without any effect of L-NMMA (P = 0.848). We did not find evidence that NO influences GH secretion. It remains to be tested, however, whether a higher dose of L-NMMA may influence L-arginine stimulated GH secretion.     

Gonadal status and body mass index jointly determine growth hormone (GH)-releasing hormone/GH-releasing peptide synergy in healthy men

CONTEXT: Sex steroid hormones potentiate whereas increased body mass index (BMI) represses GH secretion. Whether sex steroids modify the negative effect of BMI on secretagogue-induced GH secretion in men is not known. The issue is important in designing GH-stimulation regimens that are relatively insensitive to both gonadal status and adiposity. OBJECTIVE: Our objective was to compare the relationships between BMI and peptide-stimulated GH secretion in men with normal and reduced testosterone and estradiol availability. SETTING: The study was performed at an academic medical center. SUBJECTS: Healthy young men were included in the study. INTERVENTIONS: Randomized separate-day iv infusion of saline and/or maximally effective doses of L-arginine/GHRH, L-arginine/GH-releasing peptide (GHRP)-2, and GHRH/GHRP-2 in eugonadal (n=12) and experimentally hypogonadal (n=10) men was performed. OUTCOMES: Regression of paired secretagogue-induced GH responses on BMI was determined. RESULTS: In eugonadal men, peak GH concentrations correlated negatively with BMI. In particular, BMI accounted for only 38% of the response variability after L-arginine/GHRH (P=0.0165), but 62% after GHRH/GHRP-2 (P=0.0012) and 65% after L-arginine/GHRP-2 (P=0.00075). In contrast, in hypogonadal men, GH responses were uncorrelated with BMI. The negative effects of BMI on peak GH responses in eugonadal and hypogonadal states differed most markedly after stimulation with GHRH/GHRP-2 (P=0.0019). This contrast was corroborated using integrated GH responses (P=0.0007). CONCLUSIONS: Short-term experimental gonadal sex hormone depletion attenuates dual secretagogue-stimulated GH secretion in lean young men. The inhibitory effect of relative adiposity on GH secretion appears to predominate over that of acute sex steroid withdrawal.     

Estradiol supplementation enhances submaximal feed-forward drive of growth hormone (GH) secretion by recombinant human GH-releasing hormone-1,44-amide in a putatively somatostatin-withdrawn milieu

To test the clinical hypothesis that an estrogen-enriched milieu enhances GHRH action, we administered placebo (Pl) and estradiol-17 beta (E(2)) orally for 23 d to six postmenopausal women in a prospectively randomized, double-masked, within-subject crossover design with 6 wk intervening. The GHRH stimulation protocol entailed consecutive i.v. infusion of L-arginine and a single i.v. pulse of saline or one of five randomly ordered doses of recombinant human GHRH-1,44-amide (0.03, 0.1, 0.3, 1.0, or 3.0 microg/kg) in a total of 12 separate morning, fasting sessions. GH secretion was monitored by sampling blood every 10 min for 6 h; chemiluminescence assay of GH concentrations; deconvolution analysis of stimulated GH release; and nonlinear dose-response reconstruction. Supplementation with E(2), compared with Pl: 1) increased (mean +/- SEM) E(2) concentrations from 18 +/- 3 (Pl) to 164 +/- 12 pg/ml (to convert to picomoles per liter, multiply by 3.57) (P < 0.001); 2) decreased IGF-I concentrations from 181 +/- 14 to 120 +/- 11 microg/liter (P < 0.01); 3) elevated mean GH concentrations from 0.27 +/- 0.06 to 0.59 +/- 0.08 microg/liter (P = 0.014); 4) potentiated GH secretion stimulated by L-arginine alone by 1.43-fold (P = 0.012); 5) reduced the ED(50) of GHRH from 0.27 +/- 0.02 to 0.13 +/- 0.01 microg/kg (P < 0.01), denoting enhanced GHRH potency; and 6) heightened the maximal slope of the dose-response function from 1.1 +/- 0.1 to 1.4 +/- 0.05 [( microg/liter) ( microg/kg)(-1)] (P < 0.05), signifying augmented pituitary sensitivity. The foregoing facilitative mechanisms were specific because E(2) replacement did alter maximal L-arginine/GHRH-induced GH secretion, indicating unchanged secretagogue efficacy. In conclusion, inasmuch as E(2) also attenuates inhibition of GH secretion by infused somatostatin and potentiates stimulation of GH secretion by GH-releasing peptide-2, we postulate that estrogenic steroids drive pulsatile GH production in part via mechanisms that include all three of GHRH, somatostatin, and putatively GH-releasing peptide/ghrelin signaling.     

Distinctive inhibitory mechanisms of age and relative visceral adiposity on growth hormone secretion in pre- and postmenopausal women studied under a hypogonadal clamp

BACKGROUND: Aging, body composition, and sex steroids jointly determine GH production. However, the actions of any given factor are confounded by the effects of the other two. HYPOTHESIS: Age and abdominal visceral fat (AVF) mass govern GH secretion via individually distinctive mechanisms, which can be unmasked by short-term sex steroid deprivation. DESIGN/SUBJECTS: In a university setting, healthy pre- and postmenopausal volunteers underwent GnRH agonist-induced down-regulation for 6 wk to deplete ovarian sex steroids. GH secretion was evaluated by frequent blood sampling, saline vs. dual secretagogue infusions, an irregularity statistic, variable waveform deconvolution analysis, and a simplified feedback model. Computerized tomography was used to estimate AVF mass. OUTCOMES/MEASURES: In the sex steroid-deficient milieu, postmenopausal compared with premenopausal women exhibited 1) lower concentrations of IGF-I (P = 0.028) and GH (P < 0.05); 2) reduced pulsatile, but elevated basal, GH secretion (P < 0.05); 3) more irregular GH patterns (P = 0.027); 4) an attenuated GH response to simultaneous GHRH/GH-releasing peptide-2 stimulation (P < 0.01); and 5) more rapid onset of GH release within secretory bursts (P < 0.01). In contrast, AVF negatively forecast GH responses to L-arginine/GH-releasing peptide-2 (r2= 0.45; P < 0.001) and L-arginine/GHRH (r2= 0.57; P = 0.007). From these marked contrasts, model-based analyses predicted distinguishable mechanisms by which aging and AVF alter pulsatile GH production. CONCLUSION: Under limited confounding by sex steroids, age and body composition modulate GH secretion via highly selective peptidyl pathways in healthy women.     

Nitric oxide stimulates growth hormone secretion from human fetal pituitaries and cultured pituitary adenomas

Nitric oxide (NO), a highly reactive free radical, has been identified as a neurotransmitter in the central and peripheral nervous system. NO synthase (NOS) is the enzyme responsible for NO production from L-arginine and plays an important role in regulating the release of several hypothalamic peptides. In the pituitary, NO was found to increase growth hormone (GH) secretion in several in vitro and in vivomodels. However, its role in human GH regulation is unknown. The aim of this study was to investigate the regulatory effects of NO on human GH and prolactin secretion using primary cell cultures of human fetal pituitaries and cultured hormone-secreting adenomas. Incubation of the human fetal pituitaries (21-24 wk gestation) in the presence of sodium nitroprusside (SNP; 1 mM), a NO donor, for 4 h resulted in a 50-75% increase in GH secretion, similar to the stimulatory effect evoked by growth hormone-releasing hormone (GHRH) (10 nM). However, fetal PRL secretion was not affected by SNP. GH release was also stimulated (40-70% increase) by SNP in 60% of the cultured GH-secreting adenomas studied. SNP-induced GH release was inhibited in both fetal and adenomatous cells by PTI0, a NO scavenger. The addition of cGMP (0.1-1 mM), the second messenger of multiple NO actions, enhanced fetal and adenomatous GH secretion by 55-95%. Neuronal NOS (nNOS) was expressed in normal (fetal and adult) human pituitary tissues and in GH-secreting adenomas. Examination of its functional expression using L-arginine (1 microM) yielded a 35% increase in GH release from cultured GH-secreting adenoma. This response was blocked by a NOS inhibitor with high selectivity for the neuronal enzyme and by a guanylyl cyclase inhibitor. In conclusion, NO stimulates human GH in cultured fetal pituitaries and GH-secreting adenomas. Cyclic GMP is probably involved in this hormonal regulation.     

Effect of L-arginine supplementation on secretion of human growth hormone and insulin-like growth factor in adults

Based on presumptions that the infusion of amino acids can augment the release of human growth hormone (hGH) and that this metabolism is related with secretion of insulin-like growth factor I (IGF-I), the purpose of this study was to verify the effect of L-arginine supplementation on GH and IGF-I in adults. Seventeen male individuals participated on the study and were randomized to receive L-arginine (n= 10) or placebo (n= 7), seven grams per day for seven days. Before and after the supplementation period, the volunteers realized blood collection in fasting to verify both GH and IGF-I levels, as well as urine collection to verify urea excretion. At the end of the experimental period, it was verified that the group that received L-arginine augmented the urea in urine excretion (to 2684.1 +/- 475.2 mg/dl from 2967.2 +/- 409.7 mg/dl, p= 0.002), therefore it did not alter significantly the release of hormones evaluated. The group which received placebo did not alter significantly any evaluated parameters. The L-arginine supplementation during seven days was ineffective to augment both GH and IGF-I release in individual male adults.     

Involvement of nitric oxide in the regulation of growth hormone secretion in dogs

Nitric oxide (NO) is a highly reactive gas that has been suggested to function as a neurotransmitter in the neuroendocrine system. In this work, we have evaluated the role of NO pathways in growth hormone (GH) secretion by assessing the effect of L-arginine infusion, a precursor of NO formation, and L-NAME, a nitric oxide synthase (NOS) inhibitor. The experiments were carried out on 7 adult beagle dogs. A saline infusion was carried out on all the dogs as a control test. L-arginine (infusion i.v. 10 g in 100 ml of saline, from t = 0 to 30 min) and L-nitro-arginine-methyl ester, L-NAME (infusion of 300 microg/kg in 120 ml of saline, from t = -30 to 45 min) were administered alone and together with growth hormone-releasing hormone (GHRH) (i.v. bolus at 0 min, at a dose of 100 microg), the synthetic GH secretagogue GHRP-6 (i.v. bolus at 0 min, at a dose of 90 microg), and the 5-HT1D serotonin receptor agonist sumatriptan, SUM (s.c. injection at the dose of 3 mg). Plasma cGH was determined by RIA. Results were evaluated by one-way analysis of variance, followed by the Newman-Keuls test for multiple comparisons. L-arginine administration resulted in a slight increase in plasma cGH in comparison with saline controls. Combined administration of L-arginine and GHRH enhanced cGH release in comparison with GHRH alone. L-NAME alone did not modify baseline cGH levels, but completely suppressed the GH release induced by GHRH or GHRP-6. It also strongly reduced, but did not abolish the effect of the two peptides (GHRH plus GHRP-6) administered together. Finally, administration of the 5-HT1D agonist SUM induced a significant cGH secretion in all dogs, a response which was not modified when L-NAME was administered in combination with SUM. In conclusion, our data show that inhibition of NO blunts both GHRH or GHRP-6-induced cGH release, and are compatible with the hypothesis that it acts by decreasing hypothalamic somatostatin release.     

L-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide

The mechanism of L-arginine stimulation of glucose-induced insulin secretion from mouse pancreatic islets was studied. At 16.7 mmol/l glucose, L-arginine (10 mmol/l) potentiated both phases 1 and 2 of glucose-induced insulin secretion. This potentiation of glucose-induced insulin secretion was mimicked by the membrane depolarizing agents tetraethylammonium (TEA, 20 mmol/l) and K+ (60 mmol/l), which at 16.7 mmol/l glucose obliterated L-arginine (10 mmol/l) modulation of insulin secretion. Thus L-arginine may potentiate glucose-induced insulin secretion by stimulation of membrane depolarization. At 3.3 mmol/l glucose, L-arginine (10 mmol/l) failed to stimulate insulin secretion. In accordance with membrane depolarization by the electrogenic transport of L-arginine, however, L-arginine (10 mmol/l) stimulation of insulin secretion was enabled by the K+ channel inhibitor TEA (20 mmol/l), which potentiates membrane depolarization by L-arginine. Furthermore, L-arginine (10 mmol/l) stimulation of insulin secretion was permitted by forskolin (10 micromol/l) or tetradecanoylphorbol 13-acetate (0.16 micromol/l), which, by activation of protein kinases A and C respectively sensitize the exocytotic machinery to L-arginine-induced Ca2+ influx. Thus glucose may sensitize L-arginine stimulation of insulin secretion by potentiation of membrane depolarization and by activation of protein kinase A or protein kinase C. Finally, L-arginine stimulation of glucose-induced insulin secretion was mimicked by NG-nitro-L-arginine methyl ester (10 mmol/l), which stimulates membrane depolarization but inhibits nitric oxide synthase, suggesting that L-arginine-derived nitric oxide neither inhibits nor stimulates insulin secretion. In conclusion, it is suggested that L-arginine potentiation of glucose-induced insulin secretion occurs independently of nitric oxide, but is mediated by membrane depolarization, which stimulates insulin secretion through protein kinase A- and C-sensitive mechanisms.