Control Of Growth Hormone Secretion Research Articles

The Expression of Insulin in the Central Nervous System: What Have We Learned So Far?

After being discovered over a century ago, insulin was long considered to be a hormone exclusively produced by the pancreas. Insulin presence was later discovered in the brain, which was originally accounted for by its transport across the blood-brain barrier. Considering that both insulin mRNA and insulin were detected in the central nervous system (CNS), it is now known that this hormone is also synthesized in several brain regions, including the hypothalamus, hippocampus, cerebral and cerebellar cortex, and olfactory bulb. Although many roles of insulin in the CNS have been described, it was initially unknown which of them could be attributed to brain-derived and which to pancreatic insulin or whether their actions in the brain overlap. However, more and more studies have been emerging lately, focusing solely on the roles of brain-derived insulin. The aim of this review was to present the latest findings on the roles of brain-derived insulin, including neuroprotection, control of growth hormone secretion, and regulation of appetite and neuronal glucose uptake. Lastly, the impairment of signaling initiated by brain-derived insulin was addressed in regard to memory decline in humans.

The MPOWERED Trial Comparing the Effectiveness, Safety, and Patient Experiences’ of Monthly Injections and Oral Medication Used to Treat Acromegaly

What is this summary about? Oral octreotide is the first oral medication (taken by mouth, twice a day) in the class of drugs called somatostatin receptor ligands that is available in the USA for maintaining control of acromegaly. It was approved by the US Food and Drug Administration (FDA) for people who have had their disease respond to, while also tolerating, longacting monthly injectable versions of the somatostatin receptor ligands octreotide or lanreotide (referred to as ‘injectables’), that can also be referred to as somatostatin analogs. Although people with acromegaly often are able to control hormone levels with injectables, some could still experience inadequate symptom control or injection site reactions (such as pain, redness or bumps in and around the area of injection) related to this type of medicine. This summary reports the results from a phase 3 study, called MPOWERED comparing the injectables to oral octreotide. The full title of this study is called The Maintenance of Acromegaly Patient with Octreotide Capsules Compared With injections – Evaluation of Response Durability). This summary also includes insights and perspectives from an acromegaly patient advocate and from a nurse practitioner who closely follows people with acromegaly. What was the aim of the study? The main aim of the study was to look at how well oral octreotide worked and how safe it was, compared with injectables, in people with acromegaly. All study patients had control of growth hormone secretion on injectables prior to being switched to oral octreotide. Researchers also asked participants in the study questions about the impact of the treatment on their health and quality of life (known as patient-reported outcome measures). What were the results? The main finding of this study was that oral octreotide is as effective as injectables in maintaining normal growth hormone markers in the blood in patients who responded to both therapies. The side effects overall were similar between groups. In general, participants in the study treated with oral octreotide had mild to moderate side effects that typically went away as treatment was continued. The most common side effects in the oral octreotide group were flatulence (gas) and nausea. The most common side effects in the injectables group were flatulence and diarrhea. ClinicalTrials.gov NCT number: NCT02685709

Effect of pterois volitans (lionfish) venom on cholinergic and dopaminergic systems

Pterois volitans venom induces muscular fibrillation, which results from nerve transmission caused by the presence of acetylcholine (ACh). It also has cardiovascular effects that are due to its actions on muscarinic and nicotinic cholinergic receptors. In this study, we characterized the effects of P. volitans venom on nicotinic acetylcholine receptors (nAChRs) and dopaminergic neurons. After exposure to P. volitans venom, acetylcholinesterase (AChE) mRNA levels and the expression of the α2 subunit of nAChR increased in zebrafish embryos (15–20 somites). In addition, the lionfish venom blocked zebrafish α2 nAChR subunit functional expression and the ACh-induced response of human neuronal α3β2 receptors. The latter receptor was blocked by a protein fraction named F2, which was isolated from P. volitans venom using reversed phase high performance liquid chromatography (RP-HPLC). This venom causes death in dopaminergic neurons, and affects the cholinergic system. The effect of these two systems may result in retarded embryonic development of zebrafish, since the two systems function in a related manner to control growth hormone secretion.

Somatostatin Analogs and Glucose Metabolism in Acromegaly: A Meta-analysis of Prospective Interventional Studies.

Somatostatin analogs (SSAs) effectivelycontrol growth hormone secretion in first and second line treatmentof acromegaly. Their effect onglucose metabolism is still debated. to address the following questions: 1) Do SSAs affect fasting plasma glucose (FPG), fasting plasma insulin (FPI), glycosylated hemoglobin (HbA1c), glucose load (2h-OGTT), HOMA-I, HOMA-β, triglycerides (TGD), weight (W) or body mass index (BMI)? 2) Do lanreotide (LAN) and octreotide LAR (OCT) affect metabolism differently? 3)Does their effect depend on disease control? We performed a meta-analysis of prospective interventional trialstreating acromegaly with SSAs. Inclusion criteria: all studies reporting glyco-metabolic outcomes before and after SSAs with a minimum 6-month follow-up. The inclusion criteria were met by 47 studies treating 1297 subjects (631 F). SSA treatment effectively lowered FPI (effect size [ES] -6.67 mU/L, 95%CI: -8.38 to -4.95mU/L; p<0.001), HOMA-I (ES -1.57, CI: -2.42 to -0.72; p<0.001), HOMA-β (ES -47.45, CI: -73.15 to -21.76; p<0.001) and TGD (ES -0.37 mmol/L, CI: -0.47 to -0.27 mmol/L; p<0.001). SSAs worsened 2h-OGTT (ES 0.59 mmol/L, CI: 0.05 to 1.13 mmol/L; p=0.032), but not FPG. A mild but significant increase in HbA1c (ES 0.12%, CI: 0.00to 0.25%; p=0.044) was found in OCT treated subjects. SSA treatment in acromegaly patients-while improving disease control- reduces insulin levels, increases after load glucose and, ultimately, increases HbA1c levels without affecting FPG. The findings suggest that clinicians treating acromegaly with SSAs should consider targeting post-prandial glucose.

PI3K/Akt/mTOR pathway involvement in regulating growth hormone secretion in a rat pituitary adenoma cell line.

Insulin-like growth factor 1 (IGF1) controls growth hormone (GH) secretion via a negative feed-back loop that may disclose novel mechanisms possibly useful to control GH hyper-secretion. Our aim was to understand whether PI3K/Akt/mTOR pathway is involved in IGF1 negative feedback on GH secretion. Cell viability, GH secretion, Akt, and Erk 1/2 phosphorylation levels in the rat GH3 cell line were assessed under treatment with IGF1 and/or everolimus, an mTOR inhitior. We found that IGF1 improves rat GH3 somatotroph cell viability via the PI3K/Akt/mTOR pathway and confirmed that IGF1 exerts a negative feedback on GH secretion by a transcriptional mechanism. We demonstrated that the negative IGF1 loop on GH secretion requires Akt activation that seems to play a pivotal role in the control of GH secretion. Furthermore, Akt activation is independent of PI3K and probably mediated by mTORC2. In addition, we found that Erk 1/2 is not involved in GH3 cell viability regulation, but may have a role in controlling GH secretion, independently of IGF1. Our data confirm that mTOR inhibitors may be useful to reduce pituitary adenoma cell viability, while Erk 1/2 pathway may be considered as a useful therapeutic target to control GH secretion. Our results open the field for further studies searching for effective drugs to control GH hyper-secretion.

Growth hormone secretion is diminished and tightly controlled in humans enriched for familial longevity

Summary Reduced growth hormone (GH) signaling has been consistently associated with increased health and lifespan in various mouse models. Here, we assessed GH secretion and its control in relation with human familial longevity. We frequently sampled blood over 24 h in 19 middle-aged offspring of long-living families from the Leiden Longevity Study together with 18 of their partners as controls. Circulating GH concentrations were measured every 10 min and insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) every 4 h. Using deconvolution analysis, we found that 24-h total GH secretion was 28% lower (P = 0.04) in offspring [172 (128–216) mU L−1] compared with controls [238 (193–284) mU L−1]. We used approximate entropy (ApEn) to quantify the strength of feedback/feedforward control of GH secretion. ApEn was lower (P = 0.001) in offspring [0.45 (0.39–0.53)] compared with controls [0.66 (0.56–0.77)], indicating tighter control of GH secretion. No significant differences were observed in circulating levels of IGF-1 and IGFBP3 between offspring and controls. In conclusion, GH secretion in human familial longevity is characterized by diminished secretion rate and more tight control. These data imply that the highly conserved GH signaling pathway, which has been linked to longevity in animal models, is also associated with human longevity.

Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress

Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABAA receptor competitive antagonist) but not by diazepam (a GABAA receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic–pituitary–adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABAA receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABAA receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABAA receptor.

Ghrelin increases growth hormone production and functional expression of NaV1.1 and Na V1.2 channels in pituitary somatotropes.

A variety of ion channels are expressed in the plasma membrane of somatotropes within the anterior pituitary gland. Modification of these channels is linked to intracellular Ca2+ levels and therefore to hormone secretion. Previous investigations have shown that the gut-derived orexigenic peptide hormone ghrelin and synthetic GH-releasing peptides (GHRPs) stimulate release of growth hormone (GH) and increase the number of functional voltage-gated Ca2+ and Na+ channels in the membrane of clonal GC somatotropes. Here, we reveal that chronic treatment with ghrelin and its synthetic analog GHRP-6 also increases GH release from bovine pituitary somatotropes in culture, and that this action is associated with a significant increase in Na+ macroscopic current. Consistent with this, Na+ current blockade with tetrodotoxin (TTX) abolished the ghrelin- and GHRP-6-induced increase in GH release. Furthermore, semi-quantitative and real-time RT-PCR analysis revealed an upregulation in the transcript levels of GH, as well as of NaV1.1 and NaV1.2, two isoforms of TTX-sensitive Na+ channels expressed in somatotropes, after treatment with ghrelin or GHRP-6. These findings improve our knowledge on (i) the cellular mechanisms involved in the control of GH secretion, (ii) the molecular diversity of Na+ channels in pituitary somatotropes, and (iii) the regulation of GH and Na+ channel gene expression by ghrelin and GHRPs.

Ghrelin and obestatin modulate growth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons

Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.

The Ghrelin/Obestatin Balance in the Physiological and Pathological Control of Growth Hormone Secretion, Body Composition and Food Intake

Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. Ghrelin is an orexigenic and adipogenic peptide and a potent growth hormone secretagogue (GHS) modified by the enzyme ghrelin-O-acyl-transferase to bind and activate its receptor, the GHS-R. The ghrelin/GHS-R pathway is complex and the effects of ghrelin on GH secretion, adiposity and food intake appear to be relayed by distinct mechanisms involving different transduction signals and constitutive activity for the GH-R, different cofactors as modulators of endogenous ghrelin signalling and/or alternative ghrelin receptors. The discovery of obestatin in 2005 brought an additional level of complexity to this fascinating system. Obestatin was initially identified as an anorexigenic peptide and as the cognate ligand for GPR39, but its effect on food intake and its ability to activate GPR39 are still controversial. Although several teams failed to reproduce the anorexigenic actions of obestatin, this peptide has been shown to antagonise GH secretion and food intake induced by ghrelin and could be an interesting pharmacological tool to counteract the actions of ghrelin. Ghrelin and obestatin immunoreactivities are recovered in the blood with an ultradian pulsatility and their concentrations in plasma vary with the nutritional status of the body. It is still a matter of debate whether both hormones are regulated by independent mechanisms and whether obestatin is a physiologically relevant peptide. Nevertheless, a significant number of studies show that the ghrelin/obestatin ratio is modified in anorexia nervosa and obesity. This suggests that the ghrelin/obestatin balance could be essential to adapt the body's response to nutritional challenges. Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin-derived peptides are being developed and may be the key to obtaining a better understanding of their roles in different physiological and pathological conditions.

Changes in brain mRNA levels of gonadotropin-releasing hormone, pituitary adenylate cyclase activating polypeptide, and somatostatin during ovulatory luteinizing hormone and growth hormone surges in goldfish

In goldfish, circulating LH and growth hormone (GH) levels surge at the time of ovulation. In the present study, changes in gene expression of salmon gonadotropin-releasing hormone (sGnRH), chicken GnRH-II (cGnRH-II), somatostatin (SS) and pituitary adenylate cyclase activating polypeptide (PACAP) were analyzed during temperature- and spawning substrate-induced ovulation in goldfish. The results demonstrated that increases in PACAP gene expression during ovulation are best correlated with the GH secretion profile. These results suggest that PACAP, instead of GnRH, is involved in the control of GH secretion during ovulation. Increases of two of the SS transcripts during ovulation are interpreted as the activation of a negative feedback mechanism triggered by high GH levels. The results showed a differential regulation of sGnRH and cGnRH-II gene expression during ovulation, suggesting that sGnRH controls LH secretion, whereas cGnRH-II correlates best with spawning behavior. This conclusion is further supported by the finding that nonovulated fish induced to perform spawning behavior by prostaglandin F2alpha treatment increased cGnRH-II expression in both forebrain and midbrain, but decreased sGnRH expression in the forebrain.

Intrahypothalamic neurohormonal interactions in the control of growth hormone secretion.

The secretion of growth hormone (GH, somatotropin) is regulated by two neurohormones: one inhibitory, somatotropin release-inhibiting hormone (SRIH) or somatostatin, and one stimulatory, GH-releasing hormone (GHRH). There are several lines of evidence for reciprocal interactions between SRIH and GHRH neuronal networks. Anatomically, GHRH terminals contact SRIH-containing neurons in the periventricular nucleus and SRIH-containing fibres innervate GHRH-containing neurons in the arcuate nucleus. Physiologically, SRIH and GHRH are secreted into the portal blood in complementary oscillating patterns. Results from immunizations with anti-SRIH antisera suggest that endogenous SRIH blocks GHRH release from the median eminence. Intracerebroventricular injections of SRIH stimulate secretion of GHRH indirectly, probably via autoinhibition of SRIH neurons in the anterior periventricular region. High resolution autoradiography allowed us to visualize high affinity, specific [125]SRIH receptors on 30% of GHRH mRNA-containing cells in the ventrolateral portion of the arcuate nucleus. The functional importance of these receptors was demonstrated by blocking endogenous SRIH action with cysteamine, which resulted in an increase in GHRH mRNA levels and desaturation of SRIH receptors in the ventrolateral part of the arcuate nucleus. Alterations in GH production caused by hypophysectomy or acute and chronic GH hypersecretion have opposite effects on the synthesis of SRIH and GHRH, giving further evidence for reciprocal interactions between these two neurohormonal systems.

Expression of sstr1 and sstr2 in rat hypothalamus: correlation with receptor binding and distribution of growth hormone regulatory peptides.

With the aim of elucidating the role of individual somatostatin receptors in the central control of growth hormone secretion, we have examined the distribution of sstr1 and sstr2 mRNAs in the hypothalamus of the adult rat by in situ hybridization using 35S-labelled antisense riboprobes. Both receptors were expressed strongly in the preoptic area, suprachiasmatic nucleus and arcuate nucleus. High sstr1, but low sstr2, expression was evident in the paraventricular and periventricular nuclei as well as in the ventral premammillary nucleus. Conversely, moderate to high sstr2, but low sstr1, mRNA levels were detected in the anterior hypothalamic nucleus, ventromedial and dorsomedial nuclei and medial tuberal nucleus. Within the arcuate nucleus, the distribution of cells expressing sstr1 and sstr2 was comparable to that of neurons which bind somatostatin-14 selectively, one third of which have been documented to contain growth hormone-releasing hormone. Within the periventricular nucleus, the distribution of cells expressing sstr1 and, to a lesser extent, sstr2 was reminiscent of that of both [125I]somatostatin-labelled and somatostatin-immunoreactive cells. Taken together, these results imply a role for both sstr1 and sstr2 receptors in the central regulation of growth hormone-releasing hormone and somatostatin secretion, and hence of growth hormone release, by somatostatin.

Tripartite Control of Growth Hormone Secretion in Women during Controlled Estradiol Repletion

Studies of how aging attenuates GH secretion are confounded by differences in sex-steroid milieus, abdominal visceral fat mass (AVF), and IGF-I concentrations and limited in interpretability by the use of pharmacological doses of secretagogues. In a controlled estrogenic milieu, near-physiological secretagogue drive will unmask distinct influences of age, AVF, and IGF-I on GH secretion. The study was conducted at an academic medical center. Subjects included 10 healthy pre- (PRE) and 10 postmenopausal (POST) women. In a defined estradiol (E(2)) milieu, we compared GH secretion after submaximal stimulation with GH-releasing peptide (GHRP)-2 (ghrelin analog), GHRH, and l-arginine (an inhibitor of somatostatin outflow). We related GH responses to age stratum (dichotomous variable) and AVF and IGF-I concentrations (continuous variables). In the face of comparable concentrations of E(2), testosterone, and SHBG: 1) age (P < 0.001) and secretagogue type (P < 0.001) independently determined GH secretion; 2) GH responses in POST subjects were only 26-33% of those in PRE (P < or = 0.002) across all secretagogues; 3) POST women lost the PRE order of secretagogue potency (GHRP-2 > GHRH = l-arginine); and 4) in the combined cohorts, higher AVF predicted reduced l-arginine-stimulated GH secretion (R(2) = 0.46, P = 0.0013), whereas higher IGF-I concentrations forecast increased GHRP-2 and GHRH drive (R(2) > or = 0.52, P < or = 0.013). A paradigm of near-physiological secretagogue drive in an E(2)-clamped milieu unmasks tripartite deficits in peptide-signaling pathways in healthy POST, compared with PRE, women. Post hoc analyses indicate that both greater visceral adiposity and lower IGF-I concentrations mark this triple regulatory defect.

Plasma Ghrelin Levels in Children with Chronic Renal Failure on Peritoneal Dialysis

Malnutrition and loss of appetite represent a serious problem in children with chronic renal failure. Ghrelin is a newly described hormone involved in control of growth hormone secretion, stimulation of food intake, and regulation of energy balance. Plasma ghrelin levels were compared between 12 children on automated peritoneal dialysis (APD) and 9 children on conservative treatment of chronic renal failure. Eight healthy children matched for age and body mass index (BMI) served as a control group. Plasma ghrelin levels were similar in children on APD (698.3 +/- 59.7 pg/mL) and children on conservative treatment (675.4 +/- 41.9 pg/mL) compared to healthy controls (700.1 +/- 24.7 pg/mL). There was no difference in plasma ghrelin levels in children with chronic renal failure regardless of the method of treatment (peritoneal dialysis vs conservative treatment). The plasma ghrelin index was similar in all three investigated groups: APD 40.2 +/- 8.7 vs conservative treatment 39.1 +/- 5.6 vs controls 41.0 +/- 7.8 (pg/mL)/BMI (kg/m2). Plasma ghrelin levels did not correlate with age, duration of dialysis treatment, height, weight, BMI, creatinine and urea levels, adequacy parameters, or nightly glucose load. Plasma ghrelin levels in children on APD were not different from levels in children on conservative treatment or healthy controls with comparable BMI. The persistent state of toxic influence of uremic end-products could be responsible for such a lack of correlation with anthropometrical parameters. Further studies on a larger group of children on APD are needed to clarify the effect of ghrelin on nutritional status in children with chronic renal failure.

Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.

This Month in Gastroenterology

This Month in Gastroenterology

Effects of sleep deprivation on ghrelin, ACTH, GH and cortisol secretion in normal controls

Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor. Besides GH-releasing hormone (GHRH) and somatostatin it is thought to be a regulating factor of GH release. Ghrelin appears to be involved in sleep regulation. We showed recently that ghrelin promotes slow wave sleep and the nocturnal release of GH, cortisol and prolactin in humans. Similarly promotion of non-REM-sleep was reported in mice after systemic ghrelin. There are no data available about the pattern of ghrelin secretion during the recovery night after total sleep deprivation (TSD). Nocturnal ghrelin, GH, ACTH and cortisol plasma concentrations were determined by radioimmunoassay and simultaneously sleep EEG was recorded (23:00–07:00) during sleep before and after one night of TSD in 8 healthy subjects (3 females and 5 males, mean age 26.3yrs, SD 4.4). We observed a trend suggesting higher ghrelin secretion during the first half of the night after TSD (before TSD mean 466ng/ml, SD 113ng/ml, after TSD mean 545ng/ml, SD 176, p=0.093). In the night before TSD the maximum time of ghrelin secretion occured at 03:40 (SD 117min.) and after TSD this time point was 00:42 (SD 76min.), indicating an earlier ghrelin secretion after TSD (p<0.05). GH secretion during the first half of the night and total night after TSD were elevated. ACTH and cortisol were also elevated, which was most pronounced during the second half of the night (ACTH: AUC before TSD, mean 5278, SD 1814, after TSD mean 10817, SD 3314, p<0.05).

Role of Excitatory Amino Acids in the Control of Growth Hormone Secretion

Excitatory amino acids (EEAs), such as glutamate, are pivotal elements in the hypothalamic circuitry involved in the control of pituitary function. The actions of EEAs are mediated by different postsynaptic receptor subtypes, which include the ionotropic receptors N-methyl-D-aspartate (NMDA), kainate (KA), 2-amino-3-hydroxy- 5 methyl-4-isoxazol propionic acid (AMPA), as well as metabotropic receptors. In this review, we summarize the experimental work on the role of EAA neurotransmission in the control of GH secretion in the rat. Detailed characterization of the effects of agonists and antagonists of glutamate receptors on GH release revealed that activation of NMDA, KA, and AMPA receptors at different age-points resulted in clear-cut stimulation of GH secretion, although age- and sex-dependent differences were detected in the pattern of response to the different agonists. This stimulatory action was proven nitric oxide (NO)-dependent and not exerted at the pituitary level. Moreover, the effects of NMDA on GH release likely involve additional mediators other than hypothalamic GH-releasing hormone (GHRH). In contrast, the role of metabotropic receptors seems to be marginal, and only inhibitory actions were observed after activation of different receptor subtypes. Furthermore, evidence was obtained on the modulation of the EEA system by gonadal factors in the control of GH secretion, and on the physiological relevance of EEA pathways in the regulation of pulsatile GH release. The analysis of interactions between EAA receptors and other neuronal pathways evidenced the close interactions between different systems involved in the control of GH secretion. Blockade of glutamate receptors abolished the stimulatory effect of GABA and ghrelin on GH secretion and, inversely, blockade of ghrelin or GABA receptors abolished the stimulatory effect of EAAs. In conclusion, our data using the rat as animal model provide evidence for a pivotal role of glutamate pathways in the regulation of GH secretion throughout the life-span.

Ghrelin: A recently discovered gut-brain peptide (Review)

In the 70s, several new, both peptidyl and non-peptidyl, derivatives that stimulate and amplify pulsatile growth hormone (GH) secretion, independently from growth hormone releasing hormone (GHRH), were synthesized. The family of these molecules have been named growth hormone secretagogues (GHSs). The subsequent discovery of the natural receptor for GHSs (GHS-R) suggested existence of a new regulatory system, participating in GH secretion control. Three years later a natural ligand for GHS-R was identified and was designated 'ghrelin'. Subsequently, it has been found that ghrelin exerts pleiotropic activity. It influences not only GH release but also food intake, function of gastrointestinal tract and cardiovascular system, sleep patterns as well as cancer proliferation. The current knowledge on ghrelin, its structure and function, is reviewed in this article.