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At least 19 recordsLinked to original sources

PubMed1995

[Stimulation of endogenous secretion of the growth hormone. Today in diagnosis, tomorrow in therapy?].

BACKGROUND: Treatment with growth hormone (GH) restores the natural growth rate in children with growth hormone deficiency (GHD). This is, however, achieved only after daily injections extending over many years and therefore daily short-term hypersomatotropinaemia. Stimulation of endogenous secretion of GH e.g. by oral administration of growth hormone-releasing peptide (GHRP) may help in future to eliminate these adverse aspects. This treatment could be beneficial in patients with a stimulable endogenous GH secretion. METHODS AND RESULTS: In order to find potential candidates for spontaneous secretion of GH the authors examined, using a test with sermoreline (GHRH1-29NH2), 31 children (21 boys) aged 5.8-16.5 years suffering from idiopathic (GHD), previously treated by daily GH injections. GH rose after stimulation with sermoreline to more than 14 mIU/l in 18/31 children (responders). The ratio of "responders" was higher in the sub-group of children with isolated GHD, as compared with multiple pituitary deficiency (p = 0.05) and insignificantly higher in the sub-group of children born by breech delivery (p = 0.13). CONCLUSIONS: More than half the children treated nowadays with GH could profit in future from the method of spontaneous GH secretions. The success of this procedure is more likely in children with isolated GHD and in breech delivered children.

Adolescent↗

PubMed2003

PEGylation of growth hormone-releasing hormone (GRF) analogues.

Synthetically produced GRF1-29 (Sermorelin) has an amino acid composition identical to the N-terminal 29 amino acids sequence of the natural hypothalamic GHRH1-44 (Figure 1). It maintains bioactivity in vitro and is almost equally effective in eliciting secretion of endogenous growth hormone in vivo. The main drawbacks associated with the pharmaceutical use of hGRF1-29 relate to its short half-life in plasma, about 10-20 min in humans, which is caused mostly by renal ultrafiltration and enzymatic degradation at the N terminus. PEGylation has been considered as one valid approach to obtain more stable forms of the peptide, with a longer in vivo half-life and ultimately with increased pharmacodynamic response along the somatotropic axis (endogenous GH, IGF-1 levels). Different PEGylated GRF conjugates were obtained and their bioactivity was tested in vitro and in vivo by monitoring endogenous growth hormone (GH) serum levels after intravenous (i.v.) injection in rats, and intravenous and subcutaneous (s.c.) injection in pigs. It was found that GRF-PEG conjugates are able to bind and activate the human GRF receptor, although with different potency. The effect of PEG molecular weight, number of PEG chains bound and position of PEGylation site on GRF activity were investigated. Mono-PEGylated isomers with a PEG5000 polymer chain linked to Lys 12 or Lys 21 residues, showed high biological activity in vitro, which is similar to that of hGRF1-29, and a higher pharmacodynamic response as compared to unmodified GRF molecule.

Animals↗

PubMed1990

Perinatal growth hormone (GH) physiology: effect of GH-releasing factor on maternal and fetal secretion of pituitary and placental GH.

To study regulation of the secretion of human pituitary GH (hGH) and placental GH (hPGH) in the pregnant woman and human fetus, the GH-releasing factor Sermorelin [GRF-(1-29)-NH2] was administered to pregnant women at term (n = 5), just before elective cesarean section; saline was administered in control studies (n = 5). The effects of GRF-(1-29)-NH2 administration on maternal and fetal serum concentrations of hGH and GRF-(1-29)-NH2 and maternal serum levels of hPGH were evaluated at birth. The mean time span between injection and birth was 20 min (range, 15-25 min). Cord serum hGH concentrations were similar in infants of GRF-(1-29)-NH2-injected mothers and control infants. GRF-(1-29)-NH2 elicited a consistent but small rise in maternal hGH serum concentrations (P = 0.08), whereas hPGH concentrations remained unaltered. Finally, GRF-(1-29)-NH2 concentrations were undetectable in cord serum, but readily detectable in concomitantly obtained maternal serum. In conclusion, these data suggest that hGH secretion in the pregnant woman at term is suppressed at the pituitary level, that GRF does not affect hPGH secretion, and that fetal hGH secretion is independent of circulating maternal GRF, probably because of lack of transplacental GRF passage.

Cesarean Section↗

PubMed2000

Potentiation of the inhibitory effect of growth hormone-releasing hormone antagonists on PC-3 human prostate cancer by bombesin antagonists indicative of interference with both IGF and EGF pathways.

BACKGROUND: In view of the involvement of various neuropeptides and growth factors in the progression of androgen-independent prostate cancer, we investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone or in combination with an antagonist of bombesin/gastrin-releasing peptide (BN/GRP) on PC-3 human prostate cancers. METHODS: Nude mice implanted with PC-3 tumors received GHRH antagonists MZ-5-156 or JV-1-38, each at 20 microgram/day s.c. In experiment 2, treatment consisted of daily injections of JV-1-38 (20 microgram), BN/GRP antagonist RC-3940-II (10 microgram), or a combination of JV-1-38 and RC-3940-II. Serum IGF-I levels, expression of mRNA for IGF-II, and characteristics of BN/GRP and EGF receptors in tumor tissue were investigated. RESULTS: JV-1-38 induced a greater inhibition of tumor growth and suppression of IGF-II mRNA than MZ-5-156, both compounds causing a similar decrease in serum IGF-I. In experiment 2, JV-1-38 and RC-3940-II produced a comparable reduction in tumor volume (65% and 61%, respectively), but a combination of both antagonists augmented tumor inhibition to 75%. Combined treatment with JV-1-38 and RC-3940-II also led to a greater suppression of IGF-II mRNA (92%), as compared with JV-1-38 (72%) or RC-3940-II (77%). Serum IGF-I concentration was lowered only in mice treated with JV-1-38, while the downregulation of BN/GRP and EGF receptors was specific for groups receiving RC-3940-II. CONCLUSIONS: The inhibitory effects of GHRH antagonists on PC-3 human androgen-independent prostate cancer can be potentiated by concomitant use of BN/GRP antagonists. The combination of both types of analogs apparently interferes with both IGF and bombesin/EGF pathways, and might be clinically useful for the management of androgen-independent prostate cancer.

Animals↗

PubMed2005

Antagonists of growth hormone releasing hormone (GHRH) and of bombesin/gastrin releasing peptide (BN/GRP) suppress the expression of VEGF, bFGF, and receptors of the EGF/HER family in PC-3 and DU-145 human androgen-independent prostate cancers.

BACKGROUND: Antagonists of growth hormone releasing hormone (GHRH) as well as antagonists of bombesin/gastrin releasing peptide (BN/GRP) inhibit the growth of various malignancies (cancers) including prostate cancer. METHODS: We investigated the effects of GHRH antagonists MZ-J-7-118 and RC-J-29-18, BN/GRP antagonists RC-3940-II and RC-3940-Et and the combination of MZ-J-7-118 and RC-3940-II on the growth of PC-3 and DU-145 human androgen independent prostate cancers xenografted s.c. into nude mice. To elucidate the mechanisms of action of these analogs, growth factors like IGF-II (insulin-like growth factor-II), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epidermal growth factor receptor/human epidermal growth factor receptor (EGF-R/HER) family were measured in tumors as well as IGF-I in serum. RESULTS: Antagonists of GHRH and BN/GRP alone or in combination significantly inhibited growth of PC-3 and DU-145 tumors, the greatest inhibition of tumor volume being achieved by combination of MZ-J-7-118 (5 microg/day) and RC-3940-II (10 microg/day). BN/GRP and GHRH antagonists and their combination also decreased the expression of VEGF significantly in PC-3 and non-significantly in DU-145, as measured by radioimmunoassay for VEGF protein and RT-PCR for mRNA levels of VEGF. GHRH and BN/GRP antagonists reduced bFGF concentrations and the maximal binding capacity of EGF receptors, and their mRNA levels in PC-3 and DU-145 tumors. mRNA levels for HER-2 and -3 were also diminished in PC-3 tumors by GHRH and BN/GRP antagonists. No changes in HER-4 were found after treatment. Serum IGF-I and tumoral IGF-II levels were not affected by the analogs. CONCLUSIONS: BN/GRP and GHRH antagonists inhibit growth of PC-3 and DU-145 prostate cancers by suppressing the expression of tumoral growth factors such as VEGF and bFGF as well as the receptors for EGF and related HER-2 and -3. Additive effects on tumor inhibition (TI) in vivo, but not on VEGF, bFGF, or members of the EGF/HER receptor family, can be achieved by the joint administration of both classes of analogs.

Animals↗

PubMed2004

Potent trypsin-resistant hGH-RH analogues.

A series of analogues of hGH-RH-(1-29)-NH2 designed to have metabolic stability has been synthesized. Standard Boc-SPPS was employed, modified to permit the guanidinylation of amino side-chains after chain assembly but before release from the resin. [Dat1, Har(11, 12, 20, 21, 29), Ala15, Nle27, Asp28]-, [Dat1, Har(11, 20, 29), Orn12, Ala15, Nle27, Asp28]-, and [Dat1, Gap(11,12, 21, 29), Ala15, Har20, Nle27, Asp28]-hGH-RH-(1-29)-NH2 were completely resistant to trypsin and about 50 times as potent as hGH-RH-(1-29)-NH2 itself when injected subcutaneously in rats. These peptides are candidates for clinical application in the therapy of GH deficiency.

Amino Acid Sequence↗

PubMed1996

A radioimmunoassay for African catfish growth hormone: validation and effects of substances modulating the release of growth hormone.

A highly sensitive radioimmunoassay has been developed for measuring plasma growth hormone (GH) concentrations in the African catfish (Clarias gariepinus). The lower detection limit of the assay was 0.1 ng/ml and the standard curve had an ED50 value of 0.5 ng/ml. The validity of the assay was established and the effects of several neurotransmitters on the release of GH were examined. In vitro experiments, using a static culture system for dispersed pituitary cells, demonstrated that the GH release in African catfish was affected by growth hormone-releasing hormone and somatostatin. Single intraperitoneal injections with a dopamine agonist, apomorphine, produced significant and dose-dependent increases in plasma GH levels. Unlike carp, goldfish, and tilapia, a super-active analogue of salmon gonadotrophin-releasing hormone did not alter plasma GH levels in African catfish.

Animals↗

PubMed1989

Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency.

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1-29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5-29.3 ng/ml). Continuous s.c. administration of GHRH of 4-6 micrograms/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m2 daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.

Child↗

PubMed1984

Stimulation of growth hormone secretion with human growth hormone releasing factors (GRF1-44, GRF1-40, GRF1-29) in normal subjects.

Peptides of different chain lengths (GRF1-44, GRF1-40, GRF1-29) were given as a 50 micrograms i.v. bolus to five normal volunteers. Blood was collected before and until 120 min after GRF injection. No serious side effects were recorded. All GRF peptides led to a clearcut and significant increase of GH levels compared to placebo controls with the maximum occurring 15-30 min after GRF injection. There was no significant difference in the maximal GH increase after the different GRF peptides. When GRF1-44 was administered to five normal subjects over 2 days in 6- and 18-h intervals, respectively, significant increase of GH levels were recorded after each injection compared to placebo controls. Again, there was no significant difference between the maximal GH rises during the different tests. These findings show that the short GRF1-29 peptide may be used for diagnosis and therapy. In addition, in contrast to continuous infusion and administration of GRF in short intervals, GRF application in 6-h intervals leads to adequate GH responses.

Adult↗

PubMed1995

Study of the activation mechanism of human GRF(1-29)NH2 on rat mast cell histamine release.

Human growth releasing factor (GRF) (1-29)NH2 releases histamine from pleural and peritoneal rat mast cells by a non cytotoxic and non immunological mechanism. Pretreatment of cells with pertussis toxin markedly inhibits the secretion, suggesting a possible function of a Gi-protein in the activation pathway. In order to determine the role of cAMP on GRF mediated secretion, mast cells were preincubated with isobutylmethylxanthine (IBMX) or cholera toxin, since both drugs greatly and enhance cAMP levels. IBMX inhibits mediator secretion while, in contrast, cholera toxin is ineffective to modify histamine release. The PKC activator TPA amplifies the response of mast cells to human GRF, shifting the dose-response curve to the left. The pretreatment of mast cells with the phosphatase inhibitor okadaic acid exerts no effect on the dose-response function curve to GRF. The response to human GRF does not depend on extracellular calcium, but there is a good correlation between the percent of histamine released and 45calcium uptake. The kinetic of calcium uptake is fast, maximum uptake being reached in 30 seconds.

1-Methyl-3-isobutylxanthine↗

PubMed1990

A glucagon-secretin-like peptide stimulates the intrinsic nervous plexus of guinea pig gallbladder.

The role of vasoactive intestinal peptide (VIP), as a possible neurotransmitter of the intrinsic nerve plexus in the guinea pig gallbladder, was investigated by monitoring spontaneous contractile activity. VIP receptor antagonist (4 Cl-D-Phe6, Leu 17)-VIP did not produce any effect on muscular tone and spontaneous activity, whereas (N-Ac-Tyr1, D-Phe2)-GRF-(1-29)-NH2, (14-GRF analog), which is known to stimulate digestive enzyme secretion by interacting with the VIP-preferring receptors, greatly increased the amplitude and frequency of waves as well as the muscular tone. Since VIP receptor antagonist acts selectively as a competitive antagonist for the action of VIP, we conclude that the gallbladder inhibitory intrinsic plexus neurotransmitter is not VIP, but a member of the glucagon-secretin family of peptides.

Animals↗

PubMed1986

Testing with growth hormone-releasing factor (GRF(1-29)NH2) and somatomedin C measurements for the evaluation of growth hormone deficiency.

Growth hormone (GH) responses to GRF (1 microgram/kg BW i.v.) were investigated. Comparison between GRF(1-40) and GRF(1-29)NH2 in 11 young adult volunteers gave identical results. One hundred and thirty-one children and adolescents (45 with idiopathic GHD) were tested with GRF (1-29)NH2. The maximal GH levels (max GH) in response to GRF during the 120 min test period were found suitable to characterize the response. In cases without GHD no correlation to age, sex and pubertal development was observed. A maximal GH level of above 10 ng/ml was found to be normal. In 3 out of 86 children without GHD (one with Turner syndrome; two with simple obesity) max GH fell short of 10 ng/ml, while 11 of 45 cases with GHD exceeded this margin. In GHD, max GH was inversely correlated with age. There was no difference in max GH between groups with or without perinatal pathology as a presumed cause of GHD. GH levels to GRF were positively correlated with maximal GH level during sleep in GHD, but not correlated with responses seen to insulin or arginine. The value of GRF testing for the confirmation of GHD is discussed in the light of other GH stimulatory tests and basal somatomedin C measurements. It is suggested that the combination of testing with GRF and the determination of a basal SmC level offers a safe and convenient way to diagnose GHD in clinically suspected cases, though in some cases further diagnostic tests may be needed.

Adolescent↗

PubMed1996

Impairment of growth hormone responsiveness to growth hormone releasing hormone and pyridostigmine in patients affected by Prader-Labhardt-Willi syndrome.

In order to evaluate the impairment of GH response in patients affected by Prader-Labhardt-Willi (PLW) syndrome, in 18 patients we studied GH response to clonidine and to GHRH + pyridostigmine, a cholinergic drug which enhances GHRH induced GH responsiveness in obese patients. After clonidine GH response was abnormal in 14/18 subjects (mean GH peak: 4.1 +/- 1.3 micrograms/l; area under curve: 208.1 +/- 74.2 micrograms/l.h) while all but 5 patients showed an inadequate GH response to GHRH + pyridostigmine (mean GH peak: 13.4 +/- 2.5 micrograms/l; area under curve: 903.4 +/- 171.0 micrograms/l.h). However, in the three patients with low adiposity index, GH response to GHRH + pyridostigmine was significantly higher than that observed in fatter subjects. In addition, GH response to GHRH + pyridostigmine was negatively correlated to age and adiposity index. In conclusion, our data are consistent with the hypothesis of the existence of a complex derangement of GH neuroendocrine regulation in these subjects.

Adolescent↗

PubMed1996

An endogenous inactivating inward-rectifying potassium current in oocytes of Xenopus laevis.

An endogenous inward-rectifying K+ current is described, which is present in native oocytes of some Xenopus laevis donors. Experiments were performed using defolliculated oocytes from donor frogs obtained from two different suppliers. In all oocytes from animals from one source, an inward-rectifying K+ current could be elicited with negative pulses from a holding potential of -20 mV in external solutions with a high K+ concentration. Increasing external K+ concentrations increased the amplitude of this current and shifted the reversal potential towards more positive potentials. In 118 mM KCl, the inward-rectifying K+ current partially inactivated between -20 and -80 mV and completely inactivated at more negative membrane potentials; 50% steady-state inactivation occurred near -50 mV. The time course of inactivation of the inward-rectifying current could be well fitted with two exponentials. The slow time constant had values of about 500 ms and was voltage independent. In contrast, the fast time constant and the time to reach the peak inward current decreased with more negative membrane potentials. Ba2+, Cs+, quinine (all 5 mM) and 50 mM tetraethylammonium partially blocked the inward-rectifying K+ current, whereas 10 mM 4-aminopyridine was without blocking effect. The oxidant chloramine-T blocked the inward-rectifying K+ current without slowing its inactivation.

Animals↗

PubMed1984

Administration of human pancreatic growth hormone-releasing factor (GRF) analogs enhances responsiveness of cultured rat pituitary cells to GRF.

The aim of this study was to investigate whether anterior pituitary responsiveness to human pancreatic growth hormone-releasing factor containing 29 amino acids (GRF-29) can be modulated by GRF-29 itself. Male rats were injected (sc) daily for 3 days with 50 ug of GRF-29, or were treated twice daily for 14 days with 5 ug of [D-Ala-2]-GRF-29 (a potent GRF agonist). Control animals were injected with saline. After the last injection, pituitaries were removed, dispersed, cultured for 96 h and then challenged with either GRF-29 or [D-Trp-6]-LHRH (a LHRH agonist). Cultured cells from analog-treated rats were more responsive to GRF-29 stimulation than were cells obtained from controls. In contrast, neither treatment altered the response to [D-Trp-6]-LHRH. These studies indicate that periodic administration of GRF analogs can increase hypophyseal GRF responsiveness. Such control may be an important component in the physiological regulation of GH secretion and has important implications for potential therapeutic uses of GRF analogs.

Animals↗

PubMed1984

Super-active analogs of growth hormone-releasing factor (1-29)-amide.

Human pancreatic growth hormone releasing factor (1-29)-amide [hpGRF (1-29)-NH2] and the following analogs: [D-Tyr-1]-hpGRF(1-29)-NH2, [D-Ala-2]-hpGRF(1-29)-NH2, [D-Asp-3]-hpGRF(1-29)-NH2, and [N-Ac-Tyr-1]-hpGRF (1-29)-NH2 were synthesized using solid phase methodology and tested for their ability to stimulate growth hormone (GH) secretion in the rat and the pig in vivo. [D-Ala-2]-hpGRF (1-29)-NH2 was approximately 50 times more potent than the parent molecule in eliciting GH secretion in the rat. The other analogs were less active, but all were more potent than the 1-29 amide in the rat. [D-Tyr-1]-hpGRF(1-29)-NH2 was 10 times more potent, [D-Asp-3]-hpGRF(1-29)-NH2 7 times more potent, and the acetylated molecule approximately 12 times more potent than hpGRF(1-29)-NH2.

Animals↗

PubMed1990

Characterization of [125I-Tyr10]human growth hormone-releasing factor (1-44) amide binding to rat pituitary: evidence for high and low affinity classes of sites.

A sensitive binding assay was developed to determine binding characteristics of commercially available [125I-Tyr10]human growth hormone-releasing factor (hGRF) (1-44)NH2 in rat pituitary using 0.1 gland homogenate (70-75 micrograms protein) per incubation tube. Under standard assay conditions, addition of 5 mM EDTA efficiently prevented the degradation of both human and rat GRF for at least 3 h. Association of the ligand was time-dependent: equilibrium was reached within 30 min of incubation at 23 degrees C and remained stable for an additional 150 min (K1 = 5.01 +/- 0.86 nM-1.min-1). Specific binding increased linearly with the amount of protein present in the assay, from 15 to 170 micrograms per incubation tube. This binding was reversible, dissociation occurring almost completely after a 120-min period (K-1 = 8.13 +/- 0.29 x 10(-3) min-1). A concentration of 5-10 mM Mg2+ was required for optimal specific binding whereas 50 mM Mg2+ or monovalent cations such as Na+, K+, Li+ decreased it. Scatchard analysis of cold saturation studies by the Ligand program statistically revealed the presence of two distinct classes of binding sites; the first was of high affinity (0.68 +/- 0.11 nM) and low capacity (140 +/- 22 fmol/pituitary), the second was of lower affinity (590 +/- 347 nM) and higher capacity (38.7 +/- 18.7 pmol/pituitary). Similar values were obtained with various bovine serum albumin (BSA) concentrations and when using crude or washed pituitary homogenates, suggesting that the second low affinity site was not BSA or a soluble protein from the homogenate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Inhibition of growth hormone-releasing factor suppresses both sleep and growth hormone secretion in the rat.

To study the possible involvement of hypothalamic growth hormone-releasing factor (GRF) in sleep regulation, a competitive GRF-antagonist, the peptide (N-Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2, was intracerebroventricularly injected into rats (0.003, 0.3, and 14 nmol), and the EEG and brain temperature were recorded for 12 h during the light cycle of the day. Growth hormone (GH) concentrations were determined from plasma samples taken at 20-min intervals for 3 h after 14 nmol GRF-antagonist. The onset of non-rapid eye movement sleep (NREMS) was delayed in response to 0.3 and 14 nmol GRF-antagonist, the duration of NREMS was decreased for one or more hours and after 14 nmol EEG slow wave amplitudes were decreased during NREMS in postinjection hour 1. The high dose of GRF-antagonist also suppressed REMS for 4 h, inhibited GH secretion, and elicited a slight biphasic variation in brain temperature. These findings, together with previous observations indicating a sleep-promoting effect for GRF, support the hypothesis that hypothalamic GRF is involved in sleep regulation and might be responsible for the correlation between NREMS and GH secretion reported in various species.

Animals↗