Administration Of GH-releasing Hormone Research Articles

Advances in the detection of growth hormone releasing hormone synthetic analogs.

The administration of growth hormone releasing hormone (GHRH) and its synthetic analogs is prohibited by the World Anti-Doping Agency (WADA). Although there is evidence of their use, based on admissions and intelligence, they do not appear to have been found in anti-doping samples by WADA accredited laboratories. This might be due to their small concentration in urine and limited knowledge about their metabolism, especially for unapproved synthetic analogs. This study investigates the in vitro metabolism and detection of four of the larger GHRH synthetic analogs (sermorelin, tesamorelin, CJC-1295, and CJC-1295 with drug affinity complex) in fortified urine. Nineteen major in vitro metabolites were identified, selected for synthesis, purified, and characterized in house. These were used as reference materials to spike into urine together with commercially available parent peptides and a metabolite of sermorelin (sermorelin(3-29)-NH2 ) to develop a sensitive liquid chromatography-tandem mass spectrometry method for their detection to help prove GHRH administration. Limits of detection of the target peptides were generally 1ng/ml (WADA required performance limit) or less.

The intra-individual stability of GH biomarkers IGF-I and P-III-NP in relation to GHRH administration, menstrual cycle, and hematological parameters.

The intra-individual stability of growth hormone (GH) biomarkers IGF-I, P-III-NP, calculated GH-2000 score in relation to growth hormone-releasing hormone (GHRH) (Somatorelin) administration, menstrual cycle, and hematological parameters were investigated in four men and eight women, respectively. Moreover, the hematological parameters hemoglobin (Hb) and percentage of reticulocyte (RET%) were statistically analyzed in relation to the GH biomarker parameters for the GHRH administration study and the menstrual cycle study. Longitudinal monitoring of IGF-I and/or GH-2000 score proved to be a viable approach to detect the GHRH intake in men, as all four participants show values above individually calculated thresholds (calculated as mean ± 3SD from three baseline samples). The intra-individual variation for IGF-I, P-III-NP, and calculated GH-2000 score in women, over two consecutive menstrual cycles, was investigated and established to be higher (coefficients variations [CVs] between 12% and 186%) than in men (CVs between 3% and 12%). The GHRH administration did not influence the hematological parameters. A strong positive correlation between Hb and IGF-I (Rs = 0.73, p < 0.0001) and a borderline weak correlation between RET% and IGF-I (Rs = 0.28, p = 0.054) were noticed in the women. No correlation for the P-III-NP and the hematological parameters was seen for the females in the menstrual cycle study. The results fortify previous studies that longitudinal monitoring of IGF-I and/or GH-2000 score may be a promising method to detect doping with GH and GH stimulating agents in men, whereas the large intra-individual variation noted in women indicates that longitudinal monitoring of these biomarker may be harder to evaluate in women.

Neuron-specific Mafb knockout causes growth retardation accompanied by an impaired growth hormone/insulin-like growth factor I axis.

Mammalian postnatal growth is regulated primarily by the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. MafB is a basic leucine zipper (bZip) transcription factor that has pleiotropic functions. Although MafB plays a critical role in fetal brain development, such as in guidance for hindbrain segmentation, its postnatal role in neurons remains to be elucidated. To investigate this, we used neuron-specific Mafb conditional knockout (cKO) mice. In addition to an approximately 50% neonatal viability, the Mafb cKO mice exhibited growth retardation without apparent signs of low energy intake. Notably, serum IGF-I levels of these mice in the postnatal stage were lower than those of control mice. They seemed to have a neuroendocrine dysregulation, as shown by the upregulation of serum GH levels in the resting state and an inconsistent secretory response of GH upon administration of growth hormone-releasing hormone. These findings reveal that neuronal MafB plays an important role in postnatal development regulated by the GH/IGF-I axis.

Sleep-endocrine effects of growth hormone-releasing hormone (GHRH) in patients with schizophrenia

Changes in sleep-EEG after endocrine stimulation tests in patients with schizophrenia include reduced sleep efficiency, prolonged sleep latency and increased awaking after sleep onset Findings on sleep associated growth hormone (GH) secretion were ambiguous. The aim of this study was to elucidate the sleep-endocrine activity especially in the GH system of patients with schizophrenia after repeated administration of GHRH. The effect of repetitive injections of 4 × 50 μg GHRH between 22.00 and 01.00 h on sleep endocrine parameters was investigated in 9 patients diagnosed for schizophrenia. Patients did not receive any medication for one week. Concentrations of ACTH, cortisol, prolactin and GH were determined. Patients spent three consecutive nights in the sleep laboratory. Blood was taken every 20min. Results were compared with matched healthy controls.A non-significant prolonged sleep onset latency and increased time awake was found in patients compared to controls. Sleep stage 2 was significantly reduced in patients. No significant difference in ACTH and cortisol was detected, whereas the GH secretion in patients following GHRH stimulation was significantly elevated compared to controls.Our results in drug free patients confirm already known changes in sleep-EEG in these patients. The GH response to GHRH-stimulation indicates a different regulatory sensitivity of the system between daytime and night-time.

Unaltered ratio of circulating levels of growth hormone/GH isoforms in adults with Prader–Willi syndrome after GHRH plus arginine administration

Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms, the most abundant being 22kDa- and 20kDa-GH. The availability of analytical methods to measure these GH isoforms might represent a valuable diagnostic tool to investigate GH hyposecretory states, including Prader–Willi syndrome (PWS), one of the most common causes of syndromic obesity. The aim of the present study was to measure circulating levels of 22kDa- and 20kDa-GH in PWS adults (n=14; M/F: 5/9; genotype DEL15/UPD15: 12/2; age: 19.0±3.7years; BMI: 29.9±8.7kg/m2) after combined GH releasing hormone (GHRH) plus arginine (ARG) administration. The results were analysed subdividing the study population in obese vs. nonobese (6/8) and GH deficient vs. nonGH deficient (GHD) (6/8) subjects, according to appropriate BMI-related diagnostic cut-off limits of GH peak response to the provocative test. Circulating levels of 22kDa-GH were measured by a chemiluminescent method based on a detection monoclonal antibody targeting an epitope in the loop connecting helix 1 and 2 of GH, which is missing in 20kDa-GH; the 20kDa-GH was measured using a time resolved fluorescence assay based on two monoclonal antibodies with no cross-reactivity to 22-kDa GH.GHRH plus ARG significantly stimulated the secretions of 22kDa- and 20kDa-GH in nonobese (at 30, 45, 60 and 90min and at 45, 60, 90 and 120min vs. 0min, p<0.05, with GH peaks of 15.8±10.3ng/ml and 2.7±1.2ng/ml, respectively) and in nonGHD PWS (at 30, 45 and 60min and at 45, 60 and 90min vs 0min, p<0.05, with GH peaks of 12.5±9.0ng/ml and 2.0±1.8ng/ml, respectively). No significant GHRH plus ARG-induced changes in 22kDa- and 20kDa-GH were observed in obese or GHD PWS patients, the only exception being the increase of 22kDa-GH (p<0.05) 60min after the stimulus administration in GHD group (with GH peaks of 6.9±4.7ng/ml and 0.8±0.6ng/ml in obese subjects and 8.5±6.0ng/ml and 1.2±1.0ng/ml in GHD subjects for 22kDa- and 20kDa-GH, respectively). The GH responses for both isoforms were significantly higher in nonobese than in obese PWS patients (at 45 and 60min for 22kDa-GH and at 45, 60, 90 and 120min for 20kDa-GH, p<0.05), while no differences were detected between GHD vs. nonGHD groups. As previously reported in healthy subjects, the ratios of circulating levels of 22kDa- to 20kDa-GH remained constant after GHRH plus ARG both in obese/non-obese and GHD/non-GHD groups, thus suggesting the preservation of a normal balance in GH isoforms in PWS.

Growth Hormone–Releasing Hormone Effects on Brain γ-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging

Growth hormone-releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response. To examine the neurochemical effects of GHRH in a subset of participants from the parent trial. Randomized, double-blind, placebo-controlled substudy of a larger trial. Clinical research unit at the University of Washington School of Medicine. Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study. Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention. Brain levels of glutamate, inhibitory transmitters γ-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 × 2 × 2-cm3 left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phosphocreatine, and NAAG was expressed as a ratio to N-acetylaspartate. After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P < .04), NAAG levels were increased (P = .03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P = .002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r = 0.47; P = .001) and tended to be negatively correlated with MI (r = -0.34; P = .06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P = .03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects. Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00257712.

Effects of Growth Hormone–Releasing Hormone on Cognitive Function in Adults With Mild Cognitive Impairment and Healthy Older Adults

Growth hormone–releasing hormone(GHRH), growth hormone, and insulin like growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI). To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI. Randomized,double-blind,placebo-controlled trial. Clinical Research Center, University of Washington School of Medicine in Seattle. A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study. Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc),a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout(week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition. Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference,Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test,and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample. The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults.The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory(P=.08). Treatment with GHRH increased insulin like growth factor 1 levels by 117 %(P.001), which remained within the physiological range, and reduced percent body fat by 7.4%(P.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35%in adults with MCI (P.001) but not in healthy adults. Adverse events were mild and were reported by 68%of GHRH treated adults and 36% of those who received placebo. Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.” clinicaltrials.gov Identifier: NCT00257712

Responses to administration of growth hormone releasing hormone and glucose in steers receiving stair-step and extended restriction on feeding

In this study, we assessed the temporal response of growth hormone (GH)/ghrelin to the intravenous administration of GH releasing hormone (GHRH) in 11- (period 1) and 15-month-old (period 2) Korean native steers, as well as the insulin induction response to glucose administration after completion of the feeding scheme in 11-month-old Korean native steers experiencing stair-step and extended restriction feeding schemes. The experiment was divided into periods 1, 2, 3, and 4 with durations of 3, 2, 4, and 2 months, respectively. The control group (n=9) was fed according to a standard feeding program during all 4 periods. The T1 (n=9; stair-step fed group) was fed a diet with total digestible nutrients (TDN) at concentrations 20% less and more than the TDN concentration fed to the control group in periods 1 and 3 and periods 2 and 4, respectively, whereas the T2 (n=9; extended restricted group) was fed increasing levels of TDN, having concentrations of 30%, 20%, 10% less than and 20% more than the TDN concentration of control group, during periods 1, 2, 3, and 4, respectively. Randomly chosen steers (n=4, total 12 heads) from the C, T1, and T2 groups were used for the experiment of GHRH and glucose administration. Compared to the control group, the T1 showed elevated levels of plasma GH and insulin after GHRH and glucose administration (p<0.05) and significantly greater body weight gain and feed efficiency. Although the total amounts of ghrelin in plasma were significantly decreased in the T1 group after GHRH administration (p<0.05), GHRH treatment did not affect the acyl ghrelin concentration in the plasma during compensatory growth. The results illustrate that stair-step feeding can promote growth performance by altering the endocrine responses associated with energy utilization, such as the production of GH, ghrelin, and insulin, in steers.

The Absence of Somatotroph Proliferation During Continuous Stress is a Result of the Lack of Extracellular Signal‐Regulated Kinase 1/2 Activation

The integrity of homeostasis can be affected by chronic stress, and hyposomatotropism is evident in chronic stress-associated illnesses. In the present study, we demonstrated that a continuous stress (CS) severely affected somatotrophs among hormone-secreting cells in the anterior lobe (AL) of the pituitary by using a rat CS model. Among AL cells, the proliferation of somatotrophs was almost entirely suppressed in rats that had 3-5 days of CS (5dCS), although other hormone-secreting cells continued to proliferate. The cell size of somatotrophs was reduced at 5dCS (P<0.01), the number of secretory granules was increased at 3dCS (P<0.01) and serum growth hormone (GH) was on declining trend during 1 to 5dCS, suggesting that GH release was inhibited. GH-releasing hormone (GHRH) mRNA level in the arcuate nucleus was transiently decreased, whereas its receptor expression in the AL was significantly increased in CS rats. When 5dCS rats were injected with GHRH, transient GH secretion was observed, whereas proliferation of somatotrophs did not occur. The GHRH administration failed to stimulate extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and the nuclear translocation of ERK in somatotrophs. These results suggest that somatotrophs of 5dCS rats expressed sufficient GHRH receptor, which could transfer a signal for GH release. However, the GHRH-induced proliferation signal was blocked somewhere between the receptor and ERK1/2. Because significant increase of corticosterone in the initial stage (the 1-3dCS) was observed in this model, the corticosterone may affect the signalling. Although the mechanism underlying the blockage of the proliferation signal in somatotrophs under CS remains unclear, these somatotrophic disorder, suggesting that the present animal model may be useful for understanding the molecular mechanisms of chronic stress-associated illnesses.

The vagus nerve as a regulator of growth hormone secretion

The growth hormone (GH) axis is mainly regulated by the growth hormone releasing hormone (GHRH) and somatostatin (SS) hypothalamic peptides. Nevertheless, since ghrelin peptide was discovered as the natural ligand for growth hormone secretagogue receptor (GHS-R), the mechanism of GH regulation has acquired a new dimension. It was described that ghrelin possesses a relevant effect inducing GH secretion when it is administered peripherally. A role of the vagus nerve mediating ghrelin action has been described although this effect is not understood. Under this context the main objective of this work was to determine the possible involvement of the vagus in the somatotroph axis regulation. The results in this manuscript show that animals with a disruption of the vagus connection presented lower basal IGF-1 and GH levels, a decreased GH response to peripheral GHRH administration and a marked diminution in the GH response to peripheral and central ghrelin treatments. In addition, vagotomized animals showed a down-regulation of GHRH mRNA in the arcuate nucleus of the hypothalamus and a down-regulation in both GHRH and GHS receptors' mRNA at the pituitary level. In conclusion, the present work reveals that the vagus nerve is crucial in growth hormone regulation and essential for the full GH-releasing effect of ghrelin.

Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors

Acute and chronic exposure to high altitude induces various physiological changes, including activation or inhibition of various hormonal systems. In response to activation processes, a desensitization of several pathways has been described, especially in the adrenergic system. In the present study, we aimed to assess whether the hypophyseal hormones are also subjected to a hypoxia-induced decrease in their response to hypothalamic factors. Basal levels of hormones and the responses of TSH, thyroid hormones, prolactin, sex hormones, and growth hormone to the injection of TRH, gonadotropin-releasing hormone, and growth hormone-releasing hormone (GHRH) were studied in eight men in normoxia and on prolonged exposure (3-4 days) to an altitude of 4,350 m. Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle-stimulating hormone and prolactin decreased, while leutinizing hormone was unchanged. Norepinephrine and cortisol levels were elevated, while no change was observed in levels of epinephrine, dopamine, growth hormone (GH), IGF-1, and IGFBP-3. The mean response to hypothalamic factors was similar in both altitudes for all studied hormones, although total T4 was lower in hypoxia during 45 to 60 min after injection. The effect of hypoxia on the hypophyseal response to hypothalamic factors was similar among subjects, except for the GH response to GHRH administration. We conclude that prolonged exposure to high-altitude hypoxia induces contrasted changes in hormonal levels, but the hypophyseal response to hypothalamic factors does not appear to be blunted.

Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: Possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion.

Central administration of growth hormone-releasing hormone and corticotropin-releasing hormone stimulate downstream movement and thyroxine secretion in fall-smolting coho salmon ( Oncorhynchus kisutch)

The ultimate signal triggering downstream migration in anadromous salmonids is unknown. A plasma surge of T 4 (T 4 surge) occurs during downstream migration in salmonids; however, the causal relationship between migratory behavior and the T 4 surge is not well known. We first examined the progression of smolt indicators (skin silvering, condition factor (CF), gill Na +, K +-ATPase (NKA) activity and plasma T 4 levels) in underyearling, fall-smolting coho salmon ( Oncorhynchus kisutch) from August to December. In November, the fish showed the characteristics of fully developed smolts, i.e. the skin completely covered with silvery scales, CF at a nadir, and peak NKA activity and plasma T 4 levels. Based on these results, we examined the effects of four neuropeptides, thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), and gonadotropin-releasing hormone (GnRH), on the downstream movement (negative rheotaxis) and T 4 surge in fully smoltified underyearling coho salmon. The experiment was run in circular-shaped channel tanks and the neuropeptide treatment was performed as intracerebroventricular (ICV) injections. ICV injection of GHRH and CRH stimulated both downstream movement and plasma T 4 level. TRH injection stimulated plasma T 4 level but suppressed downstream movement. GnRH injection had no effect. It is hypothesized that GHRH and CRH play key roles in triggering downstream migration of anadromous salmonids, and that the accompanying T 4 surge is a consequence of the neuroendocrine processes that trigger migration.

A super-agonist of growth hormone–releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease

Chronic kidney disease is frequently associated with protein-energy wasting related to chronic inflammation and a resistance to anabolic hormones such as insulin and growth hormone (GH). In this study, we determined whether a new GH-releasing hormone super-agonist (AKL-0707) improved the anabolism and nutritional status of nondialyzed patients with stage 4-5 chronic kidney disease randomized to twice daily injections of the super-agonist or placebo. After 28 days, this treatment significantly increased 24-h GH secretion by almost 400%, without altering the frequency or rhythmicity of secretory bursts or fractional pulsatile GH release, and doubled the serum insulin-like growth factor-1 level. There was a significant change in the Subjective Global Assessment from 'mildly to moderately malnourished' to 'well-nourished' in 6 of 9 patients receiving AKL-0707 but in none of 10 placebo-treated patients. By dual-energy X-ray absorptiometry, both the mean fat-free mass and the body mineral content increased, but fat mass decreased, all significantly. In the AKL-0707-treated group, both serum urea and normalized protein equivalent of nitrogen appearance significantly decreased with no change in dietary protein intake, indicating a protein anabolic effect of treatment. Thus, our study shows that stimulation of endogenous GH secretion by AKL-0707 overcomes uremic catabolism of patients with advanced chronic kidney disease.

Normal function of the hypothalamic-pituitary growth axis in three dwarf Friesian foals

Serial blood samples were collected from three dwarfFriesian foals to examine their endogenous growthhormone (GH) profiles, and the integrity of theGH-insulin-like growth factor-1 (IGF-1) axis wastested in one of them...

Activation of the GH/IGF-1 axis by CJC-1295, a long-acting GHRH analog, results in serum protein profile changes in normal adult subjects

Objective To identify biomarkers of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) action in human serum. Background The search for new markers of GH activity has received extensive attention given that the current biomarkers (IGF-1, IGFBP-3 and collagen peptides) show substantial variability in the population, and are not reliably predictive of either the physiologic effects of GH therapy or the detection of GH abuse by athletes. GH releasing hormone (GHRH) is a polypeptide synthesized in the hypothalamus that binds to receptors on pituitary somatotropes to promote the synthesis and release of GH. Serum GH and IGF-1 levels have been shown to increase with administration of GHRH or CJC-1295, a long-acting GHRH analog. Design Sera from 11 healthy young adult men before and one week after CJC-1295 injection were analyzed by two-dimensional gel electrophoresis for proteomic changes. Serum proteins displaying significant changes before and after treatment were subsequently identified using mass spectrometry. In addition, correlations between these proteins and GH or IGF-1 levels were evaluated. Results Two protein spots that displayed decreased intensities after treatment were identified as an apolipoprotein A1 isoform and a transthyretin isoform. Three protein spots upregulated by CJC-1295 treatment included beta-hemoglobin, a C-terminal fragment of albumin, and a mix of an immunoglobulin fragment and another C-terminal albumin fragment. A linear relationship was found between the spot containing immunoglobulin and albumin fragments and IGF-1 levels. Conclusions Although the molecular mechanisms linking the identified proteins to GH and IGF-1 biological activity remain to be clarified, the results suggest that they represent potential biomarkers of GH and/or IGF-1 action.

Central administration of growth hormone-releasing hormone triggers downstream movement and schooling behavior of chum salmon ( Oncorhynchus keta) fry in an artificial stream

Anadromous salmonids migrate downstream to the ocean (downstream migration). The neuroendocrine mechanism of triggering the onset of downstream migration is not well known. We investigated the effects of 14 chemicals, including neuropeptides, pineal hormones, neurotransmitters, and neuromodulators (growth hormone-releasing hormone: GHRH, thyrotropin-releasing hormone, corticotropin-releasing hormone: CRH, gonadotropin-releasing hormone, melatonin, N-acetyl serotonin, serotonin, β-endorphin, enkephalin, dopamine, norepinephrine, epinephrine, acetylcholine, and histamine) on the onset of downstream migration in chum salmon ( Oncorhynchus keta) fry. We defined downstream migration as a downstream movement (negative rheotaxis) with schooling behavior and counted the number of downstream movements and school size in experimental circulation tanks. An intracerebroventricular injection of GHRH, CRH, melatonin, N-acetyl serotonin, or serotonin stimulated the number of downstream movements. However, GHRH was the only chemical that also stimulated an increase in schooling behavior. These results suggest that CRH, melatonin, N-acetyl serotonin, and serotonin are involved in the stimulation of downstream movement in chum salmon, while GHRH stimulates both downstream movement and schooling behavior.

Growth Hormone–releasing Hormone Plasmid Treatment by Electroporation Decreases Offspring Mortality Over Three Pregnancies

LifeTideSW5 is a growth hormone-releasing hormone (GHRH)-expressing plasmid delivered by intramuscular (IM) electroporation (EP), and the first therapeutic plasmid delivered by this physical method to be approved for use in food animals. Gestating sows (n = 997) were treated once with a single 5-mg GHRH-plasmid by EP or served as controls. Data on offspring from three parities subsequent to treatment were collected. No adverse effects related to treatment were noted. First parity post-treatment offspring from treated sows displayed a 2.93 kg (P < 0.0001) increase in carcass weight (CW), 1.0 mm (P < 0.0001) less back-fat (P2), and a 27.0 g CW/day (P < 0.0001) increase in rate of gain (ROG) compared with controls. An increase of 21.6% was recorded in the number of offspring surviving. In the second and third parities post-treatment, offspring from treated females displayed higher number of born alive and total born number, and lower stillborn rates. Third parity offspring from treated sows displayed a 1.6 kg advantage in CW (P < 0.05), 1.0 mm less P2 (P < 0.05), and a 10.0 g CW/day benefit in ROG. Furthermore, offspring from treated females had a 19.04% lower post-wean loss rate. Overall, plasmid GHRH administration decreased morbidity and mortality in treated females and their offspring over three consecutive pregnancies.

Intranasal growth hormone-releasing hormone (GHRH) impairs declarative memory consolidation and GH secretion during nocturnal wakefulness

Context and aim: The activity of the somatotropic system displays a secretory maximum during early sleep which is a period known to be essential for memory consolidation. While blocking the sleep-onset associated surge in growth hormone (GH) secretion does not affect memory performance, the contribution of growth hormone-releasing hormone (GHRH) to memory formation is unclear. We assessed the influence of intranasal GHRH on memory consolidation in waking men. Design and subjects: Twelve healthy young men (mean age 23.3+/-1.0 years) were investigated twice (GHRH and placebo) during nocturnal wakefulness. Declarative and procedural memory consolidation was examined by means of a word pair and a finger tapping task, respectively. Learning took place around 2030h, i.e., before subjects were intranasally administered 600µg GHRH and saline solution, respectively. Recall was tested at 0900h in the morning. Levels of GH, ACTH, cortisol, catecholamines, insulin and blood glucose were assessed throughout the night. Results: The number of word pairs recalled in the morning (expressed as the percentage of word pairs acquired at learning) was reduced in the GHRH condition (72.3±4.1%) compared to placebo (81.3±6.4%; p&lt;0.05). Finger tapping was not influenced. A small but distinct GH peak observed in the control condition around 2330h was blunted by intranasal GHRH administration. Conclusion: Intranasal GHRH administration impairs declarative but not procedural memory consolidation during nocturnal wakefulness. GHRH treatment also impairs GH release during the first night-half, suggesting that the effects of intranasal GHRH are mediated via an ultrashort negative feedback loop that controls GH secretion.

Absence of an Opioid Stimulatory Tone on Growth Hormone Secretion in Women With Microprolactinoma

Introduction: Literature data suggest that prolactinoma is a tumor with a complex pathogenesis and that its growth is the result of changes at the pituitary and/or hypothalamic level. Abnormal release of hypothalamic factors (including endogenous opioid peptides) may contribute to prolactinoma development. An increased endogenous opioid tone (EOT) occurs in patients with prolactinoma, and seems to play an important role in pituitary secretion, as suggested by the ability of the opiate receptor antagonist naloxone to stimulate luteinizing hormone pulsatile secretion in these patients. Objective: To investigate the effect of the EOT on growth hormone (GH) secretion in women with prolactinoma. Design: Eleven women aged 30.4 ± 6.7 years (range 20–41), with an established diagnosis of microprolactinoma, were studied. GH-releasing hormone (GHRH), 100 μg as an intravenous (IV) bolus, was administered with and without preadministration of IV naloxone, an opioid receptor antagonist, 2 mg as a bolus followed by a constant infusion of 1.6 mg/h. Blood samples were taken for 120 min after GHRH administration. Results: Naloxone did not affect the GH response to GHRH, measured as single times, mean peak values, or as integrated concentrations. Conclusion: Our data suggest that an opioid stimulatory tone on GH secretion in women with prolactinoma is absent.