Administration Of Growth Hormone-releasing Factor Research Articles

Influence of somatostatin and growth hormone-releasing factor on behavior. Clinical and therapeutic implications in neuropsychiatric disorders.

Administration of hypothalamic peptides has been reported to induce behavioral changes and to modify neurological functions such as locomotor activity and learning. Somatostatin (SS) and growth hormone-releasing factor (GRF) exert opposite effects on anterior pituitary secretion. Similarly, at the central nervous system (CNS) level, SS and GRF display antagonistic actions on behavioral parameters. The authors were able to confirm these effects in male Wistar rats by means of a computerized electronic maze measuring locomotor activity and learning. SS concentration is reduced in specific areas of the CNS in patients with late onset of senile dementia of the Alzheimer's type (SDAT). In early onset SDAT a GRF test elicits a growth hormone response much greater than that observed in normal controls of the same age or in patients with late onset SDAT. Thus, administration of GRF to patients with early onset SDAT has been followed by a significant improvement in locomotion, appetite, mental performance and social interaction. A possible therapeutic role of GRF in the management of patients with dementia remains to be explored.

Influence of age and sex on basal secretion of growth hormone (GH) and on GH-induced release by porcine GH-releasing factor pGRF(1–29NH 2) in growing pigs

The aim of this study was to determine the effect of age and sex on basal secretory patterns of growth hormone (GH) and growth hormone-releasing factor (GRF) induced GH release. Eighteen pigs (9 castrated males and 9 females) were stimulated with pGRF(1–29)NH 2 at 7,11,15,19 and 23 weeks of age. Blood samples were taken from each animal via jugular vein cannulate every 20 min, from 6 hr before to 5 hr after iv GRF administration at a dose of 4 μg/kg. GH baseline levels, amplitude of the GH peaks, area under the GH peaks and the overall mean of GH serum levels decreased (P<.001) with age in both sexes. Age also had a marked effect on GRF-induced GH release: the amplitude of GH peaks and area under the GH peaks decreased (P<.001) with age. The GH response to pGRF(1–29)NH 2 varied considerably, depending on the timing of the episodic endogenous secretion of GH. An immediate response (<30 min) was observed when GRF was injected at the end of a trough period or at the beginning of a peak, but there was no immediate response when GRF was injected at the end of a peak or at the beginning of a trough period. Our results show that both endogenous GH secretion and pGRF(1–29)NH 2-induced GH release declines with age, suggesting a decreased sensitivity of the somatotroph cells to GRF with age; and that the high variability of the GH response to pGRF(1–29)NH 2 stimulation depends greatly on the timing of the episodic endogenous GH release, thus implying a possible episodic endogenous somatostatin secretion by the hypothalamus.

Effects of insulin-like growth factor I (IGF-I) on growth hormone-releasing factor (GRF) and thyrotropin-releasing hormone (TRH) stimulation of growth hormone (GH) secretion in the domestic fowl ( Gallus domesticus)

Recent studies in mammalian species indicate that IGF-I may act as a negative feedback inhibitor of GH release through alteration of pituitary secretion or sensitivity to hypothalamic regulatory factors. Although avian GH secretion appears to be regulated by the differential release of hypothalamic inhibitory (somatostatin) and stimulatory (GRF and TRH) factors, feedback effects of IGF-I on in vivo GH release in birds have not been investigated. To study the effects of elevated IGF-I concentration on GRF- and TRH-stimulated GH secretion, 4-week-old chickens received an intravenous injection of recombinant human IGF-I either 15 min prior to (6 μg, study 1), or simultaneous with (10 μg, study 2), GRF (hGRF44NH 2, 5 μg/kg) or TRH (0.5 μg/kg) administration. Radioimmunoassay analysis of plasma collected prior to and following peptide treatment indicated that circulating IGF-I concentrations were elevated 83.9, 60.6, 77.9, and 88.8% at the time of TRH and GRF administration in studies 1 and 2, respectively. Peak GH concentrations (mean of +5- and +15-min samples) subsequent to TRH injection were significantly ( P < 0.01) depressed 45.1 and 48.2% in IGF-I-treated as compared with control chicks in the first and second studies, respectively. GRF-stimulated GH secretion was significantly ( P < 0.01) decreased by IGF-I administration in study 2 (41.3%) but not in study 1. An estimated half-life for IGF-I in the chicken is less than 15 min based on the disappearance rate of the elevation produced by exogenous IGF-I injections. Thus, IGF-I exerts a negative feedback effect on pituitary hormone secretion in avian as well as mammalian species.

Effect of daily injections of growth hormone-releasing factor and thyrotropin-releasing hormone on growth and endocrine parameters in chickens

The control of growth is a complex mechanism regulated by several metabolic hormones including growth hormone (GH) and thyroid hormones. In avian species, as well as in mammals, GH secretion is regulated by hypothalamic hypophysiotropic hormones. Since thyrotropin-releasing hormone (TRH) and growth hormone-releasing factor (GRF) are potent GH secretagogues in poultry, we were interested in determining the influence of daily intravenous administration of either peptide or both simultaneously on circulating GH and IGF-I concentrations and whether an improvement in growth rate or efficiency would be obtained. Male broiler chicks were injected once daily for a period of 21 days with either GRF (10 μg/kg), TRH (1 μg/kg) or both GRF and TRH (10 and 1 μg/kg respectively) between four and seven weeks of age. On the last day of the experiment, following intravenous injection of TRH, GRF or a combination of GRF and TRH, plasma GH levels were significantly (P<.05) increased to a similar extent in control chicks and in those which had received daily peptide injections for the previous 21 days. Circulating GH levels between 10 and 90 min post-injection were significantly (P<.05) greater and more than additive than GH levels in chicks injected with both GRF and TRH when compared to those injected with either peptide alone. Mean plasma T 3 concentrations during that same time period were significantly elevated (P<.05) above saline-injected control chick levels in birds treated with TRH or GRF and TRH respectively, regardless of whether the chicks had received peptide injections for the previous 21 days. There was no evidence of pituitary refractoriness to chronic administration of either TRH or GRF injection in terms of growth or thyroid hormone secretion. Despite the large elevation in GH concentration each day, growth rate, feed efficiency and circulating IGF-I concentrations were not enhanced. Thus the quantity or secretory pattern of GH secretion induced by TRH or GRF administration was not sufficient to increase plasma IGF-I concentration or growth.

Potentiation of cholinergic tone by pyridostigmine bromide re-instates and potentiates the growth hormone responsiveness to intermittent administration of growth hormone-releasing factor in man.

It is known that in normal subjects repeated administration of the growth hormone-releasing factor (GRF) induces a state of partial refractoriness of the somatotropes to GRF. Studies were conducted to verify whether the cholinergic system plays a role in the mechanism(s) underlying the reduced GH responsiveness to the neuropeptide. In five healthy men, the GH response to three consecutive injections of GRF (50 micrograms iv), administered at 2 h intervals, was considerably blunted after the second and third GRF bolus. Administration of the inhibitor of cholinesterase, pyridostigmine bromide (120 mg orally) 30 min before the second GRF bolus, not only restored but greatly potentiated the GH responsiveness to the second GRF bolus. The GH response to the third GRF bolus was not apparently influenced by pre-treatment with pyridostigmine. These data reinforce the view that cholinergic neurotransmission plays an important role in the control of GH secretion in human.

Growth hormone-releasing factor: a new chapter in neuroendocrinology.

The isolation and characterization of growth hormone-releasing factor (GRF) has initiated a new and exciting era in our understanding of the neuroendocrine regulation of pituitary growth hormone (GH) secretion. This report briefly describes the isolation and characterization of GRF, factors which modulate the GH response to GRF and the effects of chronic administration and deprivation of GRF on somatic growth. The intent of this report is to serve as a general introduction on biochemical and physiological aspects of GRF. The following reports from this symposium will then cover many of these topics in much greater detail.

Effects of Corticotropin-Releasing Factor and Growth Hormone-Releasing Factor on Sleep and Activity in Rats

The effects of corticotropin-releasing factor (CRF) and growth hormone-releasing factor (GRF) on electroencephalographic (EEG) and behavioral signs of sleep and wakefulness following intracerebroventricular (ICV) administration was investigated in adult male rats. Visual scoring of EEG records as well as spectral analysis revealed that CRF (0.0015-0.015 nmol) produced decreases in slow wave sleep concomitant with significant decreases in spectral power in lower frequencies (1-6 Hz) and increases in high frequencies (32-64 Hz). In contrast, GRF (2.0 nmol) produced increased EEG and behavioral signs of slow wave sleep associated with significant increases in spectral power in the low frequencies (1-2 Hz) and decreases in high frequencies (32-64 Hz). ICV administration of GRF was also found to produce decreases in locomotion when administered during the active part of the rats' circadian cycle. These EEG and behavioral findings seen following CRF and GRF are consistent with the behaviors frequently correlated with the known circadian timing of the release of corticosteroids and growth hormone during the sleep-waking cycle in rat and human.

The effects of growth hormone-releasing factor (GRF) and dopamine on growth hormone (GH) secretion in acromegaly.

GRF (1-40), dopamine (DA), DA plus GRF and placebo were administered to 6 acromegalic patients. The GRF administration induced a highly variable GH release (GH delta % 167.3 +/- 21.4; mean +/- SE). GRF did not provoke any change in PRL serum levels. During simultaneous GRF and DA administration GH release was found to be reduced (GH delta % 80.2 +/- 17.8) compared to that observed for a corresponding period of time after GRF alone (p less than 0.05). Our data underscore that in acromegaly the DA tonus inhibits GH secretion after GRF by acting directly at the pituitary level.

Plasma growth hormone (GH) responses to single and repetitive subcutaneous administration of GH releasing factor (hpGRF-44) in normal and GH deficient children

Synthetic human pancreatic GRF (hpGRF-44) was administered sc to 8 normal children with short stature and 11 patients with GH deficiency. After a dose of 100-200 micrograms hpGRF-44, mean plasma GH levels reached a peak at 15 min of 27.2 +/- 6.4 (+/- SE) ng/ml in normal children. However the responses were variable and peak plasma GH varied from 10.1 to 56.5 ng/ml. Eight of 11 patients with idiopathic GH deficiency did not respond to sc administration of 100-300 micrograms hpGRF-44. However, a plasma GH increase of more than 5 ng/ml occurred in 2 patients and to twice the basal level in 1 patient. Their GH values were 14.3, 5.2 and 3.4 ng/ml, respectively. After repetitive administration of hpGRF-44 (200 micrograms, twice a day) sc for 5 consecutive days, 2 of 8 patients restored their responsiveness, but the remaining patients did not show GH rise in response to both sc and iv bolus administration of hpGRF-44. Repetitive hpGRF-44 administrations for 5 days had no effect on somatomedin-C production.

Growth hormone (GH)-releasing factor (GRF) pretreatment enhances the GRF-induced GH secretion in rats with the pituitary autotransplanted to the kidney capsule.

The long term in vivo effects of the recently characterized human pancreas GH-releasing factor, hpGRF (1-44) were studied in chronically cannulated unrestrained rats. In order to minimize the influence of endogenous hypothalamic GRF and somatostatin on the pituitary, the experiments were carried out in rats with the pituitary autotransplanted to the kidney capsule. The integrated GH release (mean +/- SE) in response to an iv injection of hpGRF (4 micrograms/kg) was markedly enhanced (P less than 0.01) by iv pretreatment with hpGRF every 8 h for 3 days (182 +/- 47 h X ng/ml) as compared to saline-pretreated controls (36 +/- 4 h X ng/ml). TRH pretreatment did not potentiate the effect of hpGRF (47 +/- 9 h X ng/ml). It is concluded that multiple administrations of hpGRF enhance the GH response to a subsequent hpGRF injection in the rat. Moreover, autotransplantation of the pituitary to the kidney capsule may supply a useful in vivo model for further studies on the effects of different modes of GRF administration on GH secretion.

Growth hormone: its physiology and control.

Growth hormone (GH) is a protein hormone produced by the somatotrophs of the anterior pituitary gland of birds and other vertebrates. The secretion of GH in birds is under hypothalamic control; it involves three peptidergic releasing factors: growth hormone-releasing factor (GRF) (stimulatory); thyrotropin-releasing hormone (TRH) (stimulatory); and somatostatin (SRIF) (inhibitory). In addition, there is evidence for effects of biogenic amines (including serotonin and norepinephrine) and prostaglandins at the level of the hypothalamus and possibly also the pituitary gland. In all avian species examined, plasma concentrations of GH are high in young posthatching chicks but low in the adult and embryo. The difference in plasma concentrations of GH between young and adult birds is due to both greater GH secretion and reduced clearance. The lower secretion of GH in adult birds reflects fewer somatotrophs in the pituitary, changes in somatotroph structure, and reduced GH responses to TRH or GRF administration. There is only limited data on the role of GH in birds. GH appears to be required for normal growth; acting at least in part by increasing somatomedin production. However, plasma concentrations of GH do not necessarily correlate with growth rate. For instance, in chicks with reduced growth rate owing to either goitrogen or protein deficiency in the diet, plasma concentrations of GH are elevated. GH also can influence lipid metabolism by increasing lipolysis, decreasing lipogenesis, and stimulating the uptake of glucose by adipose tissue. The physiological significance of these actions is, however, not established. In addition, GH affects the secretion of other hormones, the immune system, and perhaps also the reproductive system.

Effect of intravenous administration of growth hormone-releasing factor (hpGRF-44) and Tyr-D-Trp-Ala-Trp-D-Phe-NH2 on plasma hormones and metabolites in goats.

It has recently been demonstrated that human pancreatic GH-releasing factor (hpGRF-44) and Tyr-D-Trp-Ala-Trp-D-Phe-NH2 (subsequently referred to as 'the peptide') release GH from rat pituitary glands maintained in vitro and, in the former case, increase circulating GH in rats and man. The commercial importance of discovering an agent capable of specifically enhancing GH secretion in ruminants stimulated the present study which examined: the intravenous administration of both peptides on plasma GH, prolactin, insulin, glucose, urea and non-esterified fatty acids in goats and the effect of the peptide on the release of GH from sheep pituitary glands maintained in vitro. The peptide was injected into the jugular vein of goats in three different forms and at several concentrations (dispersal by shaking, 0.07 microgram/kg; 0.7 microgram/kg; ball-milled, 7.0 micrograms/kg, 70 micrograms/kg; dimethyl sulphoxide (5%), 7.0 micrograms/kg, 70 micrograms/kg). None of the treatments stimulated a significant increase in circulating GH. Nevertheless the peptide (20 micrograms/ml medium) was found to stimulate a 50-60% increase in the production of GH from sheep pituitary glands maintained in vitro. The effect of intravenously injecting hpGRF-44 (1.0 microgram/kg) was investigated in the present and absence of passive immunization with sheep anti-somatostatin immunoglobulin G (IgG) (a bolus of 600 mg, 3 h before treatment with hpGRF-44). Plasma GH was increased (P less than 0.001) within 15 min of treatment and the magnitude of the response was the same for both the immunized and non-immunized goats. A second peak was measured after approximately 75 min which was only significant (P less than 0.05) in the immunized group.(ABSTRACT TRUNCATED AT 250 WORDS)

5E. Steroid receptors: Corticoids 163. Glucocorticoid binding macromolecules in chicken liver cytosol

The hyposecretion of growth hormone (GH) in maternal separation (MS) of rat pups is remarkably similar to the specific suppression of GH secretion to evocative tests in infants diagnosed with Reactive Attachment Disorder of Infancy (RADI). Growth hormone-releasing factor (GRF) and somatostatin (SS) provide opposing regulation of GH secretion, and both are modified by noradrenergic and serotonergic stimuli in neonatal and adult rats. In this study, GRF administration reversed MS-induced suppression of GH secretion in 10-day-old pups, but this action of GRF was prevented by pretreatment with cyproheptadine (Cypro), a serotonergic antagonist. The normalization of GH secretion after return to the dam was not altered by pretreatment with SS. Indirect 5-HT agonists, fluoxetine (FLX) and 5-HTP, both stimulated GH secretion in 10-day-old pups. All mixed serotonin- and 5-H1A-receptor agonists suppressed GH secretion in 10-day-old pups. Antagonists Cypro and ketanserin (Ket) suppressed FLX-induced GH secretion. In contrast, only Cypro suppressed 5-HTP-induced GH secretion. Maternal separation inhibited GH secretion stimulated by 5-HTP, but not by FLX. The serotonergic pathway acting on 5-HT2A receptors may be obligatory for GRF-mediated stimulation and is sensitive to inhibition by Cypro. In addition, a Ket-sensitive serotonergic parallel pathway acting on 5-HT2C receptors may also stimulate GH secretion by acting on GRF or SS. However, only the obligate 5-HT2A pathway appears to be suppressed in MS. These data and observations by others indicate that specific suppression of GH secretion in MS may derive from a reduction in GRF release through noradrenergic neurons, possibly impinging upon serotonergic terminals in the hypothalamus. This study may also provide insight into mechanisms by which GH secretion is suppressed in humans with RADI.