Induced Growth Hormone Release Research Articles

Plasma growth hormone (GH) response to GH-releasing factor (SM-8144) in children of short stature and patients with GH deficiency.

Synthetic human GRF (hGRF (1-44) NH2; SM-8144) was administered as an iv bolus to 141 normal children of short stature (NSC), 73 patients with severe idiopathic GH deficiency (IGD; group A), 30 patients with mild idiopathic GH deficiency (IGD; group B), 29 patients with secondary GH deficiency, 3 patients with primary hypothyroidism, 21 patients with Turner's syndrome and 25 patients with various other disease. Their height was below normal for their age and sex, and they were all below 25 years old without obesity. The maximal GH responses (M+SEM) were 39.5 +/- 2.2, 7.2 +/- 0.9, 27.2 +/- 3.7, 5.2 +/- 0.8, 9.7 +/- 4.4, 25.1 +/- 2.8 and 32.3 +/- 4.8 ng/ml, respectively (significance from the NSC, ; p less than 0.05, ; p less than 0.001). The GH responses to hGRF were greater than those elicited by standard pharmacological tests. There was a negative correlation between bone age and peak plasma GH response to hGRF in patients with idiopathic GH deficiency (IGD) but not in normal children (NSC). In twenty-two percent of the patients with IGD in group A the response was above 10 ng/ml and in 57% of the patients with IGD in group B the response was above 20 ng/ml, suggesting that a large percentage of patients with idiopathic GH deficiency lack hypothalamic GRF. The side effect of flushing was observed in 15.2% of all subjects. These results indicate the potential usefulness of hGRF (1-44) NH2 (SM-8144) in inducing GH release from the pituitary.

Premarin priming does not alter growth hormone release following exercise.

We evaluated the usefulness of premarin priming on exercise induced growth hormone release and the value of combining several growth hormone screening agents in a large population of prepubertal children. Two hundred five short healthy prepubertal children growing below the 5th percentile in height were studied. One hundred forty-four were screened with exercise following glucose ingestion, while 61 were primed with estrogen prior to glucose and exercise testing. Premarin priming did not significantly increase the number of our patients who responded to exercise nor to glucose; 86% and 88.5% of non-primed and primed patients, respectively, responded with a growth hormone increase greater than or equal to 8 ng/ml following exercise and glucose. Glucose loading alone was not associated with a high enough growth hormone rise to rule out growth hormone deficiency in most of our children. Age (less than or equal to 5 yr) was associated with lower post-exercise growth hormone levels and a higher failure rate to testing in both primed and non primed children. Premarin priming does not seem to alter the growth hormone releasing capacity to exercise of prepubertal children. The combined use of exercise, glucose loading and premarin priming in a single screening test does not improve on the results obtained by growth hormone exercise screening alone.

Does alprazolam, in contrast to diazepam, activate alpha 2-adrenoceptors involved in the regulation of rat growth hormone secretion?

The conventional benzodiazepine diazepam and the novel triazolobenzodiazepine alprazolam were compared with respect to effects on growth hormone (GH) release in reserpine pretreated rats. The reserpine pretreatment was undertaken to eliminate brain monoaminergic influence on GH secretion, hence obtaining a low GH baseline from which a drug induced increase could be easily detected. Previous studies have indicated that activation of brain alpha 2-adrenoceptors is an indispensable prerequisite for GH release induced by other agents such as serotonin and opiate receptor agonists. In line with these findings, diazepam was found to induce GH release in reserpine pretreated rats only when the alpha 2-receptor agonist clonidine was simultaneously administered. In contrast, alprazolam caused a dose-dependent increase in plasma GH when given alone to reserpine pretreated rats. This effect of alprazolam was effectively antagonized by either of the two selective alpha 2-receptor antagonists yohimbine or idazoxane. The data indicate that alprazolam, but not diazepam, activates brain alpha 2-adrenoceptors involved in rat GH regulation. The possibility that an alpha 2-agonistic profile of alprazolam may contribute to the suggested effectiveness of the drug in the treatment of panic disorder is discussed.

Exercise-induced increases in plasma catecholamines and growth hormone are augmented by selective alpha 2-adrenoceptor blockade in man.

A specific alpha 2-adrenoceptor antagonist (idazoxan) was used in man to examine the neuroregulation of growth hormone (GH) release and the effect of alpha 2-adrenoceptors on noradrenaline release. In the first study, GH-releasing factor (GRF)-induced GH release was unaffected in 6 normal volunteers by the prior administration of idazoxan, suggesting that the alpha 2-receptors involved in GH release are not operative at pituitary level. In the second study, 6 normal volunteers performed a bicycle exercise test with and without prior treatment with idazoxan. The exercise-induced GH response (to 13 +/- 5 mU/l) was significantly augmented by idazoxan (to 20 +/- 7 mU/l) which contrasts with the current view of GH release being regulated by stimulatory hypothalamic alpha 2-adrenoceptors and suggests that these alpha 2-adrenoceptors are capable of exerting a dual effect on GH release. The exercise-induced increase in plasma noradrenaline (to 1.45 +/- 0.19 micrograms/l) and in heart rate (to 142 +/- 5 beats/min) were also augmented by idazoxan (to 2.24 +/- 0.23 micrograms/l and 152 +/- 6 beats/min). A similar augmentation of the plasma adrenaline response to exercise was also found, whereas the blood glucose, plasma insulin and potassium response to exercise was unaffected by idazoxan. These results suggest that during exercise in man, alpha 2-adrenoceptors exert a tonic inhibitory influence on noradrenaline release which also serves to limit the exercise-induced tachycardia.

Clonidine induced growth hormone release - a predictor of central adrenergic pathway integrity

Clonidine induced growth hormone release - a predictor of central adrenergic pathway integrity

Phorbol esters affect pituitary growth hormone (GH) and prolactin release: The interaction with GH releasing factor, somatostatin and bromocriptine

Phorbol esters are tumor promotors that directly stimulate protein kinase C activity. We asked whether these agents affect basal or receptor initiated alterations in growth hormone (GH) and prolactin release. In 4 h incubations of anterior pituitary cells, phorbol esters enhanced basal and GH releasing factor (GRF)-induced GH release. Somatostatin reduced by 38% the 4-fold stimulation of GH release induced by phorbol ester. These tumor promoters also reversed the ability of bromocriptine, a dopamine agonist, to inhibit prolactin release, with no apparent effect on basal prolactin secretion. When these agents were applied for 24 h, an increase in the basal release of both GH and prolactin was apparent. These data lead us to suggest that an intact protein kinase C system may be necessary for the full expression of GRF-stimulated GH release and dopaminergic inhibition of prolactin release.

Comparison of single and combined tests for the evaluation of plasma growth hormone secretion in normal short children.

Growth hormone (GH) response to provocative tests was compared in normal short children. Seven of 23 children failed to respond to insulin hypoglycemia. Using insulin hypoglycemia followed by L-dopa only 2 of 23 children did not respond and giving bromocriptine combined with insulin hypoglycemia only 1 of 8 children failed to respond. All children submitted to propranolol followed by exercise (n = 14) and to bromocriptine followed by exercise (n = 6) responded with a satisfactory increase in plasma GH levels. The increase elicited by propranolol and exercise was higher than that induced by insulin hypoglycemia alone (p less than 0.005), exercise alone (p less than 0.05) or L-dopa after insulin hypoglycemia (p less than 0.01). The rise of GH induced by bromocriptine and exercise was higher than that obtained with insulin hypoglycemia alone (p less than 0.05). This study suggests that both adrenergic and dopaminergic mechanisms are involved in exercise induced GH release and confirms that combined tests are more useful than a single test to evaluate GH secretion.

Noradrenergic modulation of human pancreatic growth hormone-releasing factor (hpGHRF1-44)-induced growth hormone release in conscious male rabbits: involvement of endogenous somatostatin.

To clarify the role of noradrenergic neurons in the regulation of GH secretion, the effects of iv administered noradrenergic antagonists were investigated in freely moving, conscious male rabbits. During a 6-h observation period (1030-1630 h), control rabbits manifested pulsatile GH secretion with surges between 1030-1200 and 1415-1630 h. Phenoxybenzamine, (POB), an alpha-adrenergic blocker (5 mg/kg, twice), abolished the episodic GH surges; propranolol, a beta-adrenergic blocker (2.5 mg/kg, twice), did not. The bolus injection (1 or 10 micrograms) of synthetic human pancreatic GH-releasing factor (hpGHRF) with 44 amino acid residues (hpGHRF1-44) resulted in significant rises in the plasma GH of control animals. The plasma GH responses to hpGHRF1-44 were significantly larger in propranolol-treated than control rabbits. In contrast, POB completely suppressed the hpGHRF1-44-induced GH release. The injection of antisomatostatin (SRIF) serum into POB-treated rabbits did not yield a disinhibition of the episodic GH surges but restored the plasma GH rises after hpGHRF1-44 injection. These results indicate that noradrenaline++ plays an important role in regulating GH secretion in the rabbit. We propose that alpha-noradrenergic blockade suppresses GH release not only by inhibiting the release of hypothalamic GHRF but also by stimulating the secretion of SRIF and that beta-noradrenergic blockade enhances GH release by inhibiting the release of SRIF from the hypothalamus.

Presynaptic α 2-adrenergic stimulation leads to growth hormone release in the dog

In previous studies we have shown that the α 2-adrenergic receptor agonist clonidine (CLON) releases growth hormone (GH) in conscious dogs, an effect abolished by the selective α 2-receptor antagonist yohimbine (YOH) and by reserpine, but not by the α 1-receptor antagonist prazosin (1). In the present work intravenous (iv) administration of CLON in concious dogs evoked a dose-related rise in plasma GH at doses of 2–8 ug/Kg, but not at 16 and 32 ug/Kg. Acute pretreatment with the selective inhibitor of norepinephrine (NE) synthesis, DU-18288, or with a potent antagonist of presynaptic α 2-receptors, mianserin abolished the GH rise induced by CLON (4 ug/Kg iv). In contrast, a 10-day-pretreatment with YOH greatly enhanced the GH-releasing effect of CLON (2 ug/Kg iv). In all these data indicate that in the dog: 1) CLON induces GH release via activation of α 2-adrenergic receptors; 2) these receptors are likely located on presynaptic sites [experiments with reserpine (1), DU-18288, mianserin, dose-response curve with CLON 2–32 ug/Kg iv] ; 3) the adrenergic receptors involved in GH release exhibit supersensitivity upon (YOH-induced) chronic pharmacologic denervation. In view of the inhibitory action of presynaptic α 2-adrenergic receptors (autoreceptors) on NE function, it may be envisioned that in the dog noradrenergic activation is inhibitory and not stimulatory to GH release.

Gamma-aminobutyric acid (GABA)及びその代謝産物の下垂体前葉ホルモン分泌調節における役割に関する研究

Gamma-hydroxybutyric acid (GHB), a physiological metabolite of gamma-aminobutyric acid (GABA) was administered to normal persons and patients with hypothalamo-pituitary disorders to examine the effect of GHB on pituitary hormone secretion. GHB stimulated the releases of growth hormone (GH), prolactin (PRL) and cortisol but not luteinizing hormone (LH), follicle stimulating hormone (FSH) and thyrotropin (TSH) in healthy male volunteers. In patients with hypothalamic disorders, plasma GH, PRL and cortisol levels did not increase after GHB administration. In patients with diabetes insipidus, plasma GH responses to GHB were lower than those in normal control, but plasma cortisol and PRL responses were normal. In patients with hypopituitarism, plasma GH and cortisol levels did not elevate after GHB injection, but plasma PRL responses to GHB was normal in three out of patients. In patients with pituitary dwarfism, plasma PRL and cortisol levels increased after GHB injection but plasma GH did not respond to GHB. In patients with acromegaly, plasma GH responses after GHB administration was not consistent. In cases with Cushing's syndrome, plasma cortisol levels increased in patients with adrenocortical hyperplasia but not in those with adrenocortical adenoma. Although plasma GH responses after GHB injection disappeared in patients with Cushing's syndrome, plasma PRL responses was slightly greater than that in normal subjects. In a patient with Addison's disease, plasma ACTH level increased, and plasma PRL and GH responses were normal after GHB injection.To study the relationship between GHB and biogenic amines induced release of human pituitary hormones, the dopaminergic mechanism was blocked by pimozide or stimulated by CB-154 administration, and the serotonergic mechanism was blocked by parachlorophenyl-alanine (PCPA) before GHB administration. GHB induced GH release after treatment with pimozide or PCPA was not significantly different from GH release induced by GHB alone. CB-154 inhibited the increase of plasma GH induced by GHB. Plasma PRL responses to GHB was completely inhibited by CB-154 pretreatment, but not altered by pimozide or PCPA pretreatment. Plasma cortisol responses to GHB was inhibited by pimozide or PCPA pretreatment, but CB-154 had no effect on plasma cortisol responses to GHB injection. GH and cortisol releases induced by GHB was inhibited by continuous TRH infusion.These results suggest that GHB administration is a useful method for examining pituitary hormone secretion. The site of GHB action on pituitary hormone release is probably more central than pituitary in human. Not only inhibition of dopaminergic mechansim but also another mechanism may be involved in GHB induced release of human pituitary hormones.

Episodic and TRH induced growth hormone release in primary hypothyroidism of man and rat.

In 27 hypothyroid subjects studied over 20 to 120 minutes, the concentration of serum growth hormone (GH) was variable with the amplitude and frequency of the secretory patterns similar to those reported by others for normal individuals. Serum GH, after the administration of thyrotropin releasing hormone (TRH) did not differ from values observed as spontaneous surges, in contrast to a consistent increase in thyrotropin and prolactin. Episodic secretion of GH persisted in thyroidectomized rats and did not differ significantly from that present in intact controls. It is concluded that episodic GH secretion is not abolished in primary hypothyroidism and that TRH is not a constant GH secretagogue in human subjects with hypothyroidism.

Mechanism of opiate-induced release of GH in the rat

Morphine (M) is known to be a powerful releaser of both growth hormone (GH) and prolactin (PRL) in the rat. More recently, endogenous opiate peptides such as β-endorphin (E) have also been found to stimulate the release of both hormones. Although the mechanism of the release is unknown, it clearly involves the central nervous system (CNS). We have recently performed several experiments to verify whether CNS serotonergic pathways are implicated in such an effect. Pretreatment of rats with the serotonin (SER) depletor PCPA significantly enhanced GH release induced by M and by E, while PRL release was unaffected. The SER precursor 5-hydroxytryptophan antagonized M-induced GH release. However, acute treatment with E, or chronic treatment with M did not modify the activity of raphe nuclei tryptophan hydroxylase. The hypothalamic hormone TRH was capable of antagonizing M- and E- induced GH release through a CNS serotonergic pathway. It is suggested that opiates stimulate GH release by suppression of an inhibitory serotonergic tonus.

Serotoninergic control of growth hormone (GH) secretion in dogs as measured by dose responsiveness

L-5-hydroxytryptophan (5-HTP) - induced GH release has been demonstrated in animals and man, but serotoninergic control remains controversial. We developed a sensitive radioimmuno-assay for measurement of canine GH and investigated the 5-HTP dose-response relationship in unanesthetized mongrel bitches. Intravenous administration of 1, 5, 10, and 25 mg/kg doses of 5-HTP caused GH release but an increased latency in peak GH response was seen with the larger doses. Doses of 10 and 25 mg/kg induced stressful behavior and markedly increased plasma corticoid levels while lower doses were without effect. From these findings in the dog we conclude that the GH response to low dose 5-HTP is not due to stress and that alternate mechanisms are needed to explain the variable serotoninergic control of GH release demonstrated with low and high dose 5-HTP stimulation.

Prostaglandin E 2 (PGE 2)-induced growth hormone (GH) release: Effect of intrahypothalamic and intrapituitary implants

Overiectomized rats were unilaterally implanted with a 23-gauge stainless steel cannula in different hypothalamic areas or in the pituitary gland and subsequently were treated with estrogen (sc, 10 μg estradiol benzoate, Eb). Two days after the estrogen injection, an inner cannula containing PGE 2 or PHF 2α at its tip was inserted into the cannula. Other animals were implanted with empty inner cannula. Plasma GH concentrations were measured by RIA in blood samples drawn from the jugular vein while the animals were lightly etherized before (−2) and at 20, 40, 60 and 120 min following the implantation. Plasma GH levels in control animals bearing an empty cannula in the body of the arcuate nucleus-median eminence region (BARH-ME) were signifantly depressed by the ether stress. The implantation of PGF 2α in this area was completely ineffective in preventing ether stress-induced decline in plasma GH. By contrast, PGE 2 implanted in BARH-ME or the post-chiasmatic region of the hypothalamus (HARH-ME) elevated plasma GH 20 min following its implantation and partially prevented the subsequent decrease in GH levels induced by ether stress. PGE 2 implants located in several other hypothalamic areas failed to induce GH release or to prevent the decline in GH levels induced by ether stress. However, PGE 2 implanted in the pituitary gland elicited a marked increase in plasma GH at 20 min and completely prevented the subsequent ether stress-induced decline in GH levels. The results suggest that PGE 2 can act at both hypothalamic (ARH-ME) and pituitary levels to stimulate GH release. At the hypothalamus, PGE 2 may inhibit GH-inhibiting factor (GIF) release or induce release of GH releasing factor (GHRF).

Metabolic and clinical studies on patients with acromegaly treated with bromocriptine over 22 months

In twenty-two patients with active acromegaly who were untreated or unsuccessfully operated or irradiated (mean growth hormone (GH) values greater than 4 ng/ml) the following investigations were performed: routine laboratory tests, tomography of pituitary fossa, oral glucose tolerance tests, TRH and other pituitary function tests and GH profiles over 5-10 h before and during bromocriptine treatment with daily doses between 7.5 and 50 mg. In seventeen patients GH was suppressed to less than 50% by bromocriptine, in thirteen of them it was normalized on at least one occasion. A TRH induced GH release was observed in all but two responders to bromocriptine before therapy. This effect of TRH was not blunted during treatment with bromocriptine and also in the two patients with negative tests before therapy a significant GH increase was observed. In no non-responder to bromocriptine was a significant increase of GH after TRH observed. One patient showed a secondary resistance to bromocriptine during a period of treatment with griseofulvin. In the remaining sixteen patients the GH suppression has been consistent for between 3 and 22 months. A single dose of pimozide abolished the bromocriptine effect on GH totally in one patient; in others a slight or no significant effect was observed. Tissue swelling and sweating decreased in all bromocriptine responders and glucose tolerance improved in five patients. In four diabetic patients a partial or full remission of diabetes occurred. Apart from postural hypotension after the first administration in two patients no other severe side effects have been observed. Sella size and the other pituitary functions did not change during the time of the study. It seems that a high percentage of acromegalics may be successfully treated with bromocriptine.

EFFECT OF THE DOPAMINE RECEPTOR BLOCKING AGENT PIMOZIDE ON THE GROWTH HORMONE RESPONSE TO ARGININE AND EXERCISE AND ON THE SPONTANEOUS GROWTH HORMONE FLUCTUATIONS

Pimozide, a specific blocker of dopamine receptors, was administered orally to 10 diabetics for 2 days before an arginine-hydrochloride infusion. In 8 healthy volunteers and 20 diabetics exercise tests on a bicycle ergometer were performed with a load of 100 Watts and 50 Watts respectively without or after a single dose of pimozide 30 min before the test. In 4 male diabetics day profiles of growth hormone (GH) were estimated without and during treatment with pimozide for 4 days. The arginine and exercise induced GH release was found to be significantly lowered by pimozide, whereas the marked spontaneous fluctuations in the diabetics were even enhanced by pimozide. These data support the concept of the involvement of dopaminergic stimulation in the response of GH to arginine and exercise. The spontaneous fluctuations of GH, however, seem to be regulated by other neuroendocrine mechanisms.

THE STIMULATION OF GROWTH HORMONE RELEASE BY ACTH AND ITS INHIBITION BY SOMATOSTATIN

The rapid injection of 0.5 or 1.0 mg of tetracosacitid (Synacthen¿) was followed by a distinct increase of plasma growth hormone (GH) within 30 or 45 min in 5 of 7 normal volunteers. A second control test was performed in 3 of the 5 "responders" and 1 "non-responder" and showed a consistent reaction in all of them. The tests were then repeated in the 5 "responders" during an infusion of somatostatin (150 mug/h) and the GH response was totally abolished (3 subjects) or markedly reduced (2 subjects). Thus the ACTH induced GH release behaves in a manner similar to most other physiological or pharmacological stimuli of GH release. The cortisol output after ACTH was not altered by somatostatin.

IMPAIRMENT OF ARGININE INDUCED GROWTH HORMONE RELEASE AFTER THREE DAYS TREATMENT WITH DEPOT-ACTH

ABSTRACT The growth hormone (GH) response to arginine infusion in 11 normal subjects and 4 patients with Addison's disease on maintenance replacement doses of cortisone and fludrocortisone was studied before and 24 h following the administration of 1 mg Synacthen-Depot® (tetracosactid) daily for 3 days. The mean peak GH levels during arginine infusion tests were significantly decreased after ACTH-treatment (3.8 vs. 32.1 ng/ml), all peak values being below the normal range. The patients with Addison's disease either showed very low GH response in the pre-treatment test followed by a small change after ACTH (3 patients) or a low normal response in the pre-treatment test with a depressed response after ACTH (1 patient). Based on the results of the present study and those previously reported by others we suggest that the acute administration of ACTH induces GH release but that repeated administration of ACTH leads to a GH depletion of the pituitary gland and decreased response to stimulation tests. This effect is not mediated through endogenous cortisol release.

The Effect of Monoamine Precursors on the Release of Growth Hormone in the Rhesus Monkey

Intravenous injections of several monoamineprecursors and apomorphine were infused into 4 rhesus monkeys. Both L-dopa (15–200 mg/kg) and 5-HTP (20–60 mg/kg) induced an acute elevation in plasma growth hormone (GH) concentrations. 5-HTP induced behavioral and EEG slow wave sleep. L-tryptophan (50–100 mg/kg) induced a delayed and smaller elevation. Apomorphine (50-75 <i>µ</i>g) and saline infusion did not induce GH release, behavioral sleep or a change in the EEG activity.

Plasma growth hormone (GH) response to hypothalamic or extrahypothalamic electric stimulation.

Plasma growth hormone (GH) responses, as measured by radioimmunoassy, were determined in individual rats following electrical stimulation of various hypothalamic and extrahypothalamic sites. In the hypothalamus, positive GH responses (rise in plasma GH levels > 10 μg/ml within IS min) occurred only with stimulation of the ventromedial or arcuate nucleus. Effective extrahypothalamic stimulation sites included the hippocampus, basolateral amygdala and mesencephalic interpeduncular nucleus. Reserpine administration (5 mg/kg; 24 hr before stimulation) was effective in preventing GH release induced by hippocampal stimulation but had no effect on ventromedial—arcuate—induced GH release. These results suggest that GH release may be induced by electrical stimulation either of the “final common pathway” in the medial basal hypothalamus or of certain extrahypothalamic structures with known connections to this region. (Endocrinology 91: 107, 1972)