Inhibition Of Growth Hormone Secretion Research Articles

In vitro control of prolactin (PRL) and growth hormone secretion of neonatal rat pituitary glands: Effects of ovine PRL, salmon calcitonin, endothelin-3, angiotensin II, bromocryptine and somatostatin

Bromocryptine potently decreased prolactin (PRL) secretion of pituitary glands of 2-day-old rats in vitro (up to 85% inhibition; ED 50 between 0.1 and 1.0 nM) without altering the bioactivity to immunoreactivity (B/l) ratio. Bromocryptine tended to suppress growth hormone (GH) secretion although the effect did not reach statistical significance. Angiotensin-II (A-II; 1–1000 nM) stimulated PRL secretion in a dose-dependent manner without affecting secretion of GH. The B/i ration of PRL secreted in response to A-II was increased. Somatostatin (SRIF) had no effect on PRL secretion but inhibited GH secretion in a dose-dependent manner; significant inhibition (50%) was observed at 100 nM. A 6-h exposure to ovine PRL (oPRL) in concentrations equipotent with 1.2–120 ng/ml rat PRL (rPRL) in the Nb2 bioassay had no effect on immunoreactive rPRL secretion. Salmon calcitonin (sCT) and endothelin-3 (ET-3; 0.1–100 nM) failed to inhibit secretion of PRL or GH. PRL secretion was slightly stimulated by sCT with no apparent dose-response relationship. The present findings suggest that neonatal pituitary glands do not display autoregulation of PRL secretion, and sCT and ET-3 (either endogenous or milk-derived) may not function as PRL inhibiting factors in 2-day-old pups. Thus, the receptors of PRL, sCT and ET-3 on lactotropos, or their functional coupling with inhibition of basal PRL secretion, occur at a later state of development. The specificity of the PRL releasing factor (PRF) activity of A-II at this age is unique for established PRFs and might reflect a physiological function of PRL in osmoregulation. The increased B/l ratio of PRL secreted in response to A-II may be due to the release of specific PRL variants, and might be a sign of functional heterogeneity among lactotropes. The differential sensitivity of PRL and GH to the applied secretagogues suggests that the intracellular regulation of PRL and GH are compartmentalized in the mammosomatotrope cell.

Effect of parenteral administration of selected nutrients and central injection of gamma-globulin from antiserum to neuropeptide Y on growth hormone secretory pattern in food-deprived rats.

Serial changes in growth hormone (GH) secretory pattern during 72 h food deprivation and in response to refeeding after 72 h food deprivation were observed in adult male Wistar rats. In addition, the effects of intravenous administration of glucose, fatty acids or amino acids and central injection of gamma-globulin from antiserum to human neuropeptide Y (NPY) on the GH secretory pattern were examined in 72 h food-deprived rats. Rats were provided with chronic indwelling right atrial cannula and serial blood specimens were withdrawn via the cannula every 10 min using an automatic blood-sampling device. The GH secretory pattern was analyzed using a Pulsar computer program. In fed rats, episodic GH secretion with an amplitude exceeding 350 ng/ml occurred at 170-min intervals and intervening trough GH levels were less than 10 ng/ml. During the 72 h food deprivation, the amplitude of pulsatile GH secretion decreased progressively without altering the pulse frequency. When 72 h food-deprived rats were refed lab chow, the pulse frequency and the pulse amplitude increased rapidly and lasted for 6-8 h. Normal pulsatile GH secretion resumed by 10-12 h after refeeding following the 72 h food deprivation. To identify the specific nutrient (i.e. glucose, fatty acids or amino acids) serving as the signal causing restoration of the central drive to GH secretion, glucose solution (2 or 6 kcal), lipid emulsion (2 or 6 kcal) or amino acid solution (2 kcal) was administered intravenously to the 72 h food-deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Local hypothalamic adrenoceptor activation in rat: alpha 1 inhibits and alpha 2 stimulates growth hormone secretion.

We made stereotaxic microinjections of adrenoceptor agonists and the catecholamine-releasing agent, tyramine, into the preoptic anterior hypothalamic area (PO/AHA) or the medial basal hypothalamus (MBH) of unstressed rats. Growth hormone (GH) plasma concentrations were measured serially before and after intrahypothalamic injections. Noradrenaline and phenylephrine inhibited GH secretion wherever injected but were effective at lower doses in the PO/AHA. Clonidine stimulated GH secretion at both sites, at several doses in the MBH and only at one dose in the PO/AHA. Tyramine inhibited GH when injected in the PO/AHA, but not in the MBH. We conclude: (a) alpha 1 inhibition is predominant over alpha 2 stimulation of GH on or near somatostatin neurons; (b) alpha 2 stimulation predominates over alpha 1 inhibition of GH on or near GRF neurons, and (c) endogenous catecholamines in the PO/AHA have a predominantly inhibitory effect on GH secretion.

Inhibitory effects of ethanol on the growth hormone (GH)-releasing hormone-GH-insulin-like growth factor-I axis in the rat.

Ethanol administration decreases GH secretion in humans and experimental animals. The mechanism of these inhibitory effects was investigated by evaluating the spontaneous secretory pattern of GH in chronically cannulated unanesthetized rats, plasma insulin-like growth factor-I (IGF-I) concentrations, and hypothalamic GH-releasing hormone (GHRH) and somatostatin, and pituitary GH mRNA levels. Body weight gain was reduced in ethanol (5%)-liquid diet-fed rats (n = 6) for 6 days compared to that in both isocalorically pair-fed controls (n = 6) and ad libitum-fed animals (n = 6). Spontaneous GH secretion was markedly decreased (by 75-90%) in ethanol-fed rats compared to that in pair-fed and ad libitum-fed groups, while pulsatile pattern of GH release was preserved, with secretory bursts occurring every 180-220 min in all groups. Mean 6-h plasma GH levels in ethanol-, pair-, and ad libitum-fed animals were: 18.8 +/- 4.5, 113.3 +/- 14.9, and 179.6 +/- 30.1 ng/ml, respectively (P < 0.01, ethanol vs. each control). Plasma IGF-I concentrations were decreased in the ethanol-fed rats (338 +/- 16 ng/ml) compared to those in pair-fed (427 +/- 39 ng/ml; P < 0.05) and ad libitum-fed (769 +/- 25 ng/ml; P < 0.01) rats. Ethanol treatment decreased GHRH mRNA levels to 9% of those in ad libitum-fed (P < 0.01) and 20% of those in pair-fed (P < 0.05) animals, whereas it did not significantly alter somatostatin or GH mRNA levels. The results indicate that the effects of ethanol inhibit GH secretion primarily at the hypothalamic level, resulting in impaired GHRH gene expression. Since the GHRH-GH-IGF-I axis has an important role in growth regulation, the growth retardation seen in experimental models of alcohol abuse may be a consequence at least in part of the suppressive effects of ethanol on this axis.

Treatment of Acromegaly with Dopamine Agonists

This article reviews the current understanding of how dopamine agonists stimulate growth hormone secretion in normal individuals, yet suppress growth hormone secretion in acromegaly patients. Although bromocriptine normalizes growth hormone or somatomedin C hypersecretion in a minority of patients, a significant number of subjects have a clinical response. Side effects of bromocriptine treatment and newer dopamine agonists are discussed. These drugs can be useful medical therapy, either used alone in selected patients or in combination with other therapeutic modalities.

Mechanism of impaired growth hormone secretion in patients with Cushing's disease.

The function of the growth hormone-releasing hormone (GHRH)-growth hormone (GH) axis in Cushing's disease was studied by monitoring (a) the GH responses to GHRH loading and L-dopa loading, (b) the GHRH response to L-dopa loading, and (c) the daytime profiles of plasma GH concentration. GH release following GHRH and L-dopa was blunted in patients as compared to that in age-matched control subjects. However, GHRH release following L-dopa was similar in patients and controls. The plasma GH levels in four patients measured every 20 min by a highly sensitive immunoradiometric assay for GH showed pulsatile GH secretion at low levels during the observation period. These results indicate that GHRH release from the hypothalamus is preserved in patients with Cushing's disease, and support the hypothesis that glucocorticoid inhibits GH secretion by altering the hypothalamic somatostatin tone.

Effects of insulin-like growth factor-I on glucose tolerance, insulin levels, and insulin secretion.

Insulin-like growth factor-I (IGF-I) and insulin interact with related receptors to lower plasma glucose and to exert mitogenic effects. Recombinant human IGF-I (rhIGF-I) was recently shown to decrease serum levels of insulin and C-peptide in fasted normal subjects without affecting plasma glucose levels. In this study we have investigated in six healthy volunteers the responses of glucose, insulin, and C-peptide levels to intravenous rhIGF-I infusions (7 and 14 micrograms/kg.h) during standard oral glucose tolerance tests (oGTT) and meal tolerance tests (MTT), respectively. Glucose tolerance remained unchanged during the rhIGF-I infusions in the face of lowered insulin and C-peptide levels. The decreased insulin/glucose-ratio presumably is caused by an enhanced tissue sensitivity to insulin. The lowered area under the insulin curve during oGTT and MTT as a result of the administration of rhIGF-I were related to the fasting insulin levels during saline infusion (oGTT: r = 0.825, P less than 0.05; MTT: r = 0.895, P less than 0.02). RhIGF-I, however, did not alter the ratio between C-peptide and insulin, suggesting that the metabolic clearance of endogenous insulin remained unchanged. In conclusion, rhIGF-I increased glucose disposal and directly suppressed insulin secretion. RhIGF-I probably increased insulin sensitivity as a result of decreased insulin levels and suppressed growth hormone secretion. RhIGF-I, therefore, may be therapeutically useful in insulin resistance of type 2 diabetes, obesity, and hyperlipidemia.

Arginine normalizes the growth hormone (GH) response to GH-releasing hormone in adult patients receiving chronic daily immunosuppressive glucocorticoid therapy.

Glucocorticoids are thought to inhibit GH secretion through an enhancement of endogenous somatostatin tone. The aim of our study was to evaluate the effect of arginine, a secretagogue that increases GH secretion acting at the hypothalamic level, probably by decreasing somatostatin tone, on GH-releasing hormone (GHRH)-induced GH secretion in three male and five female adult patients with nonendocrine disease who were receiving daily immunosuppressive glucocorticoid therapy. Six normal subjects (four males and two females) served as controls. GHRH-induced GH secretion was evaluated after 30-min iv infusion of saline (100 mL) or arginine (30 g) in 100 mL saline. After saline administration, steroid-treated patients showed a blunted GH response to GHRH (GH peak, 8.7 +/- 2.4 micrograms/L) compared to that of normal subjects (GH peak, 23.8 +/- 3.9 micrograms/L). The GH responses to GHRH increased (P less than 0.05) after pretreatment with arginine compared to saline pretreatment in both normal subjects (GH peak, 36.6 +/- 4.0 micrograms/L) and steroid-treated patients (GH peak, 28.4 +/- 5.5 micrograms/L). The GH responses to GHRH plus arginine were not significantly different in steroid-treated and normal subjects. Thus, arginine is able to normalize the GH response to GHRH in patients receiving chronic glucocorticoid treatment. Our data are evidence that the stimulatory action of arginine and the inhibitory action of glucocorticoids on GH secretion are mediated by opposite effects on hypothalamic somatostatin tone.

Octreotide an inhibitor of growth hormone secretion, enhances positive calcium balance in children

Octreotide an inhibitor of growth hormone secretion, enhances positive calcium balance in children

Pituitary adenylate cyclase activating polypeptide, growth hormone (GH)-releasing peptide and GH-releasing hormone stimulate GH release through distinct pituitary receptors.

GH secretion has been thought traditionally to be regulated by the two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin (SRIF). Recent evidence has suggested that other factors may be involved. These factors include the natural ligand for the synthetic hexapeptide GH-releasing peptide (GHRP) and the putative hypophysiotropic factor pituitary adenylate cyclase-activating polypeptide (PA-CAP). Accordingly, we examined the effects of GHRP and PACAP on GH secretion at the single cell level using the reverse hemolytic plaque assay which allows distinction of effects on the number of secreting cells and the amount of hormone each cell secretes. Both factors stimulated GH secretion in a dose-dependent fashion, with PACAP being more effective. PACAP increased both the number of cells secreting and the mean amount of hormone secreted per cell. In contrast, GHRP increased the number of secreting cells, although it had no effect on the amount of secretion per cell. GH secretion induced by GHRH, GHRP, and PACAP was inhibited by SRIF, but the effect was predominantly on the number of cells secreting rather than the amount secreted per cell. Specific antagonists to GHRP and GHRH inhibited GH secretion induced by the respective agonist but not that induced by the other factor nor by PACAP. These findings confirm the complex nature of the regulation of GH secretion at the level of the somatotrope. At least three factors, operating via distinct receptors, are able to increase GH secretion. In addition, they ascribe a potential physiological role for the hitherto putative hypophysiotropic factor PACAP.

Stimulation and inhibition of growth hormone secretion by interleukin-1 beta: the involvement of growth hormone-releasing hormone.

The effects of intracerebroventricularly (i.c.v.) injected interleukin-1 beta (IL-1 beta: 1, 2.5, 10, and 25 ng) were studied on plasma growth hormone (GH) and prolactin (PRL) concentrations in freely moving rats chronically implanted with i.c.v. cannulas and intracardial catheters. Significant changes in PRL secretion were not found. Small i.c.v. doses of IL-1 stimulated GH secretion 15 min postinjection (significant after 2.5 ng IL-1) whereas high doses of IL-1 suppressed plasma GH concentrations. The stimulation of GH secretion by 2.5 ng IL-1 was abolished when endogenous growth hormone-releasing hormone (GHRH) was immunoneutralized by pretreating the rats with GHRH antibodies. The results indicate that IL-1 elicits GH secretion by stimulating the release of hypothalamic GHRH. The inhibition of GH secretion after high doses of IL-1 is attributed to the previously reported corticotropin-releasing-hormone-releasing activity of IL-1.

Gallbladder function in acromegalic patients taking long-term octreotide: evidence of rebound hypermotility on cessation of treatment.

Octreotide is increasingly being used in the treatment of acromegaly. It effectively suppresses growth hormone secretion but also has inhibitory effects on gastrointestinal regulatory peptides and induces gallbladder paresis, which may predispose to gallstone formation. In nine acromegalic patients receiving long-term octreotide treatment gallbladder emptying, assessed by 99Tc-EHIDA scintigraphy after a standard fatty meal, was significantly impaired (p less than 0.005) when compared with normal healthy control subjects. Asymptomatic gallstone formation occurred in one patient who had the most severely impaired gallbladder emptying. Between 24 and 96 h after cessation of octreotide, in six of seven patients studied, gallbladder emptying had not only recovered but demonstrated significant rebound hypermotility (p less than 0.005). This finding has important implications for the administration of long-term octreotide therapy and suggests that a drug-free period each week may enable evacuation of gallbladder contents and reduce the risk of gallstone formation.

Triiodothyronine (T 3) inhibition of growth hormone secretion by chicken pituitary cells in vitro

These studies examined the cellular basis for the inhibitory effects of triiodothyronine (T 3) on growth hormone-releasing factor (GRF)-evoked growth hormone (GH) release from chicken anterior pituitary cells in vitro. A primary monolayer culture of anterior pituitaries from 4- to 8-week-old White Leghorn cockerels was performed as previously described by this laboratory. Following a 72-hr preincubation period, cells were washed and incubated (2 hr) with either secretagogues or media alone (control). T 3 (20 ng/ml) or vehicle was added to cells during both the preincubation (48–72 hr) and incubation (2 hr) period. Triiodothyronine reduced ( P < 0.05) GH release (ng/ml) in response to (1) GRF; (2) the adenylyl cyclase stimulator, forskolin; (3) the cAMP analog and protein kinase A activator, 8-bromo cAMP; and (4) the phorbol ester and protein kinase C activator, phorbol 12-myristate 13-acetate. Triiodothyronine reduced ( P < 0.05) the intracellular content of GH and total GH (released GH and intracellular GH) irrespectively of whether secretagogues were also present. When GH release was expressed as a percentage of total GH [released GH/(intracellular GH + released GH)], percentage GH released in response to GRF, or the protein kinase A, protein kinase C, or calcium pathway activators was not as great in T 3-treated versus non-T 3-treated cells. These data indicate that T 3 inhibits GRF-evoked GH release by reducing the availability of intracellular stores of GH and by also inhibiting second messenger-stimulated GH release pathways.

Effect of a long-acting somatostatin analogue (BIM23014) on proliferative diabetic retinopathy: A pilot study

A pilot study on the use of a continuous infusion of somatostatin, by subcutaneous pumps in the management of proliferative diabetic retinopathy is reported. Two patients out of eight with proliferative retinopathy demonstrated improvement. One patient demonstrated regression of disc new vessels and the other a reduced area of retinal capillary non-perfusion, both demonstrated by fluorescein angiography. Control patients showed worsening of fluorescein leakage over the observation period of four to six weeks whereas the other six patients given the somatostatin infusion did not demonstrate any deterioration. The mechanism of action of somatostatin in this study is unknown but it is thought to have direct anti-angiogenic properties as well as inhibiting growth hormone secretion.

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-Tyr 1, D-Arg 2)-GRF(1–29)-NH 2, 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.

Impact of Increased Growth Hormone Secretion on Carbohydrate Metabolism in Adolescents with Diabetes

Growth hormone (GH) and fasting insulin concentrations rise during puberty in normal subjects. Any increase in GH secretion in adolescents with insulin-dependent diabetes mellitus (IDDM) might be expected to lead to further insulin resistance and metabolic disturbance. Despite the high incidence of delayed growth in IDDM, the relationship between GH, insulin-like growth factor I (IGF-I) and IGF binding protein 1 (IGFBP-1) has not been clearly established. Twenty-six adolescents with IDDM and 34 healthy siblings underwent measurement of their overnight GH secretory profiles (20.00-08.00 hours, 15-minute sampling). The diabetic subjects were studied either on their normal insulin regimen (n = 15) or during a euglycaemic clamp (n = 26). A second clamp study was undertaken (n = 7) with addition of pirenzepine to suppress GH secretion. GH profiles in the diabetic subjects were characterized by increases in both pulse amplitude and baseline GH concentrations. Deconvolution analysis also revealed an increase in the frequency of GH secretory episodes. In the subjects with diabetes, a direct link between the dawn rise in insulin requirements, increased concentrations of beta-hydroxybutyrate and the elevated concentrations of GH was established. These abnormalities were reversed by the suppression of GH pulse amplitude following pirenzepine. Serum IGF-I concentrations and IGF-I bioactivity in the diabetic subjects were low and were positively correlated with mean GH concentrations. In conclusion, well controlled adolescents with IDDM show persisting abnormalities of GH, beta-hydroxybutyrate and IGF-I despite normoglycaemia. The role of inappropriate insulin delivery in the development of these abnormalities is discussed.

Circadian patterns of cortisol, prolactin, and growth hormonal secretion during bingeing and vomiting in normal weight bulimic patients

Women who are of normal weight and have bulimia nervosa exhibit multiple neuroendocrine disturbances. We hypothesized that bingeing and vomiting behavior could be contributory because food consumption in healthy volunteers increases plasma cortisol and prolactin secretion and suppresses growth hormone secretion. Thus, we investigated the effects of bingeing and vomiting on the circadian pattern (measurements every 20 min for 24 hr) of these hormones in comparison to healthy control women eating normally. Bingeing and vomiting were associated with modest increases in cortisol and prolactin and reductions in growth hormone secretion. However, this bingeing or purging did not alter mean 24-hr pattern of cortisol and growth hormone secretion as values for bulimics were similar to controls. While mean daytime patterns of prolactin secretion were similar in bulimics and controls, bulimic patients had a significant reduction of nocturnal prolactin levels. In summary, bingeing and vomiting does not appear to have a substantial influence on hormonal secretion. However, bulimic women have blunted nocturnal prolactin patterns.

Inhibition of growth hormone secretion by activin A in human growth hormone-secreting tumour cells

Effect of activin A on growth hormone secretion was studied in primary culture of 8 human GH-secreting adenomas, which were responsive to TRH in vivo. When studied in vitro, basal GH secretion was reduced in all cases when cells were pre-incubated for 48 h with activin A at a concentration of 5 X 10(-9) mol/l or greater. Pretreatment of GH-secreting cells with 1 X 10(-9) mol/l activin A did not affect either basal secretion or cellular content of GH. These tumour cells also responded to TRH in vitro and the GH response to TRH was completely blocked in cells pretreated with activin A. Activin A slightly reduced the increase in cytoplasmic free calcium concentration induced by TRH. Furthermore, pretreatment of the cells with activin A attenuated GH secretion induced by A23187 or 12-O-tetradecanoyl phorbol-4-acetate, agents which bypass receptor-mediated generation of second messengers. These results indicate that activin A inhibits GH secretion by directly acting on human GH-secreting cells and that activin A inhibits the action of TRH by acting on multiple steps in the messenger system.

Effects of selective histamine H3-receptor ligands on prolactin and growth hormone secretion in the rat.

The effects of intracarotid (i.a.) administration of the histamine (HA) H3-receptor agonist (R)-alpha-methyl-histamine (alpha MeHA) and of the H3-antagonist thioperamide, (THIO) on basal or morphine (M)-induced prolactin (PRL) and growth hormone (GH) secretion were studied in male rats. M was administered 3 h after the H3-drugs. Neither THIO (2.5 mg/kg) nor alpha MeHA (10 mg/kg) changed basal PRL levels and only THIO enhanced the PRL-releasing effect of M (6 mg/kg). Basal GH secretion was not modified by THIO. alpha MeHA slightly increased GH secretion. THIO significantly decreased M-stimulated GH secretion (1 mg/kg, i.a.) and alpha MeHA slightly increased it. These results, in agreement with previous evidence obtained after central HA administration, indicated that endogenous brain HA facilitates PRL and inhibits GH secretion.

111In-DTPA-D-Phe 1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation

Somatostatin receptor-positive human tumors can be detected using radioiodinated analogues of somatostatin, both in vitro and in vivo. [ 123I-Tyr 3]-octreotide has been successfully used in the visualization of somatostatin receptor-positive tumors by gamma camera scintigraphy, but this radiopharmaceutical has some major drawbacks, which can be overcome with other radionuclides such as 111In. As starting material for a potentially convenient radiopharmaceutical, a diethylenetriaminopentaacetic acid (DTPA) conjugated derivative of octreotide (SMS 201–995) was prepared. This peptide, [DTPA-D-Phe 1]-octreotide (SDZ 215-811) binds more than 95 % of added 111In in an easy, single-step labeling procedure without necessity of further purification. The specific somatostatin-like biologic effect of these analogues was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in a dose-dependent fashion by octreotide, [DTPA-D-Phe 1]-octreotide and non-radioactive [ 115In-DTPA-D-Phe 1]-octreotide. The binding of [ 111In-DTPA-D-Phe 1]-octreotide to rat brain cortex membranes proved to be displaced similarly by natural somatostatin as well as by octreotide, suggesting specific binding of [ 111In-DTPA-D-Phe 1]-octreotide to somatostatin receptors. The binding of the indium-labeled compound showed a somewhat lower affinity when compared with the iodinated [Tyr 3]-octreotide, but indium-labeled [DTPA-D-Phe 1]-octreotide still binds with nanomolar affinity. In conjunction with in vivo studies, these results suggest that [ 111In-DTPA-D-Phe 1]-octreotide is a promising radiopharmaceutical for scintigraphic imaging of somatostatin receptor-positive tumors.