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Background/Aims: In prepubertal short children with idiopathic growth retardation, growth hormone (GH) peak after GH release stimuli classifies patients as growth hormone- deficient (GHD) or non-GHD. This study compared a 2-year growth response to GH therapy in 318 prepubertal short children. Methods: Patients were classified as: severe GHD (GH peaks Results: Two-year height gain did not differ statistically among the 4 groups: 1.39 ± 0.51 SD, 16.4 ± 2.3 cm; 1.23 ± 0.56 SD, 15.8 ± 2.1 cm; 1.18 ± 0.53 SD, 15.3 ± 2.0 cm, and 1.14 ± 0.53 SD, 15.4 ± 2.0 cm, respectively, as was also the case for bone age gain: 2.5 ± 0.6, 2.4 ± 0.7, 2.6 ± 0.7 and 2.3 ± 0.5 years, respectively. Conclusions: Our results suggest that GH release stimuli are of little help for deciding on GH therapy in the clinical management of prepubertal short children with idiopathic growth retardation, while well-defined anthropometric and biochemical criteria may be useful.

In thyrotoxicosis GH responses to stimuli are diminished and the hypothalamic-pituitary-adrenal axis is hyperactive. There are no data on ghrelin or GHRP-6-induced GH, ACTH and cortisol release in treated hyperthyroidism. We, therefore, evaluated these responses in 10 thyrotoxic patients before treatment and in 7 of them after treatment. GHRH-induced GH release was also studied. Peak GH (μg/L; mean ± SE) values after ghrelin (22.6 ± 3.9), GHRP-6 (13.8 ± 2.3) and GHRH (4.9 ± 0.9) were lower in hyperthyroidism before treatment compared to controls (ghrelin: 67.6 ± 19.3; GHRP-6: 25.4 ± 2.7; GHRH: 12.2 ± 2.8) and did not change after 6 months of euthyroidism (ghrelin: 32.7 ± 4.7; GHRP-6: 15.6 ± 3.6; GHRH: 7.4 ± 2.3), although GH responses to all peptides increased in ~50% of the patients. In thyrotoxicosis before treatment ACTH response to ghrelin was two fold higher (107.4 ± 26.3) than those of controls (54.9 ± 10.3), although not significantly. ACTH response to GHRP-6 was similar in both groups (hyperthyroid: 44.7 ± 9.0; controls: 31.3 ± 7.9). There was a trend to a decreased ACTH response to ghrelin after 3 months of euthyroidism (35.6 ± 5.3; P = 0.052), but after 6 months this decrease was non-significant (50.7 ± 14.0). After 3 months ACTH response to GHRP-6 decreased significantly (20.4 ± 4.2), with no further changes. In hyperthyroidism before treatment, peak cortisol (μg/dL) responses to ghrelin (18.2 ± 1.2) and GHRP-6 (15.9 ± 1.4) were comparable to controls (ghrelin: 16.4 ± 1.6; GHRP-6: 13.5 ± 0.9) and no changes were seen after treatment. Our results suggest that the pathways of GH release after ghrelin/GHRP-6 and GHRH are similarly affected by thyroid hormone excess and hypothalamic mechanisms of ACTH release modulated by ghrelin/GHSs may be activated in this situation.

Objective: Verifying the association between glycemic fluctuation and GH response in the glucagon stimulation test. Basal evaluation of growth hormone (GH) has poor diagnostic accuracy due to its pulsatile secretion. GH-stimulation tests are used for an adequate evaluation of somatotrophic axis. Various stimuli can be employed, among them glucagon, which has an elusive mechanism of action. Since hypoglycemia reportedly occurs during the test, investigation of its role as a stimulus to GH release is granted. Design: Retrospective analysis of glucagon-stimulated GH tests performed in 128 children (36.7% female; age 12.4+3.3 years), at Fleury Functional Tests Facility from July 2000 to 2006. GH and blood glucose (BG) curves, IGF-1, and IGFBP-3 have been assessed. Positive GH response was defined by a peak GH value ⩾3.3μg/L. Normal IGF-1 levels were defined as those between 2.5th and 97.5th percentiles for age and gender. Results: Hypoglycemia under 2.2mmol/L did not occur during the test. BG decrease occurred with lower magnitude and was not associated to GH response. Comparison between patients with negative and positive GH response showed, respectively, BG nadir 3.74 vs. 3.62mmol/L, glucose AUC 23.3 vs. 22.4, and glycemic decrease (below 3.3mmol/L) 19% vs. 35.5% (with P non-significant for all comparisons). Conclusion: Hypoglycemia was not seen after glucagon stimulation and decrease in BG occurred above levels physiologically expected to stimulate GH release, being apparently not associated to GH response.

Growth hormone (GH) response was studied in 8 insulin-dependent and 7 non-insulin-dependent diabetics after stimulation with L-Dopa (500 mg orally) and TRH (0.2 mg iv.). L-Dopa induced a clear GH response in insulin-dependent diabetes (IDDM) and in the control group while in non-insulin-dependent diabetes (NIDDM) peak GH levels were lower (P less than 0.05) and 4 of 7 subjects failed to respond to L-Dopa stimulation. TRH had no effect on GH levels in NIDDM and in the controls. Insulin-dependent diabetics responded to TRH stimulation and GH levels at 20 and 30 min were significantly higher as compared with NIDDM and the control group. The degree of hyperglycemia seemed not to influence GH response. The highest GH levels were noted in two patients with proliferative retinopathy. It is suggested that TRH-induced GH release may be a characteristic feature in some patients with IDDM.

Children irradiated for brain tumours constitute an increasing group of patients who will require GH therapy. High-dose cranial irradiation is necessary for cure, but inevitably causes GH deficiency within a few years. In 19 patients investigated between 2 and 9 years after irradiation, the spontaneous 24-hour GH secretion was markedly reduced. The secretory pattern indicated loss of regulating hypothalamic hormones. After exogenous GHRH was administered, the pituitary was able to respond with a prompt GH release, showing that pituitary function was unaffected. Ten prepubertal children growing at 3.8 +/- 0.3 cm/year were treated with GH, 0.1 IU/kg/day s.c. Their growth rate increased to 8.2 +/- 0.4 cm in the first year. An increased growth rate was also maintained in the second year.

In this study, dioscin was isolated from Dioscoreae Rhizoma (DR), which is the rhizome of Dioscorea batatas D(ECNE). that inhabits broad areas of Korea and Japan. To determine whether dioscin induced growth hormone (GH) release, we evaluated its induction effects on GH release both in vitro and in vivo. The 70% methanol extract of DR, and its n-hexane and n-BuOH fractions, induced rat GH (rGH) release in rat pituitary cells 10-fold, 8-fold, and 5- fold higher than the control (0.36 +/- 0.02 nM), respectively (p < 0.05 each). The dioscin-induced rGH release of the cells was concentration-dependent and its ED(50) was 1.14 x 10(-5) M. Within 90 minutes after intravenous administration of 10 microg/kg (p < 0.05 at t(max)), dioscin caused the greatest increase in rGH concentration (C(max)) in the rat plasma (34.16 +/- 14.10 ng/ml) (n = 4), which was twice as high as the control group (12.88 +/- 3.29 ng/ml) (n = 27).

In thyrotoxicosis GH response to several stimuli is impaired, but there is no data on ghrelin-induced GH release in these patients. Ghrelin is a potent GH secretagogue and it also increases glucose levels in men. The aim of this study was to evaluate the effects of ghrelin (1 microg/kg), GHRP-6 (1 mug/kg) and GHRH (100 microg), i.v., on GH levels in 10 hyperthyroid patients and in 8 controls. Glucose levels were also measured during ghrelin and GHRP-6 administration. In control subjects and hyperthyroid patients peak GH (microg/l; mean +/- SE) values after ghrelin injection (controls: 66.7 +/- 13.6; hyper: 19.3 +/- 2.4) were significantly higher than those obtained after GHRP-6 (controls: 26.7 +/- 5.1; hyper: 12.6 +/- 1.3) and GHRH (controls: 13.5 +/- 4.3; hyper: 5.3 +/- 1.3). There was a significant decrease in GH responsiveness to ghrelin, GHRP-6 and GHRH in the hyperthyroid group compared to controls. In control subjects and hyperthyroid patients basal glucose (mmol/l) values were 4.5 +/- 0.1 and 4.7 +/- 0.2, respectively. There was a significant increase in glucose levels 30 min after ghrelin injection (controls: 4.9 +/- 0.1; hyper: 5.2 +/- 0.2), which remained elevated up to 120 min. When the two groups were compared no differences in glucose values were observed. GHRP-6 administration was not able to increase glucose levels in both groups. Our data shows that GH release after ghrelin, GHRP-6 and GHRH administration is decreased in thyrotoxicosis. This suggests that thyroid hormone excess interferes with GH-releasing pathways activated by these peptides. Our results also suggest that ghrelin's ability to increase glucose levels is not altered in thyrotoxicosis.

The 1970s and 1980s were a transformative period for neuroendocrine research. During these 2 decades, many of the hypothalamic peptides regulating pituitary hormone secretion were identified and the field exploded with studies characterizing the spectrum of their biological activities. In the race to these exciting discoveries, discordant results were published regarding the central actions of the newly discovered GH-releasing factor (GRF). Two groups reported a biphasic effect of central administration of human GRF with low doses suppressing and high doses stimulating GH release in rats (1, 2). In contrast, a third group reported that administration of both low and high doses of human GRF inhibited GH secretion (3). Through meticulous scientific detective work, the source of the discrepancy was uncovered and, in the best scientific tradition, promptly published (4). Chemical characterization of the peptide that produced GH inhibition at all doses demonstrated that the putative GRF peptide consisted predominantly of corticotropin-releasing factor. Furthermore, use of new GRF samples reproduced the previously reported stimulatory effect on GH. Although how the original sample became contaminated is not known (4, 5), the source of this error is irrelevant for the purpose of scientific progress: the truth was discovered and revealed.

OBJECTIVE: Ghrelin is a potent peptide stimulating GH secretion. Besides its direct action on the pituitary, ghrelin has been reported to stimulate GH release via the vagal afferent nerve in rats. To examine the involvement of vagal nerve in ghrelin-induced GH secretion in humans, GH responses to ghrelin were compared between vagotomized patients with gastrectomy and normal subjects. METHODS: Ghrelin (0.2 microg/kg) or GHRH (1 microg/kg) was administered intravenously in vagotomized patients and normal subjects on separate days, and plasma GH responses to the stimuli were examined. RESULTS: Ghrelin caused a significant plasma GH rise in both vagotomized patients and normal subjects. Peak GH levels in vagotomized patients (37.5+/-16.9 ng/ml) were not different from those in normal subjects (29.9+/-23.1 ng/ml). The areas under the curve of GH response to ghrelin did not differ between the two groups. GHRH also increased GH levels, and peak GH levels and areas under the curve after GHRH stimulation were also comparable between vagotomized patients and normal subjects. CONCLUSIONS: In the present study, the involvement of the afferent vagal nerve in ghrelin-induced GH secretion was not confirmed in humans.

We investigated the action of bisphenol A (BPA) on cellular GH release and content, cell number, GHmRNA expression, and concentrations of cellular cyclic AMP ([cAMP]c) and calcium ion ([Ca2+]c) in primary cultured ovine anterior pituitary cells. The following results were found: (1) BPA as well as nonylphenol (NP) at 10(-6) to 10(-3) M significantly and concentration-dependently suppressed basal and GHRH-stimulated GH release, and the cellular GH content, (2) BPA suppressed the cell number in a time- and concentration-dependent manner, (3) 10(-4)M BPA suppressed GHmRNA expression to 68% of control (BPA-free), and abolished GHRH (10(-8) M)-induced increases in [cAMP]c and [Ca2+]c. From these findings we conclude that BPA possesses a suppressing action on GH synthesis and release, and this suppressing action is probably related to impairment of cellular signal transduction systems in ovine anterior pituitary cells.

Exercise is a potent stimulus for growth hormone (GH) release and a single bout of exercise can result in marked elevations in circulating GH concentrations. The magnitude of the GH response to exercise will vary according to the type, intensity and duration of exercise as well as factors such as the age, gender, body composition and fitness status of the individual performing the exercise. However, the mechanisms regulating GH release in response to exercise are not fully understood. This review considers the GH responses to sub-maximal and sprint exercise and discusses the factors that might affect GH release along with the mechanisms that have been proposed to regulate exercise-induced GH release.

In thyrotoxicosis there is an impaired GH response to GHRH, normal GH responsiveness to GHRP-6 and lack of synergistic GH response after simultaneous administration of both peptides. We have previously shown that the GHRH-induced GH release in these patients increases after an acute reduction of circulating T3 values with administration of iopanoic acid, a compound that inhibits peripheral conversion of T4 to T3. We have now studied the effect of a decrease in serum T3 levels on the GH response to GHRP-6 (1 microg/kg) plus GHRH (100 microg) in 9 hyperthyroid patients before and after 15 days of treatment with iopanoic acid (3 g every 3 days) and propylthiouracil (600 mg/day). Nine normal subjects were also studied. In all hyperthyroid patients iopanoic acid induced a rapid decrease and normalisation of serum T3 levels. In these subjects peak GH (microg/l; mean +/- SE) and AUC (microg/l x 120 min) values after GHRP-6 plus GHRH were significantly higher on day 15 compared to pretreatment values (peak, 18.3 +/- 3.0 vs 13.4 +/- 1.9; AUC, 1227.9 +/- 212.9 vs 968.5 +/- 160.4; p0.05). Despite the significant enhancement of the GH responsiveness to GHRP-6 plus GHRH after treatment with iopanoic acid, this response remained significantly blunted when compared to controls both in terms of peak GH (18.3 +/- 3.0 vs 83.7 +/- 15.2; p0.05) and AUC values (1227.9 +/- 212.9 vs 4956.5 +/- 889.3; p0.05). In conclusion, our results show that an acute decrease of circulating T3 levels enhances, but does not normalise, the GH response to GHRP-6 plus GHRH in thyrotoxicosis. This could suggest that circulating T3 does not have a major role in the mechanisms involved in the synergistic effect of these peptides.

Ghrelin is an acylated peptide, whose lipid modification is essential for its biological activities. Previous studies demonstrated that it strongly stimulates GH release and has a potent orexigenic action. Meanwhile, there is enough evidence showing that feeding states influence plasma ghrelin levels. Fasting stimulates ghrelin secretion, and feeding reduces plasma ghrelin levels. In this study we examined the regulation of plasma ghrelin by fasting in genetically obese animals considering its molecular forms. Plasma levels of active form of ghrelin as well as those of total ghrelin were reduced in ob/ob and db/db mice compared with those in their control mice. Zucker fatty (fa/fa) rats also showed lower plasma ghrelin levels by fasting than the control rats. Insulin-induced hypoglycemia, however, stimulated ghrelin secretion in the fasted fatty rats. Moreover, glucose injection was revealed to reduce plasma ghrelin levels in rats. The effect of the severity of obesity on secretory regulation of ghrelin was also studied. Older fatty rats showed low plasma ghrelin levels even after 48-h fasting. These data suggest that the short-term secretory regulation of total ghrelin and the active form of ghrelin is delayed in obese animals and that blood glucose levels may be involved in the delayed regulation.

A new technique for controllable elevation of night time growth hormone (GH) release in adult humans involves a synergy between oral intake of the naturally occurring compounds acetyl-L-carnitine (500 mg) and L-ornithine (25–100 mg) taken at night time sleep after a 3 to 4 hour fast. The set point for normal hypothalamic GH release appears to include a ‘whole body’ mitochondrial State 3 status ‘feed back loop’ controlled by systemic acetyl- L-carnitine levels.

The aim of the present study was to examine the growth hormone (GH) response to the combined and repeated administrations of growth hormone-releasing peptide-2 (GHRP-2) plus growth hormone releasing hormone (GHRH) in swine. Six cross-bred castrated male swine, 130-135 days of age were used in this study. Animals were given a single intravenous (i.v.) injection of either GHRP-2 (30μg/kg BW), GHRH (1μg/kg BW) and GHRP-2 (30μg/kg BW) plus GHRH (1μg/kg BW) or 5ml saline (served as control) in random order with two days apart. GHRP-2 or GHRH alone and in combination with together stimulated the release of GH in swine. The peak concentrations of GH and areas under the GH response curve (GH AUC) for 120min after these treatments were significantly higher (P

It is widely accepted that glucagon stimulates GH, ACTH and cortisol release in humans, though the mechanisms underlying these effects are unclear. Aim of the present study was to evaluate the stimulatory effect of intramuscolar (im) and intravenous (iv) glucagon (GLU) administration on ACTH, cortisol (F) and GH release in normal adult subjects and to compare its effect on hypothalamo-pituitary adrenal (HPA) axis with that of hCRH. To this goal, in 6 normal young women (26–32 yrs, 50–58 kg) we studied the ACTH and F responses to either im or iv GLU (1 mg, approximately 0.017 mg/kg in subjects of 54.1 ± 1.6 kg) administration as well as to iv hCRH (2.0 μg/kg) or placebo administration. The GH and glucose variations after GLU administration were also studied. Iv GLU did not modify the spontaneous decrease of ACTH and cortisol levels observed after placebo. Conversely, im GLU elicited clear-cut ACTH and F responses (peak vs baseline, mean ± SEM: 53.0 ± 15.2 vs 19.0 ± 1.5 pg/ml, p < 0.05 and 222.3 ± 23.8 vs 158.3 ± 7.0 μg/l, p < 0.05) which were higher than those recorded after hCRH (28.1 ± 4.6 vs 17.4 ± 3.1 pg/ml, p < 0.02 and 182.7 ± 22.8 vs 114.8 ± 12.3 μg/l p < 0.02), though this difference did not attain statistical significance. Also GH rise was recorded after im but not after iv GLU administration (11.6 ± 3.4 vs 3.3 ± 0.7 μg/l, p < 0.05). Thirty min after both iv and im GLU administration glucose levels showed a similar increase followed by similar decrease. The intramuscular administration of GLU induced negligible side-effects in some subject (mild and transient nausea) which, on the contrary, were clear in all subjects after its intravenous administration (nausea, vomiting, tachicardia). In conclusion, glucagon “per se” is not an ACTH, cortisol and GH secretagogue. After intramuscular administration glucagon is a stimulus of HPA axis at least as effective as hCRH. The mechanisms underlying the ACTH, cortisol and GH responses to im glucagon unlikely include glucose variations or stress.

The coexistence of galanin (GAL) with some classical neurotransmitters suggests that it may exert a role as a neuroendocrine modulator. The aim of this study was to investigate the GH response to porcine galanin (p-GAL) in prepubertal male lambs. In the experiments A and B the i.v. infusion of galanin (5 μg/kg) for 60 min was carried out alone (Experiment A) or combined with an i.m. injection of GHRH (0.5 μg/kg) 30 min after infusion (Experiment B); in the Experiment C, galanin (5 μg/kg) was infused for 300 min. Galanin infusion was not effective in increasing GH baseline levels ( P > 0.08); however galanin potentiated ( P

In addition to stimulating GH release, GH secretagogues such as GH-releasing peptide-6 (GHRP-6) stimulate small amounts of ACTH and PRL release. Although the effects on ACTH have recently been studied, there is little information about the effects of GHRP-6 on PRL. We have now studied GHRP-6-induced GH and PRL release and their regulation by estrogen (E2) in anesthetized male and female rats and in GH-deficient dwarf (dw/dw) rats that maintain high pituitary PRL stores and show elevated hypothalamic GH secretagogue receptor expression. Whereas GHRP-6 (0.1–2.5 μg, iv) did not induce PRL release in normal male or female rats, significant PRL responses were observed in dw/dw females. These responses were abolished by ovariectomy and could be strongly induced in male dw/dw rats by E2 treatment. These effects could be dissociated from GHRP-6-induced GH release in the same animals, but not from PRL release induced by TRH, which was also abolished by ovariectomy and induced in males by E2 treatment. However, the effects of GHRP-6 on PRL were unlikely to be mediated by TRH because in the same animals, TSH levels were unaffected by GHRP-6 whereas they were increased by TRH. The increased PRL response could reflect an increase in GH secretagogue receptor expression that was observed in the arcuate and ventromedial nuclei of E2-treated rats. Our results suggest that the minimal PRL-releasing activity of GHRP-6 in normal rats becomes prominent in GH-deficient female dw/dw rats and is probably exerted directly at the pituitary; these GHRP-6 actions may be modulated by E2 at both hypothalamic and pituitary sites.

To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18–29 yr) received, in randomized order, 4-h iv infusions of recombinant human IGF-I (rhIGF-I; 3 μg/kg·h) or saline (control) from 25.5–29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4–4.0) vs. 4.8 (2.8–7.9) μg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5–7 h after the end of rhIGF-I infusion [7.6 (4.6–11.7) vs. 4.3 (2.5–6.0) μg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 ± 43 vs. 263 ± 44 μg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 ± 36 vs. 202 ± 23 μg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 ± 0.4 vs. 0.88 ± 0.3 μg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.

Keywords: growth, salmon, smoltification, insulin, insulin-like growth factor I (IGF-I), growthhormone, thyroxine, photoperiod, temperature, nutritioncreases hepatic IGF-I mRNA (Cao et al. 1989;Sakamoto and Hirano 1993; Duan et al. 1994) andelevates blood IGF-I levels (Moriyama et al.1994). The majority of IGF-I in salmonid blood isprobably bound to specific binding proteins(IGFBPs), some of which are influenced by GH,insulin and nutrition (Kelley et al. 1992; Siharathand Bern 1993). The IGFBPs in blood and in tis-sues surrounding target cells undoubtedly play asignificant role in modifying the action of IGF-Iin fish, as they do in mammals, although this islargely unexplored in the context of salmon smol-tification. IGF-I inhibits GH release by negativefeedback, as shown

Vaccarino, F. J. and M. R. Taube. Intra-arcuate opiate actions stimulate Grf-dependent and protein-selective feeding. Peptides 18(2) 197–205, 1997.—Growth-hormone releasing factor (GRF) induces feeding and growth hormone (GH) release. Opiates activate GRF neurons regulating GH release. This study sought to determine whether opiate actions on GRF neurons would also stimulate feeding. In Experiment 1, Wistar male rats received intra-arcuate morphine (0, 1, 10, and 20 μ g/0.5 μ l) which increased protein intake/feeding activity. In Experiment 2, this effect was blocked when Wistar male rats received intra-SCN/MPOA pretreatments with GRF antiserum followed by intra-arcuate morphine (1 μ g/0.5 μ l) injections. The data suggest that an opioid trigger may stimulate complementary central (feeding effects) and peripheral (GH release) GRF actions via the arcuate nucleus.

A series of spiroindane growth hormone secretagogues that vary in their amino side chains is reported. Variations in these side chains markedly affect growth hormone release in vitro and in vivo . The best side chain in this series of secretagogues is α-methylalanine. L-162,752 not only stimulated GH release from rat pituitary cells, but also induced GH release in dogs upon i.v. and p.o. administration.

The aim of our study was to investigate the effect of galanin on basal and GHRH-stimulated GH secretion in a healthy group of elderly subjects and in a healthy group of young subjects for comparison. Ten old subjects (mean age 75 +/- 1.15 years) and an equal number of healthy young volunteers (mean age 26 +/- 0.71 years) underwent three stimulation tests in random order. Galanin infusion for 60 minutes (10 micrograms/kg in 100 ml saline) failed to provoke an appreciable release of circulating GH in old subjects, while it induced a significant increase of plasma GH in the young adults; GHRH administration i.v. in bolus (100 micrograms in 1 ml saline) elicited a significant GH response in both groups; however, in the older group GH response was significantly (p < 0.05) lower than in the young adults. The administration of galanin (10 micrograms/kg in 100 ml saline as an i.v. infusion for 60 min) plus GHRH (100 micrograms in 1 ml saline i.v. in bolus), potentiated GH response in old and young subjects. The combined administration of two peptides was able to elicit a clear GH release even in the older subjects who were hyporesponsive/unresponsive to galanin and/or GHRH alone. In the elderly, plasma GH values observed after the combined stimuli overlapped with GH values observed after GHRH alone in the young adults. In conclusion, our study confirms that galanin has a synergic effect with GHRH on GH release both in younger and elderly subjects. Moreover, our data confirm an impaired responsivity to GHRH in the elderly and demonstrate that galanin is able to normalize response of somatotrophs to GHRH in old people.

Growth hormone-releasing factor (GRF) regulates GH release and somatotrope proliferation via a specific G-protein-coupled receptor. Little is known about the endocrine factors that regulate the expression of the GRF receptor (GRF-R) in the pituitary gland. We have developed a sensitive solution hybridization/RNAse protection assay for GRF-R mRNA in rat pituitary extracts. GRF-R transcripts were readily detectable in similar amounts in normal male and female rats, but were markedly reduced in extracts from age-matched growth hormone (GH)-deficient dwarf (dw) rats of either sex. The reduced GRF-R expression would appear to reflect somatotrope hypoplasia rather than GH deficiency per se since a similar reduction in GRF-R expression was seen in a transgenic model of dominant dwarfism, whereas GRF-R expression was significantly elevated in rats with GH deficiency induced by hypothyroidism. We were unable to demonstrate significant effects on GRF-R expression with infusions of human GH (hGH) or insulin-like growth factor 1, which stimulate growth in dw rats, but dexamethasone treatment induced a significant, time-related increase in GRF-R mRNA levels. We conclude that this assay can usefully quantify pituitary GRF-R expression in normal rats, and its reduction in two different strains of mutant dwarf rats with somatotrope hypoplasia.

The present study was designed to examine the effects of intracerebroventricular injection of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP) on GH secretion in freely moving conscious male rats and

Ghrelin, a 28-amino acid-long peptide with an n -octanoyl modification at Ser 3 , has been isolated from rat and human stomachs as an endogenous ligand for the growth hormone secretagogue receptor. It is very important to study the ghrelin from mammals (especially, domestic animals) that serve as human companions, food resources, and model organisms. We purified feline and caprine ghrelin and observed that the administration of synthetic ghrelin increased plasma growth hormone (GH) levels in cats and goats. Therefore, we believe that ghrelin may play important roles in GH release in mammals.

It has been suggested that hypothalamic regulation of GH secretion in children may differ from that in adults. On the other hand, there is evidence that oral glucose administration affects GH secretion through hypothalamic mechanisms. Therefore, we investigated spontaneous and GHRH-stimulated (1 microgram/kg BW) GH responses after oral glucose administration (children, 1.75 g/kg BW; adults, 75 g) in peripubertal normal children (13 girls and 13 boys, aged 11.7 +/- 0.4 yr; range, 8-13) and healthy adults (12 males and 14 females, aged 25.7 +/- 1.2 yr; range, 18-39). Three studies were carried out. In study 1, serum GH levels in 8 children were suppressed (1 microgram/L) for 135 min after oral glucose administration. Afterward, there was a rise in serum GH levels. In 8 adults, the suppressive effect of glucose persisted throughout the 210-min study period, and no GH rebound appeared. In study 2, the GH responses to iv GHRH boli in 10 adults and 10 children were, respectively, inhibited, unchanged, or augmented by an oral glucose load administered 30, 60, or 120 min before GHRH challenge. In study 3, oral glucose administration to 8 adults greatly enhanced the GH response to GHRH given 180 min after the glucose, whereas in 8 children, the GH response to GHRH was unchanged. In conclusion, glucose affects basal and GHRH-stimulated GH release in a similar manner in adults and children, indicating that neuroregulatory influences of glucose on the GH axis may not differ in the two age groups. In children, however, the duration of both the initial inhibitory and subsequent stimulatory effects of glucose administration on GH secretion is shorter.

Puberty is characterized by the onset and continued development of secondary sexual characteristics and an abrupt onset of linear growth. Growth in boys occurs due to the rising levels of androgens and also indirectly mediated by growth hormone (GH) and the insulin-like growth factors. Data are presented to show marked androgen-dependence of GH increases at puberty. The mode of this increase is through an augmentation in the amplitude of the pulses rather than in their frequency. Shortly after the maximal rate of growth, the pattern of GH release reverts toward that of the prepubertal child. To investigate the neuroendocrine mechanism through which androgens increase the mean circulating GH level, deconvolutional analysis has been applied. At mid-puberty the maximal rate of GH release per secretory burst and the total amount released per burst were increased. There were no significant alterations in the duration or frequency of the GH secretory burst or in the serum half-life reflecting the metabolic clearance of the hormone. Thus, the pubertal growth spurt in boys is likely subserved by the altered neurosecretory dynamics for GH. These altered hormone levels likely produce the equally profound changes in body composition, regional fat distribution, and muscular strength that occur during puberty in boys.

Plasma GH responses to GH-releasing peptide (GHRP) were studied in 11 patients with active acromegaly. Ten of these patients showed plasma GH increases to GHRP (100 micrograms i.v.), whereas every patient showed GH increases to TRH (500 micrograms i.v.) and GHRH (100 micrograms i.v.). When GHRP was administered together with GHRH to the 10 GHRP responders, plasma GH responses were synergistically enhanced. However, combined administration of GHRP and TRH did not enhance the response. The GH response pattern and mean time to the peak value were similar to TRH but were different from GHRH. There was no correlation in the maximum GH increment between GHRP and TRH or GHRP and GHRH. It is concluded that GHRP stimulated GH release in the majority of acromegaly patients. The mode of action of GHRP might be similar to TRH and different from GHRH, although the sites of action of GHRP seemed to be different from those of TRH and GHRH.

Clonidine stimulates GH release via release of GH releasing hormone from the hypothalamus. There has been controversy as to its usefulness in the therapy of children with constitutional growth delay.To evaluate the effect of clonidine treatment we administered clonidine (0.1mg/m2) daily for more than 6 months to 31 prepubertal children (20 male and 11 female) and 24 pubertal children (16 male and 8 female) with non-endocrine short stature. Then we analyzed the height velocity (HV), height velocity SD score (HVSD), and height SD score (HSD) as indicators of their growth response to this therapy. Furthermore, we determined the serum levels of IGF- I and IGFBP-3.In prepubertal children the mean HV and HVSD were increased at 6 months, and remained high thereafter. Four children showed a 2cm increase of HV at 6 months. In pubertal children both HV and HVSD were increased at 6 months, but not increased further. Both IGF- I and IGFBP-3 were significantly increased at 6 months and remained high until 12 months. There was no evidence of accelerated bone maturation or noticeable side-effects.In conclusion, administration of clonidine could be a useful mode of treatment in some children with non-endocrine short stature because of the low cost and the convenience of oral intake. The administration period should be kept within 6 months at a time.

In recent years several synthetic peptides have been shown to be active in inducing GH secretion in different mammalian species. Among them GHRP-6, GHRP-1 and GHRP-2 have demonstrated high effectiveness and high selectivity in stimulating GH release. In the present paper we report studies on the GH-secreting properties of a GHRP analog in which Trp was substituted with the chemically more stable 2-Methyl-Trp. In studies performed in conscious 10-day old rats, the hexapeptide Hexarelin (His-D-2Me-Trp-Ala-Trp-D-Phe-Lys-NH2) resulted very active in stimulating GH secretion. In anesthetized adult male rats, i.v. administration of GHRP-6 or Hexarelin elicited prompt GH release with peak GH levels occurring within 10 min At all the doses tested, the 2 peptides possessed similar effectiveness in stimulating GH release. Hexarelin given s.c. elicited a long-lasting GH release and was slightly more effective than GHRP-6. In conclusion, these findings indicate that Hexarelin is a highly effective GH releaser and might represent a valuable diagnostic and/or therapeutic tool in clinical practice.

There is a complex relationship between thyroid hormones, GH, and the insulin-like growth factors (IGFs). Thyroid hormones act at many sites from the hypothalamic control of GH release to the tissue expression of IGF-I and its binding proteins (IGFBPs). In this review, we present current knowledge of the effects of altered thyroid status on the GH-IGF-I axis, concentrating on the changes seen in IGF-I gene expression and circulating levels of GH and IGFBPs.

To establish whether somatostatin (SRIH) exerts its inhibitory effect on the nicotine-induced release of GH by interacting with an opioid pathway, normal volunteers were treated with naloxone during (2 no-filter) cigarettes smoking and with SRIH. Nicotine significantly increased serum GH levels about 3.5 fold. Naloxone alone did not change GH rise induced by cigarette smoking. The stimulatory effect of GH by nicotine was completely blocked by SRIH. In the presence of both SRIH and naloxone, GH levels rose 1.5 fold in response to nicotine. Since naloxone only partially reversed the inhibiting action of SRIH, only a partial involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opiates might produce this inhibiting effect on GH rise in response to cigarette smoking through independent pathways.

Replacement of the phenyl in 3 with a 2-pyridyl or 4-thiazolyl group resulted in increased potency in the rat pituitary cell GH release assay and in beagles.

The secretion of growth hormone (GH) is regulated by a complex system that includes both neurotransmitters and feedback by hormonal and metabolic substrates. Over the last few years it has been recognized that GH release varies over a wide spectrum from deficient to excessive secretion. The diagnosis of GH deficiency is based on a combination of anthropometric and clinical signs on the one hand and an inadequate stimulated and/or spontaneous GH secretion on the other. There is no distinct boundary between deficient and sufficient GH secretion. The cut-off limit for normal GH release is accordingly relative and has increased over the past decade from 5 to 10 micrograms/l. The effect of GH therapy on growth can be evaluated only after treatment for at least 6 months. There is, therefore, an indisputable need for methods that would reflect growth response soon after the start of treatment. There are several promising biochemical candidates, e.g. the aminoterminal propeptide of type III procollagen, the carboxyterminal propeptide of procollagen I and the bone Gla-protein, which may turn out to be useful early indicators of the growth response to long-term GH therapy.

It has been suggested that insulin-like growth factor-1 (IGF-1) may play a role in the regulation of growth hormone (GH) secretion. However, recent studies using recombinant IGF-1 contradict this. A possible role for IGF-2 has also been postulated, but data for this are fewer. In the present study we have sought to elucidate the role of IGFs in the control of GH secretion by central administration of both IGFs at near physiological doses. Further investigation of their physiological role in GH release has been studied using specific immunoneutralization of IGFs. Sheep with indwelling intracerebroventricular (icv) cannulae were given either IGF-1 (10 μg), IGF-2 (1 or 10 μg), or a combination of IGF-1 and IGF-2 (10 μg of each). Centrally administered IGF-1 had no effect on plasma GH, but IGF-2 caused a sustained decrease (P < 0.01) in plasma GH between 45 and 105 min after injection. The combination of IGF-1 and -2 resulted in a similar decrease in GH levels (P < 0.01). A potent immunoneutralizing antiserum against IGF-1 failed to have any effect on GH levels when administered icv, but administration of antiserum against IGF-2 stimulated GH release (P < 0.01) either alone or when administered together with anti-IGF-1 serum. These results indicate that central IGF-1 does not play a role in GH regulation. In contrast, central levels of IGF-2 may be physiologically important in regulating plasma GH levels.

The effect of intravenous (iv) and intracerebroventricular (icv) administration of somatostatin on the plasma levels of growth hormone (GH) and glucose was studied in sheep. Intravenous somatostatin decreased (P less than 0.001) circulating GH when infused at the rate of 5 micrograms/min (150 ng/kg/min) over 1 hr, but when used at 1 microgram/min there was no effect on plasma GH levels during infusion. At both doses used there was an indication of an increase in GH following the cessation of somatostatin infusion. Somatostatin given at both these doses iv had no effect on plasma glucose levels. When given icv neither 1.8 micrograms, 18 micrograms nor 180 micrograms somatostatin had any significant effect of plasma GH levels, although there was a significant (P less than 0.05) elevation in GH levels 75 min after 180 micrograms somatostatin icv. Plasma glucose levels did not increase following injection of somatostatin icv at 1.8 or 18 micrograms, but there was a clear hyperglycaemic episode following 180 micrograms icv. Despite a lack of effect of somatostatin on GH release when given icv, there was a clear elevation (P less than 0.05) in plasma GH levels immediately following icv administration of a somatostatin antiserum. These data indicate that iv administration of somatostatin at pharmacological levels can depress unstimulated GH levels in sheep while administration icv does not. Central administration of somatostatin increases plasma glucose levels only at high doses and seems unlikely to be of physiological importance in glucose homeostasis.

The use of exogenous hormone treatment as a means of increasing the efficiency of animal production has, in general, been rather poorly received by both the public and government agencies. This antipathy towards hormone treatment has tended to direct research effort into finding less contentious ‘hormonefree’ methods of improving animal production. Over the last 10 years, immunological manipulation of the endocrine system has emerged as an attractive possibility in this search. In this review we briefly outline three approaches under current consideration, whereby growth hormone (GH) concentrations or activity are modified. These methods involve immunological manipulation of GH release, use of antibodies as GH mimics and antibody-mediated enhancement of GH action.

The effect of intracerebroventricular administration of IGF-1 on circulating growth hormone (GH) concentrations has been studied in sheep. Twenty sheep were fitted with jugular vein catheters and with indwelling cerebroventricular cannulae. IGF-I was injected into a lateral cerebral ventricle and changes in the circulating concentrations of GH were measured in jugular vein blood samples. Administration of saline had no effect on circulating GH concentrations over a 3-hr period, and administration of IGF-I (at 1, 3 and 10 μg/sheep) also had no significant effect on circulating GH concentrations. From these data we surmise that centrally administered IGF-I does not influence GH secretion and it seems probable that cerebrospinal fluid concentrations of IGF-I do not have a role in regulating GH release in sheep.

The effect of vasoactive intestinal peptide (VIP) on the release of growth hormone (GH) from the adenohypophysis of the goat was studied in vitro using the perifusion system. Two perifusion systems were employed to differentiate potential direct effects of VIP on the pituitary from indirect effects mediated through the hypothalamus. The first perifusion system used single chambers housing only pituitary fragments. The second system used two chambers in tandem, one containing hypothalamus and the second the pituitary fragments, the flow passing through the hypothalamic chamber first. VIP (10(-6), 10(-7), 10(-8)M) stimulated significant GH release in both perifusion systems (P less than 0.05, P less than 0.01) in a concentration related fashion. The quantity of GH release induced by the 10(-9)M and 10(-10)M VIP groups were not significant. Further, the GH released from the system that perifused the pituitary alone (10(-8)M VIP) was significantly higher than that containing both the hypothalamus and the pituitary fragments (P less than 0.05). The relative lower GH secretory response to the same dose of VIP applied to the hypothalamus-pituitary suggests that the perifused caprine hypothalamus may release an inhibitory factor, such as somatostatin in vitro. These results suggest that VIP stimulates GH release by acting directly on the adenohypophysis of the goat.

Diurnal patterns of growth hormone (GH) in peripheral plasma were compared between mature German Landrace (GL) boars (n = 6), GL sows (n = 4) and European wild boars (n = 5). Blood samples were drawn at 20-min intervals through indwelling jugular vein catheters for 24 h. Some of the animals were sampled repeatedly, so twelve 24-h profiles were available for GL boars, six for GL sows and seven for wild boars. The GH concentrations were determined by a specific radioimmunoassay. GL boars revealed significantly higher (P ≤ 0.001) GH concentrations than GL sows (boars: 5.06 ± 2.34 ng ml−1; sows: 3.70 ± 1.01 ng ml−1). In GL boars a clear diurnal pattern with distinct GH pulses during daytime and a less pulsatile GH release during the night was found, whereas in females no diurnal pattern was obvious. Mean GH levels in wild boars (1.97 ± 1.03 ng ml−1) were significantly lower (P < 0.001) than in both groups of GL pigs. The diurnal pattern of GH pulses in wild boars, however, coincided with the pattern of GH release in GL boars (r = 0.26; n = 73; P ≤ 0.05).

48 patients between one and seventeen years of age were stimulated with GRF (1-29) NH2. Seventeen of them showed a constitutional delay in growth and puberty, twenty-three suffered from growth-hormone deficiency (GHD) and eight had a suspected GHD as a result of pharmacological tests. Although the results demonstrate a high specificity for GH release in children with constitutional delay of growth and patients with functioning hypophyseal gland, the sensitivity for diagnosis of GHD was poor. The majority of GHD patients suffer from hypothalamic disorders and therefore respond to GRF. In conclusion, the GRF-stimulation test may be sufficient for differentiation of hypophyseal or hypothalamic disorders. However, GRF-stimulation test shows too many false positive results in hypothalamic growth disorders and therefore is not recommended for diagnosis of GHD.