Somatostatin inhibits alpha-2-adrenergic-induced secretion of growth hormone-releasing hormone.

The purpose of this experiment was to determine the role of growth hormone-releasing hormone (GHRH) and somatostatin (SRIH) neurons in mediating alpha(2)-adrenergic receptor-induced stimulation of growth hormone (GH) secretion in cattle. Our first objective was to determine if stimulation of alpha(2)-adrenergic receptors increases activity of GHRH neurons in the arcuate nucleus (ARC) and/or decreases activity of SRIH neurons in periventricular (PeVN) and ARC nuclei. Clonidine (an alpha(2)-adrenergic agonist) or vehicle (saline) were injected i.v. into steers and dual-label immunohistochemistry was performed to quantify the number of GHRH and SRIH neurons expressing Fos and Fos-related antigens (Fos/FRA) as markers of neuronal activity. Clonidine increased concentrations of GH in serum and decreased activity of SRIH neurons in the PeVN, but not in the ARC. Clonidine did not alter activity of GHRH neurons in the ARC. Our second objective was to determine if clonidine decreases secretion of SRIH from perifused slices of hypothalami, which contain perikarya and terminals of GHRH and SRIH neurons, and from explants of hypophysial stalk alone, which contain only terminals of GHRH and SRIH neurons. Clonidine failed to alter release of GHRH or SRIH from hypothalamic slices, but stimulated release of GHRH from explants of hypophysial stalk. Blockade of SRIH receptors enabled clonidine to stimulate release of GHRH from slices of hypothalami, but also stimulated release of SRIH. These results suggest that alpha(2)-adrenergic-induced secretion of GH occurs via a dual mechanism involving inhibition of SRIH neurons in the PeVN and direct stimulation of GHRH release from axon terminals in the median eminence.     

Normal and growth hormone (GH)-secreting adenomatous human pituitaries release somatostatin and GH-releasing hormone

Neuropeptides such as vasoactive intestinal peptide, LHRH, or TRH have been found in rat pituitary tissue and could act via paracrine or autocrine actions in this tissue. In this study we investigated whether normal human pituitary tissue and GH-secreting human pituitary adenomas could release somatostatin (SRIH) and GHRH. Fragments from three human pituitaries and dispersed cells from six GH-secreting adenomas (four adenomas were studied for GHRH release and five for SRIH release) were perifused using a Krebs-Ringer culture medium, and the perifusion medium was collected every 2 min (1 mL/fraction for 5 h). GH, GHRH, and SRIH were measured by RIA under basal conditions and in the presence of 10(-6) mol/L TRH or SRIH. Both normal pituitaries and GH-secreting pituitary adenomas released SRIH and GHRH. SRIH release commenced 90-180 min after initiation of the perifusion, at which time GH secretion had decreased significantly. TRH stimulated SRIH release from normal pituitary tissue and inhibited SRIH release from adenoma tissue. GHRH was present at the start of the perifusion, but rapidly disappeared. However, SRIH stimulated GHRH release from normal pituitary tissue, but not from adenoma tissue. Significant amounts of GHRH and SRIH were released during the experiments, suggesting their local synthesis. These results indicate that pituitary cells can release hypothalamic peptides. The liberation of these neuropeptides is regulated, and moreover, their regulation differs between normal and adenomatous pituitaries.     

Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion

Continuous infusions of growth hormone-releasing hormone (GHRH) attenuate the subsequent growth hormone (GH) response to GHRH. To test whether this phenomenon can occur in the absence of GH pool depletion, we examined the effects of continuous infusions of 10 nM GHRH and of 10 nM somatostatin (SRIH), separately or in combination, on dispersed, perifused rat anterior pituitary cells. Columns of these cells were given either GHRH alone for 5 h, GHRH and SRIH together for 3 h followed by GHRH alone, or SRIH alone for 3 h followed by GHRH or medium. SRIH blunted both basal GH release and the GH response to GHRH, without affecting the subsequent GH responses to GHRH. The GHRH infusions attenuated the subsequent GH response to GHRH, even when GH release was initially prevented by the concurrent infusion of SRIH. Furthermore, the degree of attenuation was similar in the presence or absence of SRIH, suggesting that pool depletion plays little role in the desensitization process under these experimental conditions. The results are consistent with the hypothesis that a short-term infusion of GHRH leads to attenuation of the GH response in rat anterior pituitary cells primarily through receptor effects rather than through GH pool depletion.     

The interrelationship between the effects of insulin-like growth factor I and somatostatin on growth hormone secretion by normal rat pituitary cells: the role of glucocorticoids

Both insulin-like growth factor I (IGF-I) and somatostatin (SRIH) have been shown to directly inhibit GH release and the total GH content of cultured pituitary cells. In the present study we evaluated the interrelationship between the effects of a recombinant human IGF-I analog ([Thr59]IGF-I) and SRIH on GH release by cultured normal rat pituitary cells together with the effects of glucocorticoids. In all experiments anterior pituitary cells were preincubated for 24 h without or with IGF-I, SRIH, and/or dexamethasone. Thereafter, 24-h incubations without or with IGF-I, dexamethasone, SRIH, and GHRH were performed. Both IGF-I and SRIH inhibited basal and GHRH-stimulated GH release in a dose-dependent manner; the maximal inhibitory concentrations were 5 nM IGF-I and 10 nM SRIH. These concentrations inhibited basal and GHRH-stimulated GH release by 23% and 40% (IGF-I) and 80% and 85% (SRIH), respectively. The combination of IGF-I and low concentrations of SRIH exerted an additive inhibitory effect on GHRH-stimulated GH release; IGF-I (1 nM) and SRIH (10 pM) together inhibited GH release by 50%, while the maximal inhibitory concentrations of 5 nM IGF-I and 10 nM SRIH virtually completely inhibited GH release (by 93%). Preincubation with 5 and 100 nM dexamethasone attenuated the sensitivity of somatotrophs to SRIH and completely abolished the inhibitory effects of IGF-I. This effect of dexamethasone could be reversed by coincubation with the glucocorticoid receptor antagonist RU 38486. High concentrations of 5-10 nM of the recombinant human IGF-I analog stimulated PRL cell content (5 and 10 nM) and release (10 nM), while a purified IGF-I preparation extracted from human blood exerted a parallel inhibitory effect on GH and PRL release. We conclude that 1) IGF-I and SRIH exert an additive direct inhibitory effect on basal and GHRH-stimulated GH secretion by normal cultured pituitary cells; 2) glucocorticoids directly attenuate the sensitivity of somatotrophs to SRIH, but completely prevent the inhibitory effects of IGF-I on GH secretion; and 3) in contrast to a purified IGF-I preparation extracted from human blood (which inhibits GH and PRL release) high concentrations of the recombinant IGF-I preparation (which inhibit GH release) stimulate PRL production.     

Neuropeptides of anterior pituitary origin

Several neuropeptides classically associated with the hypothalamus have been found in the anterior pituitary. The question arises whether they are locally synthesized and if they play a paracrine or autocrine role on pituitary hormone secretion. Using normal and tumoral human pituitaries we found neuropeptides (TRH, SRIH, GHRH) and dopamine in variable quantities according to the nature of the tissue. They were all present in normal pituitaries, while stimulatory hormones (TRH and GHRH) were predominantly found in tumoral tissue, implying an imbalance of pathophysiological importance between the stimulatory and inhibitory control of hypophyseal hormones (PRL and GH) in pituitary adenomas. Both normal and tumoral pituitaries released TRH, SRIH and GHRH in large amounts suggesting their local synthesis. The in situ synthesis was demonstrated for SRIH by the evidence of SRIH mRNA, the detection of SRIH immunoreactivity in peculiar cells and the presence of SRIH precursor. The possible role of these pituitary neuropeptides was suggested for instance by the negative correlation found in vitro between SRIH and GH secretions. Moreover neuropeptides could interact on each other. Indeed DA stimulated TRH release while PRL secretion decreased at the same time. Pulses of TRH had differential effects on SRIH release according to the nature of the tissue as TRH inhibited SRIH release from adenoma while it stimulated SRIH release from normal pituitary. Concerning the effects of SRIH and GHRH on GH secretion, there was an endogenous regulatory pattern comparable to that described in rat portal blood vessels. Pulses of GHRH induced GH secretion only when endogenous SRIH release was not stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hyperglycemia and activation of the beta-adrenergic system exhibit synergistic inhibitory actions on growth hormone (GH) releasing hormone-induced GH release

OBJECTIVE: Acute hyperglycemia stimulates somatostatin (SRIH) release by the hypothalamus which, in turn, suppresses growth hormone (GH) secretion from the anterior pituitary gland. Although it has been suggested that the cholinergic pathway mediates glucose-induced SRIH release, other regulatory systems have not been examined. Therefore, we investigated whether blocking or activating the beta-adrenergic pathway alters glucose-mediated inhibition of GH release. DESIGN AND METHODS: One set of experiments was performed with a beta-adrenergic antagonist, propranolol, and the other set with a beta-adrenergic agonist, isoproterenol. Each set of experiments was performed in ten healthy subjects and consisted of four tests. Test 1, a 100 microg GHRH bolus i.v. at 0 min; test 2, 100 g glucose orally at -30 min, followed by a 100 microg GHRH bolus at 0 min; test 3, after a 100 microg GHRH bolus i.v. at 0 min, a continuous infusion of propranolol (0.2 mg/kg) or isoproterenol (0.012 microg/kg) was administered between 0 and 120 min; test 4, after a 100 g glucose oral load at -30 min, and a 100 microg GHRH bolus i.v. at 0 min, a continuous infusion of propranolol (0.2 mg/kg) or isoproterenol (0.012 microg/kg) was administered between 0 and 120 min. Blood was drawn every 10 min from -30 min to 120 min to measure GH and glucose concentrations. RESULTS: Pretreatment with glucose significantly suppressed GHRH-induced GH secretion. Propranolol infusion significantly increased the GHRH-induced GH secretion, but it did not block glucose-induced suppression of GH secretion. Isoproterenol infusion alone significantly suppressed GHRH-induced GH secretion and augmented the inhibitory action of glucose on GH release. CONCLUSION: This study demonstrates that glucose-induced suppression of GHRH-stimulated GH release is independent of beta-adrenergic tone. Since previous data supports a role for SRIH in both glucose and beta-adrenergic suppression of GH release, the current results suggest that subsets of SRIH neurons are differentially responsive to these external cues. Therefore, a combined glucose and isoproterenol test may provide a useful assessment of hypothalamic somatostatinergic activity.     

Leptin regulates GH gene expression and secretion and nitric oxide production in pig pituitary cells.

The aim of this study was to investigate the direct effect of leptin on GH gene expression and secretion and the role of nitric oxide as a possible mediator in pig anterior pituitary cells. Pituitary cells from adult sows were treated for 4 or 24 h with rhleptin (from 0.1 nM to 1 microM) alone or in association with GHRH (10 nM) or hexarelin (10 nM). At the end of incubation, medium was collected for GH and nitric oxide determination by ELISA and Griess test, respectively. Total RNA was collected from cells, and GH gene expression was measured by RT-PCR. Leptin significantly (P < 0.001) stimulated GH secretion in both incubation periods. The maximum response was induced by 10 nM leptin; furthermore, a significant interaction (P < 0.002) between leptin and GHRH (P < 0.03) and between leptin and hexarelin was observed when the molecules were used in association. GH gene expression was significantly increased (at least P < 0.05) by hexarelin, GHRH, and leptin (1000 and 100 nM) after 24 h of treatment. Leptin (10 nM and 1 microM) significantly (P < 0.05) increased nitric oxide production, whereas S-nitroso-N-acetyl-penicillamine (from 0.01-1000 nM) significantly (P < 0.05) stimulated GH secretion. These data demonstrate that leptin directly influences GH regulation at the pituitary level, and nitric oxide may be involved in this function.     

Impaired inhibitory effects of somatostatin on growth hormone (GH)-releasing hormone stimulation of GH secretion after short term infusion

We examined the effect of prior exposure to somatostatin (SRIH) on its inhibition of GH and TSH responses to GHRH and TRH stimulation to determine whether SRIH desensitization has physiological significance in man. Six men received GHRH (1 microgram/kg, iv) and TRH (0.3 microgram/kg, iv) 20 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion and again 6 h later. Hormone responses were quantified by measuring the area under the curve, corrected for GH concentration at injection time. Similar results were obtained when GH responses were quantified by measuring the hormone secretory rate using the program Detect. Plasma GH and TSH responses to the two GHRH and TRH injections during saline were similar. However, the effects of prior exposure to SRIH were hormone specific. SRIH blunted GH responses to GHRH at 20 min (1609 +/- 286 micrograms/L.min vs. 451 +/- 224), but did not significantly inhibit the responses 6 h later (1422 +/- 410 micrograms/L.min vs. 1000 +/- 302). In contrast, SRIH inhibition of TSH responses to the two TRH injections was similar (first, 946 +/- 201 micrograms/L.min vs. 700 +/- 148; second, 813 +/- 175 micrograms/L.min vs. 562 +/- 66). We next used these results to study whether the previously reported attenuation of GH responses to repeated GHRH stimulation at 2-h intervals is mediated by SRIH. Eight men received GHRH (1 microgram/kg, iv) 380 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion or 90 min after starting a primed (5 mg, iv) infusion of propranolol (80 micrograms/min, iv) and again 2 h later. As in the first protocol, GH responses to GHRH were not inhibited when preceded by a 6-h SRIH infusion. However, the 6-h SRIH infusion resulted in a partial restoration of plasma GH responses to the second GHRH injection (saline infusion: first, 1429 +/- 342 micrograms/L.min; second, 254 +/- 75; SRIH infusion: first, 1042 +/- 247 micrograms/L.min; second, 468 +/- 105). beta-Blockade by propranolol resulted in enhanced GH responses to GHRH, but did not prevent the attenuation of GH responses to the second GHRH injection (first, 1937 +/- 366 micrograms/L.min; second, 614 +/- 99). The desensitization to SRIH inhibition of GH responses to GHRH after a 6-h SRIH infusion provides evidence of physiological consequences of SRIH receptor down-regulation. The impaired GH responses to repeated GHRH stimulation are mediated at least in part by enhanced SRIH secretion, which appears independent of a beta-adrenergic mechanism.     

Growth hormone expression and secretion in pig pituitary and median eminence slices are not influenced by the VGF protein

Body homeostasis is maintained by a complex system that involves the brain and the periphery via many circulating hormones. In recent years the VGF protein has been indicated as an important peptide affecting the regulation of body composition. We examined the effects of VGF on growth hormone (GH) expression and secretion in porcine pituitary slices, incubated alone (group 1) or with stalk median eminence (SME) (group 2). After 2 h (time 0), medium was removed and replaced with a fresh one; tissues were challenged with VGF (10(-6) M, 10(-8) M) alone or with ghrelin (10(-8) M) or growth hormone-releasing hormone (GHRH) (10(-8) M). Medium was replaced again 2 h (+2) and 6 h (+6) later. None of the VGF concentrations influenced GH secretion in either group; the association with GHRH or ghrelin appeared ineffective in influencing GH secretion as compared with the effects of GH mRNA expression and was not influenced by VGF treatments. The presence of SME had an additive effect on GH expression. Collectively, our results confirm previous findings on GH regulation; however, further investigations are needed to establish whether the modulation of GH secretion in the absence of nutrients involves the balance of GHRH/ghrelin receptors at pituitary levels. As for VGF, a crucial aspect to clarify is whether its lack of effects depends on our experimental conditions or, alternatively, it is not effective at all.     

Leptin regulates GH secretion in the rat by acting on GHRH and somatostatinergic functions.

Leptin is a hormonal product of adipose tissue whose expression reflects the body state of nutritional reserves. Previous experiments have demonstrated that leptin is one of the metabolic signals capable of regulating GH secretion. The aim of the present study was to evaluate whether CNS-mediated mechanisms underlie the GH-releasing activity of leptin. Freely moving mature male rats were injected i.c.v with leptin or isovolumetric amounts of diluent once daily for 3 days and were killed 2 h after the last administration. Central injection of leptin increased pituitary GH mRNA levels by 53. 2% and hypothalamic GHRH mRNA by 61.8%, and reduced somatostatin mRNA levels by 41.5%. To evaluate the direct effect of leptin on the pituitary, it was added alone or in combination with GHRH to primary cultures of anterior pituitary cells. Addition of leptin (10(-11)-10(-7) M) did not alter basal GH release nor the GH-releasing activity of GHRH. These results demonstrate that leptin is a metabolic signal that regulates GH secretion in the rat by acting on hypothalamic GH-regulatory hormones.     

Effects of hypophysiotropic factors on growth hormone and prolactin secretion from somatotroph adenomas in culture

In an attempt to characterize GH and PRL secretion in acromegaly, the effects of various stimuli on GH and PRL release by cultured pituitary adenoma cells derived from acromegalic patients were studied. In addition, the PRL responses of somatotroph adenoma cells were compared to those of prolactinoma cells. GH-releasing hormone-(1-44) (GHRH) consistently stimulated GH secretion in all 14 somatotroph adenomas studied in a dose-dependent manner. The sensitivity as well as the magnitude of the GH responses to GHRH were highly variable in individual tissues. Somatotroph adenomas that did not respond to dopamine were more sensitive and had greater GH responses to GHRH. In 8 of 9 somatotroph adenomas that concomitantly secreted PRL, the addition of GHRH likewise increased PRL release. Omission of extracellular Ca2+ blocked the stimulatory effect of GHRH on GH and PRL secretion. When cells were coincubated with 0.1 nM somatostatin, GH and PRL secretion induced by 10 nM GHRH were completely blocked in most adenomas. Similarly, coincubation of dopamine resulted in inhibition of GHRH-induced hormone secretion in some adenomas. Addition of TRH to the incubation medium, on the other hand, significantly stimulated GH secretion in 8 of 14 adenomas, while TRH stimulated PRL release in all of the adenomas. Vasoactive intestinal peptide (VIP) and corticotropin-releasing hormone (CRH) produced an increase in GH and PRL secretion in other adenomas. In prolactinoma cells, somatostatin and dopamine unequivocally suppressed PRL secretion; however, other stimuli including GHRH, VIP, and CRF were ineffective. TRH induced a significant increase in PRL secretion in only one prolactinoma. These results suggest that responsiveness to GHRH and somatostatin is preserved in somatotroph adenomas; the responsiveness to GHRH is inversely correlated to that to dopamine; and PRL cells associated with somatotroph adenomas possess characteristics similar to those of GH cells. Further, the GH stimulatory actions of TRH and VIP are different.     

Half-time of endogenous growth hormone (GH) disappearance in normal man after stimulation of GH secretion by GH-releasing hormone and suppression with somatostatin

The half-life (t1/2) of disappearance of endogenous GH from serum was studied using physiological effectors to stimulate and then suppress GH release. GH secretion was stimulated by a single iv injection of GHRH, followed 45 min later by an iv bolus dose and then a 2.5-h infusion of somatostatin (SRIH) to suppress further release. The in vivo t1/2 of GH in seven men was calculated from serum GH concentrations measured at frequent intervals after beginning the SRIH infusion. The mean t1/2 of endogenous GH was 18.9 +/- 0.8 (+/- SE) min by monoexponential analysis and 3.5 +/- 0.7 and 20.7 +/- 0.7 min by biexponential fitting. In these normal men, the decline in GH concentrations after GHRH and SRIH administration was similar to that after the administration of GHRH alone, which yielded a t1/2 of 20.3 +/- 1.9 min. We conclude that the physiological kinetics of endogenous GH removal/disappearance can be estimated in vivo in man using GHRH with or without SRIH infusion.     

Pituitary growth hormone secretion in the turbot, a phylogenetically recent teleost, is regulated by a species-specific pattern of neuropeptides.

In mammals, growth hormone (GH) is under a dual hypothalamic control exerted by growth hormone-releasing hormone (GHRH) and somatostatin (SRIH). We investigated GH release in a pleuronectiform teleost, the turbot (Psetta maxima), using a serum-free primary culture of dispersed pituitary cells. Cells released GH for up to 12 days in culture, indicating that turbot somatotropes do not require releasing hormone for their regulation. SRIH dose-dependently inhibited GH release up to a maximal inhibitory effect of 95%. None of the potential stimulators tested induced any change in basal GH release. Also, neither forskolin, an activator of adenylate cyclase, nor phorbol ester (TPA), an activator of protein kinase C, were able to modify GH release, suggesting that spontaneous basal release already represents the maximal secretory capacity of turbot somatotropes. In contrast, forskolin and TPA were able to increase GH release in the presence of SRIH. In this condition (coincubation with SRIH), pituitary adenylate cyclase-activating polypeptide (PACAP) stimulated GH release, whereas none of the other neuropeptides tested (GHRHs; sea bream or salmon or chicken II GnRHs; TRH; CRH) had any significant effect. These data indicate that inhibitory control by SRIH may be the basic control of GH production in teleosts and lower vertebrates, while PACAP may represent the ancestral growth hormone-releasing factor in teleosts, a role taken over in higher vertebrates by GHRH.     

The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II

Hypothalamic-pituitary-end-organ axes are frequently controlled by long loop negative feedback homeostatic mechanisms. Insulin-like growth factor I (IGF-I), IGF-II, and insulin receptors have recently been described in normal and neoplastic rat and acromegalic human pituitary cells, a finding which suggests the possibility that somatomedins might exert feedback at the level of the anterior pituitary. To study the kinetics of this feedback response, we used perifused dispersed rat anterior pituitary cells to learn if somatomedins or insulin could inhibit GH-releasing hormone (GHRH)-stimulated GH secretion. Cells were exposed to hourly boluses of 1 nM GHRH with or without varying doses of IGF or insulin. IGF-I inhibited GHRH-elicited GH release with an IC50 of 6.5 nM; maximal inhibition (approximately 67%) was achieved with 10 nM IGF-I. IGF-II was a less potent hormone, with 10 nM inhibiting about 30% of GHRH-stimulated GH release. Slight inhibition of stimulated GH release (less than 15%) was seen when cells were treated with insulin, but only when doses of insulin of 10 nM or more were used. In conclusion, nanomolar concentrations of IGF-I and IGF-II inhibited GHRH-elicited GH release from perifused rat pituitary cells in a dose-dependent manner; and insulin was not an effective inhibitor of stimulated GH release at physiological peptide concentrations. In conjunction with our previous findings that the concentrations of IGF-I and IGF-II receptors greatly exceed that of insulin receptors on normal rat pituitary cells, we hypothesize that the GH-inhibiting action of high dose insulin is mediated through an IGF receptor.     

Growth hormone secretagogues and hypothalamic networks

Growth hormone secretagogues (GHSs) act at distinct levels to control growth hormone (GH) secretion. At the pituitary level they reinforce or extend a tonic GH-releasing-hormone (GHRH)-induced activated state by mobilizing intracellular Ca²⁺ store. At the hypothalamic level GHS actions are more complex than originally anticipated. Chronic treatments with GHS result in loss of responsiveness to the secretagogues, an effect probably accounted for by indirect negative feedback of GHS stimulated plasma GH levels over GHRH release. Moreover, intracerebroven-tricular treatments with GHS can have paradoxical, inhibitory effects on GH secretion. Several mechanisms can account for such dual effects. GHS receptors were found to extend far beyond the arcuate nucleus and are mainly coexpressed, by GHRH, somatostatin, and neuropeptide Y (NPY) neurons. Activation of GHRH neurons by GHS can be direct or indirect. Indeed using antisense strategy we found that sst1 are physiological activators of arcuate GHRH neurons and we propose that activation of SRIH arcuate interneurons by GHS can increase GHRH neuron activity. Moreover, GHS can stimulate distinct populations of NPY neurons having opposite effects on GH secretion: arcuate NPY interneurons, act as indirect facilitators of GHRH release, whereas, on the contrary, a different subset of NPY neurons projecting to the periventricular hypothalamus (those also involved in mediating leptin effects on GH) seems able to activate SRIH release.     

Neuropeptide Y directly inhibits growth hormone secretion by human pituitary somatotropic tumours

Neuropeptide Y (NPY) is a 36 amino acid peptide, widely distributed throughout the brain and is found in hypothalamic neurones. This latter finding suggests that NPY may possess a hypophysiotropic function. A number of studies have demonstrated effects of NPY on LH and GH secretion by rat pituitary cells. We report here the results of experiments investigating the effects of NPY on GH secretion by tumorous human somatotropic pituitary cells in culture. NPY (0.25-25 nmol/l) inhibited GH secretion by 20-53%, the maximal effect depending upon the tumour studied. The potency of NPY was less than that of somatostatin (SRIH). The stimulatory effects of growth hormone releasing factor (GHRH) and theophylline were reduced by NPY, but NPY did not modify the inhibitory effect of SRIH on GH secretion. It is concluded that NPY may be involved in the control of GH secretion, at least by tumorous human pituitary somatotropes.     

Plasma levels of growth hormone-releasing hormone and somatostatin in response to a mixed meal and during sleep in children

Following a mixed meal, plasma levels of GHRH, GH, SRIH and insulin were measured in 7 prepubertal children with constitutional delay of growth and adolescence (CDGA) and in 3 children with proven GH-deficiency which responded to GHRH-injection. In children with CDGA, plasma levels of GHRH increased between 60 and 120 min (10.1 +/- 1.2 ng/l vs 25.5 +/- 4.4 ng/l; P less than 0.01). Although no GH increase occurred in patients with GH-deficiency, their plasma GHRH increases were comparable to those in CDGA children. No time relationship was present between circulating GHRH and GH, SRIH, or insulin, nor was there any correlation between their integrated hormone response areas. Sleep-induced plasma GHRH, GH and SRIH values were determined in 10 prepubertal children with CDGA. Spontaneous variations of plasma GHRH and GH values occurred with no temporal or quantitative relationship. SRIH values did not change during nocturnal sleep. In one child with GH-deficiency, comparable GHRH plasma fluctuations occurred, although GH values were all below 1 microgram/l. Our results support the concept that circulating GHRH does not only represent hypothalamic GHRH, but derives mainly from extrahypothalamic sources, possibly from the gastrointestinal tract.     

Discordant effects of insulin-hypoglycemia on growth hormone (GH)-releasing hormone-stimulated GH and thyrotropin (TSH)-releasing hormone-stimulated TSH secretion

The hypothesis that insulin hypoglycemia-induced GH release is mediated by a decrease in hypothalamic somatostatin (SRIH) secretion was tested by investigating whether insulin administration enhanced the responses of SRIH-sensitive pituitary hormones to hypothalamic hormone stimulation. Eight normal men were given a combined iv injection of GHRH (1 microgram/kg) and TRH (0.3 microgram/kg) on two occasions, on one of which regular insulin (0.1 U/kg, iv) was given 30 min before GHRH-TRH administration. Insulin hypoglycemia augmented the maximal incremental (P less than 0.01) and integrated (P less than 0.025) plasma GH responses to GHRH. In contrast, plasma TSH responses to TRH were diminished by insulin (maximal increment, P less than 0.025; integrated response, P less than 0.05). TRH-stimulated PRL secretion was not altered by prior insulin administration. The enhancement of GH responsiveness to maximal GHRH stimulation indicates mediation by a non-GHRH pathway. However, the discordant decrease in TSH responsiveness to TRH argues against a reduction in hypothalamic SRIH secretion as a mechanism for the action of insulin.     

Regulation of somatotroph cell function by the adipose tissue

Obese subjects exhibit a marked decrease in plasma growth hormone (GH) levels. However, the mechanisms by which increased adiposity leads to an impairment of GH secretion are poorly understood. Recent evidence suggests that the adipose tissue can markedly influence GH secretion via two different signals, namely free fatty acids (FFA) and leptin. FFA appear to inhibit GH secretion mainly by acting directly at pituitary level. Interestingly, reduction in circulating FFA levels in obese subjects led to a marked increase in GH responses to different GH secretagogues. This indicates that FFA exert a tonic inhibitory effect that contributes to blunted GH secretion in obese subjects. Recent data have shown that leptin is a metabolic signal that regulates GH secretion, since the administration of leptin antiserum to adult rats led to a marked decrease in spontaneous GH secretion. However, leptin prevents,the inhibitory effect exerted by fasting on plasma GH levels. The effect of leptin in adult rats appears to be exerted at hypothalamic level by regulating growth hormone releasing hormone (GHRH), somatostatin and neuropeptide Y (NPY)-producing neurones. In addition, during fetal life or following the development of pituitary tumors, leptin can also act directly at the anterior pituitary.