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J A Kennedy, R Nicolson and M L Wellby

Abstract

Elevation of non-esterified fatty acids (NEFA) in vivo is associated with abnormal control of TSH. To determine whether TSH secretion is directly inhibited by NEFA, as has been reported for GH, cultured rat anterior pituitary cells were exposed for 20 h to oleic acid in medium containing 77 × 10−5 mol/l bovine serum albumin (BSA). In a molar ratio with albumin of 1·2 (total oleic acid 9× 10 mol/l), or greater, oleic acid inhibited basal GH secretion (maximum inhibition to 40% of control) while basal TSH was less affected, a ratio of 3 (2·3 × 10−4 mol/l oleic acid) or greater causing a smaller degree of inhibition (maximum inhibition to 80% of control). In the presence of 10−9 mol/l growth hormone-releasing hormone or 108 mol/l TRH, inhibition was achieved at a ratio of 12 (9 × 10−4 mol/l oleic acid) or greater. Basal TSH was less sensitive to inhibition by thyroxine (T4) in the presence of oleic acid/albumin at a ratio of 6 or greater, and inhibition by oleic acid was less than additive with T4 at a ratio of 6 or greater. Responses to tri-iodothyronine (T3) were unaffected at a ratio of 6 (4·6 × 10−4 mol/l oleic acid), but a ratio of 12 inhibited the effects of both T3 and T4 on TSH. Oleic acid had less effect in the presence of TRH, a ratio of 12 causing a small increase in the threshold concentration of T3 and T4 for TSH inhibition. Further studies are required to determine the mechanism by which oleic acid inhibits the response of basal TSH to T4 as well as the reason for a reduced effect of oleic acid in the presence of TRH. In some critically ill patients, total serum NEFA/albumin ratios from 1·5 to 6 have been reported, indicating that the direct inhibitory effects on TSH observed in vitro occur at free NEFA concentrations achieved in vivo. However, the direct inhibitory effect on TSH may be offset to some extent by reduced responsiveness to T4 at higher oleic acid concentrations. Hence other sites of action of NEFA in vivo may also be important in limiting TSH secretion. Further studies should examine the hypothalamic hormones like TRH and somatostatin, which control the thyrotrophs, as potential sites of action of NEFA.

Journal of Endocrinology (1994) 143, 557–564

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J.-F. Wang, G. P. Becks, K. D. Buckingham and D. J. Hill

ABSTRACT

We have characterized the insulin-like growth factor-binding proteins (IGF-BPs) released by isolated sheep thyroid epithelial cells. Thyroid follicles were isolated with collagenase and cultured in Coon's modified F-12 M (OH medium) supplemented with insulin, cortisol, transferrin, glycyl-histidyl-lysine and somatostatin (5H medium) and TSH (6H medium). Conditioned OH medium specifically bound both 125I-labelled IGF-I and -II, although binding capacity was reduced following acid-gel filtration to separate endogenous IGF-BP complexes, suggesting some destruction of BPs. The binding of 125I-labelled IGF-I or -II to conditioned (OH) medium was progressively displaced by increasing amounts of unlabelled homologous peptides, while fractionation on concanavalin A-Sepharose showed that the IGF-BPs consisted of both glycoprotein and non-glycoprotein components. The molecular sizes of the IGF-BPs were resolved by separation of OH medium on SDS-PAGE and ligand blot analysis with 125I-labelled IGF-I or -II. Conditioned medium contained four specific binding species for IGF-II of 19, 30, 38 and 46 kDa; all but the smallest also binding radiolabelled IGF-I. Prior fractionation on concanavalin A-Sepharose showed that the 46 kDa binding species was a glycoprotein. Competition studies with increasing concentrations of unlabelled IGF-I or -II during ligand blotting suggested that the 46 and 30 kDa binding species had a greater affinity for IGF-II than IGF-I, while the 38 kDa had a greater relative affinity for IGF-I. Incubation of cells in 5H medium reduced the abundance of the 46 kDa binding protein, while incubation in 6H medium decreased the release of all binding protein species. Results show that isolated thyroid follicles released several forms of IGF-BP with differing relative affinities for IGF-I and -II. Gross changes seen in the presence of BPs between OH, 5H and 6H media suggest acute hormonal control of release.

Journal of Endocrinology (1990) 125, 439–448

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A. M. J. Lengyel, A. Grossman, P.-M. G. Bouloux, L. H. Rees and G. M. Besser

ABSTRACT

Dopamine and morphine modulate GH and LH release, probably at a hypothalamic locus. To investigate this in more detail, we studied the influence of these substances on somatostatin and LH-releasing hormone (LHRH) release from rat hypothalamic fragments in vitro. Hypothalamic fragments were incubated in Earle's medium. After 60 min of preincubation, medium from two 20-min incubations was collected and somatostatin and LHRH levels measured by radioimmunoassay. Dopamine (10 nmol/l–0·1 mmol/l) induced a progressive increase (r = 0·41; P <0·01) in basal somatostatin levels. K + (30 mmol/l)-induced somatostatin release was also increased (r = 0·54; P <0·01) by increasing doses of dopamine. Metoclopramide (10 μmol/l) blocked the dopamine (1 μmol/l)-induced increase in somatostatin release. No significant relationship between dopamine and LHRH was found either basally or after K + (30 mmol/l) stimulation. Basal somatostatin was negatively correlated (r = −0·63; P <0·01) with morphine concentrations. No significant correlation was found after K+ (30 mmol/l) depolarization. Basal LHRH release was not influenced by morphine, while K +(30 mmol/l)-induced release was significantly lower than controls only at a concentration of 10 nmol/l. These results suggest that dopamine and morphine act at a hypothalamic level to modulate GH release through alterations in somatostatin secretion. Dopamine and morphine have no consistent effect on hypothalamic LHRH release.

J. Endocr. (1985) 106, 317–322

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F. R. BELL, D. E. WEBBER, J. A. H. WASS, LESLEY H. REES, JOAN EVANS, LINDA M. MARGAN, V. MARKS and JANE LEWIS

Levels of endogenous somatostatin, gastric inhibitory polypeptide (GIP), glucagon and insulin were measured during gastric (abomasal) emptying in the conscious calf. Isotonic NaHCO3 infused into the duodenum increased rates of emptying of a saline test meal and of gastric acid secretion, but had no effect on basal levels of blood glucose, somatostatin, GIP, insulin or glucagon. By contrast, intraduodenal infusion of 60 mm-HCl caused complete inhibition of gastric emptying, reduction of acid secretion, and an immediate increase in plasma somatostatin from 121·3 ± 9·4 (s.e.m.) to 286·3 ± 16·3 pg/ml (P <0·01) but levels of GIP, insulin, glucagon and glucose were unaltered. Intravenous injection of somatostatin (0·5 μg/kg) suppressed the antral electromyographic recording and gastric efflux so long as plasma somatostatin levels remained above approx. 200 pg/ml. This suggests that somatostatin can be released by intraduodenal acidification and that it inhibits gastric function by an endocrine effect. Since somatostatin retards gastric emptying it may therefore have an indirect role in nutrient homeostasis by limiting discharge of gastric chyme to the duodenum.

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N Briard, F Dadoun, G Pommier, N Sauze, Y Lebouc, C Oliver and A Dutour

Endotoxin (LPS), a membrane component of gram-negative bacteria produces multiple endocrine and metabolic effects that mimic those seen in acute sepsis. It induces species-dependent alterations of the growth hormone (GH) axis that may participate in the shift of the metabolism towards catabolic events. Humans and sheep show increased GH secretion in response to LPS, as opposed to rats, which have been the most studied. The purpose of our work was to evaluate the effects in intact rams of an acute intravenous administration of a high dose of LPS on the insulin-like growth factor (IGF)-I/IGF-binding proteins (IGFBPs) system and to analyse the temporal relationship of GH axis changes with those of several hormonal and metabolic parameters such as somatostatin, cortisol, insulin, and glucose. LPS induced a late moderate decrease of total IGF-I plasma levels following a 5-h steady-state period (-26.6+/-4. 2%, P<0.05, 9 h after LPS), despite a biphasic and sustained increase of GH secretion in the same animals (2.48+/-0.39 ng/ml 2 h after LPS and 2.7+/-0.37 ng/ml 5 h after LPS vs 0.77+/-0.10 before LPS; Briard et al. 1998a). Western ligand blot analysis in IGFBPs showed an early short-lasting increase in IGFBP-1 (188.8+/-39% P<0. 05, 3 h after LPS). No significant change was seen for either IGFBP-2, -3 or -4. We observed a marked and sustained increase in cortisol (128.18+/-7.21 ng/ml 3 h after LPS, vs 21.17+/-4.22 before LPS). Insulin also increased (27.69+/-3.90 microU/ml 3 h after LPS, vs 13.48+/-1.69 before LPS) and its burst coincided with that of IGFBP-1. Moderately decreased IGF-I and increased IGFBP-1 plasma levels contrasted with the sustained increase in GH secretion that we recently described, thereby suggesting that endotoxin causes a state of resistance to GH. This may be exacerbated by reduced IGF-I bioavailability and/or action, and which may participate in the pathophysiology of the catabolic state seen in sepsis. The temporal analysis of hormone responses suggests that endotoxin-induced alterations of the IGF-I/IGFBPs system may involve the prolonged and substantial somatostatin rise that we recently demonstrated, together with an increase in glucocorticoid and cytokine as more generally assumed.

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B. Gabrielsson, K. M. Fairhall and I. C. A. F. Robinson

ABSTRACT

The guinea-pig is unusual in that it continues to grow at a normal rate after hypophysectomy. Although its pituitary gland appears to contain a GH, this has not been isolated or characterized, and nothing is known about its secretion or physiological control. We have identified guinea-pig GH, established a sensitive heterologous radioimmunoassay and adapted our automatic blood microsampling method to study spontaneous GH secretion in this species. In male guinea-pigs, GH is released in an episodic pattern, reminiscent of the rat. Large multicomponent pulses of GH secretion occur every 3–4 h between periods of low or undetectable GH release, whereas most females showed a more uniform pulsatile pattern with pulses every 1–2 h. GH was released in response to GH-releasing factor (GRF) injections (2, 10 or 20 μg [Nle27]-GRF(1–29)NH2) in a dose-dependent fashion, and i.v. infusion of somatostatin (50 μg/h) blocked spontaneous GH pulses, eliciting a rebound release (from 2·0±0·8 (s.e.m.) to 36±17 μg/l 30 min after stopping the infusion). Infusions of a GH-releasing hexapeptide (100 or 400 μg/h for 4 h) also released GH.

These results provide the first description of the pattern of GH release in the guinea-pig, and suggest that the striking episodic pattern is controlled by the same hypothalamic peptides that regulate GH in other species. Since the guinea-pig grows well in the absence of GH, this species may use GH for its metabolic, rather than growth-promoting actions. The guinea-pig may well prove a useful model, now that methods are available for studying its endogenous GH secretion.

Journal of Endocrinology (1990) 124, 371–380

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A.M. Wood, S.P. Bidey, J. Soden and W.R. Robertson

ABSTRACT

We have studied the chronic effects of TSH (100μU/ml) and insulin (10μg/ml) on intracellular pH (pHi) in FRTL-5 cells using the pH sensitive probe 2′7-bis (2-carboxyethyl-5′-6′) carboxyfluorescein. FRTL-5 cells were cultured on Petri dishes either in the presence of 4H, ie. Coons F-12 containing cortisol (10nM), transferrin (0.5μg/ml), glycyl-histidyl lysine acetate (10ng/ml) and somatostatin (10μg/ml), or with 4H+insulin (5H), 4H+TSH, or 4H+TSH+insulin (6H). pHi was measured in small groups of cells by microspectrofluorimetry both in the presence and absence of bicarbonate ions after cells had been deprived of serum for at least a day. In

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R H Rao

Abstract

The effect of glucagon on ACTH secretion was studied in anaesthetized rats injected with either saline (0·1 ml i.m.) or glucagon (0·02 mg/kg i.m.). For the first 90 min after glucagon injection, plasma ACTH fell by 50% from the basal value of 23 ±4 pmol/l (mean ± s.e.m.) to 11 ±2 (P=0·011), after which an abrupt return to baseline occurred (120 min value: 26 ± 2 pmol/l). In saline injected rats, the baseline ACTH value was not significantly different from either the 90 min value or the 120 min value (27 ±3 vs 21 ± 4 and 24 ± 3 pmol/l respectively; P>0·10). Plasma glucose after glucagon peaked at 11·6 ± 1·1 mmol/l by 15 min but subsequently fell rapidly, attaining the baseline by 60 min. Insulin levels increased sharply after glucagon, from 381 ±78 pmol/l to 3172 ±668 pmol/l at 15 min, and plateaued at approximately 1000 pmol/l thereafter. No changes in glucose or insulin were seen in saline injected rats. The magnitude of suppression of ACTH after glucagon was not affected either by sustained hyperinsulinaemia (≃ 1400 pmol/l), induced with continuous glucose infusion to maintain plasma glucose>12 mmol/l, or by pretreatment with the long-acting somatostatin analogue octreotide (50 μg/kg s.c.). However, the return to baseline between 100 and 120 min was prevented both by hyperinsulinaemia induced with sustained hyperglycaemia, and by octreotide. It is postulated that glucagon may inhibit ACTH secretion either by a direct effect on the hypothalamus or indirectly through insulin, which is known to stimulate endogenous somatostatin release.

Journal of Endocrinology (1995) 145, 51–58

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Isabel García-Tornadú, Marcelo Rubinstein, Bruce D Gaylinn, David Hill, Edith Arany, Malcolm J Low, Graciela Díaz-Torga and Damasia Becu-Villalobos

Recently, the importance of the dopaminergic D2 receptor (D2R) subtype in normal body growth and neonatal GH secretion has been highlighted. Disruption of D2R alters the GHRH–GH–IGF-I axis and impairs body growth in adult male mice. The D2R knockout (KO) dwarf mouse has not been well characterized; we therefore sought to determine somatotrope function in the adult pituitary. Using immunohistochemistry and confocal microscopy, we found a significant decrease in the somatotrope population in pituitaries from KO mice (P=0.043), which was paralleled by a decreased GH output from pituitary cells cultured in vitro. In cells from adult mice the response amplitude to GHRH differed between genotypes (lower in KO), but this difference was less dramatic after taking into account the lower basal release and hormone content in the KO cells. Furthermore, there were no significant differences in cAMP generation in response to GHRH between genotypes. By Western blot, GHRH-receptor in pituitary membranes from KO mice was reduced to 46% of the level found in wildtype (WT) mice (P=0.016). Somatostatin induced a concentration-dependent decrease in GH and prolactin (PRL) secretion in both genotypes, and 1×10−7 M ghrelin released GH in cells from both genotypes (P=0.017) in a proportionate manner to basal levels. These results suggest that KO somatotropes maintain a regulated secretory function. Finally, we tested the direct effect of dopamine on GH and PRL secretion in cells from both genotypes at 20 days and 6 months of life. As expected, we found that dopamine could reduce PRL levels at both ages in WT mice but not in KO mice, but there was no consistent effect of the neurotransmitter on GH release in either genotype at the ages studied. The present study demonstrates that in the adult male D2R KO mouse, there is a reduction in pituitary GH content and secretory activity. Our results point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level either in 1-month-old or adult mice. The similarity of the pituitary defect in the D2R KO mouse to that of GHRH-deficient models suggests a probable mechanism. A loss of dopamine signaling via hypothalamic D2Rs at a critical age causes the reduced release of GHRH from hypophyseotropic neurons leading to inadequate clonal expansion of the somatotrope population. Our data also reveal that somatotrope cell number is much more sensitive to changes in neonatal GHRH input than their capacity to develop properly regulated GH-secretory function.

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J. Miell, R. Corder, P. J. Miell, C. McClean and R. C. Gaillard

ABSTRACT

Despite causing marked inhibition of somatic growth, glucocorticoids enhance both the response to GH-releasing hormone (GHRH) and the amplitude of naturally occurring GH secretory pulses in the male rat. The relative contribution of the two major hypothalamic regulatory factors for GH (somatostatin and GHRH) to these observed effects remains speculative. In the present studies, we have investigated endogenous and stimulated GH release in rats pretreated with glucocorticoid or vehicle, and the effects of passive immunoneutralization of somatostatin or GHRH.

In an initial study, four groups of eight rats were treated with either saline or various doses of a depot preparation of betamethasone: low dose, 0·85 mg; medium dose, 1·7 mg; high dose, 3·4 mg. All doses significantly suppressed body weight gain, total adrenal weight and concentrations of both plasma corticosterone and pituitary ACTH. Seven days after betamethasone treatment, GH responses to an i.v. injection of 1 μg human GHRH(1–29) were evaluated during pentobarbitone anaesthesia. Compared with saline-treated controls (peak GH concentration of 506·0±68·5 μg/l), peak GH levels were enhanced by the low dose (704·4±47·8 μg/l, P<0·05), unaltered by the medium dose (543±65·8 μg/l) and suppressed by the high dose (312·7±55·2 μg/l, P<0·05) of betamethasone. Similarly, the area under the secretory curves was increased by 46% following the low dose (P<0·01), unaltered by the medium dose and reduced by 33% after the high dose of betamethasone.

In a second study, rats were pretreated for 7 days before blood sampling with either the medium dose of betamethasone or saline. On day 5, 48 h before blood sampling, an indwelling venous catheter was fitted enabling sampling of conscious rats. On the day of study, blood samples were taken at 30-min intervals over an initial 2-h period (10.00–12.00 h). Following the sample at 12.00 h, rats were given the reconstituted and dialysed immunoglobulin fraction from either control sheep serum (NSIgG), sheep anti-rat GHRH serum (GHRHab) or sheep anti-somatostatin serum (SRIHab), and samples were taken for a further 90 min (12.30–14.00 h). Directly after the sample at 14.00 h, GH stimulation was effected in all rats using 1 μg human GHRH(1–29) with samples taken at 5, 10, 20 and 40 min following stimulation. During the initial sampling period, mean GH levels were significantly (P<0·005) higher in steroidpretreated animals than in saline-pretreated controls (29·3±5·8 vs 13·2±1·6 μg/l), with a higher amplitude secretory pulse occurring at 11.30 h (80·7±18·6 vs 26·4±4·1 μg/l, P < 0·01). Administration of GHRHab to saline-pretreated animals did not alter mean GH levels when compared with animals receiving control NSIgG (saline plus NSIgG, 9·3±1·1; saline plus GHRHab, 8±1·1 μg/l, P = NS). In contrast, the raised mean GH levels seen in betamethasone-pretreated rats receiving NSIgG (12·3 ±1·1 μg/l) were reduced by GHRHab administration (7·6±1·1 μg/l); these levels were not different from those of the saline-pretreated group suggesting that the observed permissive effect of glucocorticoids on GH secretion is mediated through enhanced GHRH activity. SRIHab increased mean basal GH levels to a similar extent in both saline- and betamethasone-pretreated groups (17·4±1·2 μg/l and 19·3 ±1·1 μg/l respectively, P<0·01 vs comparable NSIgG group). Administration of the various immunoglobulin fractions had no effect on GHRH-stimulated GH secretion except when SRIHab was given to betamethasone-pretreated animals, resulting in a significantly increased peak response (1467±93 μg GH/l, P<0·001) when compared with either saline- or betamethasone-pretreated rats given NSIgG (643±95 and 791±92 μg/l respectively). This enhancement following SRIHab administration was not seen in saline-pretreated animals (893±180 μg GH/l).

These results imply that glucocorticoid treatment increases basal GH levels through a GHRH-dependent mechanism and also increases pituitary sensitivity to exogenous GHRH when inhibitory somatostatin tone is blocked.

Journal of Endocrinology (1991) 131, 75–86