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L H Rees

Publications and source records attributed to L H Rees.

At least 55 records · Page 3Linked to original sources
PubMed1989

Pro-opiomelanocortin gene expression and peptide secretion in human small-cell lung cancer cell lines.

Expression of the RNA coding for the ACTH-beta-lipotrophin precursor, pro-opiomelanocortin (POMC), has been demonstrated in five human small-cell lung cancer (SCLC) cell lines. Using Northern and slot-blot hybridization analysis of RNA and a bovine POMC cDNA as probe, the processed POMC RNA from SCLC cells was found to be approximately 1350 nucleotides in length, which is larger than that found in the normal human pituitary. Expression of the POMC gene was confirmed by measurement of ACTH precursors secreted by the cells, using a novel two-site immunoradiometric assay based on monoclonal antibodies, which directly quantifies both POMC and pro-ACTH but does not recognize ACTH. Levels of POMC in medium accumulated throughout the growth of the cells, in contrast to POMC RNA which showed a relatively constant level of expression. We conclude that human SCLC cell lines are valuable models for studying the aberrant expression and regulation of the human POMC gene.

Adrenocorticotropic Hormone↗
PubMed1989

Effects of ethanol and inhibitors of its metabolism on the circulating levels of Met-enkephalin in greyhounds.

The mechanisms involved in the release of Met-enkephalin-like immunoreactivity (MLI) into the circulation following oral administration of ethanol and chlorpropamide were investigated in dogs. The origin of plasma MLI and the sites where it may be metabolized were also studied. Moreover, the molecular nature of circulating MLI was characterized. In conscious animals oral administration of ethanol (0.15 ml/kg) led to a significant (P less than 0.01) rise in plasma MLI concentrations in chlorpropamide-pretreated animals from a basal level of 43 +/- 6 (mean +/- S.E.M.) to a peak of 66 +/- 8 ng/l. Similar rises in MLI concentrations were observed following administration of ethanol with disulfiram and ethanol with chlorpropamide and captopril. In contrast, the administration of ethanol alone or ethanol with 4-methylpyrazole resulted in a decrease in plasma MLI concentrations. Comparisons of two different doses of i.v. acetaldehyde, the first metabolite of ethanol, showed that plasma MLI concentrations rose significantly (P less than 0.05) only after the larger dose (8 mg/kg), rising from 45 +/- 7 to 81 +/- 18 ng/l. These results suggest that acetaldehyde is the active component in the chlorpropamide + ethanol-induced MLI secretion. Plasma MLI was also measured following acetaldehyde infusion in adrenalectomized dogs with and without hexamethonium treatment. Acute bilateral adrenalectomy resulted in a decrease (P less than 0.05) in plasma MLI concentrations, but the levels remained detectable. Moreover, subsequent acetaldehyde infusion led to rises in plasma MLI similar to those observed in animals with intact adrenals. These MLI responses were not altered by the concurrent i.v. administration of hexamethonium.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1989

Demonstration of desacetyl alpha-melanocyte-stimulating hormone in fetal and adult human anterior pituitary corticotrophs.

Immunocytochemistry, radioimmunoassay and high-performance liquid chromatography (HPLC) techniques have been used in combination to investigate the presence of immunoreactive (ir)-alpha-MSH in the normal human pituitary gland, and to investigate the possible origin of these cells from the fetal pars intermedia. Two separate antisera to alpha-MSH were employed in immunocytochemistry to distinguish between authentic alpha-MSH and the desacetyl form. Only desacetyl alpha-MSH was detected in the pituitary gland of fetal and adult man, in both the pars (zona) intermedia and the pars anterior. In the fetus, a large proportion of the ACTH-containing cells of the anterior lobe also contained ir-alpha-MSH, while ir-alpha-MSH containing cells were more sparse in adults. Radioimmunoassay of acid extracts of adult pituitary tissue showed alpha-MSH levels representing less than 0.05% of the ACTH content of the gland. HPLC analysis of these extracts confirmed that only the desacetyl form was present. These results suggest that alpha-MSH peptides are synthesized by anterior lobe cells of the human pituitary gland, which are not derived from the fetal pars intermedia. Possible regulatory mechanisms affecting cells which contain ir-alpha-MSH are discussed, and by comparison with the intermediate lobe of other species it is concluded that there is little evidence for a true intermediate lobe in the human pituitary gland.

Adult↗
PubMed1989

Peptides related to alpha-melanocyte-stimulating hormone are commonly produced by human pituitary corticotroph adenomas: no relationship with pars intermedia origin.

The presence of immunoreactive (ir)-alpha-MSH has been investigated by immunocytochemistry in 24 pituitary adenomas and one case of corticotroph hyperplasia causing Cushing's disease, in four adenomas causing Nelson's syndrome, and in ten 'silent' corticotroph adenomas. It was found that a high proportion of these adenomas have a population of cells containing ir-alpha-MSH in addition to ir-ACTH. In some instances, these adenomas were clearly not associated with the residual intermediate lobe of the pituitary. Radioimmunoassay of plasma from patients with Cushing's disease or Nelson's syndrome showed elevated levels of ir-alpha-MSH in the majority of cases. Characterization of the ir-alpha-MSH in adenoma cells by immunocytochemistry, using an antiserum selective for acetylated forms of alpha-MSH, suggested that only the desacetyl form was present in each case examined. High-performance liquid chromatography of adenoma tissue extracts revealed material co-eluting with acetylated forms of alpha-MSH in only one of six cases. These results have been compared with corticotroph adenomas in animal pituitary glands, and it is concluded that the presence of alpha-MSH peptides cannot be used as a marker for intermediate lobe tumours, and that desacetyl alpha-MSH is commonly produced by corticotroph adenomas.

Adenoma↗
PubMed1989

Levels of the small insulin-like growth factor-binding protein are strongly related to those of insulin in prepubertal and pubertal children but only weakly so after puberty.

We have looked at the relationship between fasting levels of insulin and a small insulin-like growth factor (IGF)-binding protein (IBP-1) in a cross-sectional study of 116 normal subjects aged 5-48 years. The relationship between IBP-1 and insulin was also examined within individual normal children in overnight profiles of IBP-1 and insulin obtained from two children at each stage of puberty (Tanner stages 1-5). In the cross-sectional study high levels of IBP-1 were found in early childhood and these fell throughout puberty as fasting levels of insulin rose. Multiple regression analysis revealed that both these changes were predominantly due to pubertal development rather than to age. After the age of 16 IBP-1 levels remained low despite fasting insulin levels returning to prepubertal levels. A strong negative correlation was obtained between IBP-1 and insulin in children of 5-16 years (r = -0.63; n = 60; P less than 0.001), no such relationship being found after the age of 16. In the second study, IBP-1 underwent a marked circadian variation in all cases and an inverse correlation with insulin, measured at the same time, was obtained at pubertal stages 1 to 4, but not at stage 5 (pooled data stages 1-4, r = -0.69; n = 53; P less than 0.001). We have demonstrated that a potential inhibitor of IGF-activity is inversely related to insulin throughout the period of active GH-related growth and that this relationship weakens after puberty.

Adolescent↗
PubMed1989

Relationship between growth hormone-releasing hormone and somatostatin in the rat: effects of age and sex on content and in-vitro release from hypothalamic explants.

Secretion of GH in the rat has been shown to be dependent upon age and sex. Using rat hypothalamic explants in vitro, we have studied the release and hypothalamic content of GH-releasing hormone (GHRH) and somatostatin in male and female Wistar rats at four different ages (10, 30 and 75 days, and 14 months). Basal release of GHRH was not significantly different between male and female rats, but at all ages males released more GHRH in response to stimulation by both 28 and 56 mmol potassium/l than female rats (P less than 0.05). Neither basal nor potassium-stimulated release of GHRH altered with age. In contrast, both basal and potassium-stimulated secretion of somatostatin increased significantly (P less than 0.01) with age, but was the same in the two sexes. Hypothalamic GHRH content, as assessed by the extractable tissue content following incubation, was significantly (P less than 0.01) lower in 10-day-old rats compared with older rats, but remained constant after 30 days of age. Somatostatin content, in contrast, increased progressively with age (P less than 0.01). The hypothalamic content of the two peptides was the same in both sexes. In conclusion, our findings demonstrate that male rats release more GHRH in vitro than female rats, possibly reflecting the increased pulse amplitude of GH seen in males in vivo; the progressive fall in secretion of GH previously reported during ageing appears to parallel the progressive increase in somatostatin release and content seen in our in-vitro system.

Aging↗
PubMed1989

The detection of peaks in luteinizing hormone secretion.

Fluctations in luteinizing hormone are believed to consist of irregularly spaced sharp increases separated by periods of exponential decay. A simple method is presented for analysing such fluctuations when the data consist of uniformly sampled observations of hormone. Specific allowance for the exponential decay in the absence of pulses is made via a time series model before assessing the number and extent of pulses. All calculations are done using MINITAB regression programs. The results have been compared with those obtained by three established models and are in general agreement.

Activity Cycles↗
PubMed1989

Dose-dependent effects of vasoactive intestinal polypeptide on somatostatin release from hypothalamic fragments in vitro.

1. Vasoactive intestinal polypeptide (VIP) is present in high concentrations in the hypothalamus and appears to be involved in the modulation of growth hormone (GH) secretion. The effects of VIP on hypothalamic somatostatin (SMS) release are, however, controversial. 2. To further elucidate the mechanism of action of this peptide on GH secretion we studied the effects of VIP on SMS secretion from incubated rat hypothalamic fragments in vitro. 3. At 10(-6) M, VIP induced a significant increase in basal SMS release (P less than 0.01), whereas at 10(-10) M it had an inhibitory effect. 4. We suggest that the increase in GH after in vivo administration of VIP may be modulated, at least in part, by a direct effect of this peptide on SMS neurons, while the stimulatory effect of high doses of VIP on SMS release may represent a pharmacological interaction of this peptide with growth hormone releasing hormone, peptide histidine isoleucine, or glucagon receptors.

Analysis of Variance↗
PubMed1988

Adrenal vein and arterial levels of catecholamines and immunoreactive metenkephalin in canine endotoxin shock and their response to naloxone.

The alterations in plasma levels of immunoreactive metenkephalin (ir-metenkephalin) and catecholamines in adrenal vein and arterial blood in response to endotoxin, as well as the effects of subsequent naloxone administration, have been investigated in a canine model. Animals were anaesthetised with alpha chloralose and allowed to breathe spontaneously. The left lumbar adrenal vein was cannulated and an intermittent choke allowed retrograde sampling of the adrenal effluent. Severe shock was produced by the administration of a large bolus of E. coli endotoxin (5 mg/kg) followed by a continuous infusion (2 mg/kg per hour). One hour after induction of shock the circulating volume was expanded using a colloidal gelatin solution. Thirty minutes later one group of five animals received a bolus of naloxone (2 mg/kg) followed by a continuous infusion of (1.5 mg/kg per hour), while a control group of five animals was given an equivalent volume of isotonic saline. The production of endotoxin shock was associated with marked increases in adrenal vein and systemic levels of adrenaline and noradrenaline. Naloxone administration transiently limited the fall in adrenal vein levels of adrenaline and noradrenaline (P less than 0.05) following volume replacement and was associated with a sustained increase in systemic adrenaline levels (P less than 0.05). Changes in mean arterial pressure confirmed a significant haemodynamic response to naloxone (P less than 0.05). Alterations in ir-metenkephalin levels in the adrenal vein closely followed the changes in catecholamines, whereas arterial levels rose progressively and were unaffected by naloxone. We conclude that in canine endotoxin shock the opiate antagonist naloxone can transiently increase catecholamine levels in the adrenal effluent and produce a more sustained rise in systemic adrenaline levels. Moreover, the adrenal medulla is not the only source of circulating ir-metenkephalin.

Adrenal Glands↗
PubMed1988

Neuroendocrine and cardiovascular responses to high-dose corticosteroid therapy in canine endotoxin shock.

The neuroendocrine and cardiovascular responses to endotoxin administration and the effects of subsequent high-dose corticosteroid therapy have been investigated in dogs. Shock was induced in anaesthetised animals by a large bolus of E. coli endotoxin (5 mg/kg) followed by a continuous infusion (2 mg/kg per hour). One hour after induction of shock, the circulating volume was expanded using a colloidal gelatin solution. Fifteen minutes later, one group of five animals received a bolus of methylprednisolone sodium succinate 30 mg/kg, while a control group of five animals was given an equivalent volume of isotonic saline. The administration of endotoxin produced reductions in mean arterial pressure, cardiac index and left ventricular dp/dtmax, together with increases in systemic and pulmonary vascular resistances. These haemodynamic changes were associated with increases in arterial plasma levels of adrenaline, noradrenaline, cortisol, immunoreactive beta-endorphin and immunoreactive metenkephalin. Cardiovascular improvement followed volume replacement and was associated with reductions in circulating catecholamines. No significant haemodynamic or neuroendocrine changes were demonstrated in the 2 h following steroid therapy.

Animals↗
PubMed1988

CRF in the differential diagnosis of Cushing's syndrome: a comparison with the dexamethasone suppression test.

Accurate differential diagnosis of the precise cause of Cushing's syndrome can be difficult, and conventional tests such as those based on the use of dexamethasone may be misleading. We have therefore studied the cortisol and ACTH responses to ovine corticotrophin-releasing factor (CRF-41) in 28 consecutive patients with Cushing's syndrome, and compared the diagnostic value of this test with that of the high-dose dexamethasone suppression test (8 mg/day for 48 h). Of 20 patients with confirmed Cushing's disease (pituitary-dependent Cushing's syndrome), only 16 (80%) showed the expected 50% or more suppression of serum cortisol following high-dose dexamethasone administration. Four patients each with adrenal adenomas and three patients with the ectopic ACTH syndrome failed to suppress, while a child with probable Cushing's disease showed a variable response depending on the dose used. Following CRF stimulation, 15 out of the 20 patients (75%) with Cushing's disease showed an excessive rise in serum cortisol, outside the normal range, while in five the response to CRF-41 was normal on at least one occasion. None of the patients with adrenal adenomas or the ectopic ACTH syndrome showed a cortisol response to CRF. Thus, either test on its own may be misleading in differentiating Cushing's disease from other causes of the syndrome. Every patient with Cushing's disease, however, showed either suppression in response to high-dose dexamethasone or an excessive cortisol response to CRF testing. It appears, therefore, that the combination of the high-dose dexamethasone and the CRF test, with measurement of serum cortisol, is superior to either test alone in the differential diagnosis of Cushing's syndrome.

ACTH Syndrome, Ectopic↗
PubMed1988

The cortisol response to corticotrophin-releasing factor is blunted in obesity.

Abnormalities of the adrenal cortex may be associated with extreme obesity but there is little information about hypothalamic-pituitary function. We have investigated this by measuring plasma ACTH and cortisol responses to ovine corticotrophin releasing factor (CRF-41), 0.5 microgram/kg/body weight, in 10 obese women and seven age-matched normal weight women. The cortisol response to insulin-induced hypoglycaemia and intravenous synacthen (2.5 ng/kg/body weight) were also measured on different occasions in some of the subjects. The peak ACTH response to CRF was less in the obese but this was not significant (obese ACTH +/- SEM, 31 +/- 4 ng/l, controls 39 +/- 4 ng/l) whereas the peak cortisol was significantly reduced in the obese (obese cortisol, 456 +/- 21 nmol/l, controls 638 +/- 50 nmol/l). Doubling the dose of CRF did not significantly alter either ACTH or cortisol responses in six of the obese patients. The peak cortisol response to symptomatic hypoglycaemia and following i.v. low dose synacthen stimulation was similar in the obese and normal weight women. We conclude that obese women have a normal cortisol response to hypothalamic-pituitary stimulation by hypoglycaemia and direct adrenal stimulation by synacthen but an impaired adrenal response to pituitary stimulation with CRF. Although the explanation for these findings is uncertain, our study underlines the importance of considering an individual's body weight when assessing the cortisol response to CRF stimulation.

Adrenocorticotropic Hormone↗
PubMed1988

Increased production of alpha-melanocyte-stimulating hormone in the pituitary gland of patients with untreated Addison's disease.

There is evidence that peptides related to alpha-melanocyte-stimulating hormone (alpha-MSH) are involved in regulating the zona glomerulosa of the adrenal cortex in certain species. We have investigated the amount of immunoreactive (IR)-alpha-MSH in the human pituitary gland of patients suffering from Addison's disease. We show increased numbers of cells containing demonstrable IR-alpha-MSH in the anterior lobe in these patients. Using an antiserum with specificity for the acetylated N-terminus of alpha-MSH we suggest that the major form present is desacetyl-alpha-MSH. These findings are in keeping with a role for anterior lobe derived desacetyl-alpha-MSH in the regulation of the human adrenal cortex.

Addison Disease↗
PubMed1988

A bromocriptine-responsive corticotroph adenoma secreting alpha-MSH in a patient with Cushing's disease.

Clinical and in-vitro investigations have been performed on a corticotroph adenoma removed from a patient suffering from Cushing's disease. Prior to surgery, the patient's Cushing's disease had been successfully controlled, clinically and biochemically, by long term administration of bromocriptine. After selective adenomectomy, tumour tissue was investigated by a perfused isolated cell column technique. It was shown that the tumour cells secreted immunoreactive- (IR)- ACTH and IR-alpha-MSH and that the release of both peptides was promptly suppressed by dopamine. Chromatographic analysis of the secreted IR-alpha-MSH revealed a high proportion of acetylated alpha-MSH; smaller amounts of desacetyl alpha-MSH and diacetyl alpha-MSH were present. The relevance of these findings to the proposal that certain corticotroph adenomas are derived from the intermediate lobe of the pituitary is discussed. It is concluded that there is little direct evidence for involvement of the residual zona intermedia of the adult human pituitary in the development of Cushing's disease.

Adenoma, Chromophobe↗
PubMed1988

Circadian variation of GH-independent IGF-binding protein in diabetes mellitus and its relationship to insulin. A new role for insulin?

Evidence is accumulating that a non-GH dependent insulin-like growth factor-binding protein (IGF-BP) is not only a carrier protein but also has an active role in the growth process. We have measured levels of this IGF-BP, using a specific RIA, over 12 or 24-h periods in 11 adolescents with diabetes mellitus and five normal adults. In each of the normal the IGF-BP was undetectable for most of the day but with a broad nocturnal peak observed, with levels up to 50 micrograms/l. The levels of IGF-BP were unrelated to the secretory pattern for GH but correlated inversely with the concentration of circulating insulin. In the diabetics a very similar pattern was observed, but with detectable levels throughout the day and much higher peak levels seen at night. Peak levels were up to 120 micrograms/l if a long-acting insulin preparation was administered in the evening but were 400-500 micrograms/l if the long-acting preparation was administered in the morning. The IGF-BP was strongly correlated with plasma glucose in this latter group. In a further group of diabetics overnight profiles were obtained on two separate nights, a normal night and a night with euglycaemia maintained with a glucose clamp technique. Euglycaemia failed to affect peak levels of the binding protein, although the shape of the nocturnal peak was altered consistent with the altered pattern of circulating free insulin. In this group a strong inverse correlation was obtained between the IGF-BP and free insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Antenatal fetal heart rate variation in relation to the respiratory and metabolic status of the compromised human fetus.

Three groups of women were delivered by caesarean section before labour: for an abnormal fetal heart rate (FHR) trace (21 cases, group 1), or for maternal deterioration in severe pre-eclampsia without gross fetal heart rate abnormalities (20 cases, group 2), or to avoid mechanical difficulties in labour at term (30 cases, group 3). The mean gestational ages of the first two groups were 32 weeks with a high proportion of infants small-for-gestational-age. In group 1, FHR variation (mean range of pulse intervals) was less than half (20.6 SE 1.2 ms) of the normal value at the same age (44.4 SE 1.5 ms). This was associated with hypoxaemia (mean umbilical artery PO2 of 6 mmHg at delivery), with evidence of compensation shown by an elevated amniotic fluid erythropoietin. The fetuses were hypoglycaemic and had greater umbilical artery blood alanine concentrations, but no large changes in adenine nucleotide or endorphin plasma concentrations. Although there was a minor degree of respiratory acidaemia at birth, there was not significant metabolic acidaemia. The results demonstrate that the reduced variation of 'suboptimal' and 'decelerative' fetal heart rate records is associated with fetal hypoxaemia and evidence of nutritional deprivation, but not with asphyxia.

Cesarean Section↗
PubMed1988

Acetylcholine and norepinephrine stimulate the release of corticotropin-releasing factor-41 from the rat hypothalamus in vitro.

The effects of the two putative neurotransmitters acetylcholine and norepinephrine on immunoreactive CRF-41 release from incubated rat hypothalami were studied. Acetylcholine at concentrations of 10(-11) to 10(-7) M stimulated CRF-41 release. This effect was blocked in a dose-dependent manner by the muscarinic antagonist atropine (10(-9) to (-7) M). The nicotinic antagonist hexamethonium was ineffective at a dose of 10(-7) M, but produced slight inhibition of this response at 10(-5) M. Norepinephrine at concentrations of 10(-10) to 10(-6) M also produced a dose-dependent stimulation of CRF-41 release. The beta-adrenoceptor antagonists propranolol (10(-5) M) and timolol (10(-6) M) blocked norepinephrine-induced CRF-41 release. The alpha 1-adrenoceptor antagonists thymoxamine (10(-5) M), prazosin (10(-5) M), and corynanthine (10(-4) M), and the alpha 2-antagonist idazoxan (10(-5) M), were ineffective. Potassium depolarization (56 mM) caused stimulation of CRF-41 release which was dependent on the presence of calcium in the incubation medium. Authenticity of immunoreactive CRF-41 released was demonstrated by chromatographic criteria using gel filtration and reversed phase HPLC. These results provide evidence for a stimulatory role of acetylcholine and norepinephrine on CRF-41 release, and consequently on hypothalamo-pituitary-adrenal axis in the rat, through actions at a hypothalamic level. The stimulatory effect of acetylcholine is mediated principally through muscarinic receptors and that of norepinephrine through beta-adrenoceptors.

Acetylcholine↗