Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 217 records · Page 12Linked to original sources

PubMed1989

The effect of ovine corticotrophin-releasing factor on the hormonal response to insulin-induced hypoglycaemia.

In order to investigate the role of hypothalamic corticotrophin-releasing factor (CRF41) in the mediation of the pituitary ACTH response to hypoglycaemia, eight normal adult males were studied on four occasions. Commencing at 0830 h after an overnight fast, each received, in double-blind, random order, intravenous boluses of: A, normal saline control; B, soluble insulin 0.15U/kg; C, ovine CRF41 (oCRF41) 100 micrograms; D, soluble insulin 0.15U/kg followed immediately by oCRF41 100 micrograms. Adequate hypoglycaemia (blood glucose less than 2.2 mmol/l) was achieved in each subject when insulin was given alone or with oCRF41, and there was no difference in the glucose nadir between the 2 days. Peak plasma ACTH was significantly higher after insulin plus oCRF41 than after insulin alone (P less than 0.05) or oCRF41 alone (P less than 0.01) and this enhancement of ACTH release was most marked in the first phase of the response at 30 min (P less than 0.001, b vs d). There was no difference in the peak serum cortisol response whether oCRF41 and insulin were given alone or together and although the area under the cortisol curve was greater after insulin plus oCRF41, this difference was explicable simply on the basis of the earlier onset of the cortisol response to oCRF41. There were no differences in the serum GH responses to hypoglycaemia on the 2 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1989

Response to growth hormone-releasing hormone as evidence of hypothalamic defect in optic nerve hypoplasia.

Hypothalamic-pituitary function was studied in four children with Optic Nerve Hypoplasia (ONH). All were found to be growth hormone deficient when provoked with glucagon or insulin induced hypoglycaemia (ITT), but did respond to bolus injection of GHRH. This indicates a primary hypothalamic defect. Virtual absence of pituitary tissue on high resolution CT scan explained the poor response of one child. One child has shown an excellent response to treatment with subcutaneous GHRH, which is physiologically the most appropriate treatment for this condition.

Child↗

PubMed1989

Growth hormone response to overnight growth hormone-releasing hormone infusion and oral pyridostigmine in children with short stature.

The development of a long-acting or depot preparation of growth hormone-releasing hormone (GHRH) may have many advantages over conventional treatment (with GH) of GH-deficient children. Pyridostigmine, an acetylcholinesterase inhibitor, has been shown to augment basal GH secretion and the GH response to GHRH in short children. It may thus provide adjuvant therapy to depot GHRH. The GH response to a nocturnal subcutaneous infusion of GHRH (1-29)NH2 in doses of 5 and 10 micrograms/kg/hour was investigated in five short, slowly growing children. The effect of oral pyridostigmine 60 mg on nocturnal GH secretion and the GH response to a nocturnal infusion was also examined. The subcutaneous infusion of GHRH augmented pulsatile GH release in all five children. There was a dose-related response to subcutaneous GHRH for the GH area under the curve and mean GH pulse amplitude, but no change in the number of pulses. There was a significant rise in the mean baseline GH concentration during the GHRH infusion compared with placebo. Pyridostigmine had no effect on either basal or stimulated GH secretion.

Child↗

PubMed1989

Massive prolactinoma with galactorrhoea in a prepubertal boy.

An 8 year old prepubertal boy presented with raised intracranial pressure, left proptosis and was noted to have galactorrhoea. Cranial computerized tomography revealed a large pituitary tumour infiltrating the cavernous sinus and left orbit. The serum prolactin was 180,600 mU/l (normal value less than 360 mU/l). Prolactinomas are rare in children and galactorrhoea has not previously been reported in a prepubertal child. The management of massive prolactinomas is difficult, but the child presented has made an impressive response to a combination of treatment with surgery, dopamine agonist therapy and radiotherapy.

Child↗

PubMed1989

Reversible respiratory muscle weakness in hyperthyroidism.

Breathlessness is a common complaint in patients with hyperthyroidism, and respiratory failure requiring artificial ventilation, although rare, can occur. While a proximal myopathy is frequently recognized, diaphragm muscle function has not hitherto been studied in detail in thyrotoxicosis. The strength of the quadriceps femoris and respiratory muscles was therefore assessed in seven consecutive thyrotoxic patients, on presentation and during medical treatment, when euthyroid. Prior to therapy, reduced quadriceps muscle strength, vital capacity, and global expiratory and inspiratory muscle strength were found. Diaphragmatic weakness was present in one of four patients studied by measuring transdiaphragmatic pressures during maximal sniffs and during bilateral phrenic nerve stimulation at 1 Hz (twitch). After treatment, significant improvement occurred in quadriceps muscle strength, vital capacity, and global respiratory muscle strength. Sniff and twitch transdiaphragmatic pressures also increased significantly. These results indicate that respiratory muscle weakness occurs in hyperthyroidism and that such weakness is reversible with medical treatment. It is important to realize that respiratory muscles may be directly affected when assessing thyrotoxic patients with breathlessness, as severe involvement of the respiratory muscles may cause respiratory failure.

Chronic Disease↗

PubMed1989

Opioids stimulate growth hormone (GH) release in man independently of GH-releasing hormone.

The Met-enkephalin analog DAMME [D-Ala2,MePhe4-Met-enkephalin-(o)-o1, FK 33-824] can stimulate GH secretion in man. In this study we investigated the effects of the guanyl derivative of DAMME (G-DAMME) on the serum GH response to an analog of GHRH in normal men. GHRH-(1-29)NH2 and G-DAMME each induced a rise in serum GH, and the increase was greater when both were given together. Since the GHRH-(1-29)NH2 dose (100 micrograms) used was a maximally stimulatory one, these results suggest that the enhancing effect of G-DAMME on GHRH-induced GH release may be mediated through inhibition of somatostatin release.

Adult↗

PubMed1989

Long-term effects of radiotherapy for acromegaly on circulating prolactin.

In 61 acromegalic patients, serum PRL was assessed (off medical treatment) before and 2 to 12 (mean 6.4) years after external beam radiotherapy. Before radiotherapy elevated PRL levels were present in 22 of 35 males (63%) and 12 of 26 females (46%) and were above 1000 mU/l in 11 males and 5 females. When studied for up to 5 years after radiotherapy, 22 of 23 (96%) patients who had not had surgery and who had normal PRL pre-radiotherapy showed an increased PRL level and this was also seen in 17 of 27 (63%) who had been hyperprolactinaemic initially. In contrast, 10 of 27 patients (37%) who had elevated pre-radiotherapy levels (all greater than 1000 mU/l) had a reduction in PRL values after radiotherapy. In all 11 patients who underwent surgery before radiotherapy, an increase in PRL was seen after radiotherapy. In the 21 patients followed for 10-12 years, the peak PRL value occurred 1-6 years after radiotherapy. After this, a progressive reduction of PRL to normal was seen. Normal levels were reached 4 to 10 years after radiotherapy. No correlation was found between pretreatment PRL values and final GH values in the whole group, nor between changes in PRL and the development of impaired ACTH or TSH secretion. Thus, different patterns of PRL behaviour suggest that radiotherapy treatment may either produce hyperprolactinemia from mild hypothalamic damage or ablate PRL secreting cells if they were present in the tumour before treatment. These changes do not predict final GH results or the development of hypopituitarism after radiotherapy.

Acromegaly↗

PubMed1989

Pro-opiomelanocortin mRNA size heterogeneity in ACTH-dependent Cushing's syndrome.

As an approach to understanding the abnormalities of pro-opiomelanocortin (POMC) gene regulation in human ACTH-secreting tumours, we have analysed the POMC mRNA content of nine such tumours using the Northern blot technique. Most of the tumours and normal human pituitary contained easily detectable quantities of POMC mRNA. The length of this message in most tumours was similar to, or slightly larger than, that in the normal pituitary (1150-1200 bases). Ribonuclease H studies suggested that the origin of any size heterogeneity was a longer poly(A) tail in the tumour RNA. Some tumours, however, expressed a short POMC mRNA (800 bases) which may lack the first two exons of the POMC gene as has been described. A third POMC mRNA size variant (1500 bases) was also seen in low levels in two cases, and as the principal mRNA species in one case. Primer extension and S1 nuclease protection studies suggested that most transcripts in the tumours analysed originated from the conventional promoter, and thus the use of an alternative promoter is not an adequate explanation for the expression of this gene in ectopic ACTH-secreting tumours.

ACTH Syndrome, Ectopic↗

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

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↗

PubMed1989

The effects of transsphenoidal surgery on endocrine function and visual fields in patients with functionless pituitary tumours.

Twenty-eight patients with functionless pituitary tumours have been treated by transsphenoidal surgery over the last 28 months. Mean age at presentation was 55 years. Tumor size was graded according to the extent of suprasellar extension on CT headscan from above the interclinoid line: four were small, 15 medium and nine large. Before surgery in 25 per cent of patients visual acuity and visual fields were normal. In the immediate postoperative period, 24 per cent of the patients with visual defects before surgery had normal vision, and in 38 per cent of the others it was improved. Six months after surgery, there had been further improvement; 43 per cent had normal vision and 48 per cent showed an overall improvement. In no patient did vision deteriorate following surgery. In the patients who presented with visual symptoms of one year or less, there was no correlation between the length of symptoms and the extent of visual recovery after surgery. Average age of the patients with full visual recovery was 47 +/- 4 years (mean +/- SEM); average age of the patients with only partial visual recovery was 63 +/- 3 years. Prolactin levels before surgery were elevated in 77 per cent of patients and fell significantly after operation, remaining elevated in 28 per cent of patients six months later. Fifty per cent of patients were treated with long-term hormone replacement therapy. Transsphenoidal surgery led to improved vision in the majority of patients, the results being comparable with those obtained with transfrontal surgery. Surgical complications were few, and long-term morbidity low. We suggest that the first-line treatment for patients with functionless pituitary tumours should be transsphenoidal surgery, even when large suprasellar extensions are present.

Adenoma↗

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

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↗