Glutamate neurotoxicity: a role for non-N-methyl-D-aspartate receptors?
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Animals↗
Biomedical subjects
M F Scanlon
Publications and source records attributed to M F Scanlon.
Cholinergic control of growth hormone (GH) responses to GH-releasing hormone in insulin dependent diabetics: evidence for attenuated hypothalamic somatostatinergic tone and decreased GH autofeedback.
OBJECTIVE: We have investigated the effects of cholinergic modulation with pirenzepine and pyridostigmine and of GH pretreatment on the subsequent GH response to a maximal stimulatory dose of GH-releasing hormone (GHRH) in patients with insulin dependent diabetes mellitus (IDDM). We have also investigated the relationship between the differences in metabolic control and other parameters of disease state with the differences in GH responses in IDDM. PATIENTS: Thirteen male subjects with IDDM and no clinical evidence of complications were selected based on HbA1 levels to provide a wide range of metabolic control. Seven normal subjects were also studied. DESIGN: Twelve of the subjects with IDDM and six normal subjects received pirenzepine 200 mg and pyridostigmine 120 mg pretreatment 60 minutes and GH pretreatment 3 hours before an i.v. injection of GHRH (1-44) (80 micrograms) in random order. All subjects underwent a control study with GHRH alone. MEASUREMENTS: Serum GH and plasma glucose were measured at regular intervals throughout the study. Fasting plasma glucose and HbA1 were measured before each study to provide measures of metabolic control. RESULTS: Subjects with IDDM demonstrated exaggerated GH responses to GHRH compared to normals. Pirenzepine significantly reduced GH responses in both normal and diabetic subjects. However, the GH response to GHRH after pirenzepine was higher in subjects with IDDM (mean GH:IDDM vs normals; 8.1 +/- 1.3 vs 2.9 +/- 0.7 mU/l, P < 0.05). Pyridostigmine 120 mg significantly augmented the GH response to GHRH in normal subjects. In diabetic subjects, pyridostigmine failed to increase GH response to GHRH compared to GHRH alone (mean GH: pyridostigmine vs control: 75.7 +/- 12.6 vs 38.9 +/- 5.4 mU/l, P = NS). GH responses to GHRH after pyridostigmine pretreatment in both normal and diabetic subjects did not differ and the GH response to GHRH after pyridostigmine in normal subjects did not differ from the GH response to GHRH alone in diabetic subjects. In normal subjects, GH pretreatment significantly reduced subsequent GH responsiveness to GHRH (delta peak GH 26.4 +/- 5.2 vs 7.7 +/- 5.4 mU/l, P < 0.04). In contrast, GH pretreatment did not cause any significant reduction in GH responsiveness to GHRH in diabetics (delta peak GH 53.6 +/- 9.7 vs 33.4 +/- 11 mU/l, P = NS). No significant correlation was demonstrated between measures of diabetic control and the responses to GHRH alone or after cholinergic modulation and GH pretreatment. CONCLUSION: These data suggest that ambient hypothalamic cholinergic tone in diabetes is high, and of similar degree to the enhanced cholinergic tone in normal subjects pretreated with pyridostigmine. We suggest that in diabetic subjects, the reduced responsiveness to autofeedback may be secondary to the enhanced cholinergic tone demonstrated in these patients. The mechanisms linking the uncontrolled diabetic state to this abnormal neuroregulation of GH remains unknown at present.
Adult↗
Effects of free fatty acids on somatostatin secretion, content and mRNA levels in cortical and hypothalamic fetal rat neurones in monolayer culture.
The effects of free fatty acids on somatostatin secretion, content and mRNA levels in fetal rat hypothalamic and cortical cell cultures were investigated. Somatostatin secretion and content were quantified by radioimmunoassay. Somatostatin mRNA levels were measured by Northern blot hybridization using a cRNA probe. Treatment with either caprylic acid (5 x 10(-3) M) or oleic acid (5 x 10(-5) M) for 90 min inhibited basal somatostatin secretion in both hypothalamic and cortical cell cultures. In addition, the increase in somatostatin secretion induced by incubation with veratridine (10(-4) M) or carbachol (10(-4) M) for 90 min was significantly reduced by the addition of caprylic acid, but somatostatin release stimulated by 5.6 x 10(-2) M KCl was not affected. Furthermore, treatment with these free fatty acids for 90 min markedly decreased somatostatin mRNA levels in both types of neurone culture. These inhibitory effects were transient, being observed after 90 min, but not after 5 h. These results support the probability that there is a role for free fatty acids in the regulation of somatostatin mRNA levels and somatostatin secretion in both hypothalamic and cortical cell cultures.
Animals↗
Immunochemiluminometric assays (ICMA) specific for growth hormone releasing hormone 1-44 NH2 and 1-40 OH.
We describe specific two-site immunochemiluminometric assays able to directly measure human growth hormone-releasing hormone 1-44 NH2 and 1-40 OH concentrations in unextracted plasma. A common N-terminal antibody was purified from polyclonal rabbit antisera to growth hormone-releasing hormone 1-44 NH2 on a growth hormone-releasing hormone 1-29 NH2 linked affinity column and labelled with chemiluminescent acridinium ester. C-terminal specific monoclonal antibodies to growth hormone-releasing hormone 1-44 NH2 and 1-40 OH were raised in Balb/C mice and used as solid phase antibodies. Assay of fasting specimens from normal individuals gave medians (and ranges) of 23 pg/ml (2-200) and 30 pg/ml (3-134) for growth hormone-releasing hormone 1-44 NH2 and 1-40 OH, respectively. Samples from a series of acromegalics showed that most have values in the normal range though median values were higher, 56 pg/ml for growth hormone-releasing hormone 1-44 NH2 (P < 0.001) and 52 pg/ml for 1-40 OH (P < 0.001). Using these assays it will be possible for the first time to directly study the physiology and pathophysiology of these two peptides.
Acromegaly↗
Differential effects of in vivo estrogen administration on hypothalamic growth hormone releasing hormone and somatostatin gene expression.
The aim of this study was to investigate the effect of in vivo estrogen administration on hypothalamic growth hormone releasing hormone (GHRH) and somatostatin (SS) gene expression. We found that estrogen administration (estradiol valerate 250 micrograms/every 3 days, subcutaneously) to male rats induced a decrease in both hypothalamic GHRH mRNA levels and GHRH content, that was significant after 3 and 8 days of treatment. In contrast SS mRNA levels were transiently elevated after 1 and 3 days of estrogen administration, returning to normal values after 8 days of treatment. These data suggest that the existence of sexual dimorphism in GH secretion in the rat could be mediated to some extent by gonadal hormones regulating somatostatin and GHRH gene expression in the hypothalamus.
Animals↗
Stimulatory effect of free fatty acids on growth hormone releasing hormone secretion by fetal rat neurons in monolayer culture.
The effects of free fatty acids (FFAs) on growth hormone releasing hormone (GHRH) secretion by fetal rat cortical and hypothalamic neurons in monolayer culture have been investigated. Treatment with caprylic or oleic acids for 90 min, induced a dose-dependent increase in GHRH secretion. The stimulatory effect of caprylic acid was time-dependent, being present after 90 min and 5 h but not after 24 h. Finally, GHRH release induced by 56 mM KCl or by the calcium ionophore A23187 was not modified by 5 x 10(-3) M caprylic acid. These data support a role for FFAs on GHRH secretion.
Animals↗
Endocrine functions of the hypothalamus and alterations in neuroendocrine function--focus on thyrotropin and growth hormone.
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Activity Cycles↗
Differential effects of arginine on growth hormone releasing hormone and insulin induced growth hormone secretion.
OBJECTIVE: We wished to investigate the interaction of arginine, GHRH and insulin stress on GH secretion. DESIGN: Six healthy, non-obese volunteers underwent seven separate studes in random order. They received (1) insulin alone at 0 minutes; (2) GHRH alone at 15 minutes; (3) arginine alone at 0-30 minutes; (4) arginine at 0-30 minutes and GHRH at 15 minutes; (5) insulin at 0 minutes and arginine at 0-30 minutes; (6) insulin at 0 minutes, GHRH at 15 minutes and arginine at 0-30 minutes; (7) insulin at 0 minutes and GHRH at 15 minutes. MEASUREMENTS: GH and PRL were measured from -30 to 150 minutes at intervals of 15 minutes. RESULTS: Arginine increased GH responses to GHRH and decreased GH responses to hypoglycaemia, but this inhibitory effect of arginine was reversed by GHRH. CONCLUSIONS: The findings suggest that arginine-induced GH release is mainly mediated by a decrease in somatostatinergic tone, while GH responses to insulin stress are probably mediated by both an increase in hypothalamic GHRH release and inhibition of somatostatin.
Adult↗
Acromegaly and its treatment in the McCune-Albright syndrome.
The McCune-Albright syndrome, comprising polyostotic fibrous dysplasia, cutaneous pigmentation and endocrine hyperfunction, is occasionally complicated by acromegaly due to a pituitary adenoma. We report a patient with the McCune-Albright syndrome and acromegaly, who developed secondary hypothyroidism and hypoadrenalism, in whom surgical removal of the pituitary tumour was technically difficult. A combination of a long-acting somatostatin analogue ('Sandostatin') and external irradiation were therefore used as treatment.
Acromegaly↗
Low recurrence rate after partial hypophysectomy for prolactinoma: the predictive value of dynamic prolactin function tests.
OBJECTIVE: To determine the factors influencing the outcome of transethmoidal partial hypophysectomy for suspected prolactinoma and the predictive value of pre and post-operative dynamic PRL function tests. DESIGN: A retrospective study of patients undergoing surgery for a suspected prolactinoma in Cardiff between 1979 and 1989. PATIENTS: Eighty-two hyperprolactinaemic patients (75 women, seven men) diagnosed as having a prolactinoma on the basis of dynamic PRL function tests, radiological investigation and exclusion of other causes. MEASUREMENTS: TSH and PRL responses to domperidone (10 mg i.v.) and TRH (200 micrograms i.v.) measured preoperatively, 2 months post-operatively, and annually thereafter. CT scan performed preoperatively in 58 patients. Operative findings, including adenoma size, documented in each case. RESULTS: Forty-two patients (51%) had microadenomas (less than 10 mm), 37 (46%) had macroadenomas and in three no tumour was found at operation. Preoperatively, normal responses of both TSH (incremental rise less than 2.0 mU/l) and PRL (greater than 100% rise) to domperidone were observed in two patients only: both had an abnormal vascular supply to the pituitary rather than an adenoma. Serum PRL was normalized in the early post-operative period (less than 72 h; 'early cure') in 65 patients (79%). The highest early cure rate (96%, n = 26) was in patients with adenomas of 5-9 mm, lower rates being achieved for lesions of 10-19 mm (80%, n = 30), less than 5 mm (63%, n = 19) or greater than or equal to 20 mm (57%, n = 7). The early cure rate was strongly correlated with preoperative PRL, ranging from 100% in patients with PRL less than 1000 mU/l (n = 13) to zero in those with PRL greater than 10,000 mU/l. Dopamine agonist therapy of between 5 weeks and 4 years duration prior to surgery was associated with a significantly reduced early cure rate (60 vs 94%, P less than 0.02) in macroadenoma but not microadenoma patients. Recurrent hyperprolactinaemia during mean follow-up of 51.7 months occurred in eight patients (12%), in five cases within 2 months of surgery and in the others at 26, 48 and 50 months. Recurrence could not be predicted from any preoperative parameter, but a serum PRL greater than 150 mU/l 1-3 days following microadenomectomy was associated with early recurrence and probably indicates failed surgery. An abnormal response of TSH to domperidone was documented 2 months post-operatively in 11/60 patients with normal basal PRL, and preceded all three late recurrences. Of four patients with abnormal responses of both PRL and TSH at this time, two have relapsed to date. CONCLUSIONS: In carefully selected patients, partial hypophysectomy is an acceptable alternative to medical treatment for prolactinoma. Preoperatively, dynamic tests accurately identified those patients whose hyperprolactinaemia was non-adenomatous in origin and, post-operatively, identified a subgroup of patients at increased risk of late recurrence.
Adult↗
Suppurative thyroiditis with oesophageal carcinoma.
A 68 year old, previously well woman presented with dysphagia, weight loss and a neck swelling. Investigations revealed a right-sided thyroid abscess with fistulous connection to the upper of two oesophageal carcinomas, a previously unreported association. The resistance of the thyroid to infection and the mechanisms of thyroid abscess formation in this patient are discussed.
Abscess↗
Dopamine agonists and pituitary tumor shrinkage.
The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.
Adenoma↗
Neuroendocrinology: clinical and experimental.
There have been several important publications concerning the aetiology of human pituitary tumours, in particular, delineating some of the gene mutations which may underlie this clinical problem. There have not been any major developments in clinical neuroendocrinology although advances have been made in the pharmacological development of dopaminergic drugs and the diagnosis of Cushing's disease.
Adenoma↗
Growth factors and the anterior pituitary.
Normal growth and secretion in the pituitary gland are dependent upon the co-ordinated action of a large number of extracellular growth factors, neuropeptides and peripheral hormones acting on their respective cellular receptors and via complex intracellular signalling pathways. The pituitary and hypothalamus are exposed to a large number of growth factors, several of which have well-documented effects on secretory function and may act as physiological modulators of pituitary hormone synthesis and release. IGF-I, for example, almost certainly acts as a feedback regulator of GH secretion. Despite well-documented mitogenic effects in other tissues, little is known about the role of these growth factors in normal pituitary cell turnover, compensatory hyperplasia or adenoma formation. There is now good evidence, however, that at least some of the hypothalamic releasing peptides are mitogenic for their respective pituitary cell subpopulations. The aetiology of pituitary tumours remains poorly understood but some appear to develop as a result of somatic mutation. Such mutations could enhance growth by causing altered expression of growth factors or their receptors, or constitutive activation of proteins involved in the intracellular mitogenic signal. Abnormalities have been documented at each of these levels in human pituitary tumours. The identification of an activating point mutation in the alpha subunit of Gs, the stimulatory regulatory peptide of adenylyl cyclase, in a proportion of somatotroph adenomas represents a major advance in our understanding of pituitary tumour pathogenesis. This and other findings may ultimately lead to new therapeutic approaches to the management of pituitary disease.
Animals↗
Thyrotropin response to thyrotropin-releasing hormone in elderly patients with and without acute illness.
The response of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) was measured in 70 clinically euthyroid elderly patients who were acutely ill and in 70 age- and sex-matched euthyroid controls who were free of acute disease. The incremental TSH response (delta TSH) was often blunted (less than 2 mU/l) in both groups, though more often in those with acute illness (30%) than in those without (19%). However, in patients from both groups who had a blunted delta TSH, there was often a substantial proportional rise in TSH. A substantial proportional TSH rise may be useful in differentiating between genuine thyroid disease and euthyroid sick syndrome in elderly patients with a blunted delta TSH.
Acute Disease↗
Effects of ambient glycaemic state on growth hormone responsiveness in insulin-dependent diabetes.
OBJECTIVE: We wished to examine the effects of ambient glycaemia on hypothalamic somatostatinergic tone in insulin-dependent diabetes mellitus. DESIGN: After 6-hour periods of either euglycaemia (5 mmol/l) or hyperglycaemia (15 mmol/l), exercise-induced GH secretion was measured. PATIENTS: Seven insulin dependent diabetics with no evidence of complications were recruited. RESULTS: There was no significant difference between basal GH levels during euglycaemia and hyperglycaemia (5.50 vs 5.53 mU/l). Nor was there a significant difference when mean delta GH levels (33.9 vs 27.4 mU/l) or mean area under GH curve (2331 vs 4038 mU min/l) during euglycaemia or hyperglycaemia were compared. CONCLUSIONS: We find no evidence therefore to support short-term effects of ambient glucose concentration on GH responsiveness, and by inference no direct effect of short-term changes in glycaemic control on hypothalamic release of somatostatin in the aetiology of GH hypersecretion in insulin-dependent diabetes mellitus.
Adult↗
Cholinergic blockade with pirenzepine induces dose-related reduction in glucose and insulin responses to a mixed meal in normal subjects and non-insulin dependent diabetics.
OBJECTIVE: The aim of the study was to assess the effects of cholinergic blockade with pirenzepine on glucose and insulin responses to a mixed meal in normal subjects and patients with non-insulin dependent diabetes (NIDDM). Further, to assess in normal subjects the relative importance of nocturnal GH suppression by pirenzepine. DESIGN: Placebo, 100 or 200 mg pirenzepine were given to the normal subjects 1 hour before a standard mixed meal. The effects of placebo or 200 mg pirenzepine at night on nocturnal GH secretion and subsequent breakfast carbohydrate tolerance were also studied. NIDDMs were given placebo or 200 mg pirenzepine before the meal. SUBJECTS: We studied six healthy male volunteers (ages 20-22, body mass indices 20.3-23.3) and ten NIDDMs (eight men, ages 42-74); five obese (BMI 25.5-31.8) and five non-obese (BMI 21.2-24.8). MEASUREMENTS: Serial plasma glucose and insulin concentrations were measured for 3 hours after a standard mixed meal. RESULTS: Acute pretreatment of normal male volunteers with pirenzepine produced a dose-related improvement in carbohydrate tolerance. Peak post-prandial plasma glucose levels were delayed and significantly reduced following 200 mg orally (6.5 +/- 0.1 mmol/l), but not following 100 mg (7.3 +/- 0.3), compared with placebo (7.6 +/- 0.3). Peak insulin levels were similarly delayed and reduced by the 200 mg dose only (36.5 +/- 6.1 mU/l, compared with 49.8 +/- 8.7). Suppression of nocturnal GH by 200 mg pirenzepine at night produced a small reduction in fasting plasma glucose (5.0 +/- 0.1 mmol/l, compared with 5.3 +/- 0.1, P less than 0.02) but did not improve subsequent breakfast carbohydrate tolerance. Peak plasma glucose in NIDDMs was reduced following pirenzepine (12.4 +/- 0.9 mmol/l) compared with placebo (14.3 +/- 1.0, P less than 0.01). This reduction was equally significant in obese and non-obese groups. Peak plasma insulin was also reduced by pirenzepine (22.4 +/- 3.9 mU/l) compared with placebo (42.4 +/- 5.3, P less than 0.01). Insulin suppression was quantitatively greater in obese than in non-obese patients. CONCLUSIONS: Improvement in carbohydrate tolerance after pirenzepine in normal subjects is dose related and largely independent of GH suppression. Cholinergic blockade can also improve meal carbohydrate tolerance with simultaneous reduction in plasma insulin concentrations in non-insulin dependent diabetics, particularly those with obesity.
Adult↗
Effect of pyridostigmine and pirenzepine on GH responses to GHRH in hyperthyroid patients.
OBJECTIVE: We wished to investigate whether thyrotoxicosis can influence the cholinergic modulation of GH secretion. DESIGN: Pyridostigmine was given orally, then GHRH injected i.v., and levels were measured. In a separate study, pirenzepine was injected i.v., then GHRH, and growth hormone levels were measured. PATIENTS: Thyrotoxic patients were compared with normal subjects. MEASUREMENTS: GH was measured from -30 to +120 minutes at intervals of 15 minutes. RESULTS: Pyridostigmine markedly increased GH responses to GHRH in normal subjects, but not in thyrotoxic patients. Pirenzepine abolished the GH response to GHRH in thyrotoxic patients. CONCLUSIONS: GH responses to GHRH in hyperthyroid patients were suppressed by cholinergic muscarinic receptor blockade with pirenzepine. Activation of cholinergic pathways with pyridostigmine did not increase GH responses to GHRH in these patients. This may be a consequence of increased hypothalamic cholinergic function or reduced hypothalamic GHRH activity in hyperthyroidism. Our findings demonstrate a further mechanism by means of which thyroid status may affect the secretory activity of the somatotroph.
Adolescent↗