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Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 253 records · Page 14Linked to original sources
PubMed1987

GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: studies with pyridostigmine and GHRH.

We have studied the effect of increased cholinergic tone on the GH response to growth hormone-releasing hormone (GHRH) and on GH feedback, using pyridostigmine, an acetylcholinesterase inhibitor. In six healthy male adult volunteers 120 mg oral pyridostigmine increased basal GH secretion compared to placebo and augmented the GH response to 100 micrograms i.v. GHRH (1-29) NH2; the effect was more than the additive effect of pyridostigmine and GHRH when each was given alone. Pretreatment with 2 IU methionyl-hGH given i.v. abolished the serum GH response to GHRH given 3 h later, demonstrating a negative feedback loop of GH on the response to GHRH; this inhibited response to GHRH was restored in subjects given pyridostigmine as well as methionyl-hGH. The data demonstrate that enhanced cholinergic tone releases GH, augments the serum GH response to GHRH and unblocks the negative feedback effect of methionyl-hGH pretreatment on the GH response to GHRH. These results suggest that GH negative feedback effects on its own secretion occur predominantly through increased hypothalamic somatostatin secretion; this somatostatin secretion is under inhibitory cholinergic control.

Adult↗
PubMed1987

The effect of alpha adrenergic manipulation on the 24 hour pattern of cortisol secretion in man.

We have studied the role of central alpha-1 adrenoceptor mechanisms which stimulate cortisol secretion throughout the 24 h period in man. Six normal subjects were given 24 h i.v. infusions of the alpha-1 adrenoceptor agonist methoxamine, the alpha-1 antagonist thymoxamine, and saline under double-blind conditions. The only cardiovascular effects of these adrenergic manipulations was a slight bradycardia accompanying the methoxamine infusion. The methoxamine infusion was accompanied by higher concentrations of cortisol than the saline infusion during waking hours and the food related secretory surges were exaggerated, while the converse held with thymoxamine. In contrast, the nocturnal surge of cortisol secretion was unaffected by these adrenergic manipulations. These findings suggest that an alpha-1 adrenoceptor mechanism contributes to the maintenance of cortisol secretion during waking hours, but not at night.

Adult↗
PubMed1987

Growth hormone pretreatment in man blocks the response to growth hormone-releasing hormone; evidence for a direct effect of growth hormone.

The effect of pretreatment with biosynthetic methionyl human GH (hGH) on the GH response to GHRH has been studied in normal subjects. Eight volunteers were given either 4 IU hGH or placebo s.c. 12-hourly for 72 h before a GHRH test, or a single s.c. dose of 4 IU hGH 12 h before a GHRH test. Somatomedin-C (Sm-C) levels at the time of the GHRH tests were significantly elevated after treatment with hGH compared to placebo, and the GH response to GHRH was significantly attenuated. A further six subjects were given 2 IU hGH or placebo i.v., and i.v. GHRH 3 h later; there was no rise in Sm-C for the 5 h of the study after either treatment; nevertheless, the response to GHRH was completely abolished by pretreatment with hGH. These results demonstrate that GH can regulate its own secretion independently of changes in Sm-C levels, through a mechanism other than the inhibition of GHRH release. The attenuated response to GHRH in the presence of elevated Sm-C levels may be related to Sm-C, or be a more direct effect of the recently elevated GH levels.

Adult↗
PubMed1987

Growth hormone releasing hormone in the assessment and long-term treatment of growth hormone deficiency.

The secretion of hGH after the administration of the analogue of growth hormone releasing hormone, GHRH (1-29)NH2, to 8 normal adults and 41 short children has been studied. The children were classified on the basis of their hGH response to insulin-induced hypoglycaemia; 28 had severe hGH deficiency (peak serum hGH less than 7 mIU/litre) and 13 had simple short stature (peak serum hGH greater than 15 mIU/litre). The hGH response to GHRH was similar in normal adults and short stature children, but significantly lower in the hGH deficient children. In 23 (82%) of the hGH deficient children the peak serum hGH in response to GHRH was greater than 7 mIU/litre (the maximum value seen during hypoglycaemia), and in 14 (50%) the peak serum hGH in response to GHRH was greater than 15 mIU/litre. This suggests that in the majority of hGH deficient children the defect in hGH secretion results from hypothalamic GHRH deficiency. The hGH responses of the short stature children to insulin-induced hypoglycaemia were mainly in the low range of normal, and the majority showed normal hGH responses to GHRH. Eighteen prepubertal children with definite hGH deficiency have been treated for 3-18 months with twice daily, subcutaneous injections of GHRH. This has promoted linear growth in 12 children, of whom 8 showed an increment in height velocity of 2-11 cm/year. GHRH provides a valuable method for the assessment of hGH secretion, but by itself it cannot be used to establish deficient hGH secretion; this requires a stimulation test that promotes hypothalamic GHRH secretion, such as insulin-induced hypoglycaemia. GHRH is a practical alternative therapy to hGH for some hGH-deficient children.

Adult↗
PubMed1987

Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man.

In a double-blind study in normal subjects, methoxamine, a highly selective agonist at alpha-1-adrenoceptors, significantly increased circulating ACTH and cortisol. The stimulant effect of methoxamine on cortisol secretion was dose dependent in the range 3.5-7 micrograms/kg/min, was abolished by concomitant administration of the strong alpha-1-adrenergic (and weak H1) antagonist thymoxamine but unaffected by the antihistamine, chlorpheniramine. In order to test whether the action of methoxamine on ACTH secretion was exerted centrally or peripherally, the effects of norepinephrine (NE), an alpha-1-agonist that does not cross the blood-brain barrier, were studied. Doses of NE (1-12 micrograms/min) that increased systolic blood pressure by amounts similar to the changes produced by methoxamine, did not result in any rise in plasma cortisol in normal subjects. The effect of methoxamine, which is more lipid soluble than NE, on plasma ACTH and cortisol, appears to be exerted on the CNS and not at the pituitary or via nonspecific peripheral mechanisms. In addition to its water solubility, NE differs from methoxamine in its beta-1-, beta-2- and alpha-2-agonist actions. However, prenalterol (2 mg) and salbutamol (250 micrograms), respectively beta-1- and beta-2-adrenergic agonist drugs, had no effect on the secretion of ACTH or cortisol and the alpha-2-antagonist yohimbine in an effective dose did not unmask a stimulant effect of intravenous NE on plasma cortisol. At high infusion rates, NE significantly inhibited cortisol secretion. Stimulation of central alpha-1-adrenergic mechanisms results in secretion of ACTH in man, presumably by increased release of a corticotropin-releasing factor.

Adrenocorticotropic Hormone↗
PubMed1987

Alpha 2-adrenoceptor agonists stimulate growth hormone secretion but have no acute effects on plasma cortisol under basal conditions.

Ten normal male subjects were administered clonidine (0.1 and 0.2 mg) or a highly-selective alpha 2-adrenoceptor agonist S 3341 (1 and 2 mg) on separate occasions in a double-blind randomised placebo-controlled study; blood samples were obtained for measurement of serum GH and plasma cortisol via an indwelling venous cannula for 4 h after each drug administration. Both clonidine and S 3341 were equally effective at lowering supine, and particularly standing BP; both also caused mild sedation, although this was slightly less marked for S 3341. High doses of both clonidine and S 3341 significantly increased serum GH (peak increment after clonidine: 18.8 +/- 5.5 mU/l (mean +/- SEM); peak increment after S 3341: 21.1 +/- 4.8 mU/l). Neither drug affected plasma cortisol. It is concluded that GH release may be stimulated by alpha 2-adrenoceptor agonism. As S 3341 has slightly less central activity than clonidine at the doses employed, but is at least equally potent at stimulating GH release, it is probable that the alpha 2-adrenoceptor stimulation of GH release occurs outside the blood-brain barrier. The pituitary-adrenal axis appears resistant to manipulation of alpha 2-adrenoceptors under basal conditions.

Adrenergic alpha-Agonists↗
PubMed1987

Effect of adrenaline on basal and ovine corticotrophin-releasing factor-stimulated ACTH secretion in man.

Six normal male subjects were given, in single blind random order on six separate occasions, i.v. bolus doses of synthetic ovine corticotrophin-releasing factor-41 (oCRF-41; 25 and 50 micrograms) with and without adrenaline (3 micrograms/min) i.v. for 150 min, the adrenaline infusions alone and saline placebo. The adrenaline infusions resulted in plasma adrenaline concentrations of 4.33 +/- 0.82 (S.E.M.) nmol/l and were associated with an increase in blood glucose, heart rate and systolic blood pressure and a reduction of diastolic blood pressure. Despite these evident biological effects at several sites, there was no stimulation of plasma ACTH or cortisol by adrenaline in comparison with the effect of saline, and no enhancement of the stimulatory effect of either dose of oCRF-41 on ACTH or cortisol secretion. The ACTH response to 50 micrograms oCRF-41 was greater than that to 25 micrograms, indicating that the 25 micrograms dose of oCRF-41 was submaximal and capable of further enhancement. As the plasma adrenaline concentrations during the adrenaline infusions reached the upper limit of the physiological range of plasma adrenaline in man, yet failed to enhance the ACTH or cortisol responses to a submaximal dose of oCRF-41, we conclude that circulating adrenaline neither exerts a direct stimulatory effect on pituitary corticotrophs nor enhances the effect of CRF under physiological circumstances. The adrenaline infusions attenuated the ACTH and cortisol responses to oCRF-41 and were associated with a transient reduction of basal concentrations of both hormones.

Adrenocorticotropic Hormone↗
PubMed1987

Measurement of circulating corticotrophin-releasing factor in man.

A radioimmunoassay was developed to measure corticotrophin-releasing factor (CRF-41) extracted from human plasma using Vycor glass. Assay sensitivity was 20 ng/l and intra- and interassay coefficients of variation were 10.2 and 11.4% respectively. The normal range of plasma CRF-41 was less than 20-110 ng/l (n = 46). Plasma concentrations of CRF-41 in patients with Cushing's disease. Nelson's syndrome and Addison's disease were within the normal range. No correlation was found between CRF-41 and ACTH in these syndromes. Two patients with the ectopic ACTH syndrome had increased plasma concentrations of CRF-41. In normal subjects no changes in plasma CRF-41 occurred after insulin-induced hypoglycaemia, treatment with dexamethasone or feeding, and changes in the concentrations of CRF-41 did not reflect circadian changes in plasma concentrations of cortisol. Concentrations of immunoreactive CRF in plasma of women in the third trimester of pregnancy were increased (550-9300 ng/l) and gel filtration chromatography showed that this comprised CRF-41 and a higher molecular weight form. Reversed-phase high-performance liquid chromatography also revealed multiple peaks of immunoreactive CRF in extracts of plasma and placenta.

ACTH Syndrome, Ectopic↗
PubMed1987

A phaeochromocytoma presenting with Cushing's syndrome associated with increased concentrations of circulating corticotrophin-releasing factor.

The case is described of a 61-year-old male who presented with hypertension and Cushing's syndrome which resolved on excision of a unilateral adrenal mass. Histology of the tumour revealed a benign phaeochromocytoma which immunostained for corticotrophin-releasing factor (CRF-41) but not for ACTH. Preoperative plasma concentrations of immunoreactive CRF-41 were increased, and gradients for both CRF-41 and ACTH were demonstrated across the tumour. Post-operatively, CRF-41 was undetectable in plasma. The tumour contained high concentrations of immunoreactive CRF-41 which co-eluted with synthetic human CRF-41 on reversed-phase high-performance liquid chromatography. Tumour CRF-41 stimulated the release of ACTH in a dose-dependent manner from isolated rat anterior pituitary cells. We conclude that this tumour secreted CRF-41 and ACTH and had the capacity to produce ACTH-dependent Cushing's syndrome directly by secreting ACTH and indirectly by secreting CRF-41 to stimulate ACTH secretion from the anterior pituitary.

Adrenal Gland Neoplasms↗
PubMed1987

Uptake of iodine-123 MIBG by pheochromocytomas, paragangliomas, and neuroblastomas: a histopathological comparison.

The percentage uptake of [123I]metaiodobenzylguanidine (MIBG) by tumors of the paraganglion system is compared with the number of neurosecretory granules (assessed by both light and electron microscopy) in the subsequently resected tumors in six patients. Iodine-123 MIBG was injected intravenously; the tumor uptake of [123I]MIBG varied between 0.001% and 0.14% of the injected dose per gram of tumor tissue at 22 hr. The number of neurosecretory granules in tissue sections was scored on a scale of I-III. A direct proportional correlation was found between the percentage uptake of [123I]MIBG by the tumor and the number of neurosecretory granules in the tissue sections but not with plasma or urinary catecholamines. This technique for imaging reflects the storage status of the tumor better than plasma and urinary catecholamine measurements.

3-Iodobenzylguanidine↗
PubMed1987

Quantitation of iodine-123 MIBG uptake by normal adrenal medulla in hypertensive patients.

Eighteen hypertensive patients with a clinical suspicion of pheochromocytoma and raised or borderline raised plasma catecholamine and urinary vanillyl mandelic acid (VMA) levels were studied by scintigraphy using 123I-labeled metaiodobenzylguanidine (MIBG). None of these patients had any scintigraphic evidence of pheochromocytoma at the time of study or on subsequent clinical follow-up. A quantitative approach was taken to calculate the adrenal medullary uptake of [123I]MIBG in these patients. Three different methods of quantitation were evaluated using data acquired from an anthropomorphic phantom and analysed by three independent observers. In the patient studies 34 out of 35 adrenal medullas were visualized with uptake in the range of 0.01-0.22% of the administered dose 22 hr postinjection which was calculated using the preferred quantitation method. This is an appropriate control group range for comparison with patients who have proven norepinephrine and epinephrine secreting tumors. A quantitative approach to [123I]MIBG imaging provides an important tool for studying adrenomedullary pathophysiology.

3-Iodobenzylguanidine↗
PubMed1986

Visceral and skin granuloma annulare, diabetes, and polyendocrine disease.

A middle aged man suffered with insulin dependent diabetes, autoimmune Addison's disease, myxoedema, and severe ulcerative colitis, for which he had undergone subtotal colectomy with formation of an ileostomy. Granuloma annulare confined to the anterior abdominal wall was diagnosed in 1981. In 1983 an episode of severe colicky pain and excessive working of the ileostomy occurred associated with severe hyperglycaemia and increased irritation of the granuloma annulare. Laparotomy disclosed adhesions and numerous white nodules over bowel, mesentery, and peritoneum histologically identical with the skin lesions. Two further episodes of subacute small bowel obstruction occurred, and a repeat laparotomy showed widespread intra-abdominal granuloma annulare. Visceral granuloma annulare appears not to have been reported before, and in this patient exacerbation of the skin lesion was associated with poor diabetic control.

Diabetes Complications↗
PubMed1986

The first clinical use of depot buserelin for advanced prostatic carcinoma.

The agonist analogues of the gonadotrophin-releasing hormone now provide an alternate medical treatment of prostatic cancer. For effect repeated administration is required, either by five or six times daily intranasal or once daily subcutaneous treatment. There is an obvious disadvantage to such regimens in elderly patients who may have difficulty complying with therapy. In order to circumvent these difficulties, sustained release formulations of the agonist analogues have been synthesized. We report the first clinical use of a long-acting formulation of D-Ser (TBU)6-LHRH Ethylamide (buserelin) using a novel polymer material. Twelve symptomatic patients with previously untreated carcinoma of the prostate were treated with depot buserelin, administered once monthly. In all patients, depot buserelin suppressed serum testosterone into the range seen in castrate men at a rate equivalent to that provided by five times daily intranasal therapy. No significant increase in serum testosterone, luteinizing hormone or follicle-stimulating hormone concentrations occurred during the period of follow-up. Long-acting formulations of buserelin offer an advance in the management of prostatic cancer with agonist analogues of the gonadotrophin-releasing hormone.

Aged↗
PubMed1986

Cyclic prednisolone therapy for male infertility associated with autoantibodies to spermatozoa.

Seventy-six subfertile men with significant titers of antisperm antibodies were treated with a new corticosteroid regimen, consisting of prednisolone, 40 mg daily, rising to 80 mg daily if antibody titers did not fall, given from days 1 to 10 of the partner's menstrual cycle, for up to nine cycles. Twenty-five (33%) of the partners became pregnant during a treatment cycle, more than twice the expected incidence without treatment. No serious complications occurred, although one half of the patients had transient minor side effects. This regimen appears to be encouraging and suitable for further assessment in a prospective controlled trial.

Adult↗