Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 271 records · Page 15Linked to original sources

PubMed1986

Effect of cyclosporin A in male autoimmune infertility.

Nine infertile men (mean duration of infertility, 8.3 years) with antisperm antibodies were treated with the immunosuppressive drug cyclosporin A for 6 months with a dose of 5 to 10 mg/kg/day. Seminal plasma and serum antisperm antibodies fell in three subjects on treatment, and sperm count and motility increased substantially in one. Three successful pregnancies occurred in the study group: one on treatment, one in the first cycle of artificial insemination with the husband's sperm after treatment (twin infants), and one 3 months after cessation of treatment (twin infants). Successful conceptions with cyclosporin were unrelated to falls in antisperm antibody titer.

Adult↗

PubMed1986

Growth hormone releasing hormone.

Human growth hormone releasing hormone (GHRH) was originally extracted from two pancreatic tumours in patients with acromegaly, and is now known to consist of a 44 residue amidated peptide or its C-terminal-shortened derivatives. The sequence of rat GHRH has also been determined; this 43 residue peptide shows approximately 70% homology with human GHRH, and is located mainly in the arcuate nucleus of the hypothalamus. Pulsatile GH release in the rat is principally a consequence of the pulsatile release of hypothalamic GHRH, although this appears to be associated with a transient suppression of somatostatin release. Exogenous GHRH specifically increases circulating GH in many species, and in the long term may increase growth. In normal man, several analogues of GHRH have been shown to be safe, sensitive and specific stimuli to GH release; although there may be a variable prolactin response, this is usually of small magnitude. Continuous infusion of GHRH leads to a decrement in responsiveness, due at least in part to changes in hypothalamic somatostatin. The GH response to GHRH is also modulated by obesity, blood sugar, free fatty acids, and GH itself. Many children with 'GH deficiency' (idiopathic, radiation-induced, or secondary to hypothalamopituitary tumours) respond to intravenous GHRH with an acute rise in serum GH. Early studies also indicate that long-term therapy with subcutaneous GHRH may increase growth velocity in some of these children. It is concluded that analogues of GHRH are useful in the investigation of the hypothalamopituitary axis, and may be important in the therapy of short stature.

Acromegaly↗

PubMed1986

Depot-bromocriptine treatment for prolactinomas and acromegaly.

Fifteen patients with hyperprolactinaemia and pituitary macroadenomas (5 patients), microadenomas (6 patients), or acromegaly (4 patients) were given a single intramuscular injection of 50 mg bromocriptine bound to polylactic acid microspheres, depot-bromocriptine. None of the patients had any short-term or long-term discomfort from the injection. In the 11 patients with prolactinomas, serum prolactin fell to minimum levels 12-72 h post-injection; nine patients were highly responsive to depot-bromocriptine, with a mean serum prolactin of 12.9% of basal levels 24 h post-injection, rising to 19% at 28 days. Two patients with prolactinomas were resistant to both depot-bromocriptine, and large doses of oral dopamine agonists. Initiating side-effects (nausea, vomiting, symptomatic postural hypotension) were seen in five patients in the first 24 h post-injection, but were minimal or absent thereafter. Five of six patients previously intolerant of oral dopamine agonists were able to be transferred successfully to bromocriptine 5 mg daily at 4 weeks. Of the four patients with acromegaly, raised prolactin levels were successfully lowered to normal for 4 weeks after injection; serum GH was also partially lowered, but returned to baseline levels at 2-4 weeks. In one patient serum GH was resistant to suppression by both depot bromocriptine and high doses of oral bromocriptine. One patient with a large tumour and visual field defects showed a rapid and maintained improvement in visual fields and acuity after depot-bromocriptine, and was successfully transferred to high-dose oral bromocriptine at 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗

PubMed1986

Normal circulating immunoreactive growth hormone releasing factor (hGRF) concentrations in patients with functional hypothalamic hGRF deficiency.

Using a highly specific radioimmunoassay we have measured the concentrations of human growth hormone releasing factor (ir-hGRF) in the peripheral circulation of six individuals with acquired hypothalamic hGRF deficiency. Despite their hypothalamic dysfunction venous plasma ir-hGRF increased normally in every patient after the stimulus of a mixed breakfast, from an average concentration basally of 13.6 +/- 6.0 pg/ml to a maximum of 29.0 +/- 8.4 pg/ml (mean +/- SEM) at 120 min. The findings indicate that circulating hGRF is at least in large part extrahypothalamic in origin, which in turn implies a physiological role for hGRF in the periphery.

Adolescent↗

PubMed1986

Diagnosis and management of ACTH-dependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production.

The clinical features, diagnosis and management of 16 consecutive patients with ectopic ACTH production are described and biochemical data are compared with those of 48 consecutive patients with pituitary-dependent Cushing's disease. In 10 cases the ectopic ACTH secreting tumour was completely occult to routine clinical and radiological investigation, and no basal or dynamic investigation of adrenal-pituitary function was able clearly to differentiate these patients from those with Cushing's disease. High dose dexamethasone suppression testing assessed by plasma cortisol was usually helpful but unexpected responses were seen in both diagnostic groups; the metyrapone test yielded no useful information and should now be abandoned. Hypokalaemia was seen in all patients with ectopic ACTH production but in only 10% of those with Cushing's disease who were not on diuretics at presentation. Successful diagnosis and tumour localization was most frequently achieved by a combination of CT scanning of the chest and abdomen and venous catheter sampling for ACTH. All patients in whom the ectopic ACTH-secreting tumour was obvious at presentation died of their primary tumour within 8 months, whereas seven of the 10 patients with occult tumours at presentation are alive 1.5-16.5 years later, and appear cured. Occult ectopic ACTH secretion may be impossible to distinguish from pituitary Cushing's disease. Multiple and repeated investigations are often required to make this differential diagnosis, essential for appropriate therapy.

ACTH Syndrome, Ectopic↗

PubMed1986

Autoimmune cranial diabetes insipidus: its association with other endocrine diseases and with histiocytosis X.

Thirty-nine patients with idiopathic cranial diabetes insipidus (DI) and 81 secondary to hypothalamic lesions were investigated for the presence both of associated autoimmune diseases and autoantibodies. Eleven (28%) of the idiopathic but none of the secondary DI cases had an overt autoimmune disease. A further two patients with idiopathic DI had associated organ-specific autoantibodies. Autoantibodies to vasopressin (AVP)-secreting hypothalamic cells were detected in 12 patients with idiopathic DI (31%). Seven out of 13 cases of DI secondary to histiocytosis X (HX) were also positive (54%), whereas only two (3%) of the other 68 sera from patients with secondary DI reacted with AVP cels. Of the 13 patients with DI associated with frank organ-specific autoimmune diseases or autoantibodies alone, eight (62%) were positive for AVP-cell antibodies. The finding of associated autoimmune diseases in a patient with idiopathic DI is therefore suggestive of an autoimmune origin of DI, and this can be supported by the detection in the serum of AVP cell antibodies. In cases of HX, the new finding of the presence of AVP-cell antibodies reflects hypothalamic infiltration by HX cells, and suggests that DR + 'Langerhans-like' cells play more than a passive role in the hypothalamic lesion.

Adolescent↗

PubMed1986

An analogue of met-enkephalin attenuates the pituitary-adrenal response to ovine corticotrophin releasing factor.

The met-enkephalin analogue, DAMME, suppresses the pituitary-adrenal axis in normal subjects; it is not clear whether this occurs at the level of the pituitary or above. We therefore administered synthetic ovine corticotrophin releasing factor (CRF-41) 100 micrograms i.v. to a group of normal male subjects, with or without pretreatment with DAMME 250 micrograms i.v., and monitored the response of plasma ACTH and serum cortisol. CRF-41 caused a marked stimulation of ACTH and cortisol release, but this was significantly attenuated by pretreatment with DAMME. It is therefore concluded that DAMME either directly inhibits the corticotroph at the level of the pituitary, or that it suppresses release of an additional factor which normally potentiates the action of CRF-41 on the pituitary.

Adolescent↗

PubMed1986

Management of cranial diabetes insipidus with oral desmopressin (DDAVP).

The effect of oral administration of desmopressin (DDAVP) solution was investigated in six patients with cranial diabetes insipidus of varying aetiology. All patients experienced a prompt and prolonged antidiuresis. Nine patients have been managed with oral DDAVP tablets for up to 5 months and all preferred this route of administration to intranasal application using a rhinyle. Oral DDAVP gives excellent and convenient control in cranial diabetes insipidus.

Administration, Oral↗

PubMed1986

Naloxone provokes catecholamine release in phaeochromocytomas and paragangliomas.

The effects of low- (2 mg) and high-dose (10 mg) intravenous naloxone administration on circulating plasma catecholamines in four patients with proven and two patients with suspected phaeochromocytomas have been evaluated. In three out of four patients with confirmed phaeochromocytomas or paragangliomas, 10 mg naloxone resulted in a marked rise (290-575%) in circulating noradrenaline; despite combined alpha and beta-adrenoceptor blockade, in two out of four cases systolic and diastolic pressures rose whilst pulse rate fell. No response was seen to 2 mg naloxone in any patient. No humoral or pressor response was obtained in the fourth patient, who may have been secreting maximal levels of plasma noradrenaline at the time of study. In the two patients with suspected phaeochromocytoma, there was no response to naloxone: further investigations failed to reveal a source of abnormal catecholamine secretion in these patients. It is concluded that naloxone represents a new pharmacological agent which can provoke catecholamine release in patients with phaeochromocytomas; in such patients, endogenous opioids may regulate catecholamine release either from the tumour itself or from the enhanced peripheral catecholamine stores.

Adolescent↗

PubMed1986

Immunocytochemical study of 18 tumours causing ectopic Cushing's syndrome.

Eighteen cases of Cushing's syndrome caused by ectopic production of peptide hormones were investigated by histological and immunocytochemical methods and the findings correlated with clinical and biochemical observations. Immunocytochemistry showed immunoreactive adrenocorticotrophic hormone (ACTH) or peptides derived from the ACTH precursor (pro-opiomelanocortin (POMC], or both, in a total of 10 cases: five of these also contained immunoreactive-alpha-melanocyte stimulating hormone, indicating more extensive translational processing of POMC than normally occurs in healthy corticotrophs of the anterior pituitary; in two further cases peptides capable of stimulating ACTH release from the anterior pituitary were present. In the remaining six cases immunocytochemistry failed to show the presence of ACTH, other POMC derived peptides, or peptides with ACTH releasing properties. These findings correlate well with the histological and clinical observations, in that the six tumours had been clinically overt, caused rapid death, and histologically seemed to be highly malignant. In contrast, the 12 other tumours were occult to radiological examination, patients had a much improved survival rate, and histologically the tumours seemed to be less aggressive. All but one of the tumours in this series showed a degree of neuroendocrine differentiation, indicated by the presence of neuron specific enolase. These results suggest that one feature of highly malignant tumours, which cause an ectopic endocrine syndrome, is a high secretion of peptide hormones, leaving amounts that are too small to be shown by immunocytochemistry.

ACTH Syndrome, Ectopic↗

PubMed1986

Effect of adrenergic antagonism on the growth hormone, prolactin and cortisol response to a synthetic opioid agonist in man.

The intravenous administration of 250 micrograms D-Ala2-MePhe4-Met-enkephalin-O-ol (DAMME) caused a marked increase in circulating growth hormone (GH) and prolactin (PRL), and a fall in cortisol, in 14 normal subjects. Neither the alpha 1-antagonist thymoxamine, nor the alpha 2-antagonist yohimbine, significantly altered the GH and PRL responses to DAMME, suggesting that in man the growth hormone- and prolactin-releasing effects of exogenous opioids are not mediated through adrenoceptor pathways. The fall in cortisol induced by DAMME was not affected by thymoxamine, but was significantly attenuated by yohimbine, indicating that opioids may lower circulating cortisol via an interaction with noradrenergic pathways.

Adult↗

PubMed1986

Effect of an opiate antagonist on the responses of circulating catecholamines and the renin-aldosterone system to acute sympathetic stimulation by hand-grip in man.

The effect of naloxone on the neurohumoral responses to acute sympathetic stimulation by sustained hand-grip in normal man was investigated. Six normal males were studied fasting at 08.30 h, on two occasions at 7-day intervals, with each subject sustaining 30% of his maximal hand-grip on a hand dynamometer for 5 min. Naloxone (8 mg bolus) in 20 ml normal saline, or saline alone, was given 5 min before hand-grip in a randomised double-blind cross-over trial. Blood was sampled for plasma renin activity, serum aldosterone and plasma catecholamines. The study was repeated in the absence of hand-grip. Sustained hand-grip produced significant elevations in mean blood-pressure, circulating adrenaline, noradrenaline and aldosterone. Naloxone, which had no effect on basal catecholamines, plasma renin activity or aldosterone, significantly enhanced the responses in plasma adrenaline, plasma renin activity and serum aldosterone to hand-grip. The increments in blood pressure and noradrenaline were not affected. These results suggest that endogenous opioids modulate the response of the sympathoadrenal and renin-aldosterone systems to acute sympathetic stimulation by a mild stress in man.

Adult↗

PubMed1986

Growth hormone-releasing hormone in the diagnosis and treatment of growth hormone deficient children.

A growth hormone-releasing hormone (GHRH) has recently been extracted and synthesised, and appears to be identical to human hypothalamic GHRH. Immunoreactive GHRH is found in the venous blood of normal subjects and GH-deficient children, but is probably not hypothalamic in origin and therefore not important in GH regulation. GHRH is a potent specific stimulator of GH secretion in man, and provides a valuable diagnostic test in differentiating hypothalamic from pituitary causes of GH deficiency. Preliminary data suggests that GHRH may promote linear growth in some GH deficient children. GHRH may well prove an important alternative therapy for GH deficient children especially if depot preparations or intranasal administration prove effective.

Child↗

PubMed1986

Cranial irradiation for cerebral and nasopharyngeal tumours in children: evidence for the production of a hypothalamic defect in growth hormone release.

A synthetic 29-amino acid analogue of human pancreatic GH-releasing hormone (GHRH(1-29)NH2) has recently been shown to stimulate the release of GH in normal subjects. We have studied the GH response to GHRH(1-29)NH2 in nine children irradiated for brain and nasopharyngeal tumours, who were not growing and were deficient in GH as assessed by insulin-induced hypoglycaemia. Serum GH rose in response to GHRH(1-29)NH2 in all the children, and in five the peak serum GH response was greater than 20 mu./l. The data suggest that when hypothalamo-pituitary irradiation results in GH deficiency, this is due to a failure of the synthesis or delivery of endogenous GHRH from the hypothalamus to the pituitary cells. It also suggests that it may be possible to treat such children using synthetic GHRH in place of exogenous GH.

Body Height↗

PubMed1986

Characterization of pro-opiomelanocortin-derived peptides in pituitary and ectopic adrenocorticotrophin-secreting tumours.

The molecular forms of pro-opiomelanocortin in plasma of normal subjects and plasma and tissue extracts from patients with disorders of the hypothalamic-pituitary-adrenal axis have been characterized using gel filtration chromatography under acid dissociating conditions, and the molecular forms further investigated by high pressure liquid chromatography and affinity chromatography. A large molecular weight MSH/ACTH fragment was observed in all plasma samples chromatographed, although the proportions of this fragment were significantly greater in patients with the ectopic ACTH syndrome. A similar profile was observed in tumour extracts: a greater proportion of large molecular weight precursors was observed. Immunoreactive-gamma-MSH in extracts of ectopic tumours displayed marked and variable heterogeneity, and affinity chromatography with Concanavalin A-Sepharose indicated that this was due to differential glycosylation. High pressure liquid chromatography of a peak of amino terminal pro-opiomelanocortin (N-POC(1-76)) and 22 000 mol. wt MSH/ACTH indicated two peaks in each peptide, again possibly due to differential glycosylation. A possible neurointermediate lobe origin of atypical invasive pituitary tumours is discussed.

ACTH Syndrome, Ectopic↗

PubMed1986

An in-situ isolated rat adrenal perfusion system for study of neurally mediated catecholamine secretion: effects of morphine, a Met-enkephalin analogue, and naloxone on catecholamine secretion.

An in-situ isolated rat adrenal perfusion technique has been devised to study the opioid control of neurally mediated adrenomedullary catecholamine release. Adrenomedullary catecholamine secretion was induced by electrical stimulation of the cut end of the left descending thoracic sympathetic chain on platinum electrodes. The half-maximal stimulatory potential (ED50) of the system was 8 V, 20 Hz, with 300 microseconds pulse width. Basal release of catecholamine from the adrenal was constant using a perfusion flow rate of 100-300 microliter/min, but increased significantly with increasing perfusion temperature over the range 36-38 degrees C. Following repetitive 30-s stimulation of the left thoracic sympathetic chain, and 3-min fraction collections, the total amount of catecholamine released per fraction remained within 80-100% of the maximum release for up to eight consecutive stimuli. The release of catecholamines was completely blocked by hexamethonium (0.1 mmol/l), but recovered to pre-blockade values within two further stimuli. Using the ED50 and the first three stimuli as control, the effects of morphine (10 nmol/l-l mmol/l), D-Ala2-MePhe4-Met-enkephalin-(O5)-ol (DAMME; 10 nmol/l-0.1 mmol/l) and naloxone (10 nmol/l-10 mumol/l) on the response to the next three stimuli were compared. Morphine, DAMME or naloxone did not significantly alter the amount of catecholamine released by this form of stimulation. Therefore in the rat, under the conditions used, there is no evidence for mu (mu) or delta (delta) opiate modulation of neurally mediated catecholamine release from the rat adrenal medulla.

Adrenal Glands↗

PubMed1986

Characterization by high-performance liquid chromatography of circulating growth hormone-releasing factors in normal subjects.

Four forms of circulating immunoreactive human GH-releasing factor (ir-hGRF) have been identified in each of four normal subjects, with a mean increase in total ir-hGRF of twofold over basal levels following a mixed meal. Plasma samples (200 ml) from each individual were subjected to large-scale Vycor extraction with initial purification by high-performance liquid chromatography on a reversed-phase C18 column, followed by analytical separation of the ir-hGRF components using a C3 wide-pore reversed-phase column, and subsequent radioimmunoassay of the fractions. The mean recovery of total ir-hGRF from the plasma (fasted and non-fasted) was 76 +/- 16% (2 X S.E.M.). Analytical separation of the ir-hGRF revealed four components which co-eluted with synthetic hGRF-37, hGRF-40 and hGRF-44, and a peak eluting between hGRF-40 and -44 which may represent hGRF-42. The hGRF-40 was shown to be the predominant circulating molecular form in the fasted state in each subject, and in three out of four subjects following a mixed meal. The hGRF-44 showed the greatest percentage increase over basal in all four individuals.

Chromatography, High Pressure Liquid↗

PubMed1986

Somatostatin octapeptide (SMS 201-995) in the medical treatment of acromegaly.

Parenteral somatostatin has been used to suppress growth hormone secretion in acromegalic patients, but long-term treatment is hampered by its short half-life of a few minutes in the circulation. An octapeptide analogue of somatostatin (SMS 201-995) has recently been developed that has greater potency and selectivity in suppressing growth hormone than the native hormone. In this study somatostatin and somatostatin octapeptide infusions were compared in 13 patients with active acromegaly. The octapeptide had a longer duration of action in the suppression of growth hormone than native somatostatin. A twice daily dose of 100 micrograms significantly suppressed growth hormone during the day. Prolactin was not suppressed, even in hyperprolactinaemic patients, and suppression of insulin was of short duration. Two patients had diarrhoea, but this disappeared when treatment with the octapeptide was stopped. Somatostatin is known to suppress pancreatic exocrine function, and it is therefore important to look for evidence of malabsorption during long-term treatment with the octapeptide. Somatostatin octapeptide is therefore useful in the treatment of acromegaly, but evidence of malabsorption should be watched for; nonparenteral routes of administration need to be assessed.

Acromegaly↗