bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF SMS 201–995, A LONG‐ACTING SOMATOSTATIN ANALOGUE, ON THE SECRETION AND MORPHOLOGY OF A PITUITARY GROWTH HORMONE CELL ADENOMA
Authors: GEORGE S. R. , KOVACS K. , ASA S. L. , HORVATH E. , CROSS E. G. , BURROW G. N.
Published: March 2008

The present study reports the effects of SMS 201–995, a long‐acting somatostatin analogue, on blood GH levels, glucose tolerance and tumour morphology in a 36‐year‐old, previously untreated acromegalic woman. Treatment (50 μg s.c, 8‐hourly) resulted in marked suppression of GH concentration and an improvement in glucose tolerance. After 10 d of treatment, the tumour was removed by transsphenoidal surgery and studied by histology, immunohisto‐chemistry, transmission electron microscopy and morphometry. Histologically, the tumour was an acidophilic adenoma which contained immunoreactive GH in many adenoma cells. By electron microscopy, the tumour was composed of densely granulated somatotrophs containing numerous large secretory granules and many lysosomes showing crinophagy. No cell necrosis or vascular impairment were evident. Using morphometry, the tumour was compared with 10 densely granulated somatotroph adenomas, removed from acromegalic patients not treated with somatostatin. The nuclear and cytoplasmic areas of the adenoma subjected to SMS 201–995 treatment were smaller, and the lysosomes occupied more of the cytoplasmic volume than those of controls. The nuclear/ cytoplasmic ratio, cytoplasmic volume densities of endoplasmic reticulum, Golgi apparatus, mitochondria, secretory granules and secretory granule diameters were within the range of control adenomas. In vitro, treated adenoma cells secreted GH and retained responsiveness to both GRH stimulation and somatostatin suppression. The morphologic findings after SMS 201–995 treatment, are consistent with suppression of GH release. There is no evidence that somatostatin has any direct cytotoxic or vasotoxic effects. It appears that SMS 201–995 represents a potent and promising drug in the medical treatment of acromegaly, however, more is needed to elucidate the mechanism of somatostatin suppression and to provide evidence for adenoma shrinkage.
THE EFFECTS OF DITHIOTHREITOL ON THYROID STIMULATION IN VITRO
Authors: GINSBERG J. , RAFTER D. J. , von WESTARP C. , MURRAY P. G.
Published: March 2008

There is evidence that the porcine TSH receptor contains essential disulphide bridge(s) which can be disrupted by dithiothreitol (DTT). The aim of the present study was to determine whether exposure of intact thyroid cells to DTT leads to altered thyroid stimulation. TSH‐stimulated iodine organification in cultured porcine thyroid cells was studied following short‐term DTT exposure; a dose‐dependent inhibition was observed with DTT but not oxidized DTT. Cell viability, follicle formation, and total protein synthesis were preserved. A minimum of 30 min incubation with DTT was required for inhibition. However, under identical conditions, DTT had no effect on TSH or forskolin‐stimulated cyclic AMP (cAMP) production. These results suggest that DTT inhibition of organification is mediated by post‐receptor mechanisms likely involving thyroid peroxidase. The effects of DTT on thyroid stimulation in vitro does not appear to involve disruption of the disulphide bridge(s) in the TSH receptor.
EFFECT OF ORAL FRUSEMIDE ON DIAGNOSTIC INDICES OF THYROID FUNCTION
Authors: NEWNHAM H. H. , HAMBLIN P. S. , LONG F. , LIM C‐F. , TOPLISS D. J. , STOCKIGT J. R.
Published: March 2008

We studied the acute effect of standard therapeutic doses of oral frusemide on indices of thyroid function in 34 hospital in‐patients with congestive cardiac failure. A transient decrease in total T4, elevation in the T3 resin uptake and consequent increase in the free T4 index (FT4I) were seen 2–5 h after ingestion of frusemide at a chronic morning dosage of 80,120 or 250 mg. The FT4I pre‐ vs post‐frusemide values after 250 mg of drug were 109 ± 12 vs 129 ± 18 (P < 0.05) after 120mg 92 ± 14vs 119 ± 12 (P < 001), and after 80 mg 102 ± 6 vs 112 ± 4 (P < 0.01) (mean ± SEM). Similar increases in apparent free T4 measured by an analogue tracer assay (free T4 RIA sol, Henning, Berlin) were seen after frusemide. In a time course study, the major change in the T3 uptake 120 min after frusemide ingestion correlated with the change in serum frusemide concentration. When frusemide was added to serum in vitro its influence was greatest in methods that involved least dilution of serum. In two of the patients difficulty in clinical assessment of thyroid status was compounded by the effect of oral frusemide on FT41. We conclude that oral frusemide may influence biochemical assessments of thyroid function in patients with congestive cardiac failure. It is necessary to consider the time interval between ingestion of high doses of oral frusemide and blood sampling in evaluating such results.
AN EVALUATION OF ANTI‐INSULIN RADIOIMMUNODETECTION IN PATIENTS WITH SUSPECTED INSULINOMA
Authors: CHAPMAN C. E. , FAIRWEATHER D. S. , KEELING A. A. , CHANDLER S. T. , ANDERSON P. , DYKES P. W. , BRADWELL A. R.
Published: March 2008

Nine patients with suspected insulinoma were scanned with iodine‐131 labelled anti‐insulin. The clinical diagnosis was subsequently confirmed at laparotomy in eight patients, two of whom had liver metastases. The primary insulinoma was accurately localized by anti‐insulin scanning in four patients and these tumours ranged from 1 to 3 cm in diameter. Both computerized axial tomography (CT) scanning and pancreatic angiography had given false negative results in one of these patients. Hepatic metastases were correctly identified in one of two patients. No hepatic false positive reports occurred. Positive scan areas were graded as definite, probable or possible. All four of the pancreatic positive results graded as definite or probable positive were correct. Three false positive results occurred in the region of the pancreatic body, all had been graded as possible. Anti‐insulin scanning failed to detect four subsequently proven insulinomata (3 mm‐2 cm in diameter). Pelvic uptake of anti‐insulin occurred in a patient who was found to have a para‐ovarian tumour. An homogenate of this tumour also reacted with anti‐insulin in a radioimmunoassay. A true negative pancreatic scan was obtained in this patient. We conclude that this technique is insufficiently accurate for routine clinical use.
FACTORS IN THE OUTCOME OF TRANSSPHENOIDAL SURGERY FOR PROLACTINOMA AND NON‐FUNCTIONING PITUITARY TUMOUR, INCLUDING PREOPERATIVE BROMOCRIPTINE THERAPY
Authors: BEVAN J. S. , ADAMS C. B. T. , BURKE C. W. , MORTON K. E. , MOLYNEUX A. J. , MOORE R. A. , ESIRI M. M.
Published: March 2008

Radical transsphenoidal surgery in 58 patients with large non‐functioning pituitary tumours relieved pressure symptoms and disconnection hyperprolacti‐naemia without loss of pituitary function, and verified the diagnosis. Preoperative bromocriptine did not cause any shrinkage of non‐functioning tumours (n= 8), even up to 48 weeks. Thirty‐two patients not given postoperative radiotherapy are being followed‐up, and although two show minor CT scan evidence of tumour regrowth, for the others the delay in radiotherapy is enabling reproduction where required. In 20 patients with non‐invasive macroprolactinomas radical sugery caused no loss of pituitary function but cured eight, of whom one has relapsed; none of eight invasive prolactinomas was cured by surgery. Pre‐operative bromocriptine caused marked size reduction in seven of seven macroprolactinomas, but if continued beyond 6 weeks induced tumour fibrosis and uneven shrinkage which made surgery dangerous and unproductive. Selective transsphenoidal surgery relieved hyper‐prolactinaemia in 70% of patients with meso‐ (n= 15) or microprolactinoma (n= 24) usually without loss of pituitary function: the relapse rate was 1 per 88 patient years of follow‐up. Invasive prolactinomas, and macroprolactinomas showing uneven shrinkage with a short (up to 4 weeks) course of bromocriptine should have radiotherapy rather than surgery, while the patients most suited to surgery are those with mesoprolactinomas, or some macroprolactinomas with compact intrasellar shrinkage after short‐term bromocriptine. Microprolacti‐nomas generally did not benefit from surgery as compared to conservative therapy. In none of the tumour groups were the surgical findings an accurate predictor of postoperative pituitary function.
LACK OF VEGETATIVE AND ENDOCRINE ORCADIAN RHYTHMS IN FATAL FAMILIAL THALAMIC DEGENERATION
Authors: LUGARESI A. , BARUZZI A. , CACCIARI E. , CORTELLI P. , MEDORI R. , MONTAGNA P. , TINUPER P. , ZUCCONI M. , ROITER I. , LUGARESI E.
Published: March 2008

A total lack of neuroendocrine and vegetative circadian rhythms was observed in a patient with a familial degeneration of the anterior and dorso‐medial thalamic nuclei. Our findings support the role of the thalamus in regulating the periodicity of endocrine and vegetative functions.
MALIGNANT SOMATOSTATINOMA PRESENTING WITH DIABETIC KETOACIDOSIS
Authors: JACKSON J. A. , RAJU B. U. , FACHNIE J. D. , MELLINGER R. C. , JANAKIRAMAN N. , LLOYD R. V. , VINIK A. I.
Published: March 2008

High circulating levels of somatostatin (SRIF) were detected in a patient with a metastatic tumour after development of diabetic ketoacidosis (DKA). Fasting insulin and C‐peptide levels were markedly suppressed, but plasma glucagon was not suppressed below normal. Progressive cachexia ensued; at autopsy a poorly differentiated non‐small cell neuroendocrine carcinoma metastatic to liver was found. Small gallstones were noted. Electron microscopy of tumour tissue showed neurosecretory granules and tonofilament bundles. Immunohis‐tochemical staining of tumour cells was diffusely positive for carcinoembryonic antigen, bombesin‐like immunoreactivity, and calcitonin with focal immuno‐reactivity for SRIF, serotonin, neuron‐specific enolase, chromogranin, and epithelial membrane antigen. Column chromatography of plasma and tumour extract revealed five or more peaks of material with SRIF‐like immunoreactivity (SRIF‐LI): predominantly SRIF‐28 and intermediates in tumour extract, and SRIF‐14 and an intermediate between SRIF‐28 and SRIF‐14 in plasma. DKA in this case of somatostatinoma syndrome may reflect differential effects of tumour production of larger molecular weight SRIF forms on insulin and glucagon secretion.
REDUCTION OF HUMAN AND RAT TESTICULAR FOLLICLE STIMULATING HORMONE RECEPTORS BY HUMAN MENOPAUSAL GONADOTROPHIN IN VIVO AND IN VITRO
Authors: NAMIKI M. , NAKAMURA M. , OKUYAMA A. , SONODA T. , ITATANI H. , SUGAO H. , SAKURAI T. , NISHIMUNE Y. , MATSUMOTO K.
Published: March 2008

Reduction of human and rat testicular FSH receptors by hMG was studied in vivo and in vitro. After a single injection of hMG, the number of high affinity FSH receptors were significantly reduced for 5 and 3 d in human and rat testes, respectively, without affecting their affinity. FSH receptor numbers recovered to pretreatment values by 14 d after the injection. Radioactivity in rat testes found 48 h after a s.c. injection of 125I‐labelled human FSH was less than 10% of the maximum found 10 h after the injection, showing that the prolonged reduction of FSH receptors after hMG injection was not due to occupancy of the binding sites. Occupied FSH receptors measured in rat testes accounted for about 15% of all receptors on the day after an injection of hMG and for less than 5% after the third day. In experiments in vitro using organ culture techniques, an exposure to hMG for 24 h induced a dose‐related significant loss of the specific FSH binding sites for 7 and 5 d in human and rat testes, respectively. Thereafter, the loss was gradually recovered. These findings suggest that the reduction in FSH receptors in human and rat testes by hMG is mainly due to down‐regulation of the binding sites and that the testicular organ culture method used in the present study is useful to study hormonal regulation of testicular function, especially in human testes.
FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA III: BONE MINERAL METABOLISM
Authors: KRISTIANSEN J. H. , RØDBRO P. , CHRISTIANSEN C. , JOHANSEN J. , JENSEN J. T.
Published: March 2008

Bone mineral metabolism was studied in 10 subjects with familial hypocalciuric hypercalcaemia (FHH) and 10 age‐, sex‐ and surface area matched healthy controls. Bone turnover was estimated by urinary calcium and hydroxyproline excretions relative to creatinine (Ca/Creat and OHPr/Creat, respectively), serum bone Gla‐protein (S‐BGP) and serum alkaline phosphatase (S‐ALP). Bone status was evaluated by measurement of bone mineral content (BMC) on both forearms and X‐ray examinations of the hands. Ca/Creat and OHPr/Creat (indices of bone resorption) were both significantly higher in the FHH group than in the controls. S‐BGP and S‐ALP (indices of bone formation) tended towards a higher level in the FHH subjects, but the differences were not significant. The BMC values were similar in the two study groups and did not change with time. We conclude that these patients with FHH might have a bone turnover higher than normal, and that the increased bone resorption must be paralleled by an increased bone formation.
A COMPARISON BETWEEN THE EFFECTS OF SMS 201–995, BROMOCRIPTINE AND A COMBINATION OF BOTH DRUGS ON HORMONE RELEASE BY THE CULTURED PITUITARY TUMOUR CELLS OF ACROMEGALIC PATIENTS
Authors: LAMBERTS S. W. J. , VERLEUN T. , HOFLAND L. , DEL POZO E.
Published: March 2008

The in‐vivo reaction of the plasma GH concentration to the administration of the somatostatin analogue SMS 201‐995, bromocriptine and their combination were compared with the in‐vitro effects of both compounds and their combination on GH release and the GH tumour cell content of 9 acromegalic patients. Exposure of cultured GH‐secreting pituitary tumour cells for 4–96 h to SMS 201‐995 showed a variable, but in all instances during longer incubations statistically significant inhibition of GH release, which paralleled the sensitivity of GH secretion to the drug in vivo. This inhibitory effect on GH release was in two of the eight tumours accompanied by a decrease in the GH tumour cell content after 24‐72 h of culture. These changes either reflect an inhibition of GH synthesis and/or an increase in intracellular breakdown (crinophagy) of GH and might be the basis for the tumour shrinkage which has been observed in about half of the acromegalic patients during long‐term SMS 201‐995 therapy. The inhibitory effects of bromocriptine on GH secretion were antagonized by haloperidol, while the inhibitory effect of SMS 201‐995 was not affected by the dopamine receptor antagonist. This suggests that the effects of SMS 201‐995 and bromocriptine are mediated via separate mechanisms involving different receptors. Additive but no potentiating inhibitory effects of both drugs on GH release were observed in a group of six patients in vivo and in three of six tumours in vitro.
THE HIGHER THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE THE LOWER THE RESPONSE TO BROMOCRIPTINE AND THYROTROPHIN RELEASING HORMONE IN ACROMEGALY
Authors: SMALS A. E. M. , PIETERS G. F. F. M. , SMALS A. G. H. , HERMUS A. R. M. M. , BENRAAD TH. J. , KLOPPENBORG P. W. C.
Published: March 2008

In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty‐one acromegalic patients, 18 women and 13 men (age 46‐2 ±(SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1‐44 Bachem 100 μg i.v. bolus), TRH (Thyroliberin, Hoechst 200 μg i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (δGH 1‐995 ng/ml), which correlated significantly with the basal GH levels (r=+0.85, P<0.0001, n= 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r=−0.49, P<0.01, m= 30). This decrease correlated with the basal PRL level (r=+0.45, P<0.02, n= 29) and also the GH response to TRH (r=+0.66, P <0.0001, n= 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r=−0.43, P < 0.02, n= 29). The data are consistent with the existence of GH‐secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph‐like adenomas) responsive to TRH and Br but less responsive to GHRH.
THYROTROPHIN RELEASING HORMONE INDUCED CALCITONIN SECRETION IN PATIENTS WITH MEDULLARY CARCINOMA OF THE THYROID
Authors: NAKAMURA H. , SOMEDA H. , MORI T. , IMURA H.
Published: March 2008

An i.v. bolus injection of 500 μg TRH caused a prompt increase in plasma calcitonin (CT) in two patients with medullary thyroid carcinoma (MTC). In case 1 with a sporadic MTC, plasma CT increased from 0.32 ng/ml to 0.70 ng/ml 2 min after TRH. In the second case with multiple endocrine neoplasia (MEN) type II, plasma CT increased from 0.39 ng/ml to 4.7 ng/ml 2 min after the injection. None of five normal healthy subjects and a patient with thyroid follicular adenocarcinoma had significant changes in plasma CT levels after TRH. Studies with monolayer cultures of MTC cells derived from one patient revealed that TRH stimulated CT release. Incubation of the cells with TRH of 10−6m or 10−5m for 1 h increased CT concentration in the medium to 140% or 182% of the control level, respectively. Under the same conditions, pentagastin (10−6m) increased CT concentration in the medium to 156%. These results indicate the direct stimulatory effect of TRH on CT secretion in the patients with MTC.
EFFECT OF THYROXINE REPLACEMENT THERAPY ON PLASMA INSULIN‐LIKE GROWTH FACTOR 1 LEVELS AND GROWTH HORMONE RESPONSES TO GROWTH HORMONE RELEASING FACTOR IN HYPOTHYROID PATIENTS
Authors: VALCAVI R. , DIEGUEZ C. , PREECE M. , TAYLOR A. , PORTIOLI I. , SCANLON M. F.
Published: March 2008

The aim of this study was to evaluate the effect of T4 replacement therapy on plasma insulin‐like growth factor 1 (IGF‐1) levels in patients with primary hypothyroidism to see whether recovery of pituitary GH responsiveness to GRF was associated with increased plasma IGF‐1 levels. IGF‐1 levels and GH responses to GRF (1 μg/kg) were measured in 21 patients with primary hypothyroidism before and after T4 replacement therapy. T4 increased plasma IGF‐1 levels (57.2 ± 4.4 vs 75.9 ± 8‐8 ng/ml, mean ± SEM, P<0.05) and GH responses to GRF as assessed both by peak GH levels (9 ± 1.5 ng/ml before treatment vs 16.7 ± 3 ng/ml after treatment, mean ± SEM, P <0.05) and area under curve (496 ± 92 before treatment vs 896 ± 161 after treatment, mean‐± SEM, P < 0.05). Linear regression analysis showed a positive correlation between free T3 and IGF‐1 levels after treatment (r= 0‐37, P <0.05) and a negative relationship between plasma IGF‐1 levels before treatment and a IGF following T4 replacement therapy (r= 0.45, P < 0.025). However, no correlation was found between plasma IGF‐1 levels and GH responses to GRF, suggesting that GH responses to GRF are of no predictive value in relation to the recovery of plasma’ IGF‐1 levels following T4 replacement therapy in hypothyroid patients.
SERIAL SERUM THYROGLOBULIN MEASUREMENTS IN THE MANAGEMENT OF DIFFERENTIATED THYROID CARCINOMA
Authors: BLACK E. G. , SHEPPARD M. C. , HOFFENBERG R.
Published: March 2008

Serum thyreoglobulin (Tg) was measured on repeated occasions in 416 patients with differentiated thyroid cancer for up to 7 years after initial therapy. All patients had thyroidectomy and/or ablative 131I therapy and all measurements were done while patients were receiving T4 replacement. Tg was measured using a double‐antibody radioimmunoassay. Overall correlation between serum Tg concentration and presence or absence of cancer was 95‐9%. At the time of initial measurement 295 patients had serum Tg <5 μg/1, and in the latest analysis only 1‐7% of these patients showed evidence of disease. Initially there were 19 patients of a total of 121 with serum Tg > 5 μg/l in whom no cancer was apparent. In eight of these 19 subjects recurrent or metastatic disease has been diagnosed up to 3‐5 years after the first measurement indicating that in these cases serum Tg values were ‘predictive’. Serum Tg appears to be a sensitive and specific means of detecting residual, recurrent or metastatic thyroid cancer and in most situations can replace routine, expensive and inconvenient radioactive thyroid scans; these should be performed when serum Tg values are elevated or when there is clinical evidence suggesting recurrence.
DYNAMIC TESTS OF PARATHYROID FUNCTION FOR DIAGNOSIS OF PRIMARY HYPERPARATHYROIDISM IN MALIGNANCY
Authors: LJUNGHALL S. , BENSON L. , RASTAD J. , WIDE L , AKERSTROM G.
Published: March 2008

Hypercalcaemia can be caused by malignant diseases as well as by primary hyperparathyroidism (HPT). The two disorders may occur together and an accurate discrimination between them is sometimes not possible from basal measurements of calcium and parathyroid hormone (PTH) concentrations. In primary HPT the regulation of PTH secretion is maintained, albeit the set‐point is shifted to a hypercalcaemic value. Therefore, when serum calcium is lowered by ethylene diamine tetra‐acetic acid (EDTA) infusions or calcitonin injections, patients with primary HPT display enhanced secretion of PTH already within the hypercalcaemic range, whereas parathyroid function remains suppressed in malignancy‐associated hypercalcaemia. Tests based on this principle enable a specific identification of HPT. The present report describes eight hypercalcaemic patients with disseminated malignancy where HPT could be diagnosed by the use of such stimulatory tests.
GROWTH HORMONE HYPERRESPONSIVENESS TO GROWTH HORMONE‐RELEASING HORMONE IN PATIENTS WITH SEVERE LIVER CIRRHOSIS
Authors: SALERNO F. , LOCATELLI V. , MÜLLER E. E.
Published: March 2008

Patients with severe liver disease often have high baseline plasma GH levels and/ or paradoxical GH release in response to several secretagogues, e.g. TRH. In this paper, we have investigated in a group of cirrhotic patients the GH response to GH‐releasing hormone (GHRH) and evaluated the effectiveness of GHRH to cause GH release in TRH responder and non‐responder patients. Ten patients and seven age‐ and sex‐matched control subjects were given bolus injections of GHRH (01 and 1.0 μg/kg i.v. on separate occasions). GHRH 01 μg/kg failed to cause a GH response in both control and cirrhotic subjects, but 1 ‐0 μg/kg caused a significantly higher GH response in patients than in controls. Evaluation of the GH response curve after GHRH revealed a similar pattern of secretion in the TRH‐responders (four subjects) and non‐responders (six subjects). These results suggest that the enhanced GH responsiveness to GHRH in cirrhotic patients may contribute to their high baseline GH levels and/or secretory rate, and the mechanism(s) of the paradoxical GH rise after TRH seems to be separate from that for GH hyperresponsiveness to GHRH.
THE EFFECT OF GLUCOCORTICOIDS ON CORTICOSTEROID BINDING GLOBULIN
Authors: SCHLECHTE J. A. , HAMILTON D.
Published: March 2008

To evaluate the effect of glucocorticoids on corticosteroid binding globulin (CBG), we measured the binding capacity and binding affinity of Cortisol for CBG in normal subjects, patients receiving glucocorticoids and patients with Cushing's syndrome. Normal subjects had a mean binding capacity of 3.8 (±SD 0.7) ± 10‐7 mol/l and mean binding affinity of 1.96 ± 0.48 ± 10‐8 M. Patients with Cushing's syndrome had a 40% decrease in binding capacity (2.3±0.4 ± 10‐7 mol/l) compared to control subjects and significantly lower mean binding capacity than patients receiving pharmacological (2.9 ± 0.6 ± 10‐7 mol/l) and physiological doses of glucocorticoids (3.4 ± 0.6 ± 10‐7 mol/l) (P= 0.05 one‐way analysis of variance). Patients with endogenous Cortisol excess also had significantly lower mean binding affinity (1.54 ± 0.37 ± 10‐8 M) than normal subjects and glucocorticoid treated subjects. These changes suggest that both endogenous and exogenous glucocorticoids can modulate circulating levels of CBG and may have important implications for patients receiving steroid therapy.
GROWTH HORMONE BLOCKING ANTIBODIES IN A PATIENT WITH DELETION OF THE GH‐N GENE
Authors: SCHWARZ S. , BERGER P. , FRISCH H. , MONCAYO R. , PHILLIPS J. A. , WICK G.
Published: March 2008

We present another patient with the rare disorder of isolated GH deficiency (IGHD) type 1 A. The diagnosis was confirmed by the clinical course, serology and genetic structure. Analysis of the post GH treatment serum of this patient with several thoroughly characterized monoclonal antibodies against GH established the presence of polyclonal, high titre and high avidity IgG‐class antibodies against GH. These had the ability to neutralize GH as they could inhibit the binding of radiolabelled GH to GH‐receptors on IM9 lymphoblastoid cells. DNA restriction mapping indicated a deletion of the GH‐N gene and a family DNA pattern that was consistent with the proposed autosomal recessive aetiology of this disorder. These findings explain the inability of this patient to synthesize GH and his total immunological intolerance to GH replacement therapy.
DISTURBANCES OF THE MENSTRUAL CYCLE IN BULIMIA NERVOSA
Authors: PIRKE K. M. , FICHTER M. M. , CHLOND C. , SCHWEIGER U. , LAESSLE R. G. , SCHWINGENSCHLOEGEL M. , HOEHL C.
Published: March 2008

Blood was obtained three times a week throughout one menstrual cycle or during a 6‐week period from 15 patients with bulimia nervosa and from 10 healthy age‐matched controls. Of the patients, three had amenorrhoea, eight had oligomenorrhoea and four had regular cycles. Normal follicular development, as judged from continuously low oestradiol (E2) values (<120 pg/ml or <440 pmol/1), did not occur in seven patients. Compared to patients with increasing E2 values (> 120 pg/ml), these seven had a significantly lower body weight. Among the eight patients showing follicular development (E2 > 120 pg/ ml), four reported regular cycles, but only three developed normal plasma progesterone (P4) values during the luteal phase (P4 > 3 ng/ml or > 9.5 nmol/1). The luteal phase was of normal length in only one bulimic patient.
EFFECT OF OBESITY AND WEIGHT LOSS ON THE ARGININE VASOPRESSIN RESPONSE TO INSULIN‐INDUCED HYPOGLYCAEMIA
Authors: COIRO V. , CHIODERA P.
Published: March 2008

Arginine vasopressin (AVP) response to insulin‐induced hypoglycaemia was evaluated in 16 men with normal weight and in 9 obese men. Obese subjects were restudied following substantial weight loss. The decrease in blood glucose concentrations after insulin injection (0‐15 U/kg i.v. bolus) had a similar pattern and magnitude in the normal controls and in the obese subjects both before and after weight loss. Basal plasma insulin concentrations in the obese patients were significantly higher than in the normal weight subjects, but were back to normal after weight reduction. During all tests, blood osmolality, haematocrit and blood pressure remained constant. The AVP rise during the insulin tolerance test (ITT) was significantly lower in the obese patients than in the normal controls. The mean peak plasma AVP level was 2.3 times higher than the basal value in the normal controls, but only 1.6 times in the obese patients. After weight loss, the obese men regained normal AVP responses during the ITT. These data indicate that a hypothalamic pituitary disorder affects the AVP response to insulin‐induced hypoglycaemia in obese men.
EFFECT OF PREDNISOLONE AND SALICYLATE ON SERUM THYROGLOBULIN LEVEL IN PATIENTS WITH SUBACUTE THYROIDITIS
Authors: YAMAMOTO M. , SAITO S. , SAKURADA T. , FUKAZAWA H. , YOSHIDA K. , KAISE K. , KAISE N. , NOMURA T. , ITAGAKI Y. , YONEMITSU K. , YOSHINAGA K.
Published: March 2008

Twelve patients with subacute thyroiditis were divided into two groups and treated with prednisolone or salicylate. The initially elevated T4, T3, free T4 (FT4), free T3 (FT3) and erythrocyte sedimentation rate (ESR) were reduced during the early phase within about 4 weeks in both groups. The serum levels of thyroglobulin (Tg) were elevated in both groups treated with salicylate and prednisolone (252 ± SD 117 ng/ml and 233 ± SD 157 ng/ml, respectively) at initial examination. The serum level of Tg declined during the early phase with prednisolone treatment, and it reached normal values at the end of the early phase (17 ± SD 15 ng/ml). With salicylate treatment, the decline of levels of Tg was delayed and it was elevated (80 ± SD 34 ng/ml) despite normal levels of thyroid hormones and ESR at the end of early phase. The serum level of Tg at the end of the early phase of prednisolone treated was significantly lower than that of salicylate treatment (P<001). It is suggested that the effect of prednisolone on rapid decrease of Tg may be related to its inhibitory action of intrathyroid hydrolysis.
THE EFFECT OF ORAL GLUCOSE ON THE LEUCOCYTE SODIUM PUMP IN NORMAL AND OBESE SUBJECTS
Authors: NG L. L. , HOCKADAY T. D. R.
Published: March 2008

The effect of oral glucose (40 g/m2 body surface area) on the leucocyte 22Na efflux rate constants (ERC) was studied in 13 normal weight and 10 obese subjects. The ouabain‐sensitive 22Na ERC was higher in leucocytes isolated from fasting obese subjects (median [range] for obese 2.77 [2.33‐3.11] vs normals 1.91 [1.57‐2.77] h‐1, P&0.001). There was no difference in the ouabain‐resistant 22Na ERC. Oral glucose raised the ouabain‐sensitive 22Na ERC after 2 h in normal subjects (1.91 [1.57‐2.77] to 2.41 [2.11‐3.02] h‐1, P&0.001). The ouabain‐resistant 22Na ERC fell from 0.71 [0.32‐1.10] to 0.46 [0.35‐0.68] h‐1, P &0.008. Conversely, in obese subjects, the ouabain‐sensitive ERC fell (2.77 [2.33‐3.11] to 2.59 [2.11‐2.92] h‐1, P&0‐06). There was no significant change in ouabain‐resistant 22Na ERC 2 h after oral glucose. The fasting leucocyte 22Na ouabain‐sensitive ERC correlated with fasting plasma insulin levels and insulin resistance (rs= 0.48, P&0.01 for both). The change in this ERC with oral glucose correlated with the incremental insulin response over 2 h (rs= ‐0.53, P&0‐006) and to the insulin resistance (rs= ‐0.56, P&0.003). The failure of oral glucose to stimulate the leucocyte sodium pump in obesity could partially account for the defect in dietary thermogenesis in obesity. This defect in stimulation of the sodium pump is related to insulin resistance.
PHYSIOLOGICAL GROWTH HORMONE SECRETION DURING SLOW‐WAVE SLEEP IN SHORT PREPUBERTAL CHILDREN
Authors: ADLARD P. , BUZI F. , JONES J. , STANHOPE R. , PREECE M. A.
Published: March 2008

The usefulness of a limited nocturnal GH profile has been evaluated for the assessment of physiological GH secretion. We have analysed the complete overnight GH and sleep profiles of 20 short prepubertal children, sampled at 15‐min intervals. The mean age was 9.1 years (range 4.3‐11.7 years) and mean height velocity standard deviation score (SDS) ‐ 1 0 (range ‐ 2.4 to + 0.4). The sleep stage in which the maximal GH value was reached varied considerably between the patients. Only 55% achieved the maximal GH value during the first slow‐wave sleep period, and 65% in the first 2 h of sleep. The maximal values during the first slow‐wave period correlated weakly with the sum of the nocturnal peak values and the total area under the curve of the complete GH profile. None of these parameters correlated with height velocity. We conclude that at present there is no substitute for complete overnight or 24 h GH profiles for the assessment of physiological GH secretion, but the clinical significance of the variations seen remains unclear.
THE EFFECT OF o,p'‐DDD ON ADRENAL STEROID REPLACEMENT THERAPY REQUIREMENTS
Authors: ROBINSON B. G. , HALES I. B. , HENNIKER A. J. , HO K. , LUTTRELL B. M. , SMEE I. R. , STIEL J. N.
Published: March 2008

Two patients with adrenal carcinoma treated with 2,2‐bis (2‐chlorophenyl‐4‐chlorophenyl)‐1, 1‐dichloroethane (o, p'‐DDD) as adjuvant therapy were studied. Both patients developed hypoadrenalism while on o, p'‐DDD and apparently adequate dexamethasone replacement therapy. The hypoadrenalism was overcome by increasing steroid replacement therapy. Dexamethasone levels were measured in the serum by radioimmunoassay and shown to be lowered by o, p'‐DDD therapy. A study of the absorption and disappearance of dexamethasone from the circulation in response to a (1 mg oral dose indicated that the steroid was absorbed normally but was cleared more rapidly from the circulation of these two patients than from normal controls. This may be due to a change in the type of metabolites excreted. It is suggested that many of the reported side‐effects of o,p'‐DDD may be due to hypoadrenalism and may be controlled by greatly increasing the steroid replacement dose. The adequacy of corticosteroid replacement therapy may best be assessed by monitoring the levels of ACTH.
THE CORRELATION BETWEEN SERUM AND SALIVARY MELATONIN CONCENTRATIONS AND URINARY 6‐HYDROXYMELATONIN SULPHATE EXCRETION RATES: TWO NON‐INVASIVE TECHNIQUES FOR MONITORING HUMAN CIRCADIAN RHYTHMICITY
Authors: NOWAK R. , MCMILLEN I. C. , REDMAN J. , SHORT R. V.
Published: March 2008

Athough there is a circadian rhythm in blood melatonin concentrations in humans, the problems associated with frequent blood collection limit the use of this rhythm in the investigation of the circadian system and in the diagnosis and treatment of chronobiological disorders. Therefore, to establish a convenient, non‐invasive technique for monitoring melatonin circadian rhythmicity, we compared the melatonin concentrations in blood samples collected from five subjects every 2‐4 h over a 26 h period, with the melatonin concentrations in saliva samples and with the total amount of 6‐hydroxymelatonin sulphate excreted in the urine during 2‐h periods. There was significant correlation between serum and salivary melatonin concentrations (r= 0.81, P < 0.001), and between serum melatonin concentrations and 6‐hydroxymelatonin sulphate excretion rates (r= 0‐72, P<0001). The results demonstrate that both salivary melatonin concentrations and urinary 6‐hydroxymelatonin sulphate excretion rates are reliable indices of serum melatonin concentrations. These measurements, in combination with frequent sample collection, provide two convenient, non‐invasive techniques for monitoring melatonin circadian rhythmicity.
NON‐ADENOMATOUS INAPPROPRIATE TSH HYPERSECRETION AND EUTHYROIDISM REQUIRES NO TREATMENT
Authors: HUGHES I. A. , ICHIKAWA K. , DEGROOT L. J. , JOHN R. , JONES M. K. , HALL R. , SCANLON M. F.
Published: March 2008

The syndrome of inappropriate TSH secretion is described in a euthyroid girl and her father. Based on nuclear T3 binding studies in fibroblasts, generalized tissue resistance was associated with a lower binding affinity for T3 in nuclear extracts suggestive of a structurally abnormal receptor for T3. Early recognition of the syndrome and observation of the short‐term response to thyroid medication prevented unnecessary trials of antithyroid medication and later radical ablative thyroid treatment.
THE EFFECT OF ANDROGEN BLOCKADE ON PULSATILE GONADOTROPHIN RELEASE AND LH RESPONSE TO NALOXONE
Authors: BALZANO S. , MIGLIARI R. , SICA V. , SCARPA R. M. , PINTUS C. , LOVISELLI A. , And E. USAI , BALESTRIERI A.
Published: March 2008

In order to clarify the effects of androgen blockade on the hypothalamic‐pituitary‐testicular axis in man, four patients with advanced prostate cancer, not previously treated, were given oral flutamide, 250 mg three times daily for 9 days. Before, and 7, 8 and 9 days after starting flutamide treatment, on separate days, the following tests were performed: a gonadotrophin pulsatility study, with 20 min interval blood sampling for 12 h, a naloxone test and a GnRH test. Flutamide induced a significant increase in both LH and FSH pulse frequency, while pulse amplitudes and plasma integrated concentrations (IC) of LH and FSH were unaffected. Plasma integrated concentrations of testosterone and oestradiol rose significantly, while that of prolactin was unaffected. The increase in plasma LH concentration induced by naloxone injection was abolished by flutamide treatment. On the other hand, the small FSH response to naloxone was unaffected by flutamide treatment. Response to GnRH was unaffected by flutamide. These results suggest that flutamide exerts effective androgen blockade at the hypothalamic level, since, despite increased plasma testosterone concentrations, gonadotrophin pulse frequency increased and the LH response to naloxone was abolished.
FASTING CALCIUM EXCRETION AND PARATHYROID HORMONE TOGETHER DISTINGUISH FAMILIAL HYPOCALCIURIC HYPERCALCAEMIA FROM PRIMARY HYPERPARATHYROIDISM
Authors: STUCKEY B. G. A. , KENT G. N. , GUTTERIDGE D. H. , PULLAN P. T. , PRICE R. I. , BHAGAT C.
Published: March 2008

Routine estimation of plasma calcium has made the finding of asymptomatic hypercalcaemia a frequent occurrence. A high index of suspicion for familial hypocalciuric hypercalcaemia (FHH) will lead to accurate diagnosis and avoidance of unnecessary parathyroid surgery. Four FHH kindreds with 16 hypercalcaemic members were found in an unselected referral population over 3 years. Differentiation from primary hyperparathyroidism (42 patients in the same period) was facilitated by analysis of fasting blood and urine for renal handling of calcium, phosphate and cyclic AMP. We found that a plot of serum PTH against fasting calcium excretion separated all cases of each disorder. The discriminatory power of these two variables was confirmed by multivariate discriminant function analysis. An elevated plasma chloride was found to be common to both diseases and of no value in differentiation.
MULTIPLE SYMMETRIC LIPOMATOSIS (LAUNOIS‐BENSAUDE SYNDROME): EFFECT OF ORAL SALBUTAMOL
Authors: LEUNG N. W. Y. , GAER J. , BEGGS D. , KARK A. E. , HOLLOWAY B. , PETERS T. J.
Published: March 2008

A 65‐year‐old Kenyan Asian developed rapidly progressive multiple symetrical lipomatosis over 8 years. Noradrenaline infusion showed a normal response of plasma free fatty acids. In‐vitro studies of the lipomatous tissue demonstrated intact lipolytic activities with a normal rate of free fatty acids release and cyclic AMP accumulation with or without isoprenaline and fenoterol stimulation. A clinical trial of oral salbutamol, a β2‐agonist, was performed with significant therapeutic effect. The body fat mass showed a reversal of the rapid progression while on the treatment, associated with an increase in the resting metabolic rate.
PHARMACOKINETICS OF ALDOSTERONE IN PATIENTS WITH ADDISON'S DISEASE: EFFECT OF RIFAMPICIN TREATMENT ON GLUCOCORTICOID AND MINERALOCORTICOID METABOLISM
Authors: SCHULTE H. M. , MÖNIG H. , BENKER G. , PAGEL H. , REINWEIN D. , OHNHAUS E. E.
Published: March 2008

Treatment of tuberculosis with rifampicin in patients with pre‐existing adrenal failure has been reported to induce adrenal crisis due to alteration of Cortisol metabolism by induction of hepatic mixed liver oxygenase enzymes. To determine whether mineralocorticoid metabolism is altered by rifampicin treatment, we established the pharmacokinetics of immunoreactive aldosterone. The metabolic clearance rate (MCR) and plasma half‐life of this material were measured before and after 6 days of rifampicin treatment (600 mg/day) in seven patients with Addison's disease due to tuberculosis. Antipyrine clearance and urinary 6‐β‐hydroxycortisol excretion was determined to demonstrate induction of the cytochrome P 450 dependent enzymes. Infusion of aldosterone at a constant rate of 0‐17 mg/h over 4‐5 h produced steady state concentrations after 2 h, with no difference before and after rifampicin treatment (mean ± SD, 1649 ± 144 vs 1586 ± 80 pg/ml, respectively). The disappearance curve of IR‐aldosterone from plasma was biexponential. No change could be observed in the plasma half‐lives (α‐phase 29 ± 1.9 min vs 30 ± 1.5 min, β‐phase 129 ± 3.2 minra126 ± 4.3min), the MCR (1‐47 ± 0.1 1/h/kg vs 1.46 ± 0.1 1/h/kg vs), and the volume of distribution (9.9 ± 1.9 vs 10.2 ± 0.3 1). The antipyrine half‐life decreased significantly from 12.2 ± 2.6 h to 7.6 ± 0.9 h (P± 0.05) with a rise in antipyrine clearance from 0.38 ± 0.07 to 0.80 ± 0‐23 ml/min/kg (Plt;0.05) and no change in the volume of distribution. Urinary excretion of 6‐β‐hydroxycortisol increased from 711 ± 130 μg/24 h before to 1670 ± 387/μg/24 h (P < 0‐05) after 6 days of rifampicin treatment with no changes in urinary free Cortisol excretion.
THE MATERNAL OVARY IS NOT THE SOURCE OF CIRCULATING INHIBIN LEVELS DURING HUMAN PREGNANCY
Authors: McLACHLAN R. I. , HEALY D. L. , LUTJEN P. J. , FINDLAY J. K. , de KRETSER D. M. , BURGER H. G.
Published: March 2008

The concentration of immunoreactive inhibin in serum was measured in three pregnant women with premature ovarian failure involved in a donor oocyte in‐vitro fertilization programme. Inhibin was not detectable in peripheral serum prior to conception but rose within 2‐4 weeks of embryo transfer, whereafter levels rose gradually during pregnancy (< 20 weeks 1‐22 U/ml (0.85‐1.76) versus >20 weeks 2.28 U/ml (1.42‐3.67), P < 0.01; geometric mean ± 67% confidence interval) and were similar to those observed in 24 normal pregnant women. hCG rose in parallel with inhibin during early gestation, but declined after 3 months. FSH levels were elevated before conception and were suppressed during pregnancy. In conclusion (i) immunoreactive inhibin is detectable from early gestation in women with no endogenous ovarian function indicating that the maternal ovary does not contribute significantly to inhibin secretion during pregnancy; (ii) the trophoblast is the likely source of inhibin during pregnancy; (iii) the regulation of hCG and inhibin secretion differs throughout gestation; and (iv) inhibin may have a role in FSH regulation during pregnancy and/or a local role within the feto‐placental unit.
THE PITUITARY‐LEYDIG CELL AXIS IN MEN WITH SEVERE DAMAGE TO THE GERMINAL EPITHELIUM
Authors: TSATSOULIS A. , WHITEHEAD E. , JOHN J. ST. , SHALET S. M. , ROBERTSON W. R.
Published: March 2008

Eighteen men (mean age 27, range 18‐30 years) treated for Hodgkin's disease with 6‐8 courses of MVPP (Mustine, Vinblastine, Procarbazine and Prednisolone) have had Leydig cell function assessed by their steroidogenic responses to stimulation by a single bolus dose of HCG (1000 units intramuscularly). Normal age‐matched men (n= 16) acted as controls. Baseline immunoreactive FSH was markedly raised in the patients (mean 18.1 ± SD 6‐9 vs 2.0 ± 1.5 IU/1, P< 0‐0001) reflecting damage to the germinal epithelium. Immunoreactive LH was also greater in patients (10‐3 + 3‐9 IU/1) than in controls (3‐9+1‐9 IU/1, P<00001). There were no differences between the baseline testosterone, androstenedione, oestradiol, oestrone and sex hormone binding globulin (SHBG) concentrations. The testosterone/SHBG ratios were similar in the two groups and there was no correlation between baseline LH and testosterone concentrations or testosterone/SHBG ratios. Testosterone, androstenedione, oestradiol and oestrone secretion in response to HCG stimulation were similar at 24 h and 96 h in both groups. In order to explain the paradox of elevated immunoreactive LH in the face of normal testicular steroidogenesis in such patients, LH biological activity (B) as well as LH immunoreactivity (I) and FSH and testosterone were estimated in a second similar group of patients (n= 17, mean age 27, range 17‐43 years) and in a further age‐matched control group (n= 17). Bioactive and immunoreactive LH levels were significantly increased (P< 0‐005 and P< 0‐001, respectively) in the patient group. However, the biological: immunological (B:I) LH ratios were found to be similar in the patients (2.7 ± 0.6, mean ± SD) and controls (2.8 ± 0.7). There was a significant correlation between immunoreactive LH and FSH concentrations in the patient group (r = 0‐65, P<001), but not in the controls. In conclusion Leydig cell function, as judged by the steroidogenic responses to HCG stimulation, is normal in patients with chemotherapy‐induced spermatogenic damage. The biological activity of LH is not changed, but there is a resetting of the LHLeydig cell axis
STRUMA OVARII: A CASE REPORT
Authors: LAZARUS J. H. , RICHARDS A. R. , MACPHERSON M. J. , DINNEN J. S. , WILLIAMS E. D. , OWEN G. M. , WADE J. S. H.
Published: March 2008

A patient with struma ovarii and hyperthyroidism is described. She was treated for Graves' hyperthyroidism at age 22 and received thyroxine for post‐operative hypothyroidism. Twenty years later she became thyrotoxic and was treated with antithyroid drugs and radioiodine. Diagnosis of struma ovarii was made by radioiodine profile scanning and an ovarian tumour was removed. This had the pathological features of struma ovarii and autoradiographic evidence of pre‐operatively administered 125I was seen in the lesion. The patient had positive results for long acting thyroid stimulator (LATS) and LATS‐protector (LATS‐P) pre‐ and post‐operatively. Bioassays for thyroid stimulators were positive post‐operatively but radioreceptor assays for TsAb were consistently negative. It is suggested that profile scanning is an appropriate investigation for diagnosis. It is not clear whether the lesion was autonomous or being stimulated by circulating thyroid stimulators.
GH FEEDBACK OCCURS THROUGH MODULATION OF HYPOTHALAMIC SOMATOSTATIN UNDER CHOLINERGIC CONTROL: STUDIES WITH PYRIDOSTIGMINE AND GHRH
Authors: ROSS R. J. M. , TSAGARAKIS S. , GROSSMAN A. , NHAGAFOONG L. , TOUZEL R. J. , REES L. H. , BESSER G. M.
Published: March 2008

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 μg 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.
THE EFFECT OF ALPHA ADRENERGIC MANIPULATION ON THE 24 HOUR PATTERN OF CORTISOL SECRETION IN MAN
Authors: AL‐DAMLUJI S. , CUNNAH D. , PERRY L. , GROSSMAN A. , BESSER G. M.
Published: March 2008

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.