bluuebunny/crossref_metadata_2025 huggingface dataset:
Oestrogen formation in genital and non‐genital skin fibroblasts cultured from patients with hypospadias
Authors: Staib Peter , Kau Nikolaus , Romalo Gabriela , Schweikert Hans‐Udo
Published: March 2008

OBJECTIVE Hypospadias is the most common birth defect in males. in most cases the aetiology is unknown. Since penile development is androgen dependent and oestrogen can modify androgen action, we compared the formation of oestrogen In penile tissue from patients with hypospadias to those with normal penile development.

DESIGN AND PATIENTS Oestrogen formation was assessed in fibroblast monolayers grown from biopsies of genital and non‐genital skin from 11 males with normal genital development (controls) and 18 males with severe hypospadias utilizing the incorporation of tritium into H2O resulting from the aromatization of 1β‐3H‐androstenedione.

RESULTS in paired fibroblast strains from genital and non‐genital skin of nine males with hypospadias, oestrogen formation was significantly (P < 0·025) lower In non‐genital skin. Rates of oestrogen formation were also higher in a subset of foreskins from subjects with hypospadias than In normal controls and the remaining hypospadias subjects. In addition, oestrogen formation in this subset of fibroblast strains from patients with hypospadias was markedly enhanced by incubation of Intact monolayers with either cholera toxin or forskolin, agents known to stimulate CAMP formation. Oestrogen formation in the remaining cell strains (controls and hypospadias) was also enhanced in most instances by cholera toxin and forskolin, although to a much lower degree. Thus, we identified in the hypospadias group a subgroup of fibroblast strains in which unstimulated and stimulated oestrogen formation was markedly higher than in other strains examined.

CONCLUSIONS Since oestrogen can modify certain androgen effects within cells and since formation of the male genitalia during embryogenesis is mediated by androgens, elevated oestrogen formation in male genital tissue might be a causative factor of hypospadias in some Instances.
Effect of treatment on established osteoporosis in young women with amenorrhoea
Authors: Gulekli Bulent , Davies Melanie C. , Jacobs Howard S.
Published: March 2008

BACKGROUND AND OBJECTIVE Amenorrhoea in women of reproductive age causes loss of bone mineral. This study assessed the effect of treatment of amenorrhoea on bone mineral density.

DESIGN Serial measurements of bone mineral density were obtained in women receiving treatment for amenorrhoea.

PATIENTS Eighty‐five women aged 17‐40 with a past or current history of amenorrhoea, from various causes, with median duration of 46.5 months (range 8 months‐21 years).

MEASUREMENTS Bone mineral density in the lumbar spine was measured by dual‐energy X‐ray absorptlometry. RESULTS initial vertebral bone mineral density was low, mean 0·85 (SD 0·10) g/cm2. After an interval of 19·6 (SD 7·5) months on treatment there was a highly significant increase to 0·89 (SD 0·10) g/cm2 (P < 0·0005). This was equivalent to a gain in bone mass of 21% per year (95% confidence interval 1·5–2·8%). improvement was seen in ail diagnostic groups (except polycystic ovary syndrome) and with all types of therapy. We observed no difference in the response of previously untreated patients compared with those already on treatment, nor any change in response with increasing duration of treatment. No new fractures were reported during the study. CONCLUSIONS Bone mineral density in young women with amenorrhoea is improved by appropriate treatment, but recovery is not substantial. Hence early diagnosis and therapy is essentlal to prevent bone loss.
Suramin in adrenocortical cancer: limited efficacy and serious toxicity
Authors: Arlt Wiebke , Reincke Martin , Siekmann Lothar , WInkelmann Werner , Allolio Bruno
Published: March 2008

OBJECTIVE No satisfactory treatment for adrenocortical carcinoma (ACC) is available. We investigated the efficacy and toxicity of suramin In the treatment of metastatic ACC since suramin has been recently reported to be active as a single agent therapy for patients with ACC and prostatic carcinoma.

DESIGN We collected data on 9 patients with metastatic ACC treated with suramin in four centres in Germany between 1987 and 1992.

PATIENTS Nine patients (5 women, 4 men; age range 32–67 years) were included. Biochemical evidence of steroid excess was found in 6/9, in three leading to clinical symptoms (hypertension, hyperglycaemla, hirsutism, gynaecomastia).

MEASUREMENTS Tumour responses were assessed by radiological and biochemical evaluation. Other investigations included regular measurements of blood cell counts, coagulation, hepatic and renal function parameters, and serum suramin concentrations.

RESULTS The patients received cumulative doses ranging from.2 to 30·2 g suramin over periods of 1–15 months. 3/9 achieved a partial response, 2/9 disease stabilization and 4/9 experienced progressive disease. Tumour responses were transient. Suramin treatment was without direct influence on steroid excess. Serious side‐effects included coagulopathy (6/9), thrombocytopenla (6/9), polyneuropathy (2/9) and allergic skin reactions (4/9); the death of two patients was possibly related to suramin therapy. Both toxicity and tumour response were strongly associated with serum level or cumulative dose of suramin.

CONCLUSIONS (1) Suramin is of antineoplastic efficacy in the treatment of metastatic adrenocortical carcinoma. (2) The clinical use of suramln is limited by a narrow therapeutic window with the risk of serious and possibly lethal toxicity at one extreme, and loss of efficacy at the other. Strict monitoring of suramin serum levels is mandatory aiming at levels between 200 and 250mg/l. Suramin should not be considered as first‐line treatment for metastatic adrenocortical carcinoma. (3) To improve treatment options in adrenocortical carcinoma as well as for further investigation on the usefulness of suramin, controlled prospective trials are urgently needed.
Glucose and fat metabolism in adults with growth hormone deficiency
Authors: Salomon F. , Cuneo R. C. , Umpleby A. M. , Sönksen P. H.
Published: March 2008

OBJECTIVE Adults with long‐standing GH deficiency have a decreased lean body mass and an increased fat mass. We investigated the effects of the abnormal body composition on glucose turnover and fuel metabolism.

DESIGN Cross‐sectional analysis.

PATIENTS Twenty‐four adults with acquired GH deficiency and a wide range of adiposity (body mass index from 18·8 to 42·3 kg/m2).

MEASUREMENTS In the post‐absorptive state glucose turnover was measured following intravenous injection of 3‐3H‐glucose and leucine oxidation was assessed following intravenous injection of 1‐14C‐leuclne. Glucose and fat oxidation were calculated from indirect calorimetry using protein oxidation derived from leucine oxidation.

RESULTS Total glucose turnover was 692 ± 146 μmol/min (mean ± SD) and Increased with height (r= 0·70, P= 0·0003) and with lean body mass (LBM) (r= 0·80, P < 0·0001). Glucose turnover expressed per kg LBM was in the published normal range (14·2 ± 2·1 pmol/kg LBM min). Glucose oxidation was 47 ± 27% of glucose turnover and increased with LBM (r= 0·59, P= 0·008) but not with height (r= 0·32, NS). Glucose turnover increased with increasing fat oxidation (r= 0·61, P= 0·006). The non‐oxidative part of glucose turnover was positively correlated with fat oxidation (r= 0·82, P= 0·0001) and inversely with the respiratory quotient (r= ‐0·81, P < 0·0001). Ketone body concentration (r= 0·55, P= 0·03), but not free fatty acid levels (r= 0·21, NS), correlated with fat oxidation. Fasting plasma glucagon levels were elevated (35 ± 13 vs 9 ± 19pmol/l (published controls) and inversely related to lean body mass (r= ‐0·44, P= 0·04).

CONCLUSIONS Adults with GH deficiency studied after an overnight fast have changes In glucose and fuel metabolism seen In normal subjects after more prolonged fasting suggesting that adults with hormone deficiency have reduced carbohydrate stores.
Metabolic effects of growth hormone administered subcutaneously once or twice daily to growth hormone deficient adults
Authors: Laursen Torben , Jergensen Jens O. L. , Chrlstiansen Jens S.
Published: March 2008

OBJECTIVE The aim of this study was to compare the metabolic effects of GH administered subcutaneously either once or twice daily. The actions of GH might depend upon a pulsatlle pattern of serum GH. Pulsatile and continuous intravenous delivery of GH, however, induce similar short‐term metabolic effects in GH deficient patients. An improved growth response is obtained in GH deficient children when a fixed weekly GH dose Is administered by dally subcutaneous injections instead of twice or thrice‐weekly intramuscular injections. A more pulsatile pattern and serum GH levels above zero might be achieved by further increasing the Injection frequency. Increased daytime GH levels might, however, adversely affect the circadian patterns of metabolic indices, whlch have been demonstrated to be more successfully reproduced by evening compared with morning GH administration.

DESIGN AND MEASUREMENTS In a cross‐over study, 8 GH deficient patients (age 16–43 years) were treated with 3IU/m2/24h of human GH. The dose was injected in the evening for 4 weeks and for another 4 weeks two‐thirds was injected in the evening and one‐third in the morning. At the end of each period the patients were admitted to the hospital for 37 hours. Steady‐state profiles of GH, IGF‐I, IGF binding proteins 1 and 3, Insulin, glucose, lipid Intermediates and metabolites were obtained following administration of 3IU/m2 of GH (at 1900 h (one injection) and at 1900 and 0800 h (two injections). RESULTS Similar mean integrated levels of serum GH (mUII) were obtained (7·46 ± 0·84 (one injection) vs 6·46 ±0·62 (two Injections) (P = 0·15). Mean levels ± SEM of serum IGF‐I (μg/I) were significantly increased (P < 0·01) following two daily GH Injections (330·3±48·1 (one Injection) vs 399·1±53·0 (two injections). Serum IGFBP‐3 levels were not signlflcantly different on the two occasions, while levels of the GH Independent IGFBP‐1 (μg/l) were slightly but significantly lower following twice‐dally GH injections (1·61±0·42 vs 1·13 ±0·56, respectively (P < 0·04). The pattern of IGFBP‐1 was opposite to that of insulin. Similar levels of insulin and glucose were obtained with both GH regimens, while levels of non‐esterlfied fatty acids were significantly higher following once‐dally GH injection (P < 0·001).

CONCLUSIONS Twice‐dally GH injections, apart from producing a more physiological serum GH profile, were superior to one Injection in increasing serum IGF‐I and decreasing IGFBP‐1 levels. Both of these changes tend to amplify the effects of the administered GH. Twice‐daily Injections, however, resulted Ln lower night‐time levels of lipid Intermediates.
Impaired prolactin response to arginine in patients with hyperthyroidism
Authors: Ciccarelli Enrica , Zini Michele , Grottoll Silvla , Razzore Paola , Portioli Italo , Valcavi Roberto
Published: March 2008

OBJECTIVE Reduced PRL responses to TRH or dopamine antagonists have been described in hyperthyroid patients. Arginine stimulates PRL secretion through pathways other than the activation of TRH receptors or dopamine‐dependent mechanisms. We therefore investigated PRL responses to arginine in patients with hyperthyroidism.

DESIGN L‐Arginine (30 g Infused over 30 minutes) was administered at time zero.

SUBJECTS Sixteen patients with untreated hyperthyroidism due to Graves' disease (8 female and 8 male), with a mean age (± SE) of 31·3 ± 1·4 years (range 23–42), and 12 normal subjects (6 female and 6 male, ages 30·1 ± 2·1 years, range 22–47) were studied. MEASUREMENTS Prolactin was measured by RIA between ‐30 and 120 minutes, at 15‐minute intervals. RESULTS Basal PRL levels were similar in the hyperthyroid patients and normal control subjects. The hyperthyroid women showed blunted PRL responses compared to normal women (peak PRL levels, 364 ± 44mU/l, vs 760 ± 156, P < 0·02). PRL responses to arginine, small but clearly detectable in normal men, were completely abolished in hyperthyroid men (peak PRL levels, 248 ± 48mU/l, vs 112 ± 14, P < 0·01).

CONCLUSIONS PRL responses to arginine are impaired in hyperthyroid patients. Therefore, arginine should be added to the list of PRL stimuli whose responses are blunted in hyperthyroidism, inhibition of PRL gene expression, and thus reduced pituitary PRL synthesis and storage, may explain why PRL responses to all secretagogues are reduced in these patients.
Multiple spuriously abnormal thyroid function indices due to heterophilic antibodies
Authors: Fiad T. M. , Duffy J. , McKenna T. J.
Published: March 2008

A 57‐year‐old man with a history of liver fibrosis, portal hypertension and hypersplenism had thyroid function assessed because of weight loss. Free T4 (FT4), total T4 (TT4), total T3 (lT3) and TSH were all assayed by enhanced chemiluminescent immunoassay. This demonstrated elevation of all three hormones. Because of the atypical profile obtained and because the patient appeared to be euthyroid, re‐assay of the patient's serum was performed following immunoglobulin precipitation with 50% polyethylene glycol. The levels of T4 and T3 were then found to be within the reference ranges suggesting that the serum contained interfering immunoglobulins. Anti‐immunoglobulin antibodies also neutralized the interfering substances present in the patient's serum. These observations indicate that non‐specific immunoglobulins present in the patient's serum cross‐reacted with the antibodies employed in the assays used, giving rise to spurious results. To our knowledge, this is the first report of artefactual elevation of results obtained by T4, T3 and TSH assays of a serum occurring as a result of interfering immunoglobulins. Their presence became apparent only because of the very rare coincidence of antibodies interfering with more than one assay giving rise to an atypical hormone pattern. The frequency of this phenomenon affecting a single assay and therefore more likely to go undetected, is unknown and is a cause for concern.
A case of hepatoma associated with hypoglycaemia and overproduction of IGF‐II (E‐21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin
Authors: Hunter Steven J. , Daughaday William H. , Callender Michael E. , McKnight John A. , Mcllrath Edwin M. , Teale J. Derrick , Atkinson A. Brew
Published: March 2008

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma Insulin‐like growth factor II (IGF‐11) was not elevated although 71% of plasma IGF‐II was present as big IGF‐II (molecular weight 11 kDa) which probably represents a non‐glycated form of pro‐IGF‐II. The GH response to hypoglycaemia was Impaired and plasma levels of both IGF‐l and the GH‐dependent IGF binding protein (IGFBP‐3) were low.

A recently described unextracted assay directed against the first 21 amino acids of the E‐domain (E‐21) of proinsulin‐like growth factor‐II (pro‐IGF‐II) allows direct plasma estimation (plasma E‐21) of larger molecular forms of IGF‐II without interference from normal IGF‐II and IGF binding proteins. Basal values were grossly elevated (23·7 and 23·8 nmol/l).

Treatment with GH led to an increase in the mean plasma glucose across 24 hours (4·25 ± 0·21 mol/1 (mean ± SEM) before treatment, compared with 4·86mmol/l ± 0·17 following GH (P < 0·01) and a reduction in hypoglycaemic attacks. The treatment was associated with a rise in IGFBP‐3 and small increases in insulin like growth factors. Subsequent treatment with the somatostatin analogue octreotide did not produce a significant change In plasma glucose levels or insulin‐like growth factors.

Two courses of Intrahepatic adriamycin restored elevated levels of E‐21 to normal. Total IGF‐II remained normal and IGF‐I Increased. GH treatment was successfully withdrawn with no effect on plasma glucose or growth factor levels. The patient remained free from hypoglycaemia. Twenty‐four months after his initial presentation he developed malignant ascites. Despite this evidence of tumour progression there was no recurrence of hypoglycaemia, and E‐21 and insulin‐like growth factor concentrations were normal. There was an initial response to intravenous chemotherapy with mithozantrone but subsequently he deteriorated and died 26 months after presentation.

We conclude that E‐21 was useful in the diagnosis of this case of non‐islet cell tumour hypoglycaemia. GH was a helpful initlal treatment to prevent hypoglycaemia. However, the most beneficial therapy was Intrahepatic adriamycin which had a marked effect on plasma levels of E‐21. Hypoglycaemia was eliminated. It is possible that the decrease In circulating growth factors also had a beneficial effect on tumour growth, the patient having had a prolonged remission and excellent quality of life before the eventual development of malignant ascites.
Parathyroid hormone and parathyroid hormone‐related protein in the investigation of hypercalcaemia in two hospital populations
Authors: Walls Janet , Ratcliffe Wendy A. , Howell A. , Bundred N. J.
Published: March 2008

BACKGROUND AND OBJECTIVE Parathyroid hormone‐related protein (PTHrP) produced by cancers has a central role as a humoral mediator of hypercalcaemia in patients with malignancy. Since the prevalences of hypercalcaemia of malignancy and parathyroid disease reflect the population studied, hypercalcaemia patients from a district general hospital (DGH) and an oncology centre (OC) were studied in order to assess the diagnostic role of assays for serum PTH and plasma PTHrP in different clinical settings.

DESIGN A prospective study of consecutive patients presenting with their first episode of hypercalcaemia during an 18‐month period.

PATIENTS A total of 123 patients (DGH, n= 69; OC, n= 54) had corrected serum calcium concentrations > 2·65mmol/l.

MEASUREMENTS PTH, PTHrP, calcium and albumin were measured together with urine calcium and creatinine, enabling fractional calcium excretion to be assessed. Urine cyclic adenosine monophosphate was also measured.

RESULTS Hypercalcaemia was attributed to malignancy alone in 72 patients (DGH, n= 20; OC, n= 52), benign causes in 42 (DGH, n= 42) and parathyroid disease coexisting with malignancy in 9 (DGH, n = 7; OC, n= 2). Plasma PTHrP levels were increased in 59/72 (82%) patients with hypercalcaemia due to malignancy. Measurements of both analytes contributed to a change in the final diagnosis in 12 patients (10%). Thus serum PTH was Increased In seven patients with parathyroid disease coexisting with malignancy, and plasma PTHrP was increased in five patients with previous undiagnosed malignancy. Median survival for patients with parathyroid disease and coexisting malignancy was 13 months compared with 3 months for those with hypercalcaemia due to malignancy alone (P < 0.02).

CONCLUSIONS Since hypercalcaemia was attributable to parathyroid disease In 10% of ail patients with malignancy we advise measurement of serum PTH at the Initial presentation of hypercalcaemia in ail patients, while plasma PTHrP may be useful to identify those patients in whom malignancy may not be clinically apparent, or coexist with primary hyperparathyroidism.
Bone metabolism during anti‐thyroid drug treatment of endogenous subclinical hyperthyroidism
Authors: Mudde A. H. , Houben A. J. H. M. , Kruseman A. C. Nieuwenhuijzen
Published: March 2008

OBJECTIVE There is recent evidence that both exogenous and endogenous subclinical thyrotoxicoses are associated with decreased bone mineral density. Scanty information is available on bone metabolism in these conditions when euthyroidism is restored. We evaluated the effect of anti‐thyroid drug treatment on bone metabolism in endogenous subclinical hyperthyroidism.

DESIGN Prospective follow‐up study over 2 years during treatment with methimazole, with an untreated control group.

SUBJECTS Sixteen post‐menopausal women with endogenous subclinical hyperthyroidism associated with multinodular goitre, eight of whom were treated with methimazole.

MEASUREMENTS Serum concentrations of free T4, total T3, TSH, osteocalcin, urinary excretion of hydroxyproline and forearm bone mineral density were measured at regular intervals.

RESULTS Significant changes in serum osteocalcin concentration or urinary hydroxyproline excretion were not observed in either group. Distal, but not proximal, forearm bone mineral density, expressed as a percentage of the base‐line value, was significantly (P < 0.05) higher in the treated than in the untreated subjects in the second year of treatment.

CONCLUSION Treatment with methimazole In post‐menopausal women with endogenous subclinical hyperthyroidism associated with multinodular goitre can prevent excessive loss of bone, at least in the distal forearm.
Loss of the normal relationships between growth hormone, growth hormone‐binding protein and insulin‐like growth factor‐I in adolescents with insulin‐dependent diabetes mellitus
Authors: Clayton Kharen L. , Holly Jeff M. P. , Carlsson Lena M. S. , Jones Jenny , Cheetham Tim D. , Taylor Alistair M. , Dunger David B.
Published: March 2008

OBJECTIVE It has been proposed that the dissociation between growth hormone secretion and insulin‐like growth factor‐I (IGF‐I) concentrations in insulin‐dependent diabetes mellitus arises because of partial resistance at the GH receptor. In order to explore this hypothesis further we have examined the relations between IGF‐I, GH‐binding protein (GHBP), and GH secretion in normal subjects and patients with diabetes during puberty.

DESIGN AND SUBJECTS Blood samples for the estimation of IGF‐I and GHBP levels were obtained from 104 patients with diabetes and 89 puberty matched controls. Thirty‐four of the controls and 42 of the patients with diabetes also underwent an overnight GH secretory profile with measurements of GH every 15–20 minutes between 2000 and 0800 h.

RESULTS In multivariate analysis using sex, puberty stage, and presence or absence of diabetes as dependent variables, diabetes was associated with increased GH levels (F= 23·04, P < 0·001), reduced IGF‐I (F= 10·89, P < 0·001), and reduced GHBP levels (F= 31·36, P < 0·001). A negative relation between GH and GHBP levels (r= ‐0·44, P < 0·01) was found in normal subjects but this was absent in those with diabetes. Both GHBP and IGF‐l levels in the diabetic subjects were correlated with total insulin dose (r= 0·4, P < 0·001, and r= 0·46, P < 0·001, respectively). Yet there was no direct correlation between GHBP and IGF‐I concentrations. The variation in IGF‐I levels was also related to glycosylated haemoglobin levels in the diabetics (r= ‐0·27, P= 0·01). In a stepwise multiple regression analysis insulin dose contributed 23%, HbA1 4·4% and C‐peptide levels 3·7% to the variation in IGF‐I levels.

CONCLUSIONS In adolescents with insulin dependent diabetes mellitus, the elevated OH concentrations are associated with low circulating IGF‐l and GHBP concentrations and the normal reciprocal relation between GHBP and GH is no longer evident. Although IGF‐I and GHBP are both related to insulin dose, there is no direct correlation between these variables. This may indicate that GHBP reflects GH receptor numbers but not necessarily post receptor events, and the weak positive correlation between GH and IGF‐I indicates that increased growth hormone secretion may compensate for reduced receptor numbers.
Growth hormone releasing activity by intranasal administration of a synthetic hexapeptide (hexarelin)
Authors: Laron Zvi , Frenkel Jenny , Gil‐Ad Lrit , Klinger Beatrice , Lubin Ernesto , Wuthrich Patrick , Boutignon François , Lengerts Vincent , Deghenghi Romano
Published: March 2008

OBJECTIVE Hexarelin is a new synthetic growth hormone releasing peptide. We have tested the efficacy of intranasal (i.n.) administration of hexarelin to stimulate plasma GH and have compared this to the intravenous (i.v.) administration of the peptide.

PATIENTS Ten children with familial short stature (FSS) aged 5·5‐15·5 years and two known GH deficient patients aged 24 and 28 years without GH treatment.

METHODS All 12 subjects were submitted to i.v. (1 μg/kg) and i.n. (20 μg/kg) hexarelin tests with a one‐week interval between tests. Blood samples for GH, TSH, fT4 and T3 were obtained at 0, 15, 30, 60, 90 and 120 minutes. The hormone determinations were made by standard radio‐immunoassays (RIA).

RESULTS Both the i.n. and i.v. administration of hexarelin induced a large GH response, the mean (±SD) being 72·2± 35·5 mU/l for the i.n. test and 79·6 ± 53·0 mU/l for the i.v. test. The peak GH in the i.v. test occurred at 15–30 minutes and in the i.n. test between 30 and 60 minutes. The GH deficient patients showed no GH response In either test. Plasma TSH decreased in the FSS children from a mean (±SD) of 1.0 ± 0·26 to 0·64±0 2 mU/l (P<0 005) during the i.n. test and from 1·0±0·3 to 0·7±0·3mU/l (P> 0 05) during the I.v. test. In the isolated GH deficient patient, plasma TSH decreased from 1·06±0·38 mU/l to 0·86±0·17 during the i.v. test and from 1·60±0·01 to 1·11±0·06mU/l during the i.n. test. There were no significant changes in plasma fT4 or T3 in any of the tests.

CONCLUSIONS The synthetic hexapeptide hexarelin is a potent pituitary GH stimulator when administered intra‐nasally. The GH response was similar to that observed after intravenous hexarelin. Simultaneously, there was a significant decrease in plasma TSH but the concentrations remained in the normal range. These findings appear to be of theoretical and practical relevance to the investigation and management of short children.
Dopamine and the sick euthyroid syndrome in critical illness
Authors: Van den Berghe Greet , de Zegher Francis , Lauwers Peter
Published: March 2008

OBJECTIVE The Sick euthyroid syndrome is a poorly understood hallmark of critical illness. Dopamine is a natural catecholamine with hypophysiotrophic properties, that is used as an inotropic agent of first choice in intensive care medicine. We explored the effect of dopamine infusion (5μg/kg/min) on the sick euthyroid syndrome of critically ill patients.

PATIENTS AND DESION In a prospective, randomized, controlled and open‐labelled study of critically ill, adult polytrauma patients (n= 12), we evaluated the effect of prolonged (83–296 hours) dopamine Infusion (5 μg/kg/min i.v.) on the thyroid axis. The effect of brief (15–21 hours) dopamine administration was documented in an additional randomized, controlled, cross‐over study involving 10 patients. The median age of the studied patients was 29 (16–83) years.

MEASUREMENTS Serum TSH concentrations were measured by IRMA. The TSH profiles were obtained by blood sampling every 20 minutes for 9 hours during two consecutive nights. Serum T4, T3 and reverse T3 concentrations were measured by RIA once per study night.

RESULTS Withdrawal of prolonged dopamine infusion was found to elicit a tenfold increase of serum thyrotrophin concentrations, a 57 and 82% rise of T4 and T3 respectively, and an Increase of the T3/rT3 ratio, resulting in virtual normalization of the thyroid axis within 24 hours. The brief dopamine infusion was documented to have a suppressive effect on the thyroid axis within 24 hours.

CONCLUSIONS Dopamine infusion appears to induce or aggravate the sick euthyroid syndrome in critical illness. As a consequence, the sick euthyroid syndrome of severely ill patients receiving dopamine may be not an adaptive mechanism, but a condition of latrogenic hypothyroidism.
Eighty‐six cases of Addison's disease
Authors: Kong Marie‐France , Jeffcoate William
Published: March 2008

OBJECTIVES Since there have been no recent reviews of Addison's disease, we have undertaken a retrospective case‐notes review of all identifiable cases in Nottingham to define the prevalence, incidence and causes of Addison's disease. We have also reviewed the criteria for interpretation of the short Synacthen test in diagnosis.

DESIGN A retrospective study of all patients coded for the diagnosis and admitted to Nottingham's hospitals between 1 April 1987 and 31 March 1993, identified by the hospital information Services.

PATIENTS A total of 86 cases were identifiable of whom 66 were still alive and living in the town.

RESULTS AND CONCLUSIONS The calculated prevalence was 110 per million population. The cause was attributed to autoimmune destruction of the adrenal cortex in 81 (93%). There were two cases of metastatic malignancy and three unrelated cases of late onset adrenoleukodystrophy, but none were attributable to tuberculosis. Twenty‐one new cases were diagnosed between 1987 and 1993. The calculated incidence was 5·6 per million per annum. The biochemical bash of the diagnosis was reviewed in there 21 patients and as a result firm criteria are suggested for the interpretation of the short Synacthen test criteria for normality being baseline cortisol > 250 and 30 minute peak > 600 nmol/l, taking Into account clinical circumstances.
Serum inhibin during lactation: relation to the gonadotrophins and gonadal steroids
Authors: Burger H. G. , Hee J. P. C. , Mamers P. , Bangah M. , Zissimos M. , McCloud P. I.
Published: March 2008

OBJECTIVE The aims of the study were to describe the changes in serum immunoreactive inhibin (INH) during normal lactation and to examine the relations between INH, oestradiol (E2) and follicle stimulating hormone (FSH), particularly during the first weeks post partum.

DESIGN Blood samples were obtained from normally lactating women for hormone measurements at dally intervals until discharge from hospital, and subsequently at weekly intervals until the resumption of menses, or one year post partum.

SUBJECTS Eighteen breast feeding women aged 27–36 years volunteered for the study.

MEASUREMENTS INH, FSH, luteinizing hormone (LH), prolactin (PRL), E2, and progesterone (P4) were measured by standard radioimmunoassays. Non‐linear modelling was used to quantify the hormone patterns observed.

RESULTS Hormone levels were compared with those found in the follicular phase of the normal menstrual cycle. Levels of INH fell rapidly in the first week post partum and remained at the lower end of the follicular phase range for the period of study, rising only just prior to resumption of menses. E2 fell more slowly, into the follicular phase range, reaching the lower end of that range only at about approximately 100 days post partum. FSH levels were suppressed initially below the follicular phase range, commencing to rise 4·7‐24 days post partum, reaching a plateau high in the follicular phase range 17·5–53 days post partum, and subsequently showing a slow decline. Human chorionic gonadotrophin (hCG), initially measured because of its cross‐reactivity in the LH assay, fell rapidly post partum and LH remained in the low follicular phase range for several weeks. PRL fell slowly throughout and was still elevated at 150 days post partum, while P4 fell very rapidly and was less than 1 nmol/l until just prior to first menses.

CONCLUSIONS inhibin levels fall rapidly post partum and remain low until close to the time of resumption of follicular activity and menses. The post partum rise in serum FSH appears to be much more closely related to falling oestradiol levels than to the very early and rapid fall in inhibin. Oestradiol thus appears to be the predominant negative feedback factor influencing FSH secretion during the post partum period. The low inhibin levels may allow FSH to rise to levels high in the follicular phase range under the predominant negative feedback control of oestradiol. Inhibin levels do not appear to be a suitable marker of returning fertility.
Testosterone administration increases adrenal response to adrenocorticotrophin
Authors: Polderman Kees H. , Gooren Louis J. G. , van der Veen Eduard A.
Published: March 2008

OBJECTIVES Various studies have demonstrated coexistence of ovarian and adrenal hyperandrogenism in women. This study was designed to determine whether testosterone can increase the response of the adrenal gland to stimulation by adrenocorticotrophin (ACTH).

DESIGN Non‐randomized intervention in a university teaching hospital.

PATIENTS Twenty androgen‐treated female‐to‐male transsexual patients (10 ovariectomized and 10 non‐ovariectomized) and 10 normal female controls.

MEASUREMENTS ACTH stimulation tests were performed in all subjects. Baseline values and the increase above baseline values after ACTH stimulation were assessed for cortisol and the adrenal androgens androstenedione, dehydroepiandrosterone and dehydroepiandrosterone‐sulphate.

RESULTS Increases in levels of cortisol, androstenedione and dehydroepiandrosterone after administration of ACTH were greater in testosterone‐treated transsexual patients than controls.

CONCLUSION We conclude that testosterone increases the response of the adrenal gland to stimulation by ACTH.
Acute cholinergic blockade with low dose pirenzepine reduces the insulin and glucose responses to a mixed meal in obese women with the polycystic ovary syndrome
Authors: Premawardhana L. D. K. E. , Ismail I. S. , Riad‐Fahmy D. , Miell J. P. , Peters J. R. , Scanlon M. F.
Published: March 2008

OBJECTIVES Pirenzepine, a selective muscarinic cholinergic antagonist, reduces plasma insulin and plasma glucose responses to a mixed meal in a dose dependent fashion in normals and in patients with non‐insulin dependent diabetes. We have studied the effects of pirenzepine on plasma insulin, plasma glucose, growth hormone (GH), androstenedione, testosterone, insulin‐like growth factor‐I (IGF‐I) and IGF binding protein 1 (IGFBP‐1) responses to a mixed meal in obese clinically hyperandrogenic women with the polycystic ovary syndrome.

SUBJECTS AND METHODS Six obese women with polycystic ovary syndrome (BMI range 27·3–39·8 kg/m2) were studied in random sequence, and received either placebo or pirenzepine (single doses of 50, 100, or 200 mg) one hour before a standard test meal. Blood was sampled every 15 minutes for 2 hours after the meal and every 30 minutes thereafter for a total of 4 hours.

RESULTS Mean fasting plasma insulin concentrations were increased. Peak post‐prandial plasma insulin concentrations were reduced significantly by all three doses used. Post‐prandial integrated plasma insulin concentrations were reduced by the two higher doses. Peak postprandial plasma glucose concentrations were also reduced. The late post‐prandial GH surge was significantly suppressed by all three doses. However, plasma androstenedione, testosterone, IGF‐I and IGFBP‐1 concentrations were not significantly different when placebo was compared with pirenzepine 200 mg.

CONCLUSIONS Acute cholinergic muscarinic blockade with pirenzepine significantly reduces meal stimulated plasma insulin and plasma glucose concentrations in clinically hyperandrogenic women with polycystic ovary syndrome. The ability of pirenzepine to reduce plasma insulin without worsening glycaemia is a particular advantage and may be therapeutically relevant. Further studies are under way to assess the usefulness of pirenzepine in long‐term suppression of plasma insulin in this group of patients.
Subnormal growth hormone responses to acutely administered dexamethasone in depression
Authors: Thakore Jogin H. , Dinan Timothy G.
Published: March 2008

OBJECTIVES Acute oral administration of dexamethasone (DEX) stimulates growth normone (GH) release at 3 hours in normal controls and provides us with a novel probe with which to study the somatotrophic axis. In affective illness GH release is subnormal In response to a number of stimuli. We decided to investigate the acute effects of DEX‐induced GH release in depression.

DESIGN A between subjects parallel group design was employed.

METHODS Baseline levels of GH and cortisol were taken after which 4 mg of oral DEX was administered. Plasma samples for GH estimation were taken at +60, +180, + 240 and + 300 minutes.

PATIENTS Sixteen normal subjects and 16 unipolar, non‐psychotic, melancholic DSM‐111R major depressives were studied. Depressed subjects had to score over 17 on the Hamilton Depression Rating Scale; the mean ± SEM scores were 27·4±1·0.

MEASUREMENTS Plasma GH and cortisol levels were measured by radioimmunoassay.

RESULTS Baseline mean ± SEM GH levels (depressives 2·4 ±0·6 mU/l; controls 2·6 ±0·4 mU/l) did not differ significantly between the two groups (P < 0·28). DEX‐induced GH secretion was subnormal in depressives as opposed to controls (2·1±0·7 vs 19·4±2·2 mU/l, P < 0·001). There were significant differences between the two groups at 60, 180 and 240 minutes (P < 0·05). Baseline cortisol values were significantly different between the two groups (depressives 303·3 ±31·5 nmol/l; controls 138 ± 4·7 nmol/l). An analysis of covariance, with cortisol as a covarlate, still found the depressives to have significantly subnormal GH responses as compared to the control group (P < 0·05).

CONCLUSION Dexamethasone‐induced GH release is subnormal in depression.
Measurement of thyroid stimulating immunoglobulins in a new cell line transfected with a functional human TSH receptor (JPO9 cells), compared with an assay using FRTL‐5 cells
Authors: Michelangell V. P. , Munro D. S. , Poon C. W. , Frauman A. G. , Colman P. G.
Published: March 2008

OBJECTIVES Most bioassays used to measure thyroid stimulating antibodies (TSAb) rely on the ability of patient sera to generate cAMP in cultured cells of non‐human origin. The cell line most commonly used has been the rat thyroid cell line, FRTL‐5. Recently, a new cell line (JPO9) possessing a transfected human TSH receptor has been developed. The aim of this study was to evaluate the JPO9 cells by comparing them with the widely used FRTL‐5 cells, using the method of 3H‐adenine incorporation for the direct measurement of intracellular cAMP.

DESIGN The ability of patient sera to generate cAMP production in JPO9 and FRTL‐5 cells was used as the index of thyroid stimulation. The specificity of the assay was determined using sera from patients with autoimmune thyroid and non‐thyroid autoimmune diseases.

PATIENTS We studied sera from 28 patients with newly diagnosed Graves' disease, 72 patients with Graves' disease at various stages of treatment, 8 patients with Hashimoto's thyroiditis, 40 patients with a variety of non‐thyroid autoimmune diseases and 42 control subjects.

MEASUREMENTS The intracellular 3H‐cAMP generated in JPO9 cells following preincubation with 3H‐adenine and subsequent incubation with patient or control sera, was used as a measure for TSAb. The results obtained with these cells were compared to those obtained with the widely used FRTL‐5 cells and they were also correlated with the measurement of TSH binding inhibitory immunoglobulins by a conventional radioreceptor assay.

RESULTS JPO9 cells were more sensitive and had a wider range of response to bovine TSH (bTSH) than had FRTL‐5 cells (10‐7‐10‐2 U/ml compared to 10‐5‐10‐3 U/ml respectively). Unlike FRTL‐5 cells, JPO9 cells respond well to unmodified serum and grow constitutively in the absence of TSH, thereby not requiring TSH deprivation prior to assay. The TSAb values obtained with both cell lines correlated well (r= 0·87). The JPO9 cells responded specifically to Graves' sera (23 out of 28 newly diagnosed patients were positive), whereas no patients with Hashimoto's thyroiditis and only 4 of 40 patients with non‐thyroid autoimmune diseases gave low positive results for the presence of TSAb.

CONCLUSIONS The JPO9 cells provide similar diagnostic information to FRTL‐5 cells in patients with autoimmune thyroid disease. However, because they are more sensitive, grow faster, have less fastidious growth requirements and respond to unextracted sera, compared to FRTL‐5 cells, we conclude that the JPO9 cells are preferable for the measurement of TSAb.
Reversibility of physiological growth hormone secretion in children with psychosocial dwarfism
Authors: Albanese A. , Hamill G. , Jones J. , Skuse D. , Matthews D. R. , Stanhope R.
Published: March 2008

OBJECTIVES Reversibility of GH insufficiency with a change of environment is characteristic of psychosocial dwarfism, and excludes an organic endocrinopathy. However, the change in GH pulsatility has not previously been described. We therefore wished to study spontaneous GH secretion before and after change to a more favourable environment in 11 children with psychosocial deprivation and short stature in order to evaluate if separation from the families can modify their patterns of GH secretion.

PATIENTS AND DESIGN We describe 11 prepubertal children (6 M and 5 F; 2.2–13.5 years of age) who had growth failure and psychosocial deprivation. They were diagnosed by a multidisciplinary team as having environmental growth failure after admission to hospital for 3 weeks. Six of them were discovered to have been sexually abused. During the uninterrupted hospital admission parental access was restricted. Three sets of 18‐hour GH profiles were performed on each child, except one child who had only two, during the 3‐week admission.

MEASUREMENTS Pulse analysis of GH profiles was by Fourier transformation.

RESULTS On the first day of admission spontaneous GH secretion demonstrated a spectrum of abnormalities in the pattern of basal values, pulse frequency and pulse amplitude. Such GH insufficiency showed reversibility during the 3 weeks in hospital. Indeed, there was a significant increase in GH secretion which was amplitude modulated without any significant modification in pulse frequency.

CONCLUSION Our data indicate that there is abnormal physiological GH secretion in children with psychosocial deprivation, which is associated with growth failure. Despite a pathological situation, each child retained his own characteristic pattern of GH pulsatility. The pattern of reversibility of abnormal GH pulsatility provides information for the mechanism of the control of GH secretion.
Amylin/islet amyloid polypeptide expression in medullary carcinoma of the thyroid: correlation with the expression of the related calcitonin/CGRP genes*
Authors: Alevizaki M. , Dai K. , Grlgorakls S. I. , Legon S. , Souvatzoglou A.
Published: March 2008

OBJECTIVE The amylin/lslet amyloid polypeptide (IAPP) gene is the third member of the calcitonin (CT)/calcitonin gene related peptide (CGRP) gene family, which includes the αCT/CGRP (CALC‐I) and βCGRP (CALC‐il) genes. CT is predominantly expressed in thyroid C cells, a and βCGRP (CGRP‐I and II) in neural tissue and amylin/IAPP in pancreatic β cells. Both the detailed tissue distribution and the physiological role of amylln are subjects of current research. We sought to characterize the RNAs transcribed from the IAPP gene In normal human pancreas and to investigate possible ectopic expression of this gene in neuroendocrine tumours.

DESIGN AND TISSUES RNA was extracted from normal human pancreas, five phaeochromocytomas and 12 medullary thyroid carcinomas (MTCs) and studied by Northern blotting.

RESULTS We found that in normal human pancreas the IAPP gene transcripts differ in size from those reported for human Insulinoma. Expression of the amylin/IAPP gene was detected In seven of the MTCs, while it was not detected in phaeochromocytomas. There were no apparent clinical or histological differences between IAPP positive and IAPP negative MTCs. The relative expression levels of the four mRNAs of the CT/CGRP gene family varied between the different tumours.

CONCLUSIONS Our findings are consistent with the view that ectopic hormone production may occasionally be causally related to the common origin of related genes.

The possibility that IAPP may constitute a minor component of MTC amyloid should be considered.
Effect of bisphosphonate therapy and parathyroidectomy on the urinary excretion of galactosylhydroxylysine in primary hyperparathyroidism
Authors: LoCascio Vincenzo , Braga Vania , Bertoldo Francesco , Bettica Paolo , Pasini Anna Fratta , Stefani Lucia , Moro Luigi
Published: March 2008

BACKGROUND In patients with mild or asymptomatic primary hyperparathyroidism a reliable index of bone resorption might be useful for appropriate management. Hydroxyproline is the most commonly used marker of bone resorption but its low specificity and sensitivity are known. Galactosylhydroxylysine, an aminoacid mainly represented in bone collagen, has been proposed as a more suitable index of bone resorption. In this study we evaluated the sensitivity of galactosylhydroxylysine and hydroxyproline assays in following the changes of their urinary levels in 12 patients with mild primary hyperparathyroidism before and after treatment with bisphosphonate and surgery.

METHODS Serum and fasting urine specimens were obtained from 12 women with mild primary hyperparathyroidism before and after bisphosphonate treatment (2.5 mg daily for 5 days, intravenously) and after a further 25 days; in 7 patients biochemical tests were also performed 1 and 6 days after parathyroidectomy. Galactosylhydroxylysine was assayed by an HPLC method and hydroxyproline by a RIA commercial kit.

RESULTS Baseline galactosylhydroxylysine urinary levels were far above the normal range in all the patients whilst in 8 of them baseline hydroxyproline levels were normal. Bisphosphonate treatment significantly decreased bone turnover as shown by a significant fall in serum calcium (from 2.9 to 2.6 mmol/l; P < 0.001) and in galactosylhydroxylysine and hydroxyproline (−55 and −31% respectively). Twenty‐five days after the end of treatment, resorption increased again and serum calcium and galactosylhydroxylysine, but not hydroxyproline, rose significantly towards basal levels. One day after parathyroidectomy serum calcium, galactosylhydroxylysine and PTH showed reduction below normal ranges. PTH and galactosylhydroxylysine returned to normal values at day 6 after parathyroidectomy. No changes in hydroxyproline levels were seen. Galactosylhydroxylysine, but not hydroxyproline, correlated significantly with serum calcium and PTH.

CONCLUSION Galactosylhydroxylysine appears to be a sensitive index of bone resorption, useful in the clinical assessment of bone involvement and in the management of patients with mild primary hyperparathyroidism.