bluuebunny/crossref_metadata_2025 huggingface dataset:
Seven-day administration of the gonadotropin-releasing hormone antagonist Cetrorelix in normal cycling women
Authors: Sommer Lieselotte , Zanger Kerstin , Dyong Thomas , Dorn Christoph , Luckhaus Johannes , Diedrich Klaus , Klingmüller Dietrich
Published: December 2008

Sommer L, Zanger K, Dyong T, Dorn C, Luckhaus J, Diedrich K, Klingmüller D. Seven-day administration of the gonadotropin-releasing hormone antagonist Cetrorelix in normal cycling women. Eur J Endocrinol 1994;131:280–5. ISSN 0804–4643

In contrast to gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists do not show any stimulatory effect on the pituitary but their clinical usage was precluded by severe side effects and high dose requirements. We report here on a 7-day treatment using the potent GnRH antagonist Cetrorelix ([Ac-d-Nal(2)1, d-Phe(4Cl)2, d-Pal(3)3, d-Cit6, d-Ala10]GnRH) on five women 23–33 years old. All women were ovulatory and were studied during three consecutive cycles: a control cycle, a treatment cycle and a post-treatment control cycle. Throughout the control cycles blood samples were obtained daily during cycle days 8–18 and on days 21 and 23 during the remainder of the control cycles. On the eighth day of the treatment cycle women were hospitalized at 07.00 h for 26 h. Repeated blood samples were drawn at 15-min intervals during the entire period. Subjects received 3 mg of Cetrorelix sc for the first time at 09.00 h on the eighth day of the cycle and daily at 08.00 h for the following 6 days. Blood samples were obtained daily over a period of 25 days and every third day throughout the remainder of the treatment cycle. Twenty-four hours after the first application of Cetrorelix, luteinizing hormone (LH) and estradiol were in the subnormal range and remained subnormal until the end of medication. The suppressive effect of Cetrorelix compared to pretreatment values lasted at least 6 days for LH and FSH and 11 days after the last Cetrorelix injection for estradiol. An LH surge followed by postovulatory progesterone values was found 22.6 ± 1.4 days after the last injection. During application of the GnRH antagonist, LH was reduced to 16.1 ± 0.7%, FSH to 58.7 ± 1.3% and estradiol to 17.9 ± 0.4% compared to the individual pretreatment values. The consecutive cycle after completion of treatment was comparable to the length of the pretreatment cycle. No serious side effects were observed. In summary, the results of this study give evidence of the effectiveness and safety of this new GnRH antagonist used in low dosages for possible therapeutic application in sex-hormone-dependent diseases in women.

Dietrich Klingmüller, Institut für Klinische Biochemie der Universität Bonn, Sigmund Freud Str. 25, D53105 Bonn, Germany
Interleukin 6 effects on the pituitary–thyroid axis in the rat
Authors: Bartalena Luigi , Grasso Lucia , Brogioni Sandra , Martino Enio
Published: December 2008

Bartalena L, Grasso L, Brogioni S, Martino E. Interleukin 6 effects on the pituitary–thyroid axis in the rat. Eur J Endocrinol 1994;131:302–6. ISSN 0804–4643

It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-α TNF-α), may have a role in the pathogenesis of the changes of serum thyroid hormone concentrations that are encountered in patients with non-thyroidal illness (NTI). Many of the IL-1 and TNF-α effects are believed to be mediated by the induction of IL-6 synthesis, which might, therefore, represent an important mediator of thyroid hormone changes in NTI. To address this problem, male Wistar rats were injected subcutaneously with 2.5 μg of recombinant human IL-6 (rhIL-6, in 500 μl of saline solution), with 2.5 μg of rhIL-6 preincubated with 100 μl of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T4) from 82 ± 4 nmol/l (mean± sem) to a nadir of 33 ± 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T3) from 1.6 ± 0.1 to 0.8 ± 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T4 and T3 concentrations also was observed in the control group, but the lowest values (T4, 66 ± 3 nmol/l; T3, 1.2 ± 0.1 nmol/l) were significantly higher (p < 0.0001) than in IL-6-treated rats. The IL-6-induced changes could be prevented by preincubation of rhIL-6 with its neutralizing antibody. Slight but not significant changes occurred in serum reverse T3 (rT3) concentration, so that the T4/rT3 ratio remained substantially unchanged after rhIL-6 injection, whereas the T4/T3 ratio decreased significantly from 53.6 to 39.9 (p < 0.02) in IL-6-treated rats. The effects of IL-6 on thyrotropin (TSH) were investigated after rendering the rats hypothyroid by methimazole administration for 3 weeks. Serum TSH decreased from 19.0 ± 6.8 to 13.3 ± 3.8 μg/l after 48 h (p < 0.01) in IL-6-treated rats, while it increased from 17.2 ± 2.8 to 25.8 ± 4.0 μg/l (p < 0.01) in the control group. These results show that a single injection of rhIL-6 causes a decrease in serum T4, T3 and TSH concentrations in the rat, without affecting serum rT3 levels. This is compatible with a predominantly central effect of the cytokine. The apparent lack of inhibition of 5′-deiodinating activity, a key feature of NTI, suggests that IL-6, if involved, is only one of the factors responsible for the changes of thyroid hormone secretion and metabolism observed in NTI.

Luigi Bartalena, Istituto di Endocrinologia, University of Pisa, Viale del Tirreno 64, 56018 Tirrenia-Pisa, Italy
Testicular regulation of sexual dimorphisms in the ultradian profiles of circulating growth hormone in the chicken
Authors: Pampori Nisar A , Shapiro Bernard H
Published: December 2008

Pampori NA, Shapiro BH. Testicular regulation of sexual dimorphisms in the ultradian profiles of circulating growth hormone in the chicken. Eur J Endocrinol 1994;131:313–318. ISSN 0804–4643

Ultradian patterns in plasma growth hormone (GH) concentrations were determined in adult white Leghorn roosters, hens and capons. Serial blood samples were collected every 15 min over 8 h through surgically placed chronic indwelling right atrial catheters and assayed for GH content by a homologous radioimmunoassay. In both sexes, GH levels fluctuated episodically, with peak and interpeak periods each lasting about 45 min in both roosters and hens. However, GH concentrations in the peaks and nadirs were 2.5–3.5 times greater in the plasma GH profiles of roosters as compared to hens, which resulted in roosters having higher mean GH concentrations. Caponizing completely feminized the episodic GH secretory profile. In contrast to chickens, the common sexually dimorphic feature in secretory GH profiles of mammals is the enhanced peak frequencing found in females.

Bernard H Shapiro, Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6048, USA
Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors
Authors: Massias Jean Francis , Hardouin Sandrine , Vieau Didier , Lenne Frédéric , Bertagna Xavier
Published: December 2008

Massias JF, Hardouin S, Vieau D, Lenne F, Bertagna X. Phosphorylated forms of adrenocorticotropin and corticotropin-like intermediary lobe peptide in human tumors. Eur J Endocrinol 1994;131:341–6. ISSN 0804–4643

Many peptides contribute to the heterogeneity of immunoreactive adrenocorticotropin (ACTH) in man. The use of a radioimmunoassay (RIA) specifically directed against the C-terminal end of ACTH allowed us to study precisely the following four peptides: ACTH itself, corticotropin-like intermediary lobe peptide (CLIP) or ACTH(18–39) and their phosphorylated forms on Ser31. We have set up a highperformance liquid chromatography system that separates these four molecules in a single run, to establish their relative distributions in tumors responsible for Cushing's disease or for the ectopic ACTH syndrome, and to evaluate the possible interference of phospho-Ser on various RIA or immunoradiometric assay (IRMA) recognition systems for ACTH. In this system, alkaline phosphatase treatment shifted the retention time of the phosphorylated peptides to that of their non-phosphorylated counterparts. In three tumors responsible for the ectopic ACTH syndrome, CLIP peptides were predominant in two and phosphorylated molecules represented between 22% and 50% of immunoreactive materials. In five pituitary tumors responsible for Cushing's disease, ACTH peptides were predominant and the phosphorylated molecules varied between 35% and 75% in four of them. In the same tumor the ratios of phosphorylated to non-phosphorylated CLIP or ACTH were identical. The presence of phospho-Ser31 did not affect the recognition ability of two mid-ACTH and two C-terminal ACTH RIAs, nor of the ACTH IRMA (Allegro, Nichols).

Xavier Bertagna, CJF 92-08 Endocrinologie, Faculté Cochin-Port Royal, 24 rue du Faubourg Saint Jacques, 75014 Paris, France
Retinoic acid differentially modulates triiodothyronine and retinoic acid receptors in rat liver according to thyroid status
Authors: Pallet Véronique , Audouin-Chevallier Isabelle , Verret Catherine , Garcin Henri , Higueret Paul
Published: December 2008

Pallet V, Audouin-Chevallier I, Verret C, Garcin H, Higueret P. Retinoic acid differentially modulates triiodothyronine and retinoic acid receptors in rat liver according to thyroid status. Eur J Endocrinol 1994;131:377–84. ISSN 0804–4643

Triiodothyronine (T3) receptors (TRs) and retinoic acid (RA) receptors (RARs) exert their effects on growth, differentiation and cellular homeostasis by acting as transcription factors. The binding characteristics of these receptors have been studied in liver of hypothyroid and hyperthyroid rats, with or without treatment with T3, RA or T3 + RA together. The changes in binding induced by RA treatment depended on the hormonal status of the rat. In hypothyroid rats the T3 binding capacity was unaltered by administration of T3 or RA alone but increased by 48% after treatment with T3 and RA together. In these rats administration of RA, T3 or T3 + RA increased the RAR binding capacity by 45, 79 and 112%, respectively. In hyperthyroid rats the administration of RA reduced the TR and RAR binding capacities by 22 and 37%, respectively. We found also that the affinity constants of TRs and RARs were reduced in hypothyroid rats after treatment with T3 or T3+RA. It is suggested that this change of the properties of receptors is related to a ligand-dependent conformational change in these receptors.

Paul Higueret, Laboratoire de Nutrition, Avenue des Facultés, 33405 Talence Cedex, France
Diagnosis and treatment of thyrotoxicosis in childhood A European questionnaire study
Authors: Perrild Hans , Grüters-Kieslich Anette , Feldt-Rasmussen Ulla , Grant David , Martino Enio , Kayser Lars , Delange Francois
Published: December 2008

Perrild H, Grüters-Kieslich A, Feldt-Rasmussen U, Grant D, Martino E, Kayser L, Delange F. Diagnosis and treatment of thyrotoxicosis in childhood. A European questionnaire study. Eur J Endocrinol 1994;131:467–73. ISSN 0804–4643

A covering letter and a questionnaire covering the diagnosis and treatment of thyrotoxicosis in childhood was circulated between October 1992 and February 1993 amongst 672 European members of the European Thyroid Association (ETA) and members of the European Society for Pediatric Endocrinology (ESPE). Almost 50% replied to the letter and 99 individuals or groups from 22 countries completed the questionnaire. A consensus was reached on the use of total thyroxine (T4) and/or free T4 and thyrotropin as routine diagnostic tools. Two-thirds included total triiodothyronine (T3) and/or free T3 and 32% used a thyrotropin-releasing hormone test. Surprisingly, thyroglobulin autoantibodies were used as a routine test by 78%; 63% included thyrotropin receptor antibodies and 60% microsomal antibodies, whereas only 50% measured thyroperoxidase antibodies. For thyroid imaging, 40% performed a thyroid scintigram and 56% measured the size of the thyroid gland by ultrasound. Antithyroid drugs (ATD) were the basic initial treatment of choice given by 99% of the respondents for children with uncomplicated Graves' disease. Carbimazole, methimazole and thiamazole were the most frequently used drugs, with a median initial dose of 0.8 mg · kg1 · day1. Two-thirds added betablockers and a few used sedatives. The ATD dose was adjusted for each patient by 39%, whereas 56% combined ATD with T4 for long-term treatment; 84% gave treatment for a fixed period (44% for 1–2 years). Surgery was considered the treatment of choice in children with an adenoma (83%), with a nodular (53%) or large goiter (16%) and recurrence after ATD (14%). Radioiodine was the treatment of choice by 18% of the respondents for patients with recurrence after surgery and recurrence after ATD (7%).

Hans Perrild, Department of Medicine B, Bispebjerg University Hospital, 2400 Copenhagen, Denmark
Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men
Authors: Veldhuis Johannes D , Iranmanesh Ali , Wilkowski Michael J , Samojlik Eugeniusz
Published: December 2008

Veldhuis JD, Iranmanesh A, Wilkowski MJ, Samojlik E. Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men. Eur J Endocrinol 1994;131:489–98. ISSN 0804–4643

To investigate the pathophysiology of altered growth hormone (GH) and prolactin secretion in endstage renal disease, we sampled blood at 10-min intervals for 24 h and applied deconvolution analysis to calculate hormone half-lives and pulsatile secretion rates. Two-site immunoradiometric assays were employed to quantitate presumptively intact GH and prolactin in nine middle-aged men with chronic renal failure and 14 gender-, age-, body weight- and community-matched controls. We observed that the half-lives of endogenous GH and prolactin were prolonged significantly in uremia: for GH, control 17 ±1.4 versus uremia 21 ±1.3 min (p < 0.05); for prolactin, control 66 ±9.3 versus uremia 112 ± 10 min (p < 0.01). Daily GH secretion rates exceeded sex-, age- and weight-predicted values in eight of nine uremic individuals, while values for prolactin were variable but on average twofold higher in uremia. In both the somatotropic and lactotropic axes, the frequency of secretory bursts was increased significantly (for GH, control 11 ± 1.1 versus uremia 15 ± 0.84 secretory events/24 h; for prolactin, control 20 ± 0.90 versus uremia 27 ± 1.3 pulses/24 h. p < 0.05). Although there were no significant alterations in the mean amplitude, duration or mass of GH secretory bursts, prolactin secretory burst amplitudes were elevated threefold in uremia (p < 0.01). These distinctive mechanisms brought about higher 24-h mean serum concentrations of GH (0.70 ±0.17 control versus 1.22 ± 0.32 μg/l uremia) and prolactin (7.3 ± 2.4 control versus 26 ± 6.1 μg/l uremia, p < 0.05). Lastly, serum concentrations of estradiol were increased but those of unconjugated estriol decreased in uremia. We conclude that hypersomatotropinemia and hyperprolactinemia in uremic men result from prolonged hormone half-lives combined with increased frequencies of secretory events driven by unknown stimuli within the respective axes, and/or by defects in their negative-feedback regulation. We postulate that the latter may arise from partial tissue resistance to hormone action in hemodialyzed men.

JD Veldhuis, Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA
Effect of glucocorticoid on prostaglandin F2α-induced prostaglandin E2 synthesis in osteoblast-like cells: inhibition of phosphoinositide hydrolysis by phospholipase C as well as phospholipase A2
Authors: Kozawa Osamu , Tokuda Haruhiko , Suzuki Atsushi , Kotoyori Jun , Ito Yoshiaki , Oiso Yutaka
Published: December 2008

Kozawa O, Tokuda H, Suzuki A, Kotoyori J, Ito Y, Oiso Y. Effect of glucocorticoid on prostaglandin F2α-induced prostaglandin E2 synthesis in osteoblast-like cells: inhibition of phosphoinositide hydrolysis by phospholipase C as well as phospholipase A2. Eur J Endocrinol 1994;131:510–15. ISSN 0804–4643

It is well known that osteoporosis is a common complication of patients with glucocorticoid excess. We showed previously that prostaglandin (PG) F2α stimulates the synthesis of PGE2, a potent bone resorbing agent, and that the activation of protein kinase C amplifies the PGF2α-induced PGE2 synthesis through the potentiation of phospholipase A2 activity in osteoblast-like MC3T3-E1 cells. In the present study, we examined the effect of dexamethasone on PGE2 synthesis induced by PGF2α in MC3T3-E1 cells. The pretreatment with dexamethasone significantly inhibited the PGE2 synthesis in a dose-dependent manner in the range between 0.1 and 10 nmol/l in these cells. This effect of dexamethasone was dependent on the time of pretreatment up to 8 h. Dexamethasone also inhibited PGE2 synthesis induced by melittin, known as a phospholipase A2 activator. Furthermore, dexamethasone significantly inhibited the enhancement of PGF2α- or melittin-induced PGE2 synthesis by 12-O-tetradecanoylphorbol-13-acetate, known as a protein kinase C activator. In addition, dexamethasone significantly inhibited PGF2α-induced formation of inositol phosphates in a dose-dependent manner between 0.1 and 10 nmol/l in MC3T3-E1 cells. These results strongly suggest that glucocorticoid inhibits PGF2α-induced PGE2 synthesis through the inhibition of phosphoinositide hydrolysis by phospholipase C as well as phospholipase A2 in osteoblast-like cells.

Osamu Kozawa, Department of Biochemistry, Institute for Developmental Research, Aichi Prefectural Colony, Kasugai, Aichi 480-03, Japan
G-Proteins: implications for pathophysiology and disease
Authors: Gordeladze Jan O , Johansen Per W , Paulssen Ruth H , Paulssen Eyvind J , Gautvik Kaare M
Published: December 2008

Gordeladze JO, Johansen PW, Paulssen RH, Paulssen EJ, Gautvik KM. G-Proteins: implications for pathophysiology and disease. Eur J Endocrinol 1994;131:557–74. ISSN 0804–4643

This article focuses on the involvement of G-proteins in neuroendocrine secretion, cell growth and phenotype alterations. The current concept of hormonal activation of the GTPase cycle, as well as the molecular diversity of G-protein families and receptor * G-protein * effector coupling, are described. Also described are certain G-proteins as possible proto-oncogenes and how point mutations and frame shift mutations alter G-protein function and determine the characteristics of various endocrine diseases. The article outlines in detail how receptors and G-proteins interact in prolactin and growth-hormone-secreting pituicytes, how G-proteins are involved in the growth and differentiation of preadipocytes and osteoblasts. All in all, it seems that hormonal activation through G-proteins is modulated through direct intra- and inter-signalling system cross-talk at the plasma membrane level (short-term) and through interactions on the level of transcription (HREs) from tyrosine kinases, steroid-like hormones and metabolic pathways. Pharmacological intervention to treat diseases where G-proteins are involved should take both long and short-term regulatory phenomena into consideration.

JO Gordeladze, Institute of Medical Biochemistry, University of Oslo, PO Box 1112, Blindern, 0317 Oslo, Norway
Oral dexamethasone administration: new pharmacological test for the assessment of growth hormone secretion
Authors: Pineda Jaime , Martul Pedro , Casanueva Felipe F , Dieguez Carlos , Rica Itxaso , Loridan Liliane
Published: December 2008

Pineda J, Martul P, Casanueva FF, Dieguez C, Rica I, Loridan L. Oral dexamethasone administration: new pharmacological test for the assessment of growth hormone secretion. Eur J Endocrinol 1994;131:598–601. ISSN 0804–4643

Acute intravenous (iv) dexamethasone administration has been described recently as a new test for the diagnosis of growth hormone (GH) deficiency. In the present study, a new protocol of dexamethasone administration was evaluated. Twelve normal adults and 18 normal prepubertal children were studied. The dexamethasone iv test was performed in six adults at a dose of 4 mg and 12 children at a dose of 2 mg/m2. Blood samples were collected 15 min before, at time zero and every 15 or 30 min during 5 h, resulting in a total of 16 samples. In the remaining six adults and six children, 8 and 4 mg, respectively, of dexamethasone were administered orally at the subject's home, and blood sampling started 90 min later when they arrived at the hospital. Plasma GH was measured by radioimmunassay. The dexamethasone-induced GH response (mean ± sem, μg/1) to the iv or oral protocol did not differ in either the adults (iv 8.2 ± 2.1; oral 8.0 ± 1.6) or the children (iv 14.9 ± 1.3; oral 13.6 ± 1.8). It is concluded that the simpler protocol of acute oral dexamethasone administration hereby presented can be a safe and suitable test of GH secretion.

J Pineda, Sección de Endocrinologia Pediátrica, Hospital de Cruces, 48903 Baracaldo (Vizcaya), Spain
Expression of chorionic gonadotrophin in human pituitary adenomas
Authors: Levy A , Biswas S , Burton PA , Lightman SL
Published: December 2008

Levy A, Biswas S, Burton PA, Lightman SL. Expression of chorionic gonadotrophin in human pituitary adenomas. Eur J Endocrinol 1994;131:615–22. ISSN 0804–4643

In addition to the classical anterior pituitary hormones, many human pituitary adenomas express hormone genes ectopically. Expression of glycoprotein hormone α-subunit and, less commonly, free luteinizing hormone β (LH-β) or follicle-stimulating hormone β is characteristic of endocrinologically inactive adenomas, a subgroup thought to be derived predominantly from the gonadotroph line. Thyrotrophin β expression in these tumours is unusual, and specific chorionic gonadotrophin β (CG-β) expression, identified using oligonucleotide probes that reliably distinguish LH-β and CG-β in situ, is not well described. Using in situ hybridization histochemistry with a CG-β transcript-specific oligonucleotide probe and a non-specific LH/CG-β oligonucleotide and riboprobe, we have demonstrated specific CG-β expression in two of 35 random pituitary adenomas; LH-β expression occurred in a further eight adenomas. Unlike prolactin, growth hormone and proopiomelanocortin, which are transcribed in the vast majority of cells in their respective hormone-positive tumour subtypes, the pattern of LH/CG-β was typically a scattering of single or small clusters of hormone-positive cells in a predominantly LH/CG-β-negative tumour. Finally, although bona fide CG-β expression in human pituitary adenomas does occur, it is only at an incidence similar to that described for carcinomas of other tissues.

A Levy, Department of Medicine, University of Bristol, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK
Sex hormone-binding globulin mRNA levels in human uterine endometrium
Authors: Misao Ryou , Itoh Naoki , Mori Hidehiro , Fujimoto Jiro , Tamaya Teruhiko
Published: December 2008

Misao R, Itoh N, Mori H, Fujimoto J, Tamaya T. Sex hormone-binding globulin mRNA levels in human uterine endometrium. Eur J Endocrinol 1994;131:623–9. ISSN 0804–4643

Sex hormone-binding globulin (SHBG) is a specific steroid hormone-binding protein that plays a role in transporting dihydrotestosterone, testosterone and estradiol-17β (E2), altering their concentration in blood and influencing their biological action. Recently it has been reported that immunoreactive SHBG is localized in target tissues and that SHBG mRNA was identified in human endometrial and prostatic cell lines. In the present work, SHBG mRNA was detected in human normal endometrial tissues using Northern blot analysis and polymerase chain reaction. Its level was higher (p < 0.02) in the secretory phase than in the proliferative phase. In the secretory phase, the endometrial SHBG mRNA level was correlated positively with serum E2 and progesterone level (p < 0.05). However, there was a negative correlation between endometrial SHBG mRNA level and serum E2 /progesterone ratio (p < 0.01). These findings suggest that SHBG is synthesized in the uterine endometrium and a part of its synthesis is regulated complexly by sex steroid hormones such as E2 and progesterone.

Ryou Misao, Department of Obstetrics and Gynecology, Gifu University School of Medicine, Tsukasamachi-40. Gifu 500, Japan
Effects of deflazacort and cortisone on body growth, thymus weight and gene expression of growth-related proteins in the rat
Authors: Latta Kay , Krieg Richard J , Chan Winnie , Hisano Satoshi , Chan James CM
Published: December 2008

Latta K, Krieg RJ, Chan W, Hisano S, Chan JCM. Effects of deflazacort and cortisone on body growth, thymus weight and gene expression of growth-related proteins in the rat. Eur J Endocrinol 1994;131:652–7. ISSN 0804–4643

Deflazacort is an oxazoline derivative of cortisone with presumably less serious side effects, but its effects on growth factors are unknown. The present experiments in Long Evans rats were carried out to investigate how deflazacort administration affected the growing rat, especially in relation to hepatic insulin-like growth factor I (IGF-I) and growth hormone receptor (GHR) messenger ribonucleic acid (mRNA). Four groups of animals were used: those treated with cortisone, with two different doses of deflazacort and with vehicle. Subcutaneous injections were given daily for 8 days. Thymus weight was reduced in all treated groups, with a comparable magnitude of reduction in the groups treated with cortisone and the higher dose of deflazacort (DF1). Daily weight gain was reduced significantly after cortisone treatment, but less so in the DF1 rats. Liver IGF-I and GHR mRNA were lower in the cortisone and deflazacort than in controls. However, GHR mRNA was reduced significantly only by cortisone and not by DF1. We conclude that growth failure is less severe in the DF1 rats compared to cortisone rats, which corresponds to the reduction in hepatic GHR mRNA.

Kay Latta, Kinderklinik der Medizinischen Hochschule Hannover, Konstanty-Gutschow-Str. 8, 30625 Hannover, Germany
Reduction in goiter size by 131I therapy in patients with non-toxic multinodular goiter
Authors: Wesche Maria F , Tiel-v-Buul Monique M , Smits Nico J , Wiersinga Wilmar M
Published: December 2008

Wesche MF, Tiel-v-Buul MM, Smits NJ, Wiersinga WM. Reduction in goiter size by 131I therapy in patients with non-toxic multinodular goiter. Eur J Endocrinol 1995;132:86–7. ISSN 0804–4643

A retrospective follow-up study of 131I treatment was performed in 10 females (median age 48 years, range 40–74 years) with non-toxic multinodular goiter. The median dose of 131I given was 20 mCi (range 14–65 mCi). Thyroid volume was measured by ultrasonography. The median follow-up period was 26 months (range 12–68 months). Nine patients had a reduction of goiter size: thyroid volume decreased from 88 ± 14.9 ml (mean±sem) to 49 ± 10.9 ml 1 year after 131I treatment. The relative decrease of goiter size was 48% after 1 year (N = 9) and 59% after 2 years (N = 5). One patient did not respond and was referred for operation. Side effects were mild spontaneously resolving radiation thyroiditis in one patient and subclinical hypothyroidism in four patients. In conclusion, 131I treatment of non-toxic goiter is an effective treatment at the expense of post-radiation (subclinical) hypothyroidism.

Maria F Wesche, Academic Medical Center, University of Amsterdam, Department of Internal Medicine, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Production of insulin-like growth factor binding protein (IGFBP), IGFBP-3 protease, and expression of IGF-I receptors by cells of the sheep immune system
Authors: Tonner Elizabeth , Beattie James , Flint David J
Published: December 2008

Tonner E, Beattie J, Flint DJ. Production of insulin-like growth factor binding protein (IGFBP), IGFBP-3 protease, and expression of IGF-I receptors by cells of the sheep immune system. Eur J Endocrinol 1995;132:118–22. ISSN 0804–4643

Single-cell suspensions of sheep thymus cells were cultured in serum-free medium with or without polyclonal activators (phytohaemagglutinin or concanavalin A) and the resultant conditioned medium was assayed for insulin-like growth factor binding protein (IGFBP) activity by binding of [125I]IGF-I, using charcoal to separate free from bound. All cultures produced IGFBP but mitogen stimulation significantly increased IGFBP concentrations, indicating production by lymphoid cells. Conditioned medium also degraded recombinant human [125I]IGFBP-3, suggesting IGFBP-3 protease production within the thymus. This degradation was inhibited by several protease inhibitors (phenylmethylsulphonyl fluoride, aprotinin, N-α-p-tosyl-l-lysine chloromethyl ketone), suggesting the presence of a serine protease. Cell surface [125I]IGF-I binding was demonstrated on cells from thymus, mesenteric lymph node, peripheral blood mononuclear cells and platelets. The [125I]IGF-I binding to platelets could be inhibited by unlabelled peptides, with relative potencies IGF-I > IGF-II ≫ insulin. Scatchard analysis of IGF-I competitive binding revealed a Kd of 266 pmol/l and approximately 40 receptor sites per cell. The high-affinity binding of IGF-I and competition by insulin suggested that the [125I]IGF-I binding was to an IGF-I receptor rather than to a membrane-associated IGFBP, to which insulin does not bind. These data provide further support for the role of the IGF-IGFBP axis in the immune system, particularly in relation to the thymus.

Elizabeth Tonner, Hannah Research Institute, Ayr, UK
Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy
Authors: Lindheimer Marshall D , Davison John M
Published: December 2008

Lindheimer MD, Davison JM. Osmoregulation, the secretion of arginine vasopressin and its metabolism during pregnancy. Eur J Endocrinol 1995;132:133–43. ISSN 0804–4643

This review stresses changes in osmoregulation as well as the secretion and metabolism of aŕginine vasopressin during pregnancy, focusing on human gestation. Pregnant women experience a decrease in body tonicity, plasma osmolality decreasing immediately after conception to a nadir ~ 10 mosmol/kg below non-pregnant levels early in pregnancy, after which a new steady state is maintained until term. Data from both human and rodent gestation have led to a formation of how these changes occur. The osmotic thresholds for thirst and antidiuretic hormone release decrease in parallel. Lowering the threshold to drink stimulates increased water intake and dilution of body fluids. Because arginine vasopressin (AVP) release is not suppressed at the usual level of body tonicity, the hormone continues to circulate and the ingested water is retained. Plasma osmolality declines until it is below the osmotic thirst threshold, and a new steady state with little change in water turnover is established. Pregnancy is characterized by increments in intravascular volume, but volume-sensing AVP release mechanisms appear to adjust as gestation progresses so that each new volume status is "sensed" as normal. The metabolic clearance of AVP increases fourfold, the rise paralleling that of circulating cystine aminopeptidase (vasopressinase), and enzyme produced by the placenta. Furthermore, the disposal rate of 1-deamino-8-d-AVP, and AVP analogue resistant to inactivation by vasopressinase, is unaltered in pregnancy. Thus, the increase in AVP's metabolism and the high circulating aminopeptidase levels have been implicated in certain forms of transient diabetes insipidus that occur in late pregnancy. Finally, mechanisms responsible for the altered osmoregulation in pregnancy are obscure, but chorionic gonadotropin and relaxin may be implicated in the changes.

M Lindheimer, Section of Nephrology, MC 5100, University of Chicago Hospitals, 5841 S Maryland Ave, Chicago, IL, USA
Diabetes insipidus and use of desmopressin (Minirin®) during pregnancy
Authors: Källén Bengt AJ , Carlsson Stefan S , Bengtsson Bengt KA
Published: December 2008

Källén BAJ, Carlsson SS, Bengtsson BKA. Diabetes insipidus and use of desmopressin (Minirin®) during pregnancy. Eur J Endocrinol 1995;132:144–6. ISSN 0804–4643

With the use of two central health registries in Sweden, the Hospital Discharge Registry and the Medical Birth Registry, we identified 100 infants born of women who had been hospitalized for diabetes insipidus. By checking the medical records of these women, 29 infants were identified whose mothers had diabetes insipidus prior to the pregnancy and had been treated through the pregnancy with desmopressin. These infants had a normal birth weight and gestational length; there was only one congenital malformation identified (a ventricular septum defect with a patent ductus arteriosus and simian lines). This child died at the age of 14 years in a hypophyseal disease. This is the largest material published on desmopressin during pregnancy. The results suggest that maternal diabetes insipidus and treatment with desmopressin during the whole pregnancy does not constitute a major risk for the infant.

Bengt Källén, Tornblad Institute, Biskopsgatan 7, S-223 62 Lund, Sweden
Stimulatory effect of gonadotropin-releasing hormone (GnRH) on in vitro prolactin secretion and presence of GnRH specific receptors in a subset of human prolactinomas
Authors: Brandi Anne Marie , Barrande Gaëlle , Lahlou Najiba , Crumeyrolle Michèle , Berthet Myriam , Leblanc Pierre , Peillon Françoise , Li Jacques Yuan
Published: December 2008

Brandi AM, Barrande G, Lahlou N, Crumeyrolle M, Berthet M, Leblanc P, Peillon F, Li JY. Stimulatory effect of gonadotropin-releasing hormone (GnRH) on in vitro prolactin secretion and presence of GnRH specific receptors in a subset of human prolactinomas. Eur J Endocrinol 1995;132:163–70. ISSN 0804–4643

The purpose of this study was to determine whether gonadotropin-releasing hormone (GnRH) may exert a direct action on human prolactinomas. On a series of 17 adenomas, we studied the effect of GnRH on the in vitro prolactin (PRL) secretion of dispersed and perifused cells of 10 cases and the [125I]GnRH agonist binding on frozen sections of three out of the adenomas studied in perifusion and on the membrane preparations of seven other cases. Two 20-min pulses of GnRH (10−7 mol/l) stimulated the in vitro PRL secretion of three adenomas out of 10 (increase of 200, 444 and 205%, respectively, above basal levels). The GnRH receptors of three adenomas bound GnRH agonist (Des-Gly10-(d-Ala6)-GnRH ethylamide). The binding was specific, with a high affinity (Kd = 0.60, 0.48 and 0.40 nmol/l) similar to that of two human anterior pituitaries obtained post-mortem (Kd = 0.70 and 0.40 nmol/l). Indirect immunoperoxidase revealed that the majority of the cells (60–90%) in all the adenomas studied contained immunoreactive PRL. Four of them also contained cells immunoreactive to the α-subunit of the glycoprotein hormones. In none of the prolactinomas were cells immunoreactive to antiserum of anti-β-luteinizing hormone, anti-β-follicle-stimulating hormone or anti-β-thyrotropin. All the prolactinomas that were responsive to GnRH in perifusion experiments and/or bound specifically to [125I]GnRH agonist were also immunoreactive for α-subunit. These results show that GnRH, via GnRH specific receptors, exerts a stimulation on in vitro PRL secretion in a subset of prolactinomas characterized by the presence of α-subunit.

Anne Marie Brandi, Unité INSERM 223, Faculté de Médecine Pitié-Salpêtrière, 105 Boulevard de l'Hôpital, 75013 Paris, France
Epidermal growth factor (EGF)- and transforming growth factor alpha-stimulated invasion and growth of follicular thyroid cancer cells can be blocked by antagonism to the EGF receptor and tyrosine kinase in vitro
Authors: Hölting Thomas , Siperstein Allan E , Clark Orlo H , Duh Quan-Yang
Published: December 2008

Hölting T, Siperstein AE, Clark OH, Duh Q-Y. Epidermal growth factor (EGF)- and transforming growth factor alpha-stimulated invasion and growth of follicular thyroid cancer cells can be blocked by antagonism to the EGF receptor and tyrosine kinase in vitro. Eur J Endocrinol 1995;132:229–35. ISSN 0804–4643

We have shown recently that epidermal growth factor (EGF) enhanced invasion and growth of differentiated thyroid cancer cells in vitro and in vivo. The present study analyzed the effects of transforming growth factor alpha (TGF-α) on invasion and growth of a follicular thyroid cancer cell line (FTC133) and whether blocking the EGF receptor by a monoclonal antibody (Mab528) or blocking the tyrosine kinase of the receptor by genistein abolished the EGF- and TFG-α-mediated effects. Growth and invasion (penetration of 8-μm pore polycarbonate membranes coated with Matrigel) were determined by the dimethylthiazol-diphenyltetrazolium bromide assay. Epidermal growth factor (10 ng/l) stimulated invasion of FTC133 by 42% and TGF-α (10 ng/l) stimulated invasion of FTC133 by 27% (p < 0.02). Both growth factors also enhanced growth by 62% (EGF) and 30% (TGF-α) (p < 0.003). Epidermal growth factor receptor antibodies (1 μg/ml) abolished EGF-mediated stimulation of invasion and growth completely and that of TGF-α by 93%. At 100 ng/ml genistein reversed EGF and TGF-α stimulation, and at 1 μg/ml it inhibited invasion (27%) and growth (40%) of unstimulated FTC133 (p < 0.02). We conclude that TGF-α stimulates invasion and growth of follicular thyroid cancer by binding to the EGF receptors, that EGF- and TGF-α-mediated effects can be blocked by antagonism to the EGF receptor and to tyrosine kinase, and that genistein not only neutralized EGF and TGF-α effects but also inhibited invasion and growth of unstimulated FTC133. Therefore, tyrosine kinase activity via other signalling systems must be crucial for basal invasion and growth of follicular thyroid cancer cells in culture.

Thomas Hölting, Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
In vivo and in vitro evidence for the production of inhibin-like immunoreactivity in human adrenocortical adenomas and normal adrenal glands: relatively high secretion from adenomas manifesting Cushing's syndrome
Authors: Nishi Yoshihiro , Haji Masafumi , Takayanagi Ryoichi , Yanase Toshihiko , Ikuyama Shoichiro , Nawata Hajime
Published: December 2008

Nishi Y, Haji M, Takayanagi R, Yanase T, Ikuyama S, Nawata H. In vivo and in vitro evidence for the production of inhibin-like immunoreactivity in human adrenocortical adenomas and normal adrenal glands: relatively high secretion from adenomas manifesting Cushing's syndrome. Eur J Endocrinol 1995;132:292–9. ISSN 0804–4643

To clarify whether adrenal gland secretes inhibin in vivo in physiological or pathological conditions, we measured the levels of inhibin-like immunoreactivity (inhibin-LI) in adrenal veins (A-vein) and compared them with those in inferior vena cava (IVC) using blood samples obtained at catheterization of adrenal vein in the patients with adrenal adenoma manifesting Cushing's syndrome (Cs), aldosterone-producing adenoma, clinically non-functioning adenoma and normal adrenal gland. The tumor sides of A-veins in the patients with adenomas and also both sides of A-veins in subjects with normal adrenal glands showed significantly higher contents of inhibin-LI than their IVC. When the inhibin-LI secretion rate from adrenal gland was estimated by the difference between the levels of A-vein (tumor side) and IVC, Cs adenomas showed the highest secretion rate. Similarly, the tissue inhibin-LI content and the basal secretion rate of inhibit-LI from primary cultured cells were the highest in Cs adenomas. These findings indicated that normal adrenal glands and adrenocortical adenomas produced and secreted inhibin-LI into the general circulation in vivo and Cs adenomas have relatively high capacity for secreting inhibin-LI, and the present study provided the first in vivo evidence for adrenal inhibin-LI production in pathological conditions

Yoshihiro Nishi, Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-Ku, Fukuoka 812, Japan
Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin
Authors: Yagui Kazuo , Yamaguchi Takahide , Kanatsuka Azuma , Shimada Fumio , Huang Choug I , Tokuyama Yoshiharu , Ohsawa Haruhiko , Yamamura Ken-ichi , Miyazaki Jun-ichi , Mikata Atsuo , Yoshida Sho , Makino Hideichi
Published: December 2008

Yagui K, Yamaguchi T, Kanatsuka A, Shimada F, Huang CI, Tokuyama Y, Ohsawa H, Yamamura K, Miyazaki J. Mikata A, Yoshida S, Makino H. Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur J Endocrinol 1995:132:487–96. ISSN 0804–4643

To investigate the relationship between human islet amyloid polypeptide (IAPP)/amylin expression and islet amyloid deposits in the pathogenesis of human non-insulin-dependent diabetes mellitus (NIDDM), we developed transgenic mice using a human IAPP cDNA connected to an insulin promoter. Ribonucleic acid blotting and immunohistochemistry revealed the expression of the transgene in the pancreatic beta cells. Immunogold electron microscopy showed that beta-secretory granules contained the human C-terminal flanking peptide of the IAPP precursor. Reverse-phase HPLC demonstrated human and mouse IAPP amide in the pancreas. Electron microscopy showed the accumulation of fibril-like material in a considerable number of beta-secretory granules. These results suggest that in transgenic mice, the human IAPP precursor is expressed in beta cells and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP molecules, because of their amyloidogenesis, aggregate into amyloid fibrils in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our working hypothesis is that in human NIDDM, IAPP aggregates into amyloid fibrils in beta-secretory granules, and that the fibrils are released into the extracellular space and islet amyloid deposits become substantial with time.

Azuma Kanatsuka, Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan
Correlations between bone mineral density, insulin-like growth factor I and auxological variables
Authors: Moreira-Andrés Maria N , Papapietro Karen , Cañizo Francisco J , Rejas Javier , Larrodera Luisa , Hawkins Federico G
Published: December 2008

Moreira-Andrés MN, Papapietro K, Cañizo FJ, Rejas J, Larrodera L, Hawkins FG. Correlations between bone mineral density, insulin-like growth factor I and auxological variables. Eur J Endocrinol 1995; 132:573–9. ISSN 0804–4643

Recent studies have shown growth-related changes in spinal bone mineral density (BMD) in children; however, there is less information available on the relationship between BMD and insulin-like growth factor I (IGF-I). The aim of this study was to relate the BMD of the spine and radius with serum IGF-I levels and auxological variables in normally growing children. We used dual X-ray absorptiometry to measure the BMD in the lumbar spine (L1–L4) and distal radius of 121 children (69 boys, 52 girls) aged 3–18 years whose growth velocity was normal. Lumbar and radial BMD increased with age (p < 0.001) and puberty (p < 0.001) and was highly correlated to age, weight, height, body surface and bone age (r = 0.70–0.89 and p < 0.001 for all variables). Partial correlation, with age held constant, was weaker but still significant for most auxological variables. Serum IGF-I concentrations increased slowly during childhood and markedly during early stages of puberty, and correlated with lumbar and radial BMD (r = 0.55 and 0.45, respectively; p < 0.001) and with the auxological variables (p < 0.001). When age was held constant, IGF-I levels still correlated significantly with the auxological variables and with BMD, except in the case of radial BMD in boys. By multiple regression analysis IGF-I, unlike auxological variables, did not reach significance in the ability to predict BMD. Therefore, in healthy children, serum IGF-I levels show a weaker relationship to BMD than do auxological variables.

MN Moreira-Andrés, Servicio de Endocrinología, Hospital 12 de Octubre, Carretera de Andalucia km. 5,4, 28041 Madrid, Spain
Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a
Authors: Preziati Daniela , La Rosa Luigi , Covini Giovanni , Marcelli Rosaria , Rescalli Stefania , Persani Luca , Del Ninno Ersilio , Meroni Pier Luigi , Colombo Massimo , Beck-Peccoz Paolo
Published: December 2008

Preziati D, La Rosa L, Covini G, Marcelli R, Rescalli S, Persani L, Del Ninno E, Meroni PL, Colombo M, Beck-Peccoz P. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a. Eur J Endocrinol 1995;132:587–93. ISSN 0804–4643

The occurrence of thyroid abnormalities and the appearance of organ- and non-organ-specific autoantibodies during long-term recombinant interferon alpha-2a (IFN-α) therapy were studied in 86 and 51 consecutive outpatients with hepatitis C and B virus-related chronic active hepatitis (CAH-HCV and CAH-HBV), respectively. Most patients had longstanding community-acquired hepatitis. At baseline, 9.3% of CAH-HCV and 3.9% of CAH-HBV patients showed clinical and/or biochemical signs of thyroid dysfunction. The remaining patients were euthyroid, although anti-thyroid autoantibodies were found in 33/78 (42.3%) of CAH-HCV and in 5/49 (10.2%) of CAH-HBV patients. During IFN-α treatment, increased anti-thyroid autoantibody levels were seen in 40% of CAH-HCV initially negative patients, while they became detectable in no more than 10% of CAH-HBV patients. Interferon-α-induced hypo- or hyperthyroidism was recorded in 12 of 35 CAH-HCV patients treated for 12 months (34.3%). Only one CAH-HBV patient developed hyperthyroidism. High titers of anti-nuclear auto-antibodies (ANA) were recorded at enrolment in 5/36 (13.8%) of CAH-HCV and in 3/16 (18.7%) of CAH-HBV patients. Only one CAH-HCV patient displayed anti-parietal cell antibodies (PCA). After IFN-α treatment, ANA were found in 10/28 (35.7%) and PCA in 2/28 (7.1%) of CAH-HCV patients, while an additional CAH-HBV patient developed PCA, but not ANA. However, no signs of systemic autoimmune disease were recorded. In conclusion, more than half of the patients with chronic active hepatitis C, but only one-tenth of those with hepatitis B, displayed thyroid- and/or non-organ-specific autoantibodies prior to or during treatment with IFN-α. As most of the antibody-positive patients developed permanent thyroid disorders during IFN-α therapy, the risk of development of organ-specific autoimmunity should be assessed carefully and incorporated in the cost/effectiveness analysis in patients with longstanding hepatitis who are candidates for IFN-α treatment.

Paolo Beck-Peccoz, Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Padiglione Granelli, Via F. Sforza 35, 20122-Milano, Italy