bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Graves' disease by carbimazole: high dose with thyroxine compared to titration dose
Authors: Edmonds CJ , Tellez M
Published: December 2008

Edmonds CJ, Tellez M. Treatment of Graves' disease by carbimazole: high dose with thyroxine compared to titration dose. Eur J Endocrinol 1994;131:120–4. ISSN 0804–4643

A comparative study of high-dose (HD, carbimazole 60 mg plus thyroxine 100–150 μg daily) and titration-dose (TD) regimens of carbimazole was carried out in 70 patients with Graves' disease, the patients being assigned randomly to one or other regimen. The treatment was given for 1 year and follow-up was for 2 years after stopping treatment. In both groups, recurrence of hyperthyroidism occurred, most commonly during the first 6 months (35% of HD and 44% of TD). By 2 years after stopping treatment, recurrence had occurred in 50% of the HD and 66% of the TD group. The differences were not significant. Thyroid antibodies, serum thyroglobulin and pertechnetate uptake fell similarly in both groups during treatment. Cigarette smoking was similar in both the groups and did not influence the frequency of relapse. In both HD and TD groups, when relapsing patients were examined according to whether they relapsed early (within 6 months or less) or late it was found that those who relapsed late were, in respect of goitre size, pertechnetate uptake and presence of detectable plasma TSH, similar to the patients who did not relapse at all. In conclusion, the changes in the measured variables and the progress of the patients was similar whether treated by the HD or TD regimen.

CJ Edmonds, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK
Markers of bone metabolism during short-term administration of thyroxine in healthy volunteers
Authors: Frevert Ernst U , Biester Anja , Müller Manfred J , Schmidt-Gayk Heinrich , von zur Mühlen Alexander , Brabant Georg
Published: December 2008

Frevert EU, Biester A, Müller MJ, Schmidt-Gayk H, von zur Mühlen A, Brabant G. Markers of bone metabolism during short-term administration of thyroxine in healthy volunteers. Eur J Endocrinol 1994;131:145–9. ISSN 0804–4643.

We investigated the influence of L-thyroxine (L-T4) treatment over 3 weeks on biochemical markers of bone turnover in 12 healthy young men (age 25.6 ± 1.4 years, BMI: 22.6 ± 2.5 kg/m2). Serum parameters indicating bone formation [bone Gla protein (BGP), carboxyterminal propeptide of type I procollagen (PICP), and bone-specific alkaline phosphatase (BAP)] and bone resorption [cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and the urinary excretion of pyridinoline (Pyr) and deoxypyridinoline (D-Pyr)] were measured before and after three weeks of treatment with 300 μg L-T4/d. T3 and T4 significantly increased and TSH decreased to almost undetectable levels even when measured with a third generation TSH assay. Markers of bone formation showed variable responses with a small but significant increase in BGP but not in PICP or BAP. In contrast, all parameters of bone resorption increased significantly with a good correlation between D-Pyr excretion and the serum parameter ICTP (r = 0.78, p < 0.0001). These changes in bone-turnover markers were not necessarily paralleled by comparable increments of other markers of tissue thyrotoxicosis (SHBG, pulse rate, VO2), suggesting a variability in tissue sensitivity. These rapid responding parameters, especially in the easily obtainable serum parameter ICTP, might be valuable tools in the evaluation of several states of thyroxine excess.

G Brabant, Dept. Klinische Endokrinologie, Medizinische Hochschule Hannover, D-30 623 Hannover, Germany
Evidence of oestradiol-induced changes in gonadotrophin secretion in men with feminizing Leydig cell tumours
Authors: Kuhn Jean Marc , Duranteau Lise , Rieu Max A , Lahlou Najiba , Roger Marc , Luton Jean Pierre
Published: December 2008

Kuhn JM, Duranteau L, Rieu MA, Lahlou N, Roger M, Luton JP. Evidence of oestradiol-induced changes in gonadotrophin secretion in men with feminizing Leydig cell tumours. Eur J Endocrinol 1994;131:160–6. ISSN 0804–4643

To study the sex steroid-gonadotrophin relationship, plasma oestradiol (E2), testosterone and gonadotrophin-releasing hormone (GnRH)-induced (100 μg iv) gonadotrophin response were measured in 42 male partners of infertile couples with normal sperm count (group I) and in 21 men with Leydig cell tumour (LCT, group II) in which a basal evaluation was repeated after tumour removal. Plasma free α-subunit (FAS), immunoreactive α-inhibin and luteinizing hormone (LH) pulse analysis were assessed in 10 LCT before and in six of them after surgery. Testosterone was significantly (p < 0.01) lower whereas E2 was significantly (p < 0.001) higher in group II than in group I. Gonadotrophin data were similar in both groups. The mean FAS was higher in group II than in group I and α-inhibin was higher than the normal range in 6/10 LCT. In group II, E2 levels were significantly (p < 0.01) and negatively correlated with testosterone, FSH, GnRH-induced gonadotrophin rise and LH pulse amplitude but not frequency. Significant (p < 0.001) changes were observed after surgery: E2 and α-inhibin fell; testosterone, LH and FSH rose; whereas FAS did not change significantly. The LH pulse amplitude but not frequency increased significantly (p < 0.05). In conclusion E2 oversecreted by LCT decreased LH and testosterone levels concomitantly. The GnRH-induced gonadotrophin level rose and the LH pulse amplitude decreased when the plasma E2 level rose, whereas the pulse frequency remained unaffected. A concomitant increase in α-inhibin and E2 is likely to be responsible for the drop in plasma FSH levels. These data support an action of excessive amounts of E2 at pituitary level, perhaps by decreasing the sensitivity of gonadotrophs to GnRH.

JM Kuhn, Service d'Endocrinologie, Hôpital de Bois Guillaume, 147 avenue du Maréchal Juin, 76230 Bois Guillaume, France
Aldosterone response to adrenocorticotrophin and furosemide in primary aldosteronism after prolonged spironolactone treatment
Authors: Yagi Atsuko , Ichikawa Shuichi , Sakamaki Tetsuo , Ono Zempei , Sato Kunio , Nakamura Tetsuya , Sakamoto Hironosuke , Murata Kazuhiko
Published: December 2008

Yagi A, Ichikawa S, Sakamaki T, Ono, Z, Sato K, Nakamura T, Sakamoto H, Murata K. Aldosterone response to adrenocorticotrophin and furosemide in primary aldosteronism after prolonged spironolactone treatment. Eur J Endocrinol 1994;131:215–20. ISSN 0804–4643

We evaluated the effects of prolonged spironolactone treatment on aldosterone secretion in patients with primary aldosteronism. The patients were hospitalized and underwent a furosemide test with or without dexamethasone, as well as an adrenocorticotrophin (ACTH) test. In untreated patients, neither plasma renin activity (PRA) nor plasma aldosterone showed a response in the furosemide test. In patients receiving spironolactone, furosemide increased significantly both the PRA and the plasma aldosterone concentration (from 2.6±0.8 to 7.0±2.0 μg·1−1 · h−1 (p < 0.05) and from 345.6 ± 55.8 to 492.7 ± 76.8 ng/l (p < 0.05), mean ± sem, respectively). Dexamethasone administration had no effect on the results of the furosemide test (p > 0.1). However, dexamethasone tended to decrease the basal plasma aldosterone concentration in the untreated patients, but not in the patients receiving spironolactone. In the ACTH test, the plasma aldosterone concentration increased significantly in the untreated patients (from 549.0± 69.8 to 1169.3 ± 165.5 ng/l, p <0.01), 0.01), but there was no significant aldosterone response in the spironolactone-treated patients (from 885.5 ± 204.9 to 1260.3 ± 289.2 ng/l, p> 0.1). We conclude that aldosterone secretion is mainly dependent on ACTH in the untreated patients with primary aldosteronism and is more strongly regulated by the renin–angiotensin system during spironolactone treatment.

Atsuko Yagi, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371, Japan
Pheochromocytoma expressing adrenocorticotropin and corticotropin-releasing hormone; regulation by glucocorticoids and nerve growth factor
Authors: Liu Jianqi , Heikkilä Päivi , Voutilainen Raimo , Karonen Sirkka-Liisa , Kahri Arvi I
Published: December 2008

Liu J, Heikkilä P, Voutilainen R, Karonen S-L, Kahri AI, Pheochromocytoma expressing adrenocorticotropin and corticotropin-releasing hormone; regulation by glucocorticoids and nerve growth factor. Eur J Endocrinol 1994;131:221–8. ISSN 0804–4643

A pheochromocytoma from a 59-year-old woman was found to be immunoreactive to adrenocorticotropin (ACTH), chromogranin, neurofilament-200, neuron-specific enolase and S-100 protein. Northern blot analysis showed that both proopiomelanocortin (POMC) and corticotropin-releasing hormone (CRH) genes were expressed in the pheochromocytoma but not in the surrounding adrenal cortex. In primary culture, the POMC and CRH mRNAs were increased by dexamethasone (500 μg/l for 3 days) up to 10- and 15-fold of the control, respectively. The secretion of ACTH also was stimulated eightfold with the same treatment. The stimulatory effect of dexamethasone on POMC gene expression was inhibited 70% by nerve growth factor (NGF, 200 μg/l), 30% by 12-O-tetradecanoyl phorbol 13-acetate (TPA, 160 nmol/l) (a protein kinase-C activator) and 30% by (Bu)2cAMP (1 mmol/ 1). On the other hand, NGF alone increased the CRH mRNA accumulation up to 10-fold, and further enhanced the stimulatory effect of dexamethasone on the CRH mRNA twofold, and TPA inhibited (30%) the dexamethasone-induced CRH mRNA accumulation. Furthermore, the conditioned medium of the pheochromocytoma cells increased secretion of corticosterone fourfold in the primary culture of rat fetal adrenal cells. Our results indicate abnormal expression and regulation of POMC and CRH genes in this pheochromocytoma.

Arvi I Kahri, Department of Pathology, PO Box 21 (Haartmaninkatu 3), FIN-00014 University of Helsinki, Finland
Effect of tumor necrosis factor-α on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts
Authors: Scharla Stephan H , Strong Donna D , Mohan Subburaman , Chevalley Thierry , Linkhart Thomas A
Published: December 2008

Scharla SH, Strong DD, Mohan S, Chevalley T, Linkhart TA. Effect of tumor necrosis factor-α on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts. Eur J Endocrinol 1994;131:293–301. ISSN 0804–4643

Tumor necrosis factor-α (TNF-α) is a cytokine produced by immune cells, which has multiple effects on bone cells and is therefore thought to mediate changes in bone metabolism occurring during inflammation. In the present study we have investigated the effect of TNF-α on the secretion of insulin-like growth factor I (IGF-I) and IGF binding protein 4 (IGFBP-4) by clonal mouse osteoblasts (MC3T3-E1 cells) using subconfluent in vitro cultures and serum-free conditions. The IGF-I was determined by radioimmunoassay under conditions eliminating the interference of IGFBPs. Treatment of MC3T3-E1 cultures with TNF-α for 24 h resulted in a dose-dependent decrease in IGF-I secretion (maximally to 34 ± 9.7% of control with 60 pmol/l TNF-α; mean ± sd). The TNF-α treatment also resulted in decreased messenger ribonucleic acid (mRNA) levels of IGF-I at 4 and 24 h, as detected by Northern analysis. Because basal secretion of IGFBPs is very low in MC3T3-E1 cells, effects of TNF-α on IGFBP secretion were studied in cultures in which IGFBP-4 expression was increased by calcitriol (1,25(OH)2D3) treatment. The presence of TNF-α (600 pmol/l) inhibited this calcitriol-induced stimulation of IGFBP-4 mRNA levels from 4 h onwards, with complete inhibition of the calcitriol effect occurring at 24 h. We also observed a dose-dependent inhibition of calcitriol-stimulated IGFBP-4 secretion into the culture medium (as detected by Western ligand blot), with the maximal inhibition occurring with 600 pmol/l TFN-α to 25 ± 7% of control levels. These TNF-α effects were not prevented by indomethacin treatment, suggesting that they are not dependent on prostaglandins. The DNA synthesis was reduced to 62 ± 8% of the control value by 600 pmol/l TNF-α. We conclude that secretion of IGFs and IGFBPs by osteoblasts can be modulated by TNF-α, which in turn may be responsible for some of the known effects of TNF-α on osteoblastic cell proliferation and differentiation.

Stephan H Scharla, Klinik am Kurpark, Schussenrieder Strasse 5, D-88326 Anlendorf, Germany
Stage-specific expression of c-myc messenger ribonucleic acid in porcine granulosa cells early in follicular growth
Authors: Sato Asomi , Bo Masaki , Maruo Takeshi , Yoshida Shigeki , Mochizuki Matsuto
Published: December 2008

Sato A, Bo M, Maruo T, Yoshida S, Mochizuki M. Stage-specific expression of c-myc messenger ribonucleic acid in porcine granulosa cells early in follicular growth. Eur J Endocrinol 1994;131:319–22. ISSN 0804–4643

In the present study, the expression of c-myc mRNA in porcine granulosa cells harvested from varying follicle stages was analyzed using northern blot hybridization with a c-myc probe, and compared during follicular growth. Northern blot analysis revealed that porcine granulosa cell RNA obtained from small (1–2 mm) follicles contained an abundance of c-myc transcript of 2.4kb, the size of which was identical to the c-myc transcript obtained with human early placental RNA used as the control. In contrast to small-follicle granulosa cell RNA, total RNA preparations from either medium (3–5 mm)-follicle granulosa cells or large (6–11 mm)-follicle granulosa cells exhibited no detectable transcripts with the c-myc probe. These results suggest that expression of c-myc mRNA in porcine granulosa cells is limited only at the early stage of follicular growth. The stage-specific expression of c-myc mRNA in granulosa cells early in follicular growth may play a physiological role in the autonomous growth of immature granulosa cells in early folliculogenesis, seemingly independent of pituitary gonadotropic stimulation.

Takeshi Maruo, Department of Obstetrics and Gynecology, Kobe University School of Medicine, Chuo-ku, Kobe 650, Japan
High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men
Authors: Kliesch Sabine , Behre Hermann M , Nieschlag Eberhard
Published: December 2008

Kliesch S, Behre HM, Nieschlag E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol 1994;131:347–54. ISSN 0804–4643

In order to determine the efficacy of gonadotropin and gonadotropin-releasing hormone (GnRH) therapy in hypogonadotropic hypogonadal men, we performed a retrospective clinical analysis in the outpatient clinic of a University Center for Reproductive Medicine. Twenty-six men with either hypothalamic (idiopathic hypogonadotropic hypogonadism, N = 6; Kallmann syndrome, N = 8) or pituitary disorders (N = 12) were treated with gonadotropins or GnRH for induction of spermatogenesis in 33 treatment cycles and, additionally, for induction of pregnancy in the female partner in 18 out of 33 cases (12 of 26 patients). Patients were treated with a combination of 1000–2500 IE of human chorionic gonadotropin twice per week and 75–150 IE human menopausal gonadotropin three times per week intramuscularly or subcutaneously. Alternatively, GnRH was administered at doses of 5–20 μg every 120 min subcutaneously to men with hypothalamic disorders. Treatment lasted until sperm appeared in the ejaculate or pregnancy was induced. During therapy, testosterone levels increased into the normal range. Total testicular volumes increased significantly during therapy despite low initial testicular volumes and histories of maldescended testes. Sperm appeared in the ejaculate in 30 of 33 treated patients. Pregnancies occurred in 15 out of 18 cases even with sperm counts far below the normal range. We could not detect differences in the efficacy of gonadotropin or GnRH treatment in hypogonadotropic hypogonadism. Thus, we conclude that both gonadotropin and pulsatile GnRH therapy are most effective in the induction of spermatogenesis and pregnancies in hypogonadotropic hypogonadal men, despite maldescended testes, low initial testicular volumes or sperm concentrations below the normal limit.

E Nieschlag, Institute of Reproductive Medicine of the University, Steinfurter Strasse 107, D-48149 Münster, Germany
Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause–effect relationship
Authors: Abs Roger , Stevenaert Achilles , Beckers Albert
Published: December 2008

Abs R, Stevenaert A, Beckers A. Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause–effect relationship. Eur J Endocrinol 1994;131:355–8. ISSN 0804–4643

A 51-year-old female patient with long-standing hyperthyroidism due to a thyrotropin-secreting pituitary adenoma is reported, who became thyrotoxic again shortly after successful pituitary surgery. Functional testing and scintigraphy suggested the diagnosis of autonomous functioning thyroid nodules, which was confirmed by pathological examination of the resected thyroid tissue. This is the first report revealing the transition from a pituitary-dependent to a thyroid-dependent hyperthyroidism. Autonomous functioning thyroid nodules are, however, considered an intrinsic thyroid defect. In similarity with other disorders, in which trophic hormones may induce an autonomous secretion by the target gland, this report opens the possibility that a humoral factor may play a role in the development of autonomous functioning thyroid nodules.

A Beckers, CHU-B35, Department of Endocrinology, Sart-Tilman, B-4000 Liège, Belgium
Simultaneous assay for three types of thyrotropin receptor antibody activities using FRTL-5 cells in patients with autoimmune thyroid diseases
Authors: Zhu Yi , Portmann Luc , Dénéréaz Nicole , Lemarchand-Béraud Thérèse
Published: December 2008

Zhu Y, Portmann L, Dénéréaz N. Lemarchand-Béraud T. Simultaneous assay for three types of thyrotropin receptor antibody activites using FRTL-5 cells in patients with autoimmune thyroid diseases. Eur J Endocrinol 1994;131:359–68. ISSN 0804–4643

The relationships between the different circulating thyrotropin receptor antibodies (TSH-R-abs) in autoimmune thyroid disease (AITD) are complex. In order to investigate them, we have developed an assay for the simultaneous measurement of three types of TSH-R-abs: TSH-binding inhibiting immunoglobulin (TBII); thyroid-stimulating antibody (TS-ab) and TSH-stimulation blocking antibody (TSB-ab). A large number of patients with Graves' disease (GD)—untreated and treated—Hashimoto's thyroiditis (HT), primary myxedema (PM) and non-immune goiter (NIG) were investigated. In untreated Graves' patients the frequency of positive TS-ab and TBII sera was found to be 90 and 69%, respectively, the presence of TS-ab and/or TBII being detected in 98%. After long-term antithyroid treatment administered to GD patients, the frequency of positivity of both TBII and TSab was decreased, whether hyperthyroidism was cured or not. The TSB-ab was detected in the serum of 8% of patients with GD, and the frequency of TSB-ab did not increase following treatment and alteration in thyroid function. No significant correlation was found between TSB-ab and thyroid function in Graves' patients. Besides, we found that all the GD patients presenting positive TSB-ab were also TBII positive. A follow-up study of the three TSH-R-abs was performed in 35 patients with GD during a mean of 14.3 ± 8.5 months (4–34 months) of antithyroid drug treatment. Ten out of 24 patients (42%) with positive TBII and 16 out of 32 (50%) with positive TS-ab turned from positive to negative during the time of follow-up. Regarding relapse in hyperthyroid GD, we found that TS-ab was positive in 80% and TBII was positive in 40% of the patients with Graves' relapse, indicating that the presence of TS-ab is a better index for relapse prediction in Graves' hyperthyroidism than TBII. The TSB-ab was found with higher frequency in HT and PM than in GD, i.e. 21%, 18% and 8%, respectively. The TSB-ab positivity was correlated significantly with TBII in our patients with AITD when TSB-ab was positive. This new simultaneous assay of the three TSH-R-abs should be very helpful for further investigation of the autoimmune aspects of AITD and it should help us to progress in a better understanding of the pathogeny of the different AITDs.

Thérèse Lemarchand-Béraud, Division of Endocrinology and Metabolism, University Hospital (CHUV), CH-1011 Lausanne, Switzerland
Molecular characterization of a cloned human oxytocin receptor
Authors: Kimura Tadashi , Makino Yoko , Saji Fumitaka , Takemura Masahiko , Inoue Tomoko , Kikuchi Tomoyuki , Kubota Yasue , Azuma Chihiro , Nobunaga Toshikatsu , Tokugawa Yoshihiro , Tanizawa Osamu
Published: December 2008

Kimura T, Makino Y, Saji F, Takemura M, Inoue T, Kikuchi T, Kubota Y, Azuma C, Nobunaga T, Tokugawa Y, Tanizawa O. Molecular characterization of a cloned human oxytocin receptor. Eur J Endocrinol 1994;131:385–90. ISSN 0804–4643

We describe here the binding and functional properties of a cloned human oxytocin receptor (OTR). We established a transient OTR expression system on COS-1 cells, which do not express vasopressin receptors. With the transfected cells and [3H]oxytocin, the dissociation constant (Kd) of OTR to oxytocin was 6.0 ±1.1 nmol/l; the binding properties of several oxytocin-related peptides were also examined. The functional properties of OTR were determined by an electrophysiological method, using a Xenopus laevis oocyte injected with in vitro transcribed OTR mRNA. These two methods showed that [Phe2,Orn8]vasotocin, a vasopressin agonist, was an OTR antagonist. A combination of these methods using cloned OTR cDNA is a novel and effective method for the investigation of oxytocin-related ligands.

Tadashi Kimura, Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2 Yamadaoka, Suita City, Osaka 565, Japan
Progestin treatment in the dog I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis
Authors: Selman PJ , Mol JA , Rutteman GR , Rijnberk A
Published: December 2008

Selman PJ, Mol JA, Rutteman GR, Rijnberk A. Progestin treatment in the dog. I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis. Eur J Endocrinol 1994;131:413–21. ISSN 0804–4643

The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the release of growth hormone (GH) and glucose metabolism were studied in two groups of eight ovariohysterectomized dogs. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery was studied in four dogs of each treatment group in the 6 months following cessation of progestin administration. Treatment with both MPA and PROL resulted in similar increases in plasma levels of GH and insulin-like growth factor I (IGF-I). The GH responses to both clonidine and growth hormone-releasing hormone became impaired. In neither treatment group did the elevated plasma GH levels decrease after administration of the synthetic somatostatin analogue SMS 201-995. The size and shape of the pituitary gland were not changed by progestin treatment. After cessation of progestin administration, basal plasma levels of GH and IGF-I did not return to pretreatment values. The GH response to growth hormone-releasing hormone remained impaired for at least 6 months after the last progestin administration. In both treatment groups, glucose homeostasis was sustained initially by increased insulin production. Prolonged treatment with MPA and PROL resulted in glucose intolerance. No amelioration was observed during the recovery period in either group. A small number of dogs developed diabetes mellitus. In more than 50% of the dogs in both treatment groups small mammary tumours developed. The recently discovered local production of GH probably played a role in mammary tumorigenesis. It is concluded that treatment with MPA and PROL results in similar increases in plasma levels of GH and IGF-I and leads to a similar degree of insulin resistance. The elevated GH levels can be neither stimulated nor inhibited, which is a feature compatible with autonomous secretion. These results are consistent with the recent finding of a progestin-induced ectopic production of GH in the mammary gland of the dog.

JA Mol, Department of Clinical Sciences of Companion Animals, Utrecht University, PO Box 80. 154, 3508 TD Utrecht, The Netherlands
New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2
Authors: Signore Alberto , Chianelli Marco , Ferretti Elisabetta , Toscano Anna , Britton Keith E , Andreani Domenico , Gale Edwin AM , Pozzilli Paolo
Published: December 2008

Signore A, Chianelli M, Ferretti E, Toscano A, Britton KE, Andreani D, Gale EAM, Pozzilli P. New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2. Eur J Endocrinol 1994;131:431–7. ISSN 0804–4643

Insulitis is considered the histopathological hallmark of type I (insulin-dependent) diabetes. In the nonobese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, we have labelled recombinant interleukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. We studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled α-lactalbumin was used as the control protein. In the first set of experiments we studied the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled α-lactalbumin (p < 0.003 at 20 min; p< 0.001 at 40 min; p< 0.0001 at 60 min) or Balb/c mice injected with labelled interleukin 2 (p< 0.05 at 40 min; p< 0.001 at 60 min). In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice (p < 0.04 after 22–45 min in NOD mice vs Balb/c mice). Finally, a positive correlation was found between the radioactivity in the pancreas and the extent of lymphocytic infiltration (p < 0.01 for pancreas radioactivity counted in vitro and p< 0.004 for pancreas radioactivity counted in vivo by gamma camera). This study demonstrates that 123I-labelled interleukin 2 administered iv accumulates specifically in the inflamed pancreas of diabetes-prone NOD mice, suggesting its potential application in human insulin-dependent diabetes mellitus.

A Signore, Servizio Speciale di Medicina Nucleare, II Clinica Medica, Policlinico Umberto I, 00161 Roma, Italy
Basal secretory activity of the hypothalamo–pituitary–adrenocortical axis is enhanced in healthy elderly. An assessment during undisturbed night-time sleep
Authors: Dodt Christoph , Theine Karl-Josef , Uthgenannt Dirk , Born Jan , Fehm Horst Lorenz
Published: December 2008

Dodt C, Theine K-J, Uthgenannt D, Born J, Fehm HL. Basal secretory activity of the hypothalamo–pituitary–adrenocortical axis is enhanced in healthy elderly. An assessment during undisturbed nighttime sleep. Eur J Endocrinol 1994;131:443–50. ISSN 0804–4643

The process of aging is characterized by a disturbed neuroendocrine regulation, including a changed secretory activity of the hypothalamo–pituitary–adrenocortical (HPA) axis. In the present study adrenocorticotropin (ACTH) and cortisol secretion was monitored during nocturnal sleep (controlled by somnopolygraphy) in healthy aged men (N = 10, age range 70–92 years, mean 78.2 years) and women (N = 10, age range 70–88 years, mean 78.6 years), and in young male controls (N = 16, age range 20–34 years, mean 24.9 years). Blood was drawn every 15 min. Most important, basal HPA secretory activity was enhanced distinctly in the elderly, as indicated by significantly elevated nadirs of plasma cortisol and ACTH concentrations occurring during early nocturnal sleep (p < 0.001, compared to young controls) and by elevated average levels of cortisol and ACTH between 23.00 and 03.00 h (p < 0.001). The first rise in nocturnal plasma cortisol began, on average, 67 min earlier than in young controls (p < 0.005). Changes of endocrine activity were associated with marked reductions of slow-wave sleep (SWS, p < 0.05) and rapid eye movement (REM) sleep in the elderly (p < 0.01), while time awake and in stage 1 sleep was increased. The REM sleep coincided with decreased HPA secretory activity, irrespective of age, indicating that the link between the ultradian sleep structure and the secretory HPA activity is maintained in the elderly. It is concluded that the agerelated elevation of basal HPA secretory activity is of central nervous origin, leading to a phase advance of the circadian pacemaker and an elevation of the basal secretory rate of the HPA axis. Considering complementary results from animal studies, it is suggested that basal HPA hypersecretion associated with SWS deficits in the elderly are markers for an altered function of hippocampal corticosteroid receptors which are involved in the tonic inhibition of HPA secretory activity.

C Dodt, Klinische Forschergruppe "Klinische Neuroendokrinologie", Zentrum Innere Medizin, Medizinische Universität zu Lübeck. Ratzeburger Allee 160, D-23538 Lübeck, Germany
Thyroid peroxidase immunodetection as a tool to assist diagnosis of thyroid nodules on fine-needle aspiration biopsy
Authors: De Micco Catherine , Zoro Patricia , Garcia Stéphane , Skoog Lambert , Tani Edneia M , Carayon Pierre , Henry Jean-Francois
Published: December 2008

De Micco C, Zoro P, Garcia S, Skoog L, Tani EM, Carayon P, Henry J-F. Thyroid peroxidase immunodetection as a tool to assist diagnosis of thyroid nodules on fine-need aspiration biopsy. Eur J Endocrinol 1994;131:474–9. ISSN 0804–4643

In a previous work we have reported the presence in 96.9% of malignant and 4.2% of benign thyroid tumors of an immunological abnormality of the enzyme thyroid peroxidase, impeding the fixation of the anti-thyroid peroxidase monoclonal antibody termed "MoAb47". The present study has been designed to establish the ability of thyroid peroxidase immunodetection to assist the diagnosis of malignancy in fine-needle aspiration of thyroid nodules. The fixation of anti-thyroid peroxidase monoclonal antibody was investigated by immunohistochemistry on fine-needle aspirates of 150 surgically removed thyroid nodules (20 papillary carcinomas, five follicular carcinomas, 90 colloid adenomas, nine fetal adenoma, 13 atypical adenomas, five oncocytic adenomas, six Hashimoto's thyroiditis and two Graves' disease). The percentage of positive cells has been compared to the final histological diagnosis. In samples from 113/125 benign nodules 80–100% cells presented a positive immunoreaction, whereas all samples from malignant tumors yielded less than 80% positive cells. Benign nodules exhibiting less than 80% positive cells corresponded to three degenerative colloid nodules, five atypical follicular adenomas, two oncocytomas and two thyroiditis. According to results obtained in this series, with the value of 80% as the limit for discrimination between benign and highrisk nodules, the sensitivity of thyroid peroxidase staining for diagnosis of malignancy would be 100%, its specificity 90% and its overall accuracy 92%. Thyroid peroxidase staining with monoclonal antibody MoAb47 on fine-needle aspirates is a useful adjunct to conventional cytology for the investigation of patients with thyroid nodules.

Catherine De Micco, Laboratoire d'Anatomie Pathologique, Faculté de Médecine Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20, France
Thyrotropin receptor and leukocyte adhesion molecules in autoimmune thyroid disease: a study of their gene expression by Northern blot analysis and in situ hybridization
Authors: Schuppert Frank , Reiser Markus , Heldin Niels-E , Ede Sülke , Scheumann Georg FW , Dralle Henning , von zur Mühlen Alexander
Published: December 2008

Schuppert F, Reiser M, Heldin N-E, Ede S, Scheumann GFW, Dralle H, von zur Mühlen A. Thyrotropin receptor and leukocyte adhesion molecules in autoimmune thyroid disease: a study of their gene expression by Northern blot analysis and in situ hybridization. Eur J Endocrinol 1994;131:480–8. ISSN 0804–4643

In order to characterize the role of leukocyte-activating antigens and other immunological parameters in autoimmune thyroid disease, mRNA levels of intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1, E-selectin), invariant chain (Ii) and the thymic hormone thymosin β4 (Tβ4) were investigated in 18 human thyroid glands, including eight Graves' thyroids, two Hashimoto's thyroids, two endemic goiters and six healthy controls. Northern blot analysis showed that in autoimmune thyroid disease, expression of ICAM-1 and Tβ4 was correlated to transcript levels of Ii, whereas in the healthy controls, expression of Tβ4, ICAM-1 and ELAM-1 was low or nearly absent. ELAM-1 and TSH receptor (TSH-R) expression, the latter serving as a thyroid specific marker, was increased in some diseased glands but showed no relation to the immunological parameters mentioned above. Localization of the specific mRNAs by in situ hybridization demonstrated a cell-specific expression of TSH-R (thyrocytes), ELAM-1 (vascular endothelial cells) and Tβ4 (cells of hematopoietic origin). In contrast, transcripts of Ii and ICAM-1 were found in thyrocytes, leukocytes and endothelial cells. Our results implicate a coordinate expression of ICAM-1, Tβ4 and Ii in autoimmune thyroid disease, yielding distinct cellular expression patterns. Differential expression of ICAM-1. Ii and the TSH-R in thyroid epithelial cells indicates active regulatory events within the thyrocyte.

Frank Schuppert, Department of Clinical Endocrinology, Medizinische Hochschule Hannover, Konstanty-Gutschow-Strasse 8, D-30625 Hannover, Germany
Evaluation of somatostatin biosynthesis, somatostatin receptors and tumor growth in murine medullary thyroid carcinoma
Authors: Ouazzani L , Reubi JC , Volle GE , Lausson S , Pidoux E , Moukhtar MS , Treilhou-Lahille F
Published: December 2008

Ouazzani L, Reubi JC, Volle GE, Lausson S, Pidoux E, Moukhtar MS, Treilhou-Lahille F. Evaluation of somatostatin biosynthesis, somatostatin receptors and tumor growth in murine medullary thyroid carcinoma. Eur J Endocrinol 1994;131:522–30. ISSN 0804–4643

Spontaneous medullary thyroid carcinomas (MTCs) of old rat thyroids were analyzed for the expression of somatostatin and somatostatin binding sites in tumoral C cells in relation to the stage of tumor development, the mitotic activity of tumoral tissue and calcitonin biosynthesis as a marker of C cell differentiation. High levels of both immunoreactive somatostatin and its mRNA were detected in a subpopulation of tumoral C cells, gathered in areas suggesting a clonal proliferation and located preferentially at the periphery of the tumor. These cells also displayed high levels of calcitonin and its mRNA. However, many calcitonin immunoreactive cells showed no sign of somatostatin synthesis. The proliferative activity of the somatostatin-containing areas was low and slow compared to the areas lacking somatostatin production. However, it increased during the course of tumor growth. Somatostatin binding sites, measured with in vitro receptor autoradiography using 125I-[Tyr3]-octreotide or 125I-[Leu8, dTrp22, Tyr25]SS-28, were not detected in any of the MTCs tested. In rat MTC cells, somatostatin was associated with differentiation and slow proliferation, two parameters inversely correlated with the progression of malignancy. As expected, owing to the highly regulated secretion of the differentiated endocrine cell type, its presence was correlated with low basal calcitonin levels. However, the absence of somatostatin binding sites on any type of MTC cells does not favor a direct autocrine regulation of this peptide in this murine model of human MTC.

F Treilhou-Lahille, Lab. Endocrinologie Cellulaire et Evolution, URA 1116 CNRS, Bât, 441, Université Paris-Sud Centre d'Orsay, 91405 Orsay Cédex, France
Acute stress- or lipopolysaccharide-induced corticosterone secretion in female rats is independent of the oestrous cycle
Authors: Guo Ai-Li , Petraglia Felice , Criscuolo Mario , Ficarra Guido , Nappi Rossella E , Palumbo Marco , Valentini Alberto , Genazzani Andrea R
Published: December 2008

Guo A-L, Petraglia F, Criscuolo M, Ficarra G, Nappi RE, Palumbo M, Valentini A, Genazzani AR. Acute stress- or lipopolysaccharide-induced corticosterone secretion in female rats is independent of the oestrous cycle. Eur J Endocrinol 1994;131:535–9. ISSN 0804–4643

The aim of the present study was to test whether oestrous cycle is associated with the hypothalamus–pituitary–adrenal (HPA) axis function. Thus, corticosterone secretion in rats was investigated following lipopolysaccharide (LPS), acute cold-swimming or ether stress or synthetic corticotrophin-releasing factor (CRF) administration throughout the oestrous cycle. Moreover, plasma corticosterone response to cold-swimming stress or LPS administration also was studied at different times of day on pro-oestrus of di-oestrus-I. The following observations were obtained: the morning plasma corticosterone levels in control rats did not differ with the stage of the oestrous cycle; plasma corticosterone levels increased significantly following LPS administration (2 mg/kg, ip) or following acute exposure to cold (4°C)-swimming or ether stress. However, this increase in plasma corticosterone levels was not related to the stage of the oestrous cycle; synthetic CRF injection induced an increase in plasma corticosterone levels constant on di-oestrus-I and pro-oestrus; plasma corticosterone response to LPS administration or acute cold-swimming stress showed diurnal changes, with the lowest values at 18.00 h. which was independent of the oestrous cycle. By showing the unchanged corticosterone response to LPS, to acute stress and to exogenous CRF throughout the oestrous cycle, and the independence of the diurnal pattern of stress response on the oestrous cycle, the present study suggests that the oestrous cycle has no influence on the HPA activity under the present experimental conditions in rats.

Andrea R Genazzani, Department of Obstetrics & Gynecology, University of Modena, Via del Pozzo 71, 41100 Modena, Italy
Effect of liver damage on the pharmacokinetics of dexamethasone
Authors: Kütemeyer Sylke , Schürmeyer Thomas H , von zur Mühlen Alexander
Published: December 2008

Kütemeyer S, Schürmeyer TH, von zur Mühlen A. Effect of liver damage on the pharmacokinetics of dexamethasone. Eur J Endocrinol 1994;131:594–7. ISSN 0804–4643

By measuring the pharmacokinetics of dexamethasone in 48 patients with various degrees of disturbances in liver function, we could demonstrate a decrease in the metabolic clearance of this steroid by 53% if the activity of the plasma cholinesterase was lowered to less than 2 kU/l. Results suggest that the dosage of dexamethasone given for diagnostic or therapeutic purpose needs to be adjusted in such patients.

TH Schürmeyer, Abteilung klinische Endokrinologie, Medizinische Hochschule Hannover, Konstanty-Gutschow-Str. 8, D-30625 Hannover, Germany
Induction of follicle maturation and ovulation by gonadotropin administration in women with β-thalassemia
Authors: Danesi Leila , Scacchi Massimo , Miragoli Anna M , Pincelli Angela I , Dubini Antonella , Maiolo Anna T , Cavagnini Francesco , Polli Elio E
Published: December 2008

Danesi L, Scacchi M, Miragoli AM, Pincelli AI, Dubini A, Maiolo AT, Cavagnini F, Polli EE. Induction of follicle maturation and ovulation by gonadotropin administration in women with β-thalassemia, Eur J Endocrinol 1994;131:602–6. ISSN 0804–4643

The objective of this paper was to assess the ability of gonadotropin administration to induce ovarian steroidogenesis, follicle maturation and ovulation in hypogonadal women affected by β-thalassemia. Thirteen hypogonadal thalassemic women underwent a test with gonadotropin-releasing hormone (GnRH), with estimation of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. They were then administered human menopausal gonadotropin (hMG) for a period ranging from 11 to 15 days with a total dose variable from 3300 to 4200 IU. In each patient, the initial dosage of 300 IU daily, adopted for the first 9 days, was modified subsequently according to the ovarian morphology, as shown by serial echographic examinations and by serum estradiol levels. In those patients in whom a dominant follicle was evidenced and the occurrence of pregnancy could be excluded, induction of ovulation was attempted by administration of 10000 IU of human chorionic gonadotropin (hCG). All patients displayed a reduced LH and FSH rise in response to GnRH. Upon hMG administration, they exhibited echographic evidence of follicular growth with a clear-cut increase of serum estradiol, which peaked between the 9th and the 16th day from the start of treatment. In two out of three patients in whom a dominant follicle developed, ovulation was induced successfully by hCG injection, as shown by the increase of serum progesterone and by the ultrasonographic demonstration of a corpus luteum. This study has shown that, by proper pharmacological stimulation, the steroidogenic function of the gonads and even ovulation can be reinstated in hypogonadal thalassemic women. A hypothalamic/pituitary defect appears to be the main cause of amenorrhea in these patients, although a condition of ovarian resistance is also likely.

Francesco Cavagnini, 2nd Chair of Endocrinology, University of Milan, Istituto Scientifico Ospedale San Luca, Centro Auxologico Italiano, via Spagnoletto 3, 20149 Milano, Italy
Tumour necrosis factor a during human pregnancy and labour: maternal plasma and amniotic fluid concentrations and release from intrauterine tissues
Authors: Laham Nihay , Brennecke Shaun P , Bendtzen Klaus , Rice Gregory E
Published: December 2008

Laham N, Brennecke SP, Bendtzen K, Rice GE. Tumour necrosis factor α during human pregnancy and labour: maternal plasma and amniotic fluid concentrations and release from intrauterine tissues. Eur J Endocrinol 1994;131:607–14. ISSN 0804–4643

The aims of this study were: to quantify immunoreactive tumour necrosis factor α (TNF-α) concentrations in maternal plasma and amniotic fluid obtained from women during pregnancy and labour, both at term and preterm; and to establish the effects of bacterial endotoxin and cytokines on the in vitro release of TNF-α from intrauterine tissues. Maternal plasma TNF-α concentrations did not change during pregnancy (457.2 ± 102.9 ng/l, mean ± sem, N = 52) or at the time of labour (543.5 ± 138.6 ng/l, N = 43). In contrast, amniotic fluid TNF-α concentrations increased significantly (p < 0.05) during pregnancy (early pregnancy, EP, 93.0 ± 24.8 ng/l, N = 7; preterm not-in-labour, PNIL, 186.8 ± 42.9 ng/l, N = 16; term not-in-labour, TNIL, 499.7 ± 150.9 ng/l, N = 13) and in association with preterm labour (preterm in-labour, PIL, 958.7 ± 575.6 ng/l, N = 5 vs PNIL, 186.8 ± 42.9 ng/l, N = 16). Choriodecidual and placental explants (N = 3) maintained in in vitro culture released TNF-α Furthermore, the release of TNF-α-α was increased significantly (p < 0.05) by bacterial endotoxin (lipopolysaccharide, 10 ng/l–10 mg/l) but was not affected by the following cytokines at the indicated doses: interleukin-1α (0.28 nmol/l), interleukin-6 (12.5 nmol/l), granulocyte colony-stimulating factor (2.5 nmol/l), granulocyte–macrophage colonystimulating factor (35 nmol/l), macrophage colony-stimulating factor (1.2 nmol/l), leukaemia inhibitory factor (0.45 nmol/l) and transforming growth factor-β (0.4 nmol/l). The data obtained in this study are consistent with a role for TNF-α in both preterm labour and normal labour at term.

N Laham, Department of Perinatal Medicine, Royal Women's Hospital, 132 Grattan Street, Carlton, Victoria, Australia 3053
Analysis of proteoglycan synthesis by retro-ocular tissue fibroblasts under the influence of interleukin 1β and transforming growth factor-β
Authors: Imai Yumi , Ibaraki Kyomi , Odajima Ritsuko , Shishiba Yoshimasa
Published: December 2008

Imai Y, Ibaraki K, Odajima R, Shishiba Y. Analysis of proteoglycan synthesis by retro-ocular tissue fibroblasts under the influence of interleukin 1β and transforming growth factor-β Eur J Endocrinol 1994;131:630–8. ISSN 0804–4643

Retro-ocular tissue fibroblasts are supposed to be responsible for the deposition of glycosaminoglycan in Graves' ophthalmopathy. We have reported in a preliminary fashion that interleukin 1β (IL-1β) and transforming growth factor-β (TGF-β) increased the rate of [35S]sulfate incorporation into proteoglycans two to five times the control in culture of retro-ocular tissue fibroblasts. The increase in the rate of [ S]sulfate incorporation into proteoglycan will occur as a result of: (a) net increase of proteoglycan synthesis; (b) elongation of glycosaminoglycan chains; (c) increased number of glycosaminoglycan chains; (d) oversulfation of glycosaminoglycan chains; (e) increase in cell number; (f) decreased rate of degradation. We have analyzed which mechanism is important for the increase of [35S]sulfate into proteoglycans observed in human retro-ocular tissue fibroblasts under the influence of cytokines. The last two possibilities (e, f) were ruled out because during the observation period there was no consistent proliferation of the cells and no decrease in the rate of degradation of proteoglycan examined by pulse-chase experiment. Cytokines did not change the size of glycosaminoglycan chains released from proteoglycan as measured by alkaline borohydride treatment, ruling out (b). Disaccharide analysis by HPLC after chondroitin sulfate ABC digestion revealed that glycosaminoglycan mainly contains monosulfated chondroitin disaccharides and that oversulfation was not observed under the influence of IL-1β or TGF-β, ruling out (d). The capacity to synthesize glycosaminoglycan chain in the presence of an artifical acceptor of chain elongation, β-d-xylodide, was increased significantly by IL-1β but not obviously so by TGF-β. Thus, an increased number of glycosaminoglycan chains (c) is possible for IL-1β. A preliminary northern blot analysis employing probes for mRNAs for various proteoglycan core proteins showed increased expression of versican and aggrecan in the presence of IL-1β or TGF-β. This result supports the possibility of (a). In conclusion, IL-1β and TGF-β increased [35S]sulfate incorporation into proteoglycan by increasing the net increase of proteoglycan synthesis and possibly by increasing the number of glycosaminoglycan chains attached to core protein in the case of IL-1β.

Y Shishiba, Division of Endocrinology, Department of Medicine, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, Japan