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Angelo Favino, Dieter Emrich and Alexander von zur Mühlen


A method is described for the quantitative determination of 131I-triiodothyronine and 131I-tetraiodothyronine in human plasma after oral administration of 131I-iodide.

Steps in the method are: acidified n-butanol extraction of the thyroid hormones from the plasma deprived of inorganic iodine by means of an ion exchange resin; addition of stable iodo-aminoacid carriers to the butanol extract and its evaporation to dryness under reduced pressure; bidimensional thin layer chromatography of the rediluted extract on cellulose in combined organic alkaline and organic acid systems; staining of the carriers with eerie sulphate-sodium arsenite reagent and diluted methylene blue; radioactivity measurements of the cellulose scraped from the stained spots in a well type scintillation counter.

The reliability of the method was established by recovery experiments and by duplicate chromatography of plasma to which mixtures of 131I-T3 and 131I-T4 and 131I-iodide were added. Its specificity was confirmed by autoradiography. Good agreement was found with the results yielded by simultaneous paper chromatography of the same extracts. The method requires smaller amounts of plasma and allows quicker determinations than paper chromatographic procedures. Relative determinations of 131I-T3 and 131I-T4 are reported in some euthyroid and hyperthyroid patients given therapeutic and diagnostic doses of 131I-iodide.

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Sylke Kütemeyer, Thomas H Schürmeyer and Alexander von zur Mühlen

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

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Wernfrid Völker, Werner G. Gehring, Renate Berning, Rüdiger C. Schmidt, Jörg Schneider and Alexander von zur Mühlen


This study was designed to clarify whether previously resistant cases of adenomatous hyperprolactinaemia to bromocriptine might be improved by additive tamoxifen therapy. Ten hyperprolactinaemic women under bromocriptine (2.5–10 mg) with hypophyseal tumours of different extent were treated with a combined therapy of bromocriptine and tamoxifen (10–20 mg). Two of them had undergone incomplete resection of chromophobe adenomata. The others refused surgery or irradiation. Two other women without basal therapy because of side effects from bromocriptine, received the combined therapy from the beginning of the study. In 6 out of 10 women the addition of tamoxifen resulted in a marked suppression of prolactin serum values. Amenorrhoea and glactorrhoea ceased in 4 of them. One woman conceived. One reported a marked improvement of libido. One stated that side effects under bromocriptine disappeared through the addition of tamoxifen. The 2 women who previously were suffering from side effects were able to take bromocriptine when tamoxifen was added. Four patients were non-responders. Serum prolactin remained unchanged as well as the clinical follow-up. The effectiveness of the combined therapy was not related to the extent of the tumour or to the clinical or biochemical baseline date.

We conclude that the suppressive effect of bromocriptine on prolactin secretion is enhanced by the addition of tamoxifen in most cases of adenomatous hyperprolactinaemia. Side effects of bromocriptine are considerably reduced. Anti-oestrogens are competitive inhibitors of the binding of oestradiol to the receptor. Oestrogen play an important role in the development of prolactin secreting adenomata. Our finding of responders and non-responders to tamoxifen suggests that the anti-oestrogen competes for greater or lesser concentrations of receptor sites in prolactinomata.

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Chun-Cheung Wong, Klaus-D. Döhler, Michael J. Atkinson, Heinz Geerlings, Rolf-Dieter Hesch and Alexander von zur Mühlen


The influence of age, strain and season on the diurnal pattern of serum hormone levels from the pituitary-thyro-parathyroid complex was studied in male laboratory rats. Distinct 24 h periodicity in the serum levels of thyroid stimulating hormone (TSH) and triiodothyronine (T3) was observed in all groups of rats. There was no influence of age (40, 60 and 90 days old Sprague-Dawley rats), but a significant influence of strain (Sprague-Dawley vs. BH/Ztm rats) and season (summer vs. winter) on the diurnal pattern of serum TSH and T3 levels. Significant 24 h periodicity in serum thyroxine (T4) levels existed during winter in BH/Ztm rats, but not in Sprague-Dawley (SD) rats of any age. Adult SD rats demonstrated 24 h periodicity in serum levels of T4 only in summer. No diurnal periodicity in serum levels of parathyroid hormone (PTH) was observed in any group of rats.

There were significant changes in 24 h mean serum levels of TSH and T3 throughout pubertal development. Twenty-four h mean serum levels of T3 and T4 were significantly higher in summer than in winter. Twenty-four h mean serum levels of T4 were significantly lower in BH/Ztm rats than in SD rats. Significant correlation was observed between serum concentrations of T3 and T4, TSH and T4, and between TSH and T3 in some groups of rats, but not in all.

The results indicate that 24 h periodicity of serum hormone levels from the pituitary-thyroid complex of male laboratory rats may vary with age and strain of the animals and with the season of experiment performance.

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Ernst U Frevert, Anja Biester, Manfred J Müller, Heinrich Schmidt-Gayk, Alexander von zur Mühlen and Georg Brabant

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

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Frank Schuppert, Markus Reiser, Niels-E Heldin, Sülke Ede, Georg FW Scheumann, Henning Dralle and Alexander von zur Mühlen

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

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Angela Brabant, Georg Brabant, Thomas Schuermeyer, Ulrich Ranft, Friedrich W. Schmidt, Rolf D. Hesch and Alexander von zur Mühlen


The potentially inhibitory action of endogenous or exogenous synthetic glucocorticoids on TSH secretion was investigated. Pulsatile and circadian TSH and cortisol rhythms were measured in healthy subjects (12 rhythms), but no correlation between the hormones could be detected. Acute stimulation of endogenous cortisol secretion by CRH tests (1 μg/kg of ovine CRH) at 20.00 h in 9 healthy volunteers did not significantly alter the nightly increase in TSH. Chronic elevation of endogenous cortisol serum levels in patients with Cushing's disease revealed a heterogeneous pattern. In 2 patients serum TSH and thyroid hormone levels showed a normal 24-h rhythm, whereas the other 2 patients had low TSH serum levels. Acute treatment of 9 healthy volunteers with 0.5, 1 or 2 mg dexamethasone po at 23.00 h resulted in a significant dose-dependent suppression of mean basal TSH levels 9 h later. Treatment with 30mg of prednisone for 1 week in 7 patients with Crohn's disease did not influence basal TSH. The TSH response to TRH was only temporarily suppressed on day 3, but not on day 7 of treatment. The results suggest that under physiological conditions glucocorticoids have no regulatory influence on pulsatile and circadian TSH secretion.

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Klaus Prank, Egbert Schulze, Olaf Eckert, Tim W Nattkemper, Markus Bettendorf, Christiane Maser-Gluth, Terrence J Sejnowski, Arno Grote, Erika Penner, Alexander von zur Mühlen and Georg Brabant

Objective: Non-linear relations between multiple biochemical parameters are the basis for the diagnosis of many diseases. Traditional linear analytical methods are not reliable predictors. Novel nonlinear techniques are increasingly used to improve the diagnostic accuracy of automated data interpretation. This has been exemplified in particular for the classification and diagnostic prediction of cancers based on expression profiling data. Our objective was to predict the genotype from complex biochemical data by comparing the performance of experienced clinicians to traditional linear analysis, and to novel non-linear analytical methods.

Design and methods: As a model, we used a well-defined set of interconnected data consisting of unstimulated serum levels of steroid intermediates assessed in 54 subjects heterozygous for a mutation of the 21-hydroxylase gene (CYP21B) and in 43 healthy controls.

Results: The genetic alteration was predicted from the pattern of steroid levels with an accuracy of 39% by clinicians and of 64% by linear analysis. In contrast, non-linear analysis, such as self-organizing artificial neural networks, support vector machines, and nearest neighbour classifiers, allowed for higher accuracy up to 83%.

Conclusions: The successful application of these non-linear adaptive methods to capture specific biochemical problems may have generalized implications for biochemical testing in many areas. Nonlinear analytical techniques such as neural networks, support vector machines, and nearest neighbour classifiers may serve as an important adjunct to the decision process of a human investigator not ‘trained’ in a specific complex clinical or laboratory setting and may aid them to classify the problem more directly.