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Georg Brabant, E. Jean Wickings and Eberhard Nieschlag

Abstract.

Histidyl-proline-diketopiperazine (DKP) - a stable degradation product of TRH - has been shown to selectively inhibit prolactin secretion in vitro in rat pituitary tissue. In this study the effects of DKP on serum prolactin in intact and anaesthetized male rhesus monkeys and on TRH-stimulated prolactin levels have been investigated.

In conscious monkeys 400 μg DKP significantly suppressed prolactin levels by 27%, and under ketamine anaesthesia, serum prolactin was suppressed in a dose-dependent manner by 150 and 400 μg DKP. The maximum prolactin response and the cumulative response to TRH (20 μg) was significantly and specifically inhibited by 400 μg DKP, while the lower dose was without effect. TSH levels were not affected by DKP in any instance.

Hence DKP can specifically inhibit prolactin release in the rhesus monkey, and may be discussed as a possible regulatory factor in prolactin secretion.

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

Abstract.

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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Robin Haring, Sebastian E Baumeister, Matthias Nauck, Henry Völzke, Brian G Keevil, Georg Brabant and Henri Wallaschofski

Objective

Low total testosterone (TT) serum concentrations in men have been associated with various cardiometabolic risk factors. But given error-prone immunoassays used for TT assessment, upcoming mass spectrometry methods question the validity of these risk associations. Thus, we performed the first comparative study quantifying potential differences in the association of TT with cardiometabolic risk factors between the two methods.

Methods

We used data from 1512 men aged 20–81 years, recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP), Germany. TT concentrations were repeatedly measured by chemiluminescent immunoassay (CLIA, Immulite 2500) and liquid chromatography–tandem mass spectrometry (LC–MS/MS). We tested for significant differences between coefficients from CLIA- and LC–MS/MS-based multiple linear regression models associating TT with major cardiometabolic risk factors including adiposity, lipid metabolism, blood pressure, diabetic status, and inflammation.

Results

TT measurements by CLIA and LC–MS/MS yielded a Pearson correlation coefficient of 0.84. Only three of the ten tested associations for TT with cardiometabolic risk factor showed significant differences between the two measurement methods: in comparison to LC–MS/MS, CLIA-based TT assessment significantly underestimated risk associations of TT with waist circumference (β: −0.54 vs −0.63), BMI (β: −0.19 vs −0.22), and serum glucose levels (β: −0.006 vs −0.008).

Conclusion

In this comparative study, the CLIA platform showed a reasonable measurement error and yielded comparable risk associations, providing little support to measure TT concentrations in men from the general population exclusively by LC–MS/MS.

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Henry Völzke, Matthias Nauck, Rainer Rettig, Marcus Dörr, Claire Higham, Georg Brabant and Henri Wallaschofski

Context

It is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these associations.

Objectives

The aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context.

Design

We analyzed data from the population-based Study of Health in Pomerania.

Methods

We used data from 3863 subjects (1971 women) aged 20–79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays.

Results

Hyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption.

Conclusions

Our data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.

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Ria Adriaanse, Georg Brabant, Erik Endert, Frederique J Bemelman and Wilmar M Wiersinga

Adriaanse R, Brabant G, Endert E, Bemelman FJ, Wiersinga WM. Pulsatile thyrotropin and prolactin secretion in a patient with mixed thyrotropin- and prolactin-secreting pituitary adenoma. Eur J Endocrinol 1994;130:113–20. ISSN 0804–4643

The circadian and pulsatile thyrotropin (TSH) and prolactin (PRL) release was investigated in a patient with slight hyperthyroidism due to a mixed TSH- and PRL-secreting pituitary adenoma. Blood was withdrawn every 10 min for 24 h (before and after medical treatment); pulse characteristics were analyzed by Desade and Cluster programs (values as mean±sd). The inappropriately high mean 24-h TSH concentration of 3.55 ±0.31 mU/l was associated with a higher mean 24-h TSH pulse amplitude but unaltered mean 24-h TSH pulse frequency relative to healthy controls. The nocturnal TSH surge (absolute surge 0.5 mU/l, relative surge 16%) was low, related to a loss of the usual nocturnal increase of TSH pulse amplitude and TSH pulse frequency. Chronic treatment with octreotide resulted in a modest clinical and biochemical improvement of the hyperthyroid state; addition of bromocriptine at a later stage had no further beneficial effect. At the end of the follow-up period the mean 24-h TSH paradoxically had increased to 5.33 ±0.81 mU/l. The nocturnal TSH surge also increased (absolute surge 1.9 mU/l, relative surge 42%), but circadian changes in TSH pulsatility remained absent. In the untreated period the increased mean 24-h PRL concentration of 234 ± 24 μg/l was associated with an increased mean 24-h PRL amplitude, whereas the 24-h PRL pulse frequency (N = 4) was lower relative to controls. No circadian PRL rhythm was present. After octreotide and bromocriptine treatment the mean 24-h PRL concentration and mean 24-h PRL pulse amplitude were unchanged, but a clear nocturnal increase of PRL now was observed. Analysis of the temporal coupling between TSH and PRL release by bivariate autoregressive modeling revealed significant cross-correlations in all three periods investigated (coefficients in the range 0.34–0.76, median 0.52; p<0.01) between TSH and PRL concentrations with a lag time of 10–20 min. We conclude that pulsatile TSH and PRL release in this mixed TSH- and PRL-secreting pituitary adenoma was autonomous in nature. The observed dampening of the nocturnal increase of TSH and PRL is putatively related to a lack of TRH receptors in these tumors. The observed co-secretion of TSH and PRL suggests synthesis of both hormones by the same cell.

R Adriaanse, Department of Endocrinology F5-171, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

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Peter Weber, Ulrich Krause, Gabi Gaffga, Georg Brabant, Friedrich Manz, Hendrik Lehnert, Jürgen Schrezenmeir and Jürgen Beyer

Abstract.

To evaluate the pathophysiological role of TSH in goitrogenesis we investigated pulsatile TSH secretion in 11 patients with a non-toxic goitre and in 11 healthy controls. Thyroid volume was 40 ± 10 ml in the goitre group and 15 ± 4 ml in the controls as measured by ultrasound. Blood was sampled continously via an indwelling venous catheter at 10-min intervals over 24 h. Neither the mean 24-h serum TSH levels (goitre 1.1 ± 0.5 vs controls 0.9 ± 0.4 mU/l) nor the nocturnal surge of TSH were significantly different between the two groups. The average of the TSH pulse frequency (goitre 10.8 ± 3.7 vs controls 9.6 ± 3.5 pulses/24-h) and of the TSH pulse amplitude (goitre 0.4 ± 0.2 vs controls 0.3 ± 0.1 mU TSH/l as analysed by DESADE programme (detection of secretory activity by discrete deconvolution) did not differ in the two groups. Furthermore, there was no correlation between the volume of the thyroid gland and the dynamics of the TSH secretion. We conclude that our data do not suggest a relevant pathophysiological role of TSH secretion in the development of non-toxic goitre in man.

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Georg Brabant, Robin P Peeters, Shiao Y Chan, Juan Bernal, Philippe Bouchard, Domenico Salvatore, Kristien Boelaert and Peter Laurberg

Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.

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Judith Gebauer, Eva-Maria Fick, Annika Waldmann, Thorsten Langer, Ilonka Kreitschmann-Andermahr, Hendrik Lehnert, Alexander Katalinic and Georg Brabant

Objective

Due to the increasing success and survival rates in the primary treatment of malignancies derived from the CNS as well as the hematopoietic system, endocrine late effects of cancer and its therapy are of growing importance. Despite evaluation of these late effects in patients treated for cancer in childhood, the impact on adults remains largely unclear.

Methods

1035 adult patients primarily diagnosed with a CNS malignancy, a Hodgkin (HL) or non-Hodgkin lymphoma (NHL) between 1998 and 2008 were recruited via the regional epidemiological cancer registry covering ∼2.8 million inhabitants in the federal state of Schleswig-Holstein, Northern Germany. The prevalence of endocrine disorders and current psychosocial impairment was assessed employing several questionnaires (SF-36v1, WHO-5).

Results

Fully completed questionnaires of 558 patients were available for subsequent analysis showing markedly reduced overall performance and psychological status when compared to German reference data. Thyroid disorders were reported in 16.3% of patients with 10.4% suffering from hypo- and 5.9% from hyperthyroidism. Overall, 17.6% stated to be affected by diabetes mellitus with an increased rate of 21.1% among NHL patients and 11.5% of participants were affected by osteoporosis.

Conclusion

Compared to German population based studies on the prevalence of diabetes mellitus, osteoporosis and thyroid disorders the frequency of all these endocrine problems was significantly increased in CNS, HL, and NHL cancer survivors. These data confirm that not only children and adolescents but also adult cancer patients are at risk for therapy associated endocrine late effects.

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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