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Rudolf Hoermann, Reinhard Mueller, Bernhard Saller and Klaus Mann

Abstract. The insensitivity of Graves' thyroid to stimulation of cAMP formation by TSH as well as Graves' immunoglobulins in vitro is well known. The present study was performed to find out Graves' sera which may induce a final activation i.e. stimulation of T3 release in Graves' thyroid slices despite this insensitivity of tissue and to characterize determinants responsible for the efficiency of those sera.

Out of 20 sera from patients with active untreated Graves' disease 6 were found to stimulate T3 release from Graves' thyroid in vitro. These 6 sera were effective in stimulating different Graves' glands, irrespective of pretreatment with propranolol, thiamazole (methimazole) or thiamazole plus iodine. In contrast, a significant response to bTSH was not observed in any Graves' gland. For comparison, 17/20 of the same sera were able to stimulate T3 release when tested on human goitrous thyroid. Sera which stimulated Graves' slices revealed no higher stimulating activities in goitrous tissue than serum samples which did not. All sera were additionally assessed for TSH binding inhibiting immunoglobulins in a radioreceptor assay. Remarkably, Graves' thyroid stimulating sera had a low or absent TSH binding inhibiting activity.

Thus, hormone release from Graves' thyroid in vitro – in contrast to that from goitrous tissue – could only be activated by a minority of Graves' sera. These Graves' thyroid stimulating sera could be characterized to contain a selected spectrum of biologically active antibodies with a high TSH agonistic potency stimulating in the presence of a negligible TSH binding inhibiting activity. We conclude the qualitative composition of the antibody spectrum in the individual sera, such as the occurrence of so-called 'TSH superagonists', rather than the height of antibody titre as determined by various methods seems to be relevant for their Graves' thyroid stimulating potency.

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Bernhard Saller, Rudolf Hoermann, Michael M. Ritter, Roland Morell, Torsten Kreisig and Klaus Mann

Abstract.

In the treatment of endemic goitre, the concept of giving levothyroxine in combination with iodine offers a promising therapeutic approach by influencing not only TSH secretion but also intrathyroidal iodine content. However, little is known about the doses of iodine necessary to correct intrathyroidal iodine deficiency. To get more information on this important issue, we conducted a prospective, double-blind study on the effect of a monotherapy with 500 μg iodide/day and a combined treatment with 100 μg levothyroxine and 100 μg iodide/day on thyroid iodine concentration as measured by fluorescence scintigraphy. In a group of 12 patients, a 4-month treatment with 100 μg levothyroxine and 100 μg iodide/day did not significantly affect thyroid iodine concentration (0.35±0.14 vs 0.37±0.11 mg/g). The application of 500 μg iodide/day in these patients during a second 4-month period resulted in a sharp increase in thyroid iodine concentration from 0.37±0.11 to 0.61±0.14 mg/g (p<0.01). Another group of 8 patients first treated with 500 μg iodide/day also showed a significant increase in iodine concentration from 0.35±0.14 to 0.65±0.20 mg/g (p<0.01). After switching to the combination regimen during a second 4-month period, thyroid iodine concentration slightly decreased, particularly in those patients with high iodine concentrations after monotherapy with iodide (0.65±0.20 vs 0.50±0.12 mg/g, p<0.05). In conclusion, treatment with 500 μg iodide/day could sharply increase thyroid iodine concentration in patients with endemic goitre. In contrast, a combination of 100 μg levothyroxine and 100 μg iodide/day had no significant effect on thyroid iodine concentration.

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Bernhard Saller, Anders F Mattsson, Peter H Kann, Hans P Koppeschaar, Johan Svensson, Marjolein Pompen and Maria Koltowska-Häggström

Objective: This study set out to determine the change in quality of life (QoL) and healthcare utilization during 2 years of growth hormone (GH) replacement therapy in adults with GH deficiency. Data were compared from three European countries.

Design: Analysis was made from KIMS, the Pfizer International Metabolic Database on adult GH deficiency.

Methods: QoL and healthcare utilization were measured at baseline and after 1 and 2 years of GH replacement in patient cohorts from Sweden (n = 302), The Netherlands (n = 103) and Germany (n = 98). QoL was assessed by the QoL-Assessment in Growth Hormone Deficient Adults (QoL-AGHDA) questionnaire, and the KIMS Patient Life Situation Form was used to evaluate healthcare utilization.

Results: QoL improved significantly (P < 0.0001) and comparably in all three cohorts. The improvement was seen during the first year of treatment and QoL remained improved during the second year. The number of days in hospital was reduced by 83% (P < 0.0001) during GH replacement. There were no country-specific differences either at baseline or during follow-up. The same was true for the number of days of sick leave (reduction of 63%; P = 0.0004). Significant reductions were recorded in the number of doctor visits in each of the three cohorts after 2 years of GH replacement (P < 0.05).

Conclusions: This study provides a detailed comparative analysis of GH replacement therapy in GHD patients in three European countries. Despite some differences in treatment strategies, the beneficial effects on QoL, patient-reported outcomes and healthcare utilization are essentially similar in the healthcare environment of Western European countries.

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Harald Jörn Schneider, Bernhard Saller, Jens Klotsche, Winfried März, Wolfgang Erwa, Hans-Ullrich Wittchen and Günter Karl Stalla

Objective: Insulin-like growth factor-I (IGF-I) has been suggested to be a prognostic marker for the development of cancer and, more recently, cardiovascular disease. These diseases are closely linked to obesity, but reports of the association of IGF-I with measures of obesity are divergent. In this study, we assessed the association of age-dependent IGF-I standard deviation scores with body mass index (BMI) and intra-abdominal fat accumulation in a large population.

Design: A cross-sectional, epidemiological study.

Methods: IGF-I levels were measured with an automated chemiluminescence assay system in 6282 patients from the DETECT study. Weight, height, and waist and hip circumference were measured according to the written instructions. Standard deviation scores (SDS), correcting IGF-I levels for age, were calculated and were used for further analyses.

Results: An inverse U-shaped association of IGF-I SDS with BMI, waist circumference, and the ratio of waist circumference to height was found. BMI was positively associated with IGF-I SDS in normal weight subjects, and negatively associated in obese subjects. The highest mean IGF-I SDS were seen at a BMI of 22.5–25 kg/m2 in men (+0.08), and at a BMI of 27.5–30 kg/m2 in women (+0.21). Multiple linear regression models, controlling for different diseases, medications and risk conditions, revealed a significant negative association of BMI with IGF-I SDS. BMI contributed most to the additional explained variance to the other health conditions.

Conclusions: IGF-I standard deviation scores are decreased in obesity and underweight subjects. These interactions should be taken into account when analyzing the association of IGF-I with diseases and risk conditions.

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Michael Buchfelder, Peter Herbert Kann, Christian Wüster, Ulrich Tuschy, Bernhard Saller, Georg Brabant, Andrea Kleindienst and Panagiotis Nomikos

Group-author : the German KIMS Board

Objective: Several studies documented metabolic and psychological benefits of GH substitution in deficient adults, most of them suffering from benign pituitary adenomas. Since GH substitution is considered to promote tumour regrowth, adequate treatment is performed with some reservation. Therefore, we aimed to elucidate the effect of GH replacement therapy on tumour recurrence following surgery.

Methods: In patients with hormonally inactive pituitary adenomas undergoing tumour surgery, a retrospective case–control study was performed. Pre- and postoperative magnetic resonance (MR) images of GH-treated and untreated patients were matched for best fit by two independent observers. The treated patients were retrieved from the surveillance programme of the German KIMS database and the untreated from the database of the Department of Neurosurgery, University of Erlangen. A total of 55 matched pairs were followed for at least 5 years. Tumour recurrence and progression rates were determined according to the postoperative MR.

Results: There were 16 tumour progressions in the treatment group and 12 in the control group. Statistical analysis revealed no significant increase in either recurrence (P = 0.317) or progression (P = 0.617) within the follow-up period of 5 years when GH was adequately replaced.

Conclusions: This study provides further observational data of substitution therapy in GH-deficient adults with pituitary adenomas. Comparing long-term surgical results, we found no evidence that GH substitution should be withheld in deficient patients. Even residual tumour does not constitute a contraindication to GH replacement. However, since pituitary tumours are slow growing, an observational period of 5 years may not have been long enough to verify any absolute influence on recurrence potential.

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Ulla Feldt-Rasmussen, Georg Brabant, Dominique Maiter, Björn Jonsson, Andy Toogood, Maria Koltowska-Haggstrom, Aase Krogh Rasmussen, Michael Buchfelder, Bernhard Saller and Beverly M K Biller

Objective

We studied whether the severity of GH deficiency (GHD) defined as i) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, and glucagon), ii) number of additional pituitary deficits, or iii) baseline IGF1 SDS could impact the response to GH treatment. We further explored whether iv) IGF1 SDS after 24 months of GH replacement or v) ΔIGF1 SDS from baseline to 24 months was related to the phenotypic response to GH treatment.

Design, patients, and measurements

The patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into three groups of approximately equal size (tertiles) according to the stimulated GH-peak values and baseline IGF1 SDS and were studied at baseline, 12, and 24 months of GH therapy.

Results

Lower baseline IGF1 SDS predicted better response in weight, BMI, total cholesterol, and triglycerides, while IGF1 SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol, and improved quality of life (QoL). Age-correlated negatively with the response in body weight, BMI, waist, IGF1 SDS, and total and LDL-cholesterol.

Response in weight and BMI was greater in men than in women, whereas women showed greater improvement in QoL than men. Patients with more severe GHD as assessed by lower GH-peaks and more pituitary hormone deficiencies had a greater increase in IGF1 SDS. The increase in IGF1 SDS was associated with a reduction in waist/hip ratio and an increase in weight, BMI, and triglycerides. There was no correlation with other lipids, blood pressure, or glucose.

Conclusion

Our findings indicate that baseline and 24 months, IGF1 and its degree of increase during GH replacement were more important than stimulated peak GH to predict the phenotypic response.

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Harald Jörn Schneider, Jens Klotsche, Bernhard Saller, Steffen Böhler, Caroline Sievers, David Pittrow, Günther Ruf, Winfried März, Wolfang Erwa, Andreas M Zeiher, Sigmund Silber, Hendrik Lehnert, Hans-Ullrich Wittchen and Günter Karl Stalla

Objective

We aimed at investigating the association of age-dependent IGF-I SDS with diabetes, dyslipidemia, hypertension, and heart diseases, in a large patient sample.

Background

IGF-I has been suggested to be associated with several diseases and a prognostic marker for the development of cardiovascular diseases and risk factors. The findings, though, have been inconsistent possibly due to the methodological factors.

Methods

We studied 6773 consecutive primary care patients, aged 18+ years, in a cross-sectional, epidemiological study in primary care, Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment study. All patients underwent a standardized clinical diagnostic and laboratory assessment. IGF-I levels were measured with an automated chemiluminescence assay system. We calculated the odds ratios (OR) for diseases in quintiles of IGF-I, and additionally analyzed the association of age-dependent IGF-I SDS with these conditions.

Results

After multiple adjustments for confounders, we found increased ORs for coronary artery disease in patients with high IGF-I. Women, but not men, with low IGF-I also showed increased ORs for coronary artery disease. Dyslipidemia was positively associated with IGF-I. Type 2 diabetes showed a curvilinear association with IGF-I SDS.

Conclusions

The findings suggest the existence of multiple and complex interactions between IGF-I and several health conditions. The complex nature of disease- and subgroup-specific associations along with the methodological factors can be held responsible for divergent findings in previous studies.

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Rolf C Gaillard, Anders F Mattsson, Ann-Charlotte Åkerblad, Bengt-Åke Bengtsson, José Cara, Ulla Feldt-Rasmussen, Maria Kołtowska-Häggström, John P Monson, Bernhard Saller, Patrick Wilton and Roger Abs

Objective

Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients.

Design

In KIMS (Pfizer International Metabolic Database) 13 983 GH-deficient patients with 69 056 patient-years of follow-up were available.

Methods

This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05.

Results

All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04–1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044).

Conclusions

GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.