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Till Ittermann, Robin Haring, Sybille Sauer, Henri Wallaschofski, Marcus Dörr, Matthias Nauck and Henry Völzke

Objective

Results of cohort studies on the association between decreased serum TSH levels and mortality are conflicting. Some studies demonstrated an increased mortality risk in subjects with decreased serum TSH levels, others did not. Even meta-analyses revealed contradictory results. We undertook the present study to investigate the association between decreased serum TSH levels and mortality in the large population-based Study of Health in Pomerania (SHIP).

Design and methods

Data from 3651 individuals from SHIP without known thyroid disorders or thyroid treatment were analyzed. Serum TSH, free triiodothyronine, and free thyroxine levels were determined by immunochemiluminescent procedures. Decreased TSH was defined as serum TSH levels below 0.25 mIU/l. Cox regression was used to associate decreased TSH levels with mortality.

Results

The median duration of follow-up was 8.5 years (30 126 person years). During follow-up, 299 individuals (6.9%) died corresponding to a death rate of 9.92 deaths per 1000 person years. Survival time was shorter in subjects with decreased serum TSH levels compared to euthyroid individuals. After adjustment for age and sex, however, there was no association between decreased serum TSH levels and all-cause mortality (hazard ratio: 0.95; 95% confidence interval: 0.67; 1.36). Likewise, decreased serum TSH levels were neither associated with cardiovascular nor with cancer mortality.

Conclusions

There is no independent association of decreased serum TSH levels with all-cause, cardiovascular, and cancer mortality in the adult northeast German population. Although our study has some strengths, we cannot finally conclude on therapeutical implications in individuals with subclinical thyroid diseases.

Free access

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.

Free access

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.

Free access

Marie-Luise Eggert, Henri Wallaschofski, Anne Grotevendt, Matthias Nauck, Henry Völzke, Stefanie Samietz and Nele Friedrich

Background

Previous intervention studies in patients with GH disorders suggested an impact of IGF1 and IGF-binding protein 3 (IGFBP3) on lipid metabolism, whereas population-based studies revealed conflicting results. Therefore, we aimed to assess the cross-sectional and longitudinal associations between IGF1 or IGFBP3 serum levels and lipids (total, LDL, or HDL cholesterol and triglycerides) in a large-scale study.

Methods

Data of 2935 subjects (1356 women) from the population-based Study of Health in Pomerania (SHIP) were used. ANOVA, quantile regression, and logistic regression models adjusted for age, waist circumference, physical activity, and alcohol consumption were performed.

Results

In cross-sectional analyses, we detected that IGF1 and IGFBP3 levels were positively related to total and LDL cholesterol and inversely related to HDL cholesterol in both sexes. Furthermore, IGFBP3 levels showed a positive relationship to triglycerides. In total, IGFBP3 levels were more strongly associated to lipids than IGF1. In longitudinal analysis, we found no influence of baseline IGF1 or IGFBP3 serum concentration on incidentally elevated or reduced lipid levels. However, the positive relationship between IGFBP3 and incidentally elevated triglycerides barely missed statistical significance in women.

Conclusion

The present study showed strong cross-sectional associations between IGF1 or IGFBP3 and lipids, whereas no longitudinal relationships were revealed. Therefore, our findings suggest IGF1 and IGFBP3 as a risk marker rather than a risk factor for alterations in lipid metabolism. Further studies are needed to elucidate the mechanisms underlying the association between the GH/IGF axis and lipid metabolism.

Free access

Harald J Schneider, Michael Buchfelder, Henri Wallaschofski, Anton Luger, Gudmundur Johannsson, Peter H Kann and Anders Mattsson

Objective

There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response.

Design

This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database).

Methods

We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses.

Results

In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815).

Conclusions

A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.

Free access

Marcus Dörr, Klaus Empen, Daniel M Robinson, Henri Wallaschofski, Stephan B Felix and Henry Völzke

Background

Thyroid dysfunction is associated with detrimental cardiovascular effects. We analyzed whether thyroid status is related to carotid artery plaques and prevalent strokes.

Design, patients and measurements

Data from 2128 subjects (1157 men and 971 women) aged ≥45 years without thyroid diseases participating in the Study of Health in Pomerania were analyzed. The presence of carotid plaques was assessed by B-mode ultrasound and prevalent stroke was assessed by interview. The sample was divided according to the reference range of serum TSH levels into decreased (<0.25 mIU/l), normal (0.25–2.12 mIU/l), and elevated (>2.12 mIU/l). Logistic regression models were adjusted for common confounders including age, sex, BMI, hypertension, diabetes mellitus, smoking, school education, plasma fibrinogen and serum cholesterol levels, and statins.

Results

The prevalence of carotid plaques at any site was higher in subjects with decreased serum TSH levels (81.7%) compared with normal serum TSH levels (70.2%) and elevated serum TSH levels (65.6%; P<0.001). Fully adjusted logistic regression models revealed increased odds for carotid plaques (odds ratio (OR) 1.67; 95% confidence interval (CI) 1.11–2.51; P<0.05) as well as for prevalent strokes (OR 1.98; 95% CI 1.05–3.73; P<0.05) in subjects with decreased serum TSH levels, while there was no association between elevated serum TSH levels and carotid plaques or stroke respectively.

Conclusions

Thyroid function was associated with the presence of carotid artery plaques and prevalent strokes in this population-based sample. Periodical screening and early treatment of atherosclerotic risk factors should be performed in subjects with decreased serum TSH levels.

Free access

Till Ittermann, Carsten Oliver Schmidt, Axel Kramer, Harald Below, Ulrich John, Michael Thamm, Henri Wallaschofski and Henry Völzke

Objective

The role of smoking in the pathogenesis of thyroid enlargement is currently under debate. It has been hypothesized that the effect of smoking on increased thyroid volume is larger in regions with than in regions without iodine deficiency. The aim of this paper was to investigate the association of smoking with thyroid volume progression and incident goiter for different age-strata in a region with improved iodine supply.

Design and methods

The population-based Study of Health in Pomerania compromised 3300 subjects with complete 5-year examination follow-up. Data from 2484 participants without known history of thyroid disorder or thyroid medication were analyzed. Thyroid size was evaluated by ultrasound. Determinants of thyroid volume progression and incident goiter, i.e., newly occurred goiter between baseline and follow-up, were analyzed by linear and logistic regression respectively.

Results

Participants aged 20–39 years who were current smokers at baseline and at follow-up had a lower risk of incident goiter (odds ratio: 0.33; 95% confidence interval (CI): 0.15; 0.71; P=0.005). In this subpopulation, age was inversely related to thyroid volume progression. In subjects aged 60–79 years, smoking at baseline and follow-up was a risk factor for thyroid volume progression (β: 3.37; 95% CI: 0.84; 5.89; P=0.009). After exclusion of individuals who had actual goiter in ultrasound at baseline, this association disappeared.

Conclusion

We conclude that the inverse association between smoking and goiter in young adults and the lacking association of smoking with goiter and thyroid volume progression in adult non-goitrous subjects indicate that smoking has a declining impact on thyroid growth in the study region. Our findings mirror the improved iodine supply of Northeast Germany.

Free access

Hiroyoshi Akutsu, Jürgen Kreutzer, Gerald Wasmeier, Dieter Ropers, Christian Rost, Matthias Möhlig, Henri Wallaschofski, Michael Buchfelder and Christof Schöfl

Context

Information about the risk and course of coronary artery disease (CAD) in acromegaly is limited.

Objective

To evaluate CAD risk in acromegalic patients at diagnosis and after successful treatment during follow-up.

Subjects and methods

Twenty-five consecutive patients (age 45.1±10.6 years, 15 women) were studied at the time of diagnosis, and 19 patients were re-evaluated after 4.6±1.1 years. The European Society of Cardiology (ESC) risk score was calculated, and a cardiac computed tomography was performed for detection and quantification (Agatston score (AS)) of coronary artery calcium (CACs). Fifty age-, sex-, and CAD risk-matched subjects and CAC data from the population-based Heinz Nixdorf Recall (HNR) study served as controls.

Results

In 21 of the 25 patients, the 10-year risk of developing CAD according to the ESC risk score was low (<10%) and high (>20%) in four patients. The AS was lower than in controls (2.6±7.9 vs 66±182; P=0.014) and less patients had a positive CAC (AS>0) (20 vs 48%, P=0.024), which in the acromegalic patients was less than expected from the HNR study. The AS did not correlate with GH excess or disease duration. In 19 acromegalic patients, who were in remission and re-evaluated after 4.6±1.1 years, the ESC risk (P=0.102) and the AS (P=0.173) did not change significantly and no symptomatic CAD event occurred.

Conclusion

CAD risk in newly diagnosed acromegalic patients was low and remained stable after successful treatment. CAC was lower than in controls suggesting that GH excess per se does not carry an additional CAD risk.

Free access

Joern Moock, Christin Albrecht, Nele Friedrich, Henry Völzke, Matthias Nauck, Maria Koltowska-Haggström, Thomas Kohlmann and Henri Wallaschofski

Objective

To analyse 12-month response to GH treatment in a single-country cohort of hypopituitary adult patients with GH deficiency (GHD) in regards to health-related quality of life (HRQoL) and insulin-like growth factor-1 (IGF-1) compared with values from general population sample. Moreover, association between the response in HRQoL and the IGF-1 values in patients and in the background population was investigated.

Design

HRQoL was assessed by quality of life assessment of GH deficiency in adults (QoL-AGHDA) in 651 patients retrieved from the German KIMS (Pfizer International Metabolic Database) before and after 12 months of GH replacement and in a sample drawn from a cross-sectional study in Germany (n=2734). IGF-1 was measured in KIMS patients and in the population-based study with the same assay technique.

Results

In KIMS patients, mean QoL-AGHDA scores before GH replacement were 9.2±6.8 (8.7±6.8) in women (men) and in the general population sample 4.5±5.3 (4.3±5.0) in women (men). Mean differences in QoL-AGHDA scores were statistically significant for all age categories (P<0.05). The mean IGF-1 SDS of KIMS patients before GH replacement was −1.1±1.4 (−0.8±1.4) in women (men). After GH replacement, a significant increase of IGF-1 concentration and a significant decrease of QoL-AGHDA scores near to age- and gender-specific population-based values were observed.

Conclusions

This study confirms an improvement in HRQoL and an increase of IGF-1 SDS in GH-replaced adults, which approximated the values of general population. However, there was no association between IGF-1 values and HRQoL assessment as one of the important treatment outcomes.

Free access

Klaus Empen, Roberto Lorbeer, Henry Völzke, Daniel M Robinson, Nele Friedrich, Alexander Krebs, Matthias Nauck, Thorsten Reffelmann, Ralf Ewert, Stephan B Felix, Henri Wallaschofski and Marcus Dörr

Objective

IGF1 mediates multiple physiological and pathophysiological responses in the cardiovascular system. The aim of this study was to analyze the association between serum IGF1 as well as IGF-binding protein 3 (IGFBP3) levels and endothelial function measured by flow-mediated dilation (FMD).

Design

Cross-sectional population-based observational study.

Methods

The study population comprised 1482 subjects (736 women) aged 25–85 years from the Study of Health in Pomerania. Serum IGF1 and IGFBP3 levels were determined by chemiluminescence immunoassays. FMD measurements were performed using standardized ultrasound techniques. FMD values below the sex-specific median were considered low.

Results

In males, logistic regression analyses revealed an odds ratio (OR) of 1.27 (95% confidence interval (CI) 1.07–1.51; P=0.008) for decreased FMD for each decrement of IGF1 s.d. after adjustment for major cardiovascular confounders. In females, no significant relationship between serum IGF1 and FMD was found (OR 0.88, CI 0.74–1.05; P=0.147). After exclusion of subjects with the current use of antihypertensive medication, these findings were similar (males: OR 1.40, CI 1.12–1.75; P=0.003; females: OR 0.95, CI 0.77–1.16; P=0.595). There was no association between serum IGFBP3 levels and FMD in both sexes.

Conclusions

Low serum IGF1 levels are associated with impaired endothelial function in males. In women, serum IGF1 is not associated with endothelial function.