Rotterdam, Netherlands
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Korevaar T.I.M.,Generation R Study Group | Korevaar T.I.M.,Erasmus Medical Center | Korevaar T.I.M.,Rotterdam Thyroid Center | De Rijke Y.B.,Erasmus Medical Center | And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: The thyroid has a high vascular density and this vascularity may be influenced by pregnancy-specific angiogenic factors. Proangiogenic placental growth factor (PlGF) and antiangiogenic soluble FMS-like tyrosine kinase-1 (sFlt1; a vascular endothelialgrowthfactor [VEGF]andPlGF antagonist) are important pregnancy-specific angiogenesis regulators.Wepreviously showed that fetal levels of sFlt1 and PlGF are associated with newborn thyroid function. However, the maternal thyroid may also be affected as PlGF and VEGF are secreted into the maternal circulation and cause a concomitant increase of sFlt1 to overcome adverse effects of angiogenesis overstimulation. Design, Setting, and Participants: Maternal sFlt1, PlGF, TSH, FT4, or human chorionic gonadotropin (hCG) levels were determined during early pregnancy (∼18 wk) in 5517 women from the Generation R study. Analyses were adjusted for relevant covariates and interaction between hCG and angiogenic factors was investigated. Results: Increasing levels of sFlt1 were associated with a decrease in FT4 and T4 (both P<.001), and an increased risk of subclinical hypothyroidism (odds ratio [OR] for high levels, 2.37; 95% CI, 1.16-4.83; P<.02) and isolated hypothyroxinemia (linear P<.02; OR, 3.05; 95% CI, 1.42-6.55; P< .004). Increasing levels of PlGF were associated with a decrease in TSH and FT4 levels (both P<.001), and an increased risk of isolated hypothyroxinemia (linear P < .002; OR, 1.77; 95% CI, 1.02-3.06; P<.04). High levels of hCG decreased the difference in FT4 between low and high sFlt1. In women with high PlGF levels, the hCG-mediated increase in FT4 levels was attenuated. Conclusion: sFlt1 and PlGF are novel determinants of maternal thyroid (dys)function during early pregnancy and the response of the maternal thyroid function to hCG stimulation. These data provide novel insights into the pregnancy specific thyroid function physiology and suggest that high levels of pro-and anti-angiogenic factorsmaybe a risk factor for adverse pregnancy outcomes via their effects on maternal thyroid function. Copyright © 2015 by the Endocrine Society.


PubMed | Rotterdam Thyroid Center, Leiden University and Rotterdam University
Type: Journal Article | Journal: European journal of endocrinology | Year: 2016

Thyroid dysfunction has been associated with kidney function decline, but mainly in cross-sectional studies. Therefore, we aimed to determine the association between thyroid and kidney function in a prospective population-based cohort study longitudinally.Prospective cohort study.Participants aged 45 years from the Rotterdam Study with thyroid and kidney function assessment were included. Kidney function and new onset chronic kidney disease (CKD) were defined using estimated glomerular filtration ate (eGFR), with CKD defined as eGFR <60mL/min/1.73mWe included 5103 participants (mean age of 63.6 years) with a mean follow-up of 8.1 years. Cross-sectionally, higher TSH levels were associated with lower eGFR (Beta (): -1.75mL/min; 95% confidence interval (CI): -2.17, -1.33), in multivariable models adjusting for several cardiovascular risk factors including smoking, hypertension and history of coronary heart disease among others. In contrast, longitudinally, higher TSH levels were associated with less annual eGFR decline (: -0.06mL/min; CI: -0.11, -0.01) and lower CKD incidence (odds ratio 0.85, CI; 0.75, 0.96). Compared with euthyroid participants, subclinical hyperthyroid individuals had an increased risk for CKD whereas hypothyroid individuals had a decreased risk (P for trend=0.04).Hyperactive thyroid function is associated with increased risk of kidney function decline while hypothyroidism is associated with a decreased CKD risk. More insight is needed in the pathophysiological pathways connecting high thyroid function and kidney function decline.


Zevenbergen C.,Erasmus Medical Center | Zevenbergen C.,Rotterdam Thyroid Center | Klootwijk W.,Erasmus Medical Center | Klootwijk W.,Rotterdam Thyroid Center | And 17 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Thyroid hormones (TH) are important for normal brain development and abnormal TH regulation in the brain results in neurocognitive impairments. The type 2 deiodinase (D2) is important for local TH control in the brain by generating the active hormone T3 from its precursor T4. Dysfunction of D2 likely results in a neurocognitive phenotype. No mutations in D2 have been reported yet.Objective: The objective of the study was to identify D2 mutations in patients with intellectual disability and to test their functional consequences.Design, Setting, and Patients: The patients were selected from the multicenter Thyroid Origin of Psychomotor Retardation study, which is a cohort of 946 subjects with unexplained intellectual disability. Based on characteristic serum TH values, the coding region of the DIO2 gene was sequenced in 387 patients. Functional consequences were assessed by in vitro D2 assays or intact cell metabolism studies using cells transfected with wild-type or mutant D2.Results: Sequence analysis revealedtwoheterozygous mutations: c.11T>A (p.L4H) in three subjects and c.305C>T (p.T102I) in one subject. Sequence analysis of family members revealed several carriers, but no segregation was observed with thyroid parameters or neurocognitive phenotype. Extensive tests with different in vitro D2 assays did not show differences between wild-type and mutant D2.Conclusion: This study describes the identification and functional consequences of novel genetic variation inTHactivatingenzymeD2. Family studiesandfunctional tests suggest that these variantsdonot underlie the neurocognitive impairment. Altogetherourdata provide evidence of the existence of rare but apparently harmless genetic variants of D2. Copyright © 2014 by the Endocrine Society.


Beukhof C.M.,Rotterdam Thyroid Center | Medici M.,Rotterdam Thyroid Center | Van Den Beld A.W.,Rotterdam Thyroid Center | Hollenbach B.,Charité - Medical University of Berlin | And 6 more authors.
PLoS ONE | Year: 2016

Objective It is still a matter of debate if subtle changes in selenium (Se) status affect thyroid function tests (TFTs) and bone mineral density (BMD). This is particularly relevant for the elderly, whose nutritional status is more vulnerable. Design and Methods We investigated Se status in a cohort of 387 healthy elderly men (median age 77 yrs; inter quartile range 75-80 yrs) in relation to TFTs and BMD. Se status was determined by measuring both plasma selenoprotein P (SePP) and Se. Results The overall Se status in our population was low normal with only 0.5% (2/387) of subjects meeting the criteria for Se deficiency. SePP and Se levels were not associated with thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3) or reverse triiodothyronine (rT3) levels. The T3/T4 and T3/rT3 ratios, reflecting peripheral metabolism of thyroid hormone, were not associated with Se status either. SePP and Se were positively associated with total BMD and femoral trochanter BMD. Se, but not SePP, was positively associated with femoral neck and ward's BMD. Multivariate linear analyses showed that these associations remain statistically significant in a model including TSH, FT4, body mass index, physical performance score, age, smoking, diabetes mellitus and number of medication use. Conclusion Our study demonstrates that Se status, within the normal European marginally supplied range, is positively associated with BMD in healthy aging men, independent of thyroid function. Thyroid function tests appear unaffected by Se status in this population. © 2016 Beukhof et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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