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EP Corssmit, E Endert, HP Sauerwein, and JA Romijn

OBJECTIVE: Recombinant human interferon alpha (rhIFN-alpha) is used therapeutically in malignant disorders and chronic hepatitis. The present study was assessed to study the effects of rhIFN-alpha on the hypothalamic-pituitary-testicular (HPT) axis. DESIGN AND METHODS: We performed a saline-controlled cross-over study in six healthy men, sequentially measuring the serum concentrations of gonadotropins, testosterone, the free androgen index (FAI) and sex hormone-binding globulin (SHBG) after a bolus subcutaneous injection of rhIFN-alpha. RESULTS: rhIFN-alpha induced a sustained decrease of both testosterone (from 19.5+/-1.88 to a nadir of 5.49+/-0.51nmol/l at the end of the study) and FAI (from 98.7+/-14.7 to a nadir of 32. 1+/-5.3 at the end of the study), whereas concentrations of LH, FSH and SHBG were not different between the two studies. CONCLUSIONS: Our results suggest that rhIFN-alpha affects the HPT axis at the testicular level, either directly or indirectly, and changes feedback relationships between the pituitary and the testis.

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PR Gallas, RP Stolk, K Bakker, E Endert, and WM Wiersinga

BACKGROUND: The prevalence of thyroid dysfunction in pregnancy and in the first postpartum year (postpartum thyroid dysfunction (PPTD)) in women with diabetes mellitus type 1 (DM1) is known to be higher than in the general population. To assess prevalence, incidence and risk factors in The Netherlands we performed a prospective cohort study. DESIGN: From 1994 to 1998, 126 women with DM1 from eight Dutch clinics were included. TSH, free thyroxine, free tri-iodothyronine and anti-thyroid peroxidase antibodies (TPO-ab) were measured pre-pregnancy, in the first and last trimester of pregnancy and at 1.5, 3, 6, 9 and 12 months after delivery. RESULTS: Eighty-two women completed the study. Thyroid dysfunction during pregnancy was observed in 22.5% (first trimester) and 18.4% (third trimester), and mostly consisted of subclinical hypothyroidism. Baseline characteristics of women with thyroid dysfunction in pregnancy did not differ from those without thyroid dysfunction. Overt PPTD was seen in 15.9%. Incidence of PPTD was 10%. Patients with PPTD were slightly older than those without PPTD and the prevalence of TPO-ab was higher in these women. CONCLUSION: In women with DM1 the prevalence of thyroid dysfunction during pregnancy and overt PPTD is 3-fold higher than in the general Dutch population. Risk factors are age and TPO-ab. Given the possible impact on psychomotor development of the offspring and on well-being of the mother these data suggest there is a case for screening (pre-)pregnant women with DM1 for TSH and TPO-ab.

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MJ Diekman, MP Harms, E Endert, W Wieling, and WM Wiersinga

OBJECTIVE: Total peripheral vascular resistance (TPR) decreases in thyrotoxicosis and increases in hypothyroidism. Several mechanisms may be involved, including adaptation to changes in heat production and direct non-genomic effects of tri-iodothyronine (T3) on vascular smooth muscle cells. The aim of this study was to see if changes in TPR are related to changes in plasma concentrations of the endothelial hormones adrenomedullin and endothelin-1 as well as other hormones affecting vasculature. DESIGN: A prospective study. SUBJECTS: Eleven hypothyroid patients (pretreatment: thyroid-stimulating hormone (TSH) 68 (38-201) mU/l, T3 0.7 (0.35-1.5) nmol/l, fT4 3.0 (2.0-5.9) pmol/l, median (range)) and 14 with hyperthyroidism (pretreatment: TSH 0.02 (<0.01-0.06) mU/l, T3 6.4 (2.3-13.0) nmol/l, fT4 56.1 (22.9-70.0) pmol/l) were studied before treatment and 3 months after reaching the euthyroid state. Blood collection was carried out simultaneously with the recording of finger arterial pressure (FINAP). Cardiac output and TPR were derived from stroke volume computations by modelling flow from the FINAP signal. RESULTS: Thyroid-function tests of hypothyroid and thyrotoxic patients did not differ after restoration of the euthyroid state. TPR, expressed in arbitrary units (AU), decreased after correction of hypothyroidism (from 1.32+/-0.65 to 0.96+/-0.36 AU, P=0.04) and increased after correction of hyperthyroidism (from 0.75+/-0.18 to 1.10+/-0.35 AU, P=0.007). Adrenomedullin concentrations did not change during the transition from the hypothyroid state 3.2(0.9-11.0) pmol/l to the euthyroid state 4.9(0.9-8.6) pmol/l, but decreased after treatment of hyperthyroidism, from 5.2(0.9-11.0) pmol/l to 2.2(0.9-5.4) pmol/l. Plasma endothelin-1 was undetectable in all samples. Changes in TPR upon treatment correlated with log DeltafT4 (r=-0.65, P=0.001), log DeltaT3, (r=-0.57, P=0.006), Delta noradrenaline (r=0.54, P=0.02) and Delta ANP (atrial natriuretic peptide) (r=-0.59, P=0.004). Multiple linear regression analysis indicated that only T3 was an independent determinant of TPR. Changes in T3 accounted for 46% of the variability in the changes in TPR. CONCLUSIONS: TPR is reduced in thyrotoxicosis and increased in hypothyroidism. Restoration of the euthyroid state normalizes TPR. Changes in TPR are not related to plasma adrenomedullin concentrations, but 46% could be explained by changes in T3. Altered ANP secretion and adrenergic tone may contribute to the T3-induced changes in TPR.

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AG van Wassenaer, JH Kok, FW Dekker, E Endert, and JJ de Vijlder

OBJECTIVE: To investigate the effect on thyroid hormone metabolism of the administration of thyroxine to very preterm infants. DESIGN AND METHODS: Two hundred infants of less than 30 weeks gestation were enrolled into a randomized, double-blind, placebo-controlled trial. Thyroxine (T4) (at a fixed daily dose of 8 microg/kg birthweight) or placebo was started 12-24h after birth and discontinued 6 weeks later. Plasma concentrations of T4, tri-iodothyronine (T3), reverse T3 (rT3), TSH, and thyroxine-binding globulin were measured weekly during trial medication and 2 weeks thereafter. RESULTS: The T4 and the placebo group each comprised 100 infants. Antenatal, perinatal, and postnatal clinical characteristics were comparable in both groups. T4 and rT3 were significantly increased in the T4 group. TSH concentrations were depressed in the T4 group and T3 was significantly decreased, probably as a result of TSH depression. The T4/T3 and T4/rT3 ratios differed significantly between the two study groups. CONCLUSIONS: Daily T4 administration during the first 6 weeks after birth to infants of less than 30 weeks gestation prevents hypothyroxinemia, but decreases plasma T3 concentrations. Our finding possibly implies that very preterm infants should receive supplements of both T4 and T3.

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EJ Van Someren, J Swart-Heikens, E Endert, PH Bisschop, DF Swaab, PJ Bakker, JA Romijn, and E Fliers

BACKGROUND: Cranial radiation therapy (CRT) is required for successful treatment of a variety of brain tumours in childhood. OBJECTIVE: To investigate whether childhood CRT leads to altered sleep-wakefulness organization in adulthood, and to identify the determinants of such alterations. SUBJECTS AND METHODS: Subjective (questionnaires) and objective (actigraphy) measures of circadian rhythmicity and sleep were assessed in 25 individuals, 8-29 years after CRT for medulloblastoma (n=17) or other intracranial tumours (n=8), and in a group of 34 age-matched healthy individuals. Serum GH peak during insulin-induced hypoglycaemia and serum concentrations of prolactin and leptin (expressed per fat mass) were determined in the CRT group. RESULTS: The CRT group showed a markedly increased sleep duration (8.66 h, compared with 7.66 h in controls). In addition, the sleep-wake rhythm showed greater amplitude and less fragmentation, and less tolerance for alterations in the timing of sleep. Regression analysis showed both radiation dosage and neuroendocrine status to be determinants of sleep changes, suggesting that some of the alterations may be normalized with hormone supplementation. CONCLUSION: The present study shows that high-dose cranial radiation therapy in childhood is associated with objective and subjective changes in the sleep-wake rhythm in adulthood.

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M de Fost, A S P van Trotsenburg, H M van Santen, E Endert, C van den Elzen, E J Kamsteeg, D F Swaab, and E Fliers


Familial neurohypophyseal (central) diabetes insipidus (DI) is caused by mutations in the arginine vasopressin–neurophysin II (AVP–NPII) gene. The majority of cases is inherited in an autosomal dominant way. In this study, we present the clinical features of a mother and her son with autosomal dominant neurohypophyseal DI caused by a novel mutation.


A thirty-four-year-old woman and her three-year-old son were evaluated because of polyuria and polydipsia since the age of 1.5 years onwards. Both patients were subjected to a water deprivation test confirming the diagnosis of central DI. Magnetic resonance imaging of the brain of the mother showed a hypothalamus without apparent abnormalities and a relatively small neurohypophysis without a hyperintense signal. Mutation analysis showed a c.322G>T (p.?/p.Glu108X) in Exon 2 of the AVP–NPII gene in both mother and son.


This study reports neurohypophyseal DI in a mother and her son due to a novel mutation in Exon 2 of the AVP–NPII gene. Clinical and pathophysiological aspects of this disease are shortly reviewed and discussed.

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Laura P B Elbers, Carla Moran, Victor E A Gerdes, Bregje van Zaane, Joost C M Meijers, Erik Endert, Greta Lyons, Krishna Chatterjee, Peter H Bisschop, and Eric Fliers


Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor β (THRB or THRB) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in THRB-expressing tissues. We tested the hypothesis that the hypercoagulable state in hyperthyroidism is mediated via the THRB.


We conducted a cross-sectional study from November 2013 to January 2015 in 3 hospitals in the Netherlands and the United Kingdom.


Patients with RTH due to defective THRB (n=18), patients with hyperthyroidism (n=16) and euthyroid subjects (n=18) were included. TH concentrations and markers of coagulation and fibrinolysis were measured. Data are expressed as median (interquartile range).


Free thyroxine (FT4) levels were slightly higher in hyperthyroid patients than in RTH patients (53.9 (30.5–70.0) and 34.9 (28.4–42.2)pmol/L, respectively, P=0.042). Both groups had raised FT4 levels compared with euthyroid subjects (14.0 (13.0–15.8)pmol/L, P≤0.001). Levels of von Willebrand factor (VWF), factor (F) VIII, fibrinogen and d-dimer were significantly higher in hyperthyroid patients than in RTH patients (VWF 231 (195–296) vs 111 (82–140)%, FVIII 215 (192–228) vs 145 (97–158)%, fibrinogen 3.6 (3.0–4.4) vs 2.8 (2.5–3.2)g/L, d-dimer 0.41 (0.31–0.88) vs 0.20 (0.17–0.26)mg/L, respectively, P≤0.001), while there were no differences between RTH patients and euthyroid controls.


Parameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared with patients with RTH due to defective THRB, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4 concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via the THRB.