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Free access

A history of cranial radiotherapy is associated with a higher visceral to subcutaneous fat ratio in men with pituitary insufficiency

Anke J Borgers, Anneke Alkemade, Henk W Venema, Eric Fliers, and Peter H Bisschop

Objective

Endocrine deficiencies, like GH and estrogen deficiencies, are likely candidates to explain increased visceral to subcutaneous fat ratio in patients with pituitary insufficiency. However, recent reports pointed to cranial radiotherapy (CRT) as an additional determinant of an unfavorable fat distribution. Therefore, we determined the effect of CRT on abdominal fat distribution in men with treated pituitary insufficiency.

Design

Cross-sectional study.

Methods

Thirty-five consecutive male subjects (16 men with and 19 men without CRT aged 62±12 and 56±14 years respectively, P=0.175) visiting our Endocrine Outpatient Clinic for pituitary insufficiency were invited to participate in this study. A standardized single-slice abdominal CT scan at the level of fourth lumbar vertebra was performed to determine visceral fat area, subcutaneous fat area, and visceral to subcutaneous fat ratio. In addition, we assessed body mass index, total fat percentage with bioelectrical impedance analysis, resting energy expenditure with indirect calorimetry, calorie intake using a diary, and serum hormone concentrations.

Results

Subjects with CRT had a smaller subcutaneous fat area (225.1 (71.1–480.7) vs 269.0 (133.2–59.9) cm2, P=0.022) and a higher visceral to subcutaneous fat ratio (0.79 (0.39–1.55) vs 0.63 (0.23–0.88), P=0.001) than subjects without CRT. Both the groups were comparable for body mass index, waist–hip ratio, resting energy expenditure, and calorie intake. Importantly, serum hormone concentrations were similar.

Conclusion

In men treated for pituitary insufficiency, previous CRT is associated with a higher visceral to subcutaneous fat ratio.

Free access

Screw needle cytology of thyroid nodules is associated with a lower non-diagnostic rate compared to fine needle aspiration

Tamira K Klooker, Anne Huibers, Klaas in 't Hof, Els J M Nieveen van Dijkum, Saffire S Phoa, Susanne van Eeden, and Peter H Bisschop

Background

Fine needle aspiration (FNA) cytology is the method of choice to exclude malignancy in thyroid nodules. A major limitation of thyroid FNA is the relatively high rate (13–17%) of non-diagnostic samples. The aim of this study is to determine the diagnostic yield of a screw needle compared to the conventional FNA.

Methods

We retrospectively analysed thyroid nodule cytology of all patients that underwent thyroid nodule fine needle or screw needle aspiration between July 2007 and July 2012 in a single academic medical centre. Cytology results were categorized according to the Bethesda classification system.

Results

In total, 644 punctures of thyroid nodules from 459 patients were available for analysis. The screw needle was used 531 times, and the conventional fine needle 113 times. The percentage of non-diagnostic cytology was significantly lower in the screw needle samples than in the fine needle samples (3% vs 17%, P<0.001).

Conclusion

This study shows a significantly better diagnostic performance of the screw needle compared to the conventional fine needle in cytology of thyroid nodules.

Free access

The effects of sex-steroid administration on the pituitary–thyroid axis in transsexuals

Peter H Bisschop, Arno W Toorians, Erik Endert, Wilmar M Wiersinga, Louis J Gooren, and Eric Fliers

Objective: Estrogen and androgen administration modulate the pituitary–thyroid axis through alterations in thyroid hormone-binding globulin (TBG) metabolism, but the effects of sex steroids on extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in humans are unknown.

Design and methods: We studied 36 male-to-female and 14 female-to-male euthyroid transsexuals at baseline and after 4 months of hormonal treatment. Male-to-female transsexuals were treated with cyproterone acetate (CA) 100 mg/day alone (n=10) or in combination with either oral ethinyl estradiol (or-EE) 100 μg/day (n=14) or transdermal 17β-estradiol (td-E) 100 μg twice a week (n=12). Female-to-male transsexuals were treated with i.m. testosterone 250 mg twice a week. A t-test was used to test for differences within groups and ANOVAwith post hoc analysis to test for differences between the groups.

Results: Or-EE increased TBG (100 ± 12%, P<.001) and testosterone decreased TBG (−14 ± 4%, P =0.01), but free T4 did not change. Td-E and CA did not affect TBG concentrations. TSH was not different between groups at baseline or after treatment. CA decreased T3/T4 ratios (−9 ± 3%, P=0.04), suggesting that T4 to T3 conversion was lower. Testosterone increased T3/T4 ratios (30 ± 9%, P=0.02), which probably reflects higher T4 to T3 conversion.

Conclusion: Oral but not transdermal estradiol increases TBG, whereas testosterone lowers TBG. Testosterone increases T3/T4 ratios. Estradiol does not affect T3/T4 ratios, irrespective of the route of administration.

Free access

The hypercoagulable state in hyperthyroidism is mediated via the thyroid hormone β receptor pathway

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

Objective

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.

Design

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

Methods

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).

Results

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.

Conclusions

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.

Free access

Effects of intravenous thyrotropin-releasing hormone on 18F-fluorodeoxyglucose uptake in human brown adipose tissue: a randomized controlled trial

Charlotte A Heinen, Zhi Zhang, Lars P Klieverik, Tim C de Wit, Edwin Poel, Maqsood Yaqub, Anita Boelen, Andries Kalsbeek, Peter H Bisschop, A S Paul van Trotsenburg, Hein J Verberne, Jan Booij, and Eric Fliers

Objective

Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including β3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans.

Design

A randomized, placebo-controlled, double-blind, cross-over trial.

Methods

We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512).

Results

Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P = 0.066). MRglu showed a significant increase after TRH administration (P = 0.014). The increase in 18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations.

Conclusion

Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.

Restricted access

Compression of the optic chiasm is associated with reduced photoentrainment of the central biological clock

Tessel M Boertien, Eus J W Van Someren, Adriaan D Coumou, Annemieke K van den Broek, Jet H Klunder, Wing-Yi Wong, Adrienne E van der Hoeven, Madeleine L Drent, Johannes A Romijn, Eric Fliers, and Peter H Bisschop

Objective

Pituitary tumours that compress the optic chiasm are associated with long-term alterations in sleep–wake rhythm. This may result from damage to intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting from the retina to the hypothalamic suprachiasmatic nucleus via the optic chiasm to ensure photoentrainment (i.e. synchronisation to the 24-h solar cycle through light). To test this hypothesis, we compared the post-illumination pupil response (PIPR), a direct indicator of ipRGC function, between hypopituitarism patients with and without a history of optic chiasm compression.

Design

Observational study, comparing two predefined groups.

Methods

We studied 49 patients with adequately substituted hypopituitarism: 25 patients with previous optic chiasm compression causing visual disturbances (CC+ group) and 24 patients without (CC– group). The PIPR was assessed by chromatic pupillometry and expressed as the relative change between baseline and post-blue-light stimulus pupil diameter. Objective and subjective sleep parameters were obtained using polysomnography, actigraphy, and questionnaires.

Results

Post-blue-light stimulus pupillary constriction was less sustained in CC+ patients compared with CC– patients, resulting in a significantly smaller extended PIPR (mean difference: 8.1%, 95% CI: 2.2–13.9%, P = 0.008, Cohen’s d = 0.78). Sleep–wake timing was consistently later in CC+ patients, without differences in sleep duration, efficiency, or other rest–activity rhythm features. Subjective sleep did not differ between groups.

Conclusion

Previous optic chiasm compression due to a pituitary tumour in patients with hypopituitarism is associated with an attenuated PIPR and delayed sleep timing. Together, these data suggest that ipRGC function and consequently photoentrainment of the central biological clock is impaired in patients with a history of optic chiasm compression.

Free access

Thyroid incidentalomas in patients with multiple endocrine neoplasia type 1

Lutske Lodewijk, Pim J Bongers, Jakob W Kist, Elfi B Conemans, Joanne M de Laat, Carla R C Pieterman, Anouk N A van der Horst-Schrivers, Ciska Jorna, Ad R Hermus, Olaf M Dekkers, Wouter W de Herder, Madeleine L Drent, Peter H Bisschop, Bas Havekes, Inne H M Borel Rinkes, Menno R Vriens, and Gerlof D Valk

Objective

Currently, little is known about the prevalence of thyroid tumors in multiple endocrine neoplasia type 1 (MEN1) patients and it is unclear whether tumorigenesis of these thyroid tumors is MEN1-related. The aim of the study was to assess the prevalence of thyroid incidentalomas in MEN1 patients compared with nonMEN1 patients and to verify whether thyroid tumorigenesis is MEN1-related.

Design

A cross-sectional study.

Methods

The study included two groups: patients with MEN1 and a matched non-MEN1 control group without known thyroid disease, who underwent an ultrasound of the neck for the localization of parathyroid adenoma. Ninety-five MEN1 patients underwent ultrasound of the neck and were matched on gender and age with non-MEN1 patients. The prevalence of thyroid incidentalomas described in the ultrasound report was scored. Multinodular goiters, solitary nodes, and cysts were scored as incidentalomas. Presence of nuclear menin expression was evaluated by menin immunostaining of the thyroid tumors.

Results

In the MEN1 group, 43 (45%) patients had a thyroid incidentaloma compared with 48 (51%) in the non-MEN1 group, of which 14 (15%) and 16 (17%), respectively, were solitary nodes. Menin was expressed in the nuclei of all evaluated thyroid tumors.

Conclusions

MEN1 patients do not have a higher prevalence of thyroid incidentalomas compared with primary hyperparathyroidism patients without the diagnosis of MEN1. Menin was expressed in the thyroid tumors of MEN1 patients.

Free access

The phenotype of SDHB germline mutation carriers: a nationwide study

Nicolasine D Niemeijer, Johannes A Rijken, Karin Eijkelenkamp, Anouk N A van der Horst-Schrivers, Michiel N Kerstens, Carli M J Tops, Anouk van Berkel, Henri J L M Timmers, Henricus P M Kunst, C René Leemans, Peter H Bisschop, Koen M A Dreijerink, Marieke F van Dooren, Jean-Pierre Bayley, Alberto M Pereira, Jeroen C Jansen, Frederik J Hes, Erik F Hensen, and Eleonora P M Corssmit

Objective

Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations.

Design

Retrospective descriptive study.

Methods

Retrospective descriptive study in seven academic centers.

Results

We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0–36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423 + 1G > A).

Conclusions

In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.

Free access

Unenhanced CT imaging is highly sensitive to exclude pheochromocytoma: a multicenter study

Edward Buitenwerf, Tijmen Korteweg, Anneke Visser, Charlotte M S C Haag, Richard A Feelders, Henri J L M Timmers, Letizia Canu, Harm R Haak, Peter H L T Bisschop, Elisabeth M W Eekhoff, Eleonora P M Corssmit, Nanda C Krak, Elise Rasenberg, Janneke van den Bergh, Jaap Stoker, Marcel J W Greuter, Robin P F Dullaart, Thera P Links, and Michiel N Kerstens

Background

A substantial proportion of all pheochromocytomas is currently detected during the evaluation of an adrenal incidentaloma. Recently, it has been suggested that biochemical testing to rule out pheochromocytoma is unnecessary in case of an adrenal incidentaloma with an unenhanced attenuation value ≤10 Hounsfield Units (HU) at computed tomography (CT).

Objectives

We aimed to determine the sensitivity of the 10 HU threshold value to exclude a pheochromocytoma.

Methods

Retrospective multicenter study with systematic reassessment of preoperative unenhanced CT scans performed in patients in whom a histopathologically proven pheochromocytoma had been diagnosed. Unenhanced attenuation values were determined independently by two experienced radiologists. Sensitivity of the 10 HU threshold was calculated, and interobserver consistency was assessed using the intraclass correlation coefficient (ICC).

Results

214 patients were identified harboring a total number of 222 pheochromocytomas. Maximum tumor diameter was 51 (39–74) mm. The mean attenuation value within the region of interest was 36 ± 10 HU. Only one pheochromocytoma demonstrated an attenuation value ≤10 HU, resulting in a sensitivity of 99.6% (95% CI: 97.5–99.9). ICC was 0.81 (95% CI: 0.75–0.86) with a standard error of measurement of 7.3 HU between observers.

Conclusion

The likelihood of a pheochromocytoma with an unenhanced attenuation value ≤10 HU on CT is very low. The interobserver consistency in attenuation measurement is excellent. Our study supports the recommendation that in patients with an adrenal incidentaloma biochemical testing for ruling out pheochromocytoma is only indicated in adrenal tumors with an unenhanced attenuation value >10 HU.