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Open access

Ayako Sato, Katsuya Matsuda, Takahiro Motoyama, Zhanna Massazhanova, Ryota Otsubo, Hisayoshi Kondo, Yuko Akazawa, Miyoko Higuchi, Ayana Suzuki, Mitsuyoshi Hirokawa, Akira Miyauchi, Takeshi Nagayasu, and Masahiro Nakashima

We have previously reported that the expression of p53-binding protein 1 (53BP1) in nuclear foci (NF), a marker reflecting DNA damage response (DDR), detected using immunofluorescence (IF) is useful to estimate the malignant potency of diverse cancers. In this prospective study, we clarified the impact of 53BP1 expression via IF as a biomarker to differentiate thyroid follicular tumors (FTs) with liquid-based cytology (LBC). A total of 183 consecutively obtained-LBC samples, which were preoperatively suspected as FTs, were analyzed. Before histological diagnosis, the type of 53BP1 immunoreactivity in LBC was classified as follows: low DDR type, one or two NF; high DDR type, three or more NF; large foci type, larger than 1.0 μm; abnormal type, intense nuclear staining. Among the 183 cases, 136 cases were postoperatively diagnosed as FTs including adenomatous goiter (AG, n=30), follicular adenoma (FA, n=60), FT-uncertain malignant potency (FT-UMP, n=18), and follicular carcinoma (FC, n=28), and 47 cases were diagnosed as tumors other than FTs or technically inadequate materials. Total 136 FT cases were collated with the type of 53BP1 immunoreactivity in LBC. The mean incidence expressing abnormal 53BP1 expression was significantly higher in FC than FA (9.5% vs. 2.6%, p-value <0.001). When adopting 4.3% as a cut-off value to distinguish FC from FA, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.3, 83.3, 71.4, and 94.3%, respectively. Therefore, IF analysis of 53BP1 expression can be employed as a novel technique to diagnosis FTs and distinguish between different types of FTs using LBC.

Open access

W N H Koek, N Campos-Obando, B C J van der Eerden, Y B De Rijke, Ma Ikram, Ag Uitterlinden, Jptm Van Leeuwen, and Mc Zillikens

Background: Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age.

Methods: We used laboratory values of serum calcium, phosphate and albumin from three different samples (years 2005, 2010 and 2014) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into 3 age groups: 1-17, 18-44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex

Results: In all 3 samples there was a significant sex*age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found.

In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups 18-44 and ≥45 years. In women, serum calcium levels were also significantly higher in the age group 1-17 and the age group ≥45 years compared to the 18-44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1-17 years and lowest in the group 18-44 years.

Conclusion: There are age dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex differences are not yet fully elucidated.

Open access

Bo Zhu, Yumei Chen, Fang Xu, Xiaolu Shen, Xuanyu Chen, Jieqiang Lv, and Songying Zhang

Background: Androgens excess results in endoplasmic reticulum (ER) stress, which is an important cause of β cells dysfunction. Here, we investigated the molecular regulation of androgens excess, ER stress, and β-cell function in polycystic ovary syndrome (PCOS).

Methods: PCOS mouse model was established by injection of dehydroepiandrosterone (DHEA). Primary cultured mouse islets were used to detect testosterone (TE)-induced ER stress. The response of ER stress, apoptosis, and hyperinsulinemia were analyzed in INS-1 cells with or without TE exposure. Androgen receptor (AR) antagonist and ER stress inhibitor treatment was performed to evaluate the role of TE in ER stress and proinsulin secretion of PCOS mice.

Results: PCOS mice had higher ER stress in islets. TE exposure induced ER stress and apoptosis significantly through sustaining insulin overexpression in β cells, which in turn impaired proinsulin maturation and secretion. Blocking this process could significantly relieve ER stress and apoptosis and improve insulin homeostasis.

Conclusion: ER stress activated by androgens excess in PCOS contributes to β cell dysfunction and hyperinsulinemia.

Open access

Jens F. Rehfeld

The birth certificate for endocrinology was Bayliss’ and Starling’s demonstration in 1902 that regulation of bodily functions is not only neuronal, but due also to blood-borne messengers. Starling named these messengers hormones. Since then, transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones not only are produced and released to blood from endocrine cells. They are released also from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin, which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Todays’ multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells – irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone; growth factor; neurotransmitter; adipokine; cytokine; myokine; or fertility factor.

Open access

Selma Flora Nordqvist, Victor Brun Boesen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Laszlo Hegedüs, Steen Joop Bonnema, Per Karkov Cramon, Torquil Watt, Mogens Groenvold, and Jakob Bue Bjorner

Objective: ThyPRO is the standard thyroid patient-reported outcome (PRO). The change in scores that patients perceive as important remains to be ascertained. The purpose of this study was to determine values for minimal important change (MIC) for ThyPRO.

Methods: A total of 435 patients treated for benign thyroid diseases completed ThyPRO at baseline and 6 weeks following treatment initiation. At 6-weeks follow-up, patients also completed Global Rating of Change items. For each 0-100 scale, two MIC values were identified: an MIC for groups, using the ROC curve method and an MIC for individual patients, using the reliable change Index.

Results: ROC analyses provided group-MIC estimates of 6.3 to 14.3 (score range 0-100). Evaluation of area under the curve (AUC) supported the robustness for 9 of 14 scales (AUC > 0.7). Reliable change index estimates of individual-MIC were 8.0 to 21.1. For all scales but two, the individual-MIC values were larger than the group-MIC values.

Conclusions: Interpretability of ThyPRO was improved by the establishment of MIC values, which was 6.3 to 14.3 for groups and 8.0 to 21.1 for individuals. Thus, estimates of which changes are clinically relevant, are now available for future studies. We recommend using MIC values found by ROC analyses to evaluate changes in groups of patients, whereas MIC values identified by a dual criterion, including the reliability of changes, should be used for individual patients, e.g. to identify individual responders in clinical studies or practice.

Open access

Irfan Vardarli, Manuel Weber, Frank Weidemann, Dagmar Fuehrer, Ken Herrmann, and Rainer Görges

Objective: The usefulness of routine calcitonin measurement for early detection of medullary thyroid carcinoma (MTC) in patients with nodular thyroid disease (NTD) has been investigated in various studies. Recently, a Cochrane review has been published on this issue, but a meta-analysis is lacking yet. Therefore, we performed this meta-analysis.

Methods: We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of routine calcitonin measurement for detecting MTC in patients with NDT were selected. Statistics were performed by using Stata software, risk of bias was assessed using Review Manager version 5.3.

Results: 17 studies, involving 74,407 patients were included in the study. Meta-analysis, using the bivariate random effects model and the hierarchical summary receiver operating characteristic (HSROC) curve revealed the following pooled estimates: sensitivity 0.99 (95% CI, 0.81-1.00), specificity 0.99 (95% CI, 0.97-0.99), positive likelihood ratio (L+) 72.4 (95% CI, 32.3-162.1), and negative likelihood ratio (L-) 0.01 (95% CI, 0.00-0.23). Meta-regression analysis showed that the threshold of basal calcitonin is an independent factor, but in particular performing of stimulation test is not an independent factor.

Conclusions: We showed that routine basal serum calcitonin measurement in the management of patients with thyroid nodules is valuable for the detection of MTC. However, the published cut-off values should be considered and, if applicable, the patients monitored in a wait-and-see strategy by experienced physicians to avoid overtreatment.

Open access

Marc Ingenwerth, Tim Brandenburg, Dagmar Führer-Sakel, Moritz Goetz, Frank Weber, Henning Dralle, Hans-Ulrich Schildhaus, Kurt Werner Schmid, and Sarah Theurer

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbour somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behaviour and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥ 50 %) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (p < 0.0001) and lymph node metastases (p < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behaviour. DLL3 expression in >50% of tumor cells virtually excludes MTC without stromal desmoplasia.DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.

Open access

Bliss Anderson and Daniel L Morganstein

Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors.

We review the presentation and management of the common endocrine immune related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.

Open access

Liangming Li, Yuan Wei, Chunlu Fang, Shujing Liu, Fu Zhou, Ge Zhao, Yaping Li, Yuan Luo, Ziyi Guo, Weiqun Lin, and Wenqi Yang

Exercise has been recommended as an important strategy to improve glucose metabolism in obesity. Adipose tissue fibrosis is associated with inflammation and is implicated in glucose metabolism disturbance and insulin resistance in obesity. However, the effect of exercise on the progression of adipose tissue fibrosis is still unknown. The aim of the present study was to investigate whether exercise retarded the progression of adipose tissue fibrosis and ameliorated glucose homeostasis in diet-induced obese mice. To do so, obesity and adipose tissue fibrosis in mice were induced by high-fat diet feeding for 12 weeks and the mice subsequently received high-fat diet and exercise intervention for another 12 weeks. Exercise alleviated high-fat diet-induced glucose intolerance and insulin resistance. Continued high-fat diet feeding exacerbated collagen deposition and further increased fibrosis-related gene expression in adipose tissue. Exercise attenuated or reversed these changes. Additionally, PPARγ, which has been shown to inhibit adipose tissue fibrosis, was observed to be increased following exercise. Moreover, exercise decreased the expression of HIF-1α in adipose fibrosis, and adipose tissue inflammation was inhibited. In conclusion, our data indicate that exercise attenuates and even reverses the progression of adipose tissue fibrosis, providing a plausible mechanism for its beneficial effects on glucose metabolism in obesity.

Open access

Stine A. Holmboe, Ravi Jasuja, Brian Lawney, Lærke Priskorn, Niels Joergensen, Allan Linneberg, Tina Kold Jensen, Niels Erik Skakkebæk, Anders Juul, and Anna-Maria Andersson


Calculating the free testosterone level has gained increasing interest and different indirect algorithms have been suggested. The objective was to compare free androgen index (FAI), free testosterone estimated using the linear binding model (Vermeulen: cFTV) and the binding framework accounting for allosterically coupled SHBG monomers (Zakharov: cFTZ) in relation to cardiometabolic conditions.


A prospective cohort study including 5,350 men, aged 30-70 years, participating in population-based surveys (MONICA I–III and Inter99) from 1982-2001 and followed until December 2012 with baseline and follow-up information on cardiometabolic parameters and vital status.


Using age-standardized hormone levels, FAI was higher among men with baseline cardiometabolic conditions, whereas cFTV and cFTZ levels were lower compared to men without these conditions as also seen for total testosterone. Men in highest quartiles of cFTV or cFTZ had lower risk of developing type 2 diabetes (cFTV: HR=0.74 (0.49-1.10), cFTZ: HR=0.59 (0.39-0.91)) than men in lowest quartile. In contrast, men with highest levels of FAI had a 74% (1.17-2.59) increased risk of developing type 2 diabetes compared to men in lowest quartile.


The association of estimated free testosterone and the studied outcomes differ depending on algorithm used. cFTV and cFTZ showed similar associations to baseline and long-term cardiometabolic parameters. In contrast, an empiric ratio, FAI, showed opposite associations to several of the examined parameters and may reflect limited clinical utility.