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Open access

Louise Vølund Larsen, Delphine Mirebeau-Prunier, Tsuneo Imai, Cristina Alvarez-Escola, Kornelia Hasse-Lazar, Simona Censi, Luciana A Castroneves, Akihiro Sakurai, Minoru Kihara, Kiyomi Horiuchi, Véronique Dorine Barbu, Francoise Borson-Chazot, Anne-Paule Gimenez-Roqueplo, Pascal Pigny, Stephane Pinson, Nelson Wohllk, Charis Eng, Berna Imge Aydogan, Dhananjaya Saranath, Sarka Dvorakova, Frederic Castinetti, Attila Patocs, Damijan Bergant, Thera P Links, Mariola Peczkowska, Ana O Hoff, Caterina Mian, Trisha Dwight, Barbara Jarzab, Hartmut P H Neumann, Mercedes Robledo, Shinya Uchino, Anne Barlier, Christian Godballe and Jes Sloth Mathiesen

Objective

Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.

Design and methods

An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017.

Results

Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis.

Conclusions

Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.

Open access

Emmely M de Vries, Hermina C van Beeren, Albert C W A van Wijk, Andries Kalsbeek, Johannes A Romijn, Eric Fliers and Anita Boelen

Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation of the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four-hour fasting increased liver Dio3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced Dio3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both Dio3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, Dio3 mRNA expression increased five-fold after 48-h fasting. Treatment of 3T3-L1 adipocytes with mTOR inhibitors induced Dio3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce Dio3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.

Open access

Teresa Vilariño-García, Antonio Pérez-Pérez, Esther Santamaría-López, Nicolás Prados, Manuel Fernández-Sánchez and Víctor Sánchez-Margalet

Introduction

Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions.

Objective

We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS.

Materials and methods

Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of <0.05 was considered statistically significant.

Results

We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression.

Conclusions

These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.

Open access

Britt J van Keulen, Conor V Dolan, Bibian van der Voorn, Ruth Andrew, Brian R Walker, Hilleke Hulshoff Pol, Dorret I Boomsma, Joost Rotteveel and Martijn J J Finken

Objective

Sex differences in disease susceptibility might be explained by sexual dimorphism in hypothalamic-pituitary-adrenal axis activity, which has been postulated to emerge during puberty. However, studies conducted thus far lacked an assessment of Tanner pubertal stage. This study aimed to assess the contribution of pubertal development to sexual dimorphism in cortisol production and metabolism.

Methods

Participants (n = 218) were enrolled from a population-based Netherlands Twin Register. At the ages of 9, 12 and 17 years, Tanner pubertal stage was assessed and early morning urine samples were collected. Cortisol metabolites were measured with GC-MS/MS and ratios were calculated, representing cortisol metabolism enzyme activities, such as A-ring reductases, 11β-HSDs and CYP3A4. Cortisol production and metabolism parameters were compared between sexes for pre-pubertal (Tanner stage 1), early pubertal (Tanner stage 2–3) and late-pubertal (Tanner stage 4–5) stages.

Results

Cortisol metabolite excretion rate decreased with pubertal maturation in both sexes, but did not significantly differ between sexes at any pubertal stage, although in girls a considerable decrease was observed between early and late-pubertal stage (P < 0.001). A-ring reductase activity was similar between sexes at pre- and early pubertal stages and was lower in girls than in boys at late-pubertal stage. Activities of 11β-HSDs were similar between sexes at pre-pubertal stage and favored cortisone in girls at early and late-pubertal stages. Cytochrome P450 3A4 activity did not differ between sexes.

Conclusions

Prepubertally, sexes were similar in cortisol parameters. During puberty, as compared to boys, in girls the activities of A-ring reductases declined and the balance between 11β-HSDs progressively favored cortisone. In addition, girls showed a considerable decrease in cortisol metabolite excretion rate between early and late-pubertal stages. Our findings suggest that the sexual dimorphism in cortisol may either be explained by rising concentrations of sex steroids or by puberty-induced changes in body composition.

Open access

Rocío del Carmen Bravo-Miana, Ana Belén Della Vedova, Ana Lucía De Paul, María Mónica Remedi, María Laura Guantay, Mónica Beatriz Gilardoni, Claudia Gabriela Pellizas and Ana Carolina Donadio

Tumor-stroma crosstalk leads to a tumor-promoting microenvironment. In this milieu, extracellular vesicles (EVs) are protagonists in cell-cell communication. Despite thyroid cancer being the most common endocrine malignancy, the contribution of the tumor microenvironment to thyroid cancer progression is still largely underexplored. We focused on the role of thyroid tumor cell-fibroblast interaction and EVs as mediators of tumor-stroma interplay, in the promotion of thyroid tumor aggressiveness. Thyroid tumor (TPC-1, 8505c) or non-tumor thyroid cells (NThyOri) were co-cultured with human fibroblasts (Fb). Thyroid cell migration was investigated by the wound-healing assay and actin-network staining. Cell-CD147 expression was characterized by flow cytometry. EVs, obtained by ultracentrifugation of conditioned media (CMs), were characterized by transmission electron-microscopy and CD81 and CD147 expression. Metalloproteinases (MMPs) were evaluated by zymography in CMs. A migratory phenotype was triggered in thyroid tumor cells treated with CMs from Fb or from Fb-thyroid tumor cell co-cultures. Fb-thyroid cell co-cultures induced the secretion of proMMP9 and proMMP2 and led to a significant MMP2 activation in CMs. Fb, thyroid cells and Fb-thyroid cell co-cultures released EVs, and remarkably, EVs released by Fb-thyroid tumor cell co-cultures induced the secretion of proMMP2 and the expression of MMP2 from normal Fb. A significant CD147 expression was demonstrated in Fb-thyroid tumor cell-derived EVs. These findings reveal the role of Fb and thyroid tumor cell-Fb interaction in the promotion of a microenvironment suitable for thyroid tumor progression. Moreover, they highlight, for the first time, the role of thyroid tumor cell-Fb interaction in the production of specialized EVs.

Open access

Thomas Reinehr, Martin Carlsson, Dionisios Chrysis and Cecilia Camacho-Hübner

Background

The precision of adult height prediction by bone age determination in children with idiopathic growth hormone deficiency (IGHD) is unknown.

Methods

The near adult height (NAH) of patients with IGHD in the KIGS database was compared retrospectively to adult height prediction calculated by the Bayley–Pinneau (BP) prediction based on bone age by Greulich–Pyle (GP) in 315 children and based on the Tanner-Whitehouse 2 (TW2) method in 121 children. Multiple linear regression analyses adjusted for age at GH start, age at puberty, mean dose and years of of GH treatment, and maximum GH peak in stimulation test were calculated.

Results

The mean underestimation of adult height based on the BP method was at baseline 4.1 ± 0.7 cm in girls and 6.1 ± 0.6 cm in boys, at 1 year of GH treatment 2.5 ± 0.5 cm in girls and 0.9 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 0.4 ± 0.6 cm in girls and 3.8 ± 0.5 cm in boys. The mean underestimation of adult height based on the TW2 method was at baseline 5.3 ± 2.0 cm in girls and 7.9 ± 0.8 cm in boys, at 1 year of GH treatment adult height was overestimated in girls 0.1 ± 0.6 cm in girls and underestimated 4.1 ± 0.4 cm in boys, while at last bone age determination adult height was overestimated in mean by 3.1 ± 1.5 cm in girls and 3.6 ± 0.8 cm in boys.

Conclusions

Height prediction by BP and TW2 at onset of GH treatment underestimates adult height in prepubertal IGHD children, while in mean 6 years after onset of GH treatment these prediction methods overestimated adult height.

Open access

Ning Yao, Chunbei Zhou, Jun Xie, Xinshu Li, Qianru Zhou, Jing Chen and Shuang Zhou

Objective

The remarkable success of iodine deficiency disorders (IDD) elimination in China has been achieved through a mandatory universal salt iodization (USI) program. The study aims to estimate the relationship between urinary iodine concentration (UIC) and iodine content in edible salt to assess the current iodine nutritional status of school aged children.

Methods

A total of 5565 students from 26 of 39 districts/counties in Chongqing participated in the study, UIC and iodine content in table salt were measured. Thyroid volumes of 3311 students were examined by ultrasound and goiter prevalence was calculated.

Results

The overall median UIC of students was 222 μg/L (IQR: 150-313 μg/L). Median UIC was significantly different among groups with non-iodized salt (iodine content <5 mg/kg), inadequately iodized salt (between 5 and 21 mg/kg), adequately iodized (between 21 and 39 mg/kg) and excessively iodized (>39 mg/kg) salt (P < 0.01). The total goiter rate was 1.9% (60/3111) and 6.0% (186/3111) according to Chinese national and WHO reference values, respectively. Thyroid volume and goiter prevalence were not different within the three iodine nutritional status groups (insufficient, adequate and excessive, P > 0.05).

Conclusions

The efficient implementation of current USI program is able to reduce the goiter prevalence in Chongqing as a low incidence of goiter in school aged children is observed in this study. The widened UIC range of 100–299 μg/L indicating sufficient iodine intake is considered safe with a slim chance of causing goiter or thyroid dysfunction. Further researches were needed to evaluate the applicability of WHO reference in goiter diagnose in Chongqing or identifying more accurate criteria of normal thyroid volume of local students in the future.

Open access

Kate E Lines, Mahsa Javid, Anita A C Reed, Gerard V Walls, Mark Stevenson, Michelle Simon, Kreepa G Kooblall, Sian E Piret, Paul T Christie, Paul J Newey, Ann-Marie Mallon and Rajesh V Thakker

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.

Open access

Kristin Ottarsdottir, Margareta Hellgren, David Bock, Anna G Nilsson and Bledar Daka

Purpose

We aimed to investigate the association between SHBG and the homeostatic model assessment of insulin resistance (HOMA-Ir) in men and women in a prospective observational study.

Methods

The Vara-Skövde cohort is a random population of 2816 participants living in southwestern Sweden, aged 30–74. It was recruited between 2002 and 2005, and followed up in 2012–2014. After excluding participants on insulin therapy or hormone replacement therapy, 1193 individuals (649 men, 544 women) were included in the present study. Fasting blood samples were collected at both visits and stored in biobank. All participants were physically examined by a trained nurse. SHBG was measured with immunoassay technique. Linear regressions were computed to investigate the association between SHBG and HOMA-Ir both in cross-sectional and longitudinal analyses, adjusting for confounding factors.

Results

The mean follow-up time was 9.7 ± 1.4 years. Concentrations of SHBG were significantly inversely associated with log transformed HOMA-Ir in all groups with estimated standardized slopes (95% CI): men: −0.20 (−0.3;−0.1), premenopausal women: −0.26 (−0.4;−0.2), postmenopausal women: −0.13 (−0.3;−0.0) at visit 1. At visit 2 the results were similar. When comparing the groups, a statistically significant difference was found between men and post-menopausal women (0.12 (0.0;0.2) P value = 0.04). In the fully adjusted model, SHBG at visit 1 was also associated with HOMA-Ir at visit 2, and the estimated slopes were −0.16 (−0.2;−0.1), −0.16 (−0.3;−0.1) and −0.07 (−0.2;0.0) for men, premenopausal and postmenopausal women, respectively.

Main conclusion

Levels of SHBG predicted the development of insulin resistance in both men and women, regardless of menopausal state.

Open access

Wei Sun, Boyuan Zheng, Zhihong Wang, Wenwu Dong, Yuan Qin and Hao Zhang

Summary

Background

In patients with papillary thyroid cancer (PTC) with clinical negative central lymph nodes (cN0), the use of prophylactic central lymph node dissection remains controversial. Contralateral central lymph node metastasis (CCLNM) occurs in 3.88–30.63% of patients with cN0 PTC. Therefore, the present meta-analysis aimed to obtain evidence for CCLNM risk factors in unilateral cN0 PTC.

Materials and methods

Relevant studies were identified in the PubMed, SCIE, and Wanfang databases up to Oct 31, 2019. The included patients had undergone lobectomy or total thyroidectomy with bilateral central lymph node dissection and were diagnosed pathologically with PTC. Revman 5.3 software was applied for statistical analysis.

Results

Thirteen studies comprising 2449 patients were included. The factors associated with increased CCLNM risk in patients with cN0 disease were: age <45 years (odds ratio (OR) = 1.89, 95% CI = 1.43–2.49, P < 0.00001), male sex (OR = 1.67, 95% CI = 1.24–2.24, P = 0.0007), extrathyroidal extension (OR = 1.63; 95% CI = 1.17–2.28; P = 0.004), tumor size ≥1 cm (OR = 2.63, 95% CI 1.85–3.74, P < 0.00001), lymphovascular invasion (OR = 4.27, 95% CI = 2.47–7.37, P < 0.00001), and ipsilateral central lymph node metastasis (OR = 11.42, 95% CI = 5.25–24.86, P < 0.00001). However, no association was found for capsular invasion, multifocality, or Hashimoto thyroiditis.

Conclusion

The meta-analysis identified that age <45 years, tumor ≥1 cm, male sex, lymphovascular invasion, extrathyroidal extension, and ipsilateral central lymph node metastasis are related to CCLNM in patients with unilateral CN0 PTC. These factors should influence the use of prophylactic central lymph node dissection in this group of patients.