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Open access

Virginie Grouthier, Zeina Chakhtoura, Isabelle Tejedor, Yasmina Badachi, Vincent Goffin and Philippe Touraine

Objective: Multiple fibroadenomas (MFA) of the breast is a rare benign disease, thus its natural history is poorly understood. The aim of our study was to describe the radiological evolution of MFA, and to evaluate the influence of different factors on this evolution.

Methods: This was a longitudinal cohort study. All patients included had two clinical and radiological assessments (breast ultrasound (US) and magnetic resonance imaging (MRI)) at least 5 years apart.

Results: Seventy-two women were followed for 7.6 ± 2.1 years. The radiological evolution showed a decrease in the number of fibroadenomas (FA) in almost 40% of cases on the MRI and in 52% of cases on the US. There was a decrease of size in 92% of cases. An increase in the number of FAs was found in about 40% of cases with, for the majority, a decrease of size (73.1% by US and 89% by MRI). Older age at the 1st FA (p<0.0001) and at the diagnosis of MFA (p<0.0001), pregnancy (p=0.003) and progestin use (p<0.001), particularly lynestrenol (p<0.0001), had a beneficial effect on the evolution of MFA.

Conclusion: This is the first longitudinal study describing women with MFA. The radiological evolution of MFA seamed favorable and similar to that expected for a single FA. We identified factors influencing the evolution of the disease, including progestin treatments such as lynestrenol, which could have a beneficial effect. Our cohort should be followed further in order to expand our knowledge of MFA, especially concerning the risk of breast cancer.

Open access

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


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


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.


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.


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


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.


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.


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).


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

Tomas P Griffin, Caroline M Joyce, Sumaya Alkanderi, Liam M Blake, Derek T O'Keeffe, Delia Bogdanet, Md Nahidul Islam, Michael C Dennedy, John E Gillan, John J Morrison, Timothy O'Brien, John A Sayer, Marcia Bell and Paula M O'Shea

Introduction: Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.

Methods: The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.

Results: The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL:2.30) mmol/L), suppressed iPTH (<6ng/L), elevated 25(OH)D (264 (URL:55) nmol/L) and elevated 1,25(OH)D (293 (URL:<280) pmol/L). Ionized calcium was 1.55 (URL:1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband’s mother was heterozygous for the W275R variant and her father was homozygous for the R439C variant. All were normocalcaemic with normal 25(OH)D.

Conclusions: In this family, compound heterozygosity for a known pathogenic mutation R439C, in combination with a novel variant W275R was associated with hypercalcaemia and frequently elevated 25(OH)D:24,25 (OH)2D ratios (>50) and may be associated with a variable phenotype or incomplete penetrance.

Open access

Jung Soo Lim, Seung-Eun Lee, Jung Hee Kim and Jae Hyeon Kim

Purpose: To evaluate the clinical characteristics and prognostic factors in patients with adrenocortical carcinoma (ACC) in South Korea.

Methods: A nationwide, registry-based survey was conducted to identify pathologically proven ACC at 25 tertiary care centers in South Korea between 2000 and 2014. Cox proportional hazard model and log-rank test were adopted for survival analysis.

Results: Two hundred four patients with ACC were identified, with a median follow-up duration of 20 months (IQR 5-52 months). The median age at diagnosis was 51.5 years (IQR 40-65.8 years), and ACC was prevalent in women (n=110, 53.9%). Abnormal pain was the most common clinical symptom (n=70, 40.2%), and ENSAT stage 2 was most common (n=62, 30.4%) at the time of diagnosis. One hundred sixty-nine patients underwent operation, while 17 were treated with other modalities. The remission rate was 48%, and median recurrence-free survival time was 46 months. Estimated 5-year recurrence-free rate was 44.7%. There were more women, large tumor, atypical mitosis, venous invasion, and higher mitotic count in cancer recurrence group. Estimated 5-year overall survival and disease-specific survival rates were 64.5% and 70.6%, respectively. Higher ENSAT stage and advanced pathologic characteristics were risk factors for all-cause mortality of ACC. Large tumor size and cortisol-secreting tumor were additional risk factors for ACC-specific death.

Conclusions: We report the first epidemiologic study regarding ACC in an Asian population. ENSAT stage 4; lymph node involvement; non-operative group; and invasion of vein, sinusoid, or capsule were associated with an increased risk for all-cause mortality.

Open access

Zeeshan Javed, Maria Papageorgiou, Leigh A Madden, Alan S Rigby, Eric S Kilpatrick, Stephen L Atkin and Thozhukat Sathyapalan

Context: Endothelial microparticles (EMPs) are novel, surrogate biomarkers of endothelial function and have been shown to be elevated in women with polycystic ovary syndrome (PCOS). It remains poorly understood how pharmacological options for managing PCOS affect EMP levels.

Objective: To characterise and compare the effects of empagliflozin vs. metformin on the circulating levels of EMPs in overweight/ obese women with PCOS.

Methods: This was a randomised, comparative, 12-week single-centre trial conducted at the Academic Diabetes, Endocrinology and Metabolism Research Centre, Hull, UK. This analysis includes data from thirty-nine overweight/obese women with PCOS who completed the study and were randomised to empagliflozin (15 mg/day) (n = 19) or metformin (1500 mg/day) (n = 20). Blood samples were collected at baseline and 12 weeks after treatment and analysed for specific surface proteins expressed by circulating EMPs using flow cytometry.

Results: In the empagliflozin group, ICAM-1 (p=0.006), E-selectin (p=0.016) and VCAM-1 (p=0.001) EMPs increased significantly following 12 weeks of treatment, but no changes were seen in PECAM-1 (p=0.93) or endoglin (p=0.13) EMPs. In the metformin group, VCAM-1 EMPs (p<0.001) increased significantly after 12 weeks of treatment, whereas all other EMPs remained unchanged. When data were expressed as the percentage change from baseline in each group, no significant differences were seen between groups for any biomarker (p-values from 0.22 to 0.80).

Conclusions: Short-term administration of empagliflozin and metformin in overweight/obese women with PCOS appear to increase EMPs expressed by endothelial cells during their activation.

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

Rosalie Cabry, Philippe Merviel, Aicha Madkour, Elodie Lefranc, Florence Scheffler, Rachel Desailloud, Veronique Bach and Moncef Benkhalifa

The negative impact of endocrine-disrupting pesticides on human fertility is now a key issue in reproductive health. There are much fewer literature data about the impact of pesticide exposure on women than on men, and very few studies of women participating in an in vitro fertilization (IVF) programme. In the present review, we found that (i) various pesticides with an endocrine-disrupting action are associated with poor oocyte maturation and competency, embryonic defects, and poor IVF outcomes, and (ii) some pesticide compounds are linked to specific causes of female infertility, such as premature ovarian insufficiency, polycystic ovarian syndrome, and endometriosis. IVF participants living in agricultural regions should be informed about the fertility decline, low ongoing pregnancy rates and elevated risk of miscarriage associated with exposure to high doses of pesticides.

Open access

Hichem Bouguerra, Amal Gorrab, Stephan Clavel, Hammouda Boussen, Jean François Louet and Asma Gati

Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, peroxisome proliferator activated receptor coactivator-1 α (PGC-1α). Using adenoviral approaches, we show that acute elevation of PGC-1α enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified new regulatory functions of PGC-1α and leptin in regulating the expression of hypoxia-inducible factor-1 alpha (HIF-1α by tumor cells, a transcriptional factor with pleiotropic role in cancer. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC-1α mRNA level, an enhanced activity of oxidative phosphorylation and are more resistance to NK92 lysis in comparison with luminal BC cells (MCF7 and MDA-361). Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC-1α activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients.

Open access

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


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.


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.


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.