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Open access

María Dolores Rodríguez Arnao, Amparo Rodríguez Sánchez, Ignacio Díez López, Joaquín Ramírez Fernández, Jose Antonio Bermúdez de la Vega, Diego Yeste Fernández, María Chueca Guindulain, Raquel Corripio Collado, Jacobo Pérez Sánchez, Ana Fernández González and ECOS Spain Study Collaborative Investigator Group


Non-adherence to r-hGH treatments occurs in a variable percentage of subjects. One problem found when evaluating adherence is the great variability in methods of detection and definitions utilized in studies. This study assessed the level of adherence in subjects receiving r-hGH with the easypod™ electronic device.


National, multicenter, prospective and observational study involving 238 subjects (144 with GH deficiency (GHD), and 86 with small for gestational age (SGA), 8 with Turner Syndrome), who received r-hGH with easypod™ for at least 3 months before inclusion. The follow-up period was 4 years.


Overall adherence was 94.5%; 97.5% after 6 months, 95.3% after 1 year, 93.7% after 2, 94.4% after 3 and 95.5% after 4 years of treatment. No differences in adherence were observed between prepubertal and pubertal groups and GHD and SGA groups. Change in height after 1 and 2 years, change in height SDS after 1 and 2 years, HV after 1 year, HV SDS after at 1 and 4 years, change in BMI after 1 year and change in BMI SDS at 1 and 2 years showed significant correlation with adherence. No significant differences in adherence according to IGF-I levels were found in follow-up visits or between groups.


The easypod™ electronic device, apart from being a precise and objective measure of adherence to r-hGH treatment, allows high compliance rates to be achieved over long periods of time. Adherence significantly impacts growth outcomes associated with r-hGH treatment.

Open access

Giorgio Bedogni, Andrea Mari, Alessandra De Col, Sofia Tamini, Amalia Gastaldelli and Alessandro Sartorio

Few data are available on the association between serum lipids and insulin secretion (ISEC) in children. We evaluated the association of triglycerides (TG), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) with ISEC in 1150 non-diabetic obese children and adolescents using multivariable robust median regression. The following models were employed: 1) IGI or incAUCR as the ISEC response variable; 2) QUICKI, OGIS, the Stumvoll index or the Matsuda insulin sensitivity index as the insulin sensitivity (ISEN) predictor; 3) TG, HDL-C and LDL-C as the predictors of interest; 4) 120 min-glucose, age, sex and body mass index as confounders. LDL-C and TG were not associated with ISEC in any model. In 3 out of 4 IGI models, an increase of 1 interquartile range (IQR) of HDL-C was associated with a decrease of median incAUCR ranging from -9 (robust 95%CI -17 to -2) to -8 (-14 to -1) pmol/mmol. In 2 out of 4 incAUCR models, an increase of 1 IQR of HDL-C was associated with a decrease of median IGI ranging from -8 (-15 to -1) to -7 (-11 to -2) pmol/mmol. TG and LDL-C are not associated and HDL-C is inversely associated with ISEC in obese children and adolescents.

Open access

Dong Cen, Hui Liu, Zhe Wan, Zhongjie Lin, Yanting Wang, Junjie Xu and Yuelong Liang


Gallbladder neuroendocrine neoplasm (GB-NEN) is a relatively rare neoplasm, accounting for 0.5% of all neuroendocrine neoplasm cases and 2.1% of gallbladder cancers. Because of the limited understanding of GB-NEN, the aim of this study was to explore the clinicopathology and survival of GB-NEN patients selected from the Surveillance, Epidemiology, and End Results (SEER) database.


A total of 248 GB-NEN patients from the SEER database diagnosed between 2004 and 2015 were included. Kaplan–Meier curves were used to examine the survival time. Multivariate Cox proportional hazard models were used to estimate hazard ratios with 95% confidence intervals to analyze the impact of factors on overall survival and cancer-specific survival.


The majority of the GB-NEN patients were women (67.3%), white (77%), and married (61.7%). Most tumors were <2 cm in size (31.0%), G3 stage (25.8%), and distant SEER stage (41.1%). 62.9% and 64.5% of cases showed an absence of lymph node metastasis and tumor metastasis, respectively. Patients who received gallbladder surgery had significantly better survival outcomes (P < 0.001). However, patients who received both gallbladder surgery and lymph node resection did not have better survival outcome compared with patients who received only gallbladder surgery. Multivariate Cox proportional hazard models indicated that older age, unmarried status, large tumor size (>5 cm), and distant SEER stage were significant independent predictors for decreased overall survival time and cancer-specific survival time (P < 0.05).


Age, marital status, tumor size, and SEER stage were predictors for the survival of GB-NEN patients. Gallbladder surgery was associated with better survival, but the combination of gallbladder surgery and lymphadenectomy had no effect on survival outcomes.

Open access

Amalie Rasmussen Rasmussen Lanng, Lærke Smidt Gasbjerg, Natasha Chidekel Bergmann, Sigrid Bermann, Mads Marstand Helsted, Matthew Paul Gillum, Bolette Hartmann, Jens Juul Holst, Tina Vilsbøll and Filip K Knop

Background: Ingestion of the calorically dense compound alcohol may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised as a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear.

Objective: To examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21).

Design and methods: In a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 g alcohol per kg body weight), respectively, on two separate experimental days.

Results: Isoethanolaemia during the two alcohol administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 minutes and thereafter fell below baseline concentrations. GIP and GLP-1 concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI but decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (9-fold) and similarly during IGEI and IVEI.

Conclusions: Alcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI as well as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.

Open access

Dorte Glintborg, Katrine Rubin, Mads Nybo, Bo Abrahamsen and Marianne Andersen

Aim: To investigate risk of thyroid disease in Danish women with PCOS.

Design: National register-based study on women with PCOS in Denmark. 18,476 women had a diagnosis of PCOS in the Danish National Patient Register. PCOS Odense University Hospital (PCOS OUH, N=1,146) was an embedded cohort of women with PCOS and clinical and biochemical examination. Three age-matched controls were included for each woman with PCOS (N=54,757). The main outcome measures were thyroid disease (hypothyroidism, Graves’ disease, goitre, thyroiditis) according to diagnosis codes and/or inferred from filled medicine prescriptions. Associations between baseline TSH and development of cardio-metabolic disease was examined in PCOS OUH.

Results: The median (quartiles) age at inclusion was 29 (23-35) years and follow up duration was 11.1 (6.9–16.0) years. The Hazard ratio (95% CI) for thyroid disease development was 2.5 (2.3; 2.7) (p<0.001). The event rate of thyroid disease was 6.0 per 1000 patient years in PCOS Denmark versus 2.4 per 1000 patient years in controls (p<0.001). Women in PCOS OUH with TSH ≥2.5 mIU/L (n=133) had higher BMI (median 29 vs. 27 kg/m2), wider waist, higher triglycerides and free testosterone by the time of PCOS diagnosis compared to women in PCOS OUH with TSH <2.5 mIU/L (n=588). Baseline TSH did not predict later development of cardio-metabolic diseases in PCOS OUH.

Conclusions: The event rate of thyroid disease was significantly and substantially higher in women with PCOS compared to controls.

Open access

Frederique Van de Velde, Marlies Bekaert, Anja Geerts, Anne Hoorens, Arsène-Hélène Batens, Samyah Shadid, Margriet Ouwens, Yves Van Nieuwenhove and Bruno Lapauw


Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR.


To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent.


This cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD.


A positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR.


In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.

Open access

Kaisu Luiro, Kristiina Aittomaki, Pekka Jousilahti and Juha S. Tapanainen

OBJECTIVE: To study the use of hormone therapy (HT), morbidity and reproductive outcomes of women with primary ovarian insufficiency (POI) due to FSH resistant ovaries (FSHRO).

DESIGN: A prospective follow-up study in a university-based tertiary clinic setting

METHODS: Twenty-six women with an inactivating A189V FSH receptor mutation were investigated by means of a health questionnaire and clinical examination. Twenty-two returned the health questionnaire and fourteen were clinically examined. Main outcome measures in the health questionnaire were reported HT, morbidity, medication and infertility treatment outcomes. In the clinical study, risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS) were compared to age-matched controls from a national population survey (FINRISK). Average number of controls was 326 per FSHRO subject (range 178-430). Bone mineral density and whole-body composition were analyzed with DXA. Psychological and sexual well-being was assessed with Beck Depression Inventory (BDI21), Generalized Anxiety Disorder 7 (GAD-7) and female sexual function Index (FSFI) questionnaires.

RESULTS: HT was initiated late (median 18 years of age) compared with normal puberty and the median time of use was shorter (20-22 years) than the normal fertile period. Osteopenia was detected in 9/14 of the FSHRO women despite HT. No major risk factors for CVD or diabetes were found.

CONCLUSIONS: HT of twenty years seems to be associated with a similar cardiovascular and metabolic risk factor profile as in the population control group. However, optimal bone health may require an early-onset and longer period of HT, which would better correspond to the natural fertile period.

Open access

Clara Odilia Sailer, Sophia Julia Wiedemann, Konrad Strauss, Ingeborg Schnyder, Wiebke Kristin Fenske and Mirjam Christ-Crain

Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium ≥150 mmol/L) by hypertonic saline infusion. Copeptin – a marker indicating vasopressin activity – serum sodium and osmolality, plasma IL-8 and TNF-α were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-α levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.12, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.

Open access

Jiashu Li, Aihua Liu, Haixia Liu, Chenyan Li, Weiwei Wang, Cheng Han, Xinyi Wang, Yuanyuan Zhang, Weiping Teng and Zhongyan Shan

Thyroid dysfunction is a frequently found endocrine disorder among reproductively aged women. Subclinical hypothyroidism is the most common condition of thyroid disorders during pregnancy and is defined as manifesting a thyroid-stimulating hormone concentration exceeding the trimester-specific reference value, with a normal free thyroxine concentration. Here, we evaluated the prospective association between spontaneous miscarriage and first-trimester thyroid function. We conducted a case–control study (421 cases and 1684 controls) that was nested. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) status were measured. We found that higher TSH was related to spontaneous miscarriage (OR 1.21; 95% CI, 1.13–1.30, P < 0.001). Compared with women with TSH levels of 0.4–<2.5 mIU/L, the risk of miscarriage was increased in women with TSH levels of 2.5–<4.87 mIU/L (OR 1.47; 95% CI, 1.16–1.87) and TSH greater than 4.87 mIU/L (OR 1.97; 95% CI, 1.22–3.18). After controlling for the confounding factor, TPOAb positivity status and FT4, the results were similar. The present study showed that higher TSH was associated with miscarriage in early pregnancy. In fact, TSH levels between 2.5 and 4.87 mIU/L increased the risk for miscarriage, with TSH greater than 4.87 mIU/L increasing the risk even further.

Open access

Sarah Byberg, Jesper Futtrup, Mikkel Andreassen and Jesper Krogh

Objectives: Recent large cohort studies suggest an association between high plasma prolactin and cardiovascular mortality. The objective of this systematic review was to systematically assess the effect of reducing prolactin with dopamine agonist on established cardiovascular risk factors in patients with prolactinomas.

Design: Bibliographical search was done until February 2019 searching the following databases: Pubmed, Embase, WHO and LILAC. Eligible studies had to include participants with verified prolactinomas where metabolic variables were assessed before and after at least two weeks treatment with dopamine agonists.

Methods: Baseline data and outcomes were independently collected by two investigators.

Results: Fourteen observational studies enrolling 387 participants were included. The pooled standardized mean difference of the primary outcome revealed a reduction of BMI and weight of -0.21 (95% CI. - 0.37 to - 0.05; p=0.01; I2 = 71 %), after treatment. Subgroup analysis suggested that the reduction of weight was primarily driven by studies with high prolactin levels at baseline (p=0.04). Secondary outcomes suggested a small decrease in waist circumference, a small to moderate decrease in triglycerides, fasting glucose levels, HOMA-IR, HbA1c and hsCRP, and a moderate decrease in LDL, total cholesterol and insulin.

Conclusion: This systematic review suggests a reduction of weight as well as an improved lipid profile and glucose tolerance after treatment with dopamine agonist in patients with prolactinomas. These data are based on low quality evidence.