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Tal Oron, Liora Lazar, Ilan Feldhamer, Mira Manor, Nira Koren-Morag, Ariel Tenenbaum, and Joseph Meyerovitch


The need for personalization of the reference values of thyroid function tests has been previously suggested. We aimed at determining TSH reference values in a large cohort of children according to age, sex, BMI, and ethnicity.


A population-based cohort study.


The study cohort included 75 549 healthy children aged 5–18 years. Data analyzed included age, gender, TSH, FT4 levels, BMI and ethnicity. Multivariate logistic regression analysis examined the associations between the study parameters.


TSH in the Jewish population is lower than in the non-Jewish population (median: 2.1 IU/L (IQR: 1.5) vs 2.2 IU/L (IQR: 1.5), P < 0.0001). TSH is significantly affected by BMI for children defined as underweight, normal weight, overweight or obese, levels increased as weight diverged from the normal range (median levels: 2.1 IU/L (IQR: 1.4), 2.0 IU/L (IQR: 1.3), 2.1 IU/L (IQR: 1.4), 2.4 (IQR: 1.5), respectively, P < 0.001). The 2.5 percentile is affected by gender and BMI (P < 0.02 and P < 0.001, respectively), while the 97.5 percentile is affected by ethnic origin and BMI (P < 0.001 for both). New TSH reference intervals (RI) adjusted according to BMI and ethnicity are suggested. Comparison of the old and new RI demonstrate the significance of RI personalization: 25.1% of the children with TSH levels above the old RI are within the new RI, while 2.3% of the children who were in the old RI are below the new RI.


TSH reference values in children are affected by BMI and ethnicity. Reference values should be individualized accordingly to improve future clinical decision-making and treatment.

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Bruno Donadille, Sophie Tuffet, Clement Cholet, Mariana Nedelcu, Nathalie Bourcigaux, Laurence Iserin, Laurence Monnier-Cholley, Alexandra Rousseau, and Sophie Christin-Maitre


Turner syndrome (TS) is a rare disorder affecting 1/2500 female newborn. Aortic dilatation (AD) and aortic dissection represent a major concern in TS. The aims of our study were to describe the aortic root growth, potential aortic dilatation (AD) risk factors and cardiovascular outcomes in a cohort of patients with TS.


Among 204 adult patients included, 197 were studied using a standardized 1.5 Tesla MRI protocol. AD was defined as an aortic diameter ≥20 mm/m2 at the Valsalva sinuses and/or at the ascending aorta, when indexed to body surface area.


At baseline, AD was present in 81/197 (41.1%) and 32/197 (16.2%) of patients, at the levels of Valsalva and ascending aorta, respectively. The aortic Valsalva diameter was larger in patients treated for thyroiditis (P < 0.001). Potential risk factors of AD were aging (P < 0.001) and the presence of bicuspid aortic valve (BAV) (P = 0.002). The hazard ratio (HR) of AD occurrence in the presence of BAV was 2.2 (95% CI: 1.33–3.71). After a median follow-up period of 5.1 years (n = 143), AD was present in 58/143 (40.6%) and 25/143 (17.5%) of patients at the levels of Valsalva and ascending aorta, respectively. The median aortic growth of the Valsalva sinuses remained stable. At the ascending aorta, it increased by 0.14 ± 0.61 mm/year. Only one aortic-related death was observed.


AD is common in adult patients with TS. However, our results are rather reassuring, as the median aortic diameters remained stable after 5.1 years and few aortic events were observed.

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I C M Pelsma, N R Biermasz, A M Pereira, W R van Furth, N M Appelman-Dijkstra, M Kloppenburg, H M Kroon, and K M J A Claessen


Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess results in both reversible and irreversible musculoskeletal damage, including increased vertebral fracture (VF) risk. The prevalence of VFs is approximately 60% in controlled acromegaly patients, and these VFs can progress in time. We aimed to identify the course of VFs in a cohort of acromegaly patients in long-term remission and their associated risk factors during prolonged follow-up.


Thirty-one patients with acromegaly (49% female, median age 60 years (IQR 53–66)), who were in remission for ≥2 years, were included in this longitudinal, prospective, follow-up study. Spine radiographs of vertebrae Th4 to L4 were assessed for VFs using the Genant score, at baseline, after 2.6 years and 9.1 years. Progression was defined as either a new fracture or a ≥1-point increase in Genant score.


The prevalence of VF at baseline was 87% (27/31 patients). Progression of VFs was observed in eleven patients (35.5%) during the 9.1-year follow-up period, with a total incidence rate of 65.5 per 1000 person years (males 59.8 per 1000 person years vs females 71.6 per 1000 person years). Patients treated with surgery or radiotherapy had a higher risk of VF progression in this cohort (P = 0.030).


In this cohort of long-term, well-controlled acromegalic patients, the prevalence and progression of VFs was high, showing that the deleterious effects of GH and IGF-1 excess on bone persist despite achievement of longstanding remission.

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Claire L Wood, Kieren G Hollingsworth, Eric Hughes, Sadhanandham Punniyakodi, Robert Muni-Lofra, Anna Mayhew, Rod T. Mitchell, Michela Guglieri, Timothy D Cheetham, and Volker Straub



Pharmacological doses of glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD). Delayed puberty and bone fragility are consequences of GC treatment. The aim of this study was to determine the acceptability of a 2-year pubertal induction regimen using 4-weekly testosterone injections and examine changes in physique, bone integrity, muscle pathology (assessed by magnetic resonance imaging) and muscle function.


15 prepubertal males with DMD, aged 12-17 years and receiving GC, were treated with an incremental testosterone regimen for 2 years. Participants completed a Treatment Satisfaction Questionnaire (TSQM). Data on BMI, bone density, muscle pathology and function were collected at baseline and 2 years later.


Testosterone injections were well tolerated, with high TSQM scores. Baseline BMI z-score was 2.16 (0.90) and 1.64 (1.35) 2 years later. Median testosterone levels were 9.7nmol/l (IQR 5.7-11.1) 6 – 9 months after the last injection with an associated increase in testicular volume. Lumbar spine z-score was 0.22 (SD 2.21) at baseline and 0.35 (SD 2.21) after 2 years. Upper and lower limb muscle contractile cross sectional area increased in all participants during the trial (p=0.05 and p<0.01 respectively). There was a reduction in T2 relaxation times in most muscle groups with stable upper limb muscle function.


Incremental monthly testosterone injections were well tolerated, promoted endogenous testosterone production and had a positive impact on the skeleton and contractile muscle bulk with evidence suggesting a beneficial impact on the underlying disease process.

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Anuradhaa Subramanian, Jan Idkowiak, Konstantinos A Toulis, Shakila Thangaratinam, Wiebke Arlt, and Krishnarajah Nirantharakumar

Context: The incidence of gestational diabetes mellitus (GDM) has been on the rise, driven by maternal obesity. In parallel, pubertal tempo has increased in the general population, driven by childhood obesity.

Objective: To evaluate the available evidence on pubertal timing of boys and girls born to mothers with GDM.

Data Sources: We searched MEDLINE, EMBASE, CINAHL Plus, Cochrane library and grey literature for observational studies up to October 2019.

Study selection and extraction: Two reviewers independently selected studies, collected data and appraised the studies for risk of bias. Results were tabulated and narratively described.

Results: Seven studies (six for girls and four for boys) were included. Study quality score was mostly moderate (ranging from 4 to 10 out of 11). In girls born to mothers with GDM, estimates suggest earlier timing of pubarche, thelarche and menarche although for each of these outcomes only one study each showed a statistically significant association. In boys, there was some association between maternal GDM and earlier pubarche, but inconsistency in the direction of shift of age at onset of genital and testicular development and first ejaculation. Only a single study analysed growth patterns in children of mothers with GDM, describing a 3-month advancement in the age of attainment of peak height velocity and a slight increase in pubertal tempo.

Conclusions: Pubertal timing may be influenced by the presence of maternal GDM, though current evidence is sparse and of limited quality. Prospective cohort studies should be conducted, ideally coupled with objective biochemical tests.

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Anastasia Gant Kanegusuku, Katherine Araque, Joanna Klubo-Gwiezdzinska, and Steven J Soldin


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Rolf H.h. Groenwold and Olaf M Dekkers


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Anna Sjöström, Inga Bartuseviciene, and Charlotte Hoybye

Objective: The challenge of finding the rare patients with diabetes insipidus in need of vasopressin treatment is demanding. The guidelines for performing the fluid deprivation test and to interpret the results are abundant. We evaluated the discriminative capacity of the fluid deprivation test in patients with polyuria to define a cut off for a more effective discrimination between diabetes insipidus and other polyuria syndromes.

Research design and methods: Retrospective review and data collection of all ambulatory fluid deprivation tests, of patients with mild polyuria and polydipsia (< 3 L/day), performed between 2000–2018. Serum osmolality, urine osmolality, urine volumes and clinical information of diagnosis were retrieved from the patient’s medical records.

Results: The study group consisted of 153 patients , 123 were diagnosed with non-diabetes insipidus and 30 with diabetes insipidus. After 12 h fasting (baseline) median duration of the fluid deprivation test was 5 h (fasting range 12–21 h). At baseline there was a significant difference between median serum and urine osmolality between the groups (p < 0.05). The best cut-off for the diagnosis of diabetes insipidus, was the combination of < 400 mosmol/kg in urine and > 302 mosmol/kg in serum. With this cut-off a sensitivity of 90 % and specificity of 98 % was achieved.

Conclusion: Already after 12 h fasting our proposed cut off clearly differentiated between diabetes insipidus, and non- diabetes insipidus suggesting a possibility to considerably reduce the duration of the fluid deprivation test.

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Frédéric Illouz, Philippe Chanson, Emmanuel Sonnet, Thierry Brue, Amandine Ferriere, Marie-laure Raffin-sanson, Marie-Christine Vantyghem, Gerald Raverot, Mathilde Munier, Patrice Rodien, and Claire Briet

Objective: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL.

Design: Retrospective study.

Methods: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency.

Results: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after 1 to 3 injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency.

Conclusions: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumor reduction is the aim of the treatment.

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Poupak Fallahi, Silvia Martina Ferrari, Giusy Elia, Francesca Ragusa, Sabrina Rosaria Paparo, Stefania Camastra, Valeria Mazzi, Mario Miccoli, Salvatore Benvenga, and Alessandro Antonelli

Tyrosine kinase inhibitors (TKIs) are emerging as potentially effective options in the treatment of cancer, acting on the pathways involved in growth, avoidance of apoptosis, invasiveness, angiogenesis, and local and distant spread. TKIs induce significant adverse effects, that can negatively affect patients’ quality of life. The most common adverse events (AEs) include fatigue, hand–foot skin reaction, decreased appetite, nausea, diarrhoea, hypertension, vomiting, weight loss, endocrinopaties and metabolic disorders.

Patients in therapy with TKIs can develop endocrine-metabolic disorders, including dyslipidemia (∼50%), diabetes (∼15–40%), and dysthyroidism (∼20%). In some cases, patients show an improved glycemia or hypoglycemia. The effects of TKIs on adrenal or gonadal function are still not completely known. It was shown a higher prevalence of subclinical hypocortisolism in patients treated with imatinib, while an increase of cortisol was reported in patients receiving vandetanib. Long-term treatment with imatinib could impact significantly the ovarian reserve and embryo developmental capacity.

It is important to evaluate patients, measure glucose levels, and manage hyperglycemia. Mild treatment-related hyperglycemia can be controlled modifying the diet and with exercise, while grade 3 and 4 hyperglycemia can lead to dose reductions and/or oral antihyperglycemic therapy.

Regarding thyroid dysfunctions, it is recommendable to measure the thyroid-stimulating hormone (TSH)/free thyroxine (FT4) levels before starting the therapy, and every 3–4 weeks during the first 6 months as changes in FT4 levels precede the changes in TSH by 3–6 weeks.

Additional studies are necessary to definitely clarify the mechanism of TKIs-induced endocrine-metabolic effects.