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Free access

L F Chan, H L Storr, P N Plowman, L A Perry, G M Besser, A B Grossman, and M O Savage

Background/objective: Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing’s disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT.

Patients and methods: Between 1983 and 2006, 12 paediatric CD patients (10 males and 2 females) of mean age 11.4 years at diagnosis (range 6.4–17.4) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of 12, 11 patients were cured by RT (cure interval 0.13–2.86 years) defined by mean serum cortisol of <150 nmol/l on 5-point day curve and midnight sleeping cortisol of <50 nmol/l. Long-term data are available for six male patients, who received RT at the age of 7.0–17.6 years. The mean follow-up from the completion of RT was 10.5 years (6.6–16.5).

Results: At a mean of 1.0 year (0.11–2.54) following RT, GH deficiency (peak GH <1–17.9 mU/l) was present in five out of six patients. On retesting at a mean of 9.3 years (7.6–11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2–50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up. All the six patients had testicular volumes of 20–25 ml at the age of 14.5–28.5 years.

Conclusion: This series of patients illustrates the absence of serious long-term pituitary deficiency after RT and emphasises the importance of continued surveillance.

Free access

Régis Coutant, Helmuth-Günther Dörr, Helena Gleeson, and Jesús Argente

The IGF1 generation test (IGFGT) is often used during the assessment of suspected GH insensitivity (GHI). We report the results of a survey undertaken in 2010 to determine the use of IGFGT amongst members of the European Society for Paediatric Endocrinology to evaluate suspected GHI. The literature surrounding the usefulness and limitations of IGFGT are reviewed, and recommendations provided for its use. Of 112 paediatric endocrinologists from 30 countries who responded to the survey, 91 (81%) reported that they had used the IGFGT in the previous 2 years; >10 IGFGT protocols were used. The IGFGT impacted treatment decisions for 97% of the respondents and was a prerequisite for recombinant human IGF1 treatment for 45% of respondents. From a literature review, sensitivity of the IGFGT was evaluated as 77–91% in molecularly proven cases of GHI; specificity was ≤97%, depending on the protocol. The positive predictive value of the IGFGT is likely to be low, as the frequency of normality is predictably higher than that of abnormality in GH signalling. Given the limitations of the IGFGT in the most severe cases of GHI syndrome (GHIS), the ability of the IGFGT to detect less severe GHIS is doubtful. In a pragmatic approach, the IGFGT may not be useful for the diagnosis of GHIS.

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Wolfgang Wuttke

The German Endocrine Society (Deutsche Gesellschaft fur Endocrinologie; DGE) was founded in 1953 and currently has more than 1300 members. They are engaged in research, teaching or are practising endocrinologists. About half of the members are medically qualified and the others are biologists, biochemists or agricultural scientists. This multidisciplinary membership fosters the exchange and integration of ideas, and this is one of the particular strengths of the DGE.

The DGE is a member of the European Federation of Endocrine Societies (EFES) and also of the International Society of Endocrinology.

The Society is organized into sections that cover the major topics in endocrinology: Molecular and Cellular Endocrinology; Calcium Regulating Hormones and Bone Metabolism; Thyroid; and Paediatric and Applied Endocrinology. Sections of Gynaecological Endocrinology and Reproductive Medicine and Neuroendocrinology are currently being formed. Another important activity of the Society is the Commission for Hormone Toxicology, which consists of experts who advise on

Free access

Helen L Storr, Farhad Afshar, Matthew Matson, Ian Sabin, Kate M Davies, Jane Evanson, P Nicholas Plowman, G Michael Besser, John P Monson, Ashley B Grossman, and Martin O Savage

Objective: Early diagnosis and effective treatment of paediatric Cushing’s disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS.

Subjects and methods: From 1983–2004, 27 paediatric patients (16 males, 11 females; mean age±s.d., 13.1±3.2 yr; range, 6.4–17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age±s.d., 14.2±2.5 yr; range, 8.2–17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age±s.d., 11.5±3.6 yr; range, 6.4–17.8 yr) had post-operative cortisol levels above 50 nM (2–20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269–900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease.

Results: The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student’s t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of ≥ 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of ≥ 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1–17.9 mU/l) 9/16 and diabetes insipidus 3/16.

Conclusion: Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate.

Free access

Timothy Shao Ern Tan, Leena Patel, Jaya Sujatha Gopal-Kothandapani, Sarah Ehtisham, Esieza Clare Ikazoboh, Richard Hayward, Kristian Aquilina, Mars Skae, Nicky Thorp, Barry Pizer, Mohammed Didi, Conor Mallucci, Joanne C Blair, Mark N Gaze, Ian Kamaly-Asl, Helen Spoudeas, and Peter E Clayton

Objectives

The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades.

Methods

Meta-data was retrospectively reviewed over two periods before (1973–2000 (Group A: n = 100)) and after (1998–2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre.

Results

Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged.

Conclusion

The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

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Anne Fjellestad-Paulsen, Nadia Tubiana-Rufi, Alan Harris, and Paul Czernichow

Abstract. The antidiuretic effect and pharmacokinetics of 10 to 20 μg of intranasal (IN) and 200 to 400 μg of oral (po) 1-deamino-8-D-arginine vasopressin (DDAVP) were studied in 10 paediatric diabetes insipidus patients. A significant increase in urine osmolality was obtained with all doses, maximum within 2 h and still present at 8 h. At 12 h after administration, the ratio urine osmolality/plasma osmolality was above 1 only after 20 μg intranasally and 400 μg perorally. The free water clearance decreased rapidly with all doses and was similar in magnitude and duration for both the intranasal and peroral routes of administration and remained negative for more than 8 h. The maximum plasma concentrations of DDAVP, measured with a specific and sensitive RIA method, was dose-dependent and there was not significant difference in time until maximum concentration was obtained or in plasma half-life between the two routes of administration. The ratio established, 1:20, by calculating the area under the curve showed a bio-equivalence between 10 μg IN and 200 μg po and between 20 μg IN and 400 μg po of DDAVP. This work further emphasized the effectiveness of the oral route and the rapidity of absorption. By continuous monitoring of DDAVP plasma values we have demonstrated that peak values were reached within one hour after administration. This study demonstrates that the doses needed to treat diabetes insipidus patients by the oral route will be approximately 20 times greater than by the nasal route.

Free access

Francesco Ferraù and Márta Korbonits

Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

Free access

Amy R Frost, Margaret M Band, and Gerard S Conway

Objective

To investigate the prevalence of coeliac disease (CD) in an adult population with Turner's syndrome (TS).

Design

A clinic population with TS was screened using a serological test for CD.

Methods

Two hundred and fifty six patients with TS were included in the study. Five patients had existing diagnoses of CD. The remaining 251 asymptomatic patients were screened using an IgA endomysium antibody (EMA) test. Positive cases were offered endoscopy with duodenal biopsy. HLA typing was undertaken in existing cases and new EMA-positive cases.

Results

Of the 251 patients screened, eight were found to be EMA positive (3.2%). Seven patients proceeded to duodenal biopsy on which all were confirmed histologically to have CD (2.8%). The prevalence of subclinical CD in the population can therefore be estimated between 2.8 and 3.2%. The total population prevalence of CD, including the previously diagnosed cases, is estimated between 4.7 and 5.1%. Ten patients with histologically confirmed CD underwent HLA typing of which eight were HLA-DQ2 positive, one was HLA-DQ8 positive and one was negative to both HLA-DQ2 and HLA-DQ8.

Conclusions

This study demonstrates an increased prevalence of CD in an adult population with TS over the general population. This is consistent with previous data published in paediatric populations.

Free access

Amy R Frost, Margaret M Band, and Gerard S Conway

Objective

To investigate the prevalence of coeliac disease (CD) in an adult population with Turner's syndrome (TS).

Design

A clinic population with TS was screened using a serological test for CD.

Methods

Two hundred and fifty six patients with TS were included in the study. Five patients had existing diagnoses of CD. The remaining 251 asymptomatic patients were screened using an IgA endomysium antibody (EMA) test. Positive cases were offered endoscopy with duodenal biopsy. HLA typing was undertaken in existing cases and new EMA-positive cases.

Results

Of the 251 patients screened, eight were found to be EMA positive (3.2%). Seven patients proceeded to duodenal biopsy on which all were confirmed histologically to have cluster of differentiation (2.8%). The prevalence of subclinical cluster of differentiation in the population can therefore be estimated between 2.8 and 3.2%. The total population prevalence of CD, including the previously diagnosed cases, is estimated between 4.7 and 5.1%. Ten patients with histologically confirmed cluster of differentiation underwent HLA typing of which eight were HLA-DQ2 positive, one was HLA-DQ8 positive and one was negative to both HLA-DQ2 and HLA-DQ8.

Conclusions

This study demonstrates an increased prevalence of cluster of differentiation in an adult population with TS over the general population. This is consistent with previous data published in paediatric populations.

Restricted access

Stefano Cianfarani, Daniela Germani, Paola Rossi, Anna Spagnoli, and Delio Mercanti

Cianfarani S, Germani D, Rossi P, Spagnoli A, Mercanti D. Do insulin-like growth factor binding proteins (IGFBPs) modulate the IGF-I growth promoting and differentiating effects in human neuroblastoma cells? Eur J Endocrinol 1996;135:716–23. ISSN 0804–4643

The insulin-like growth factors (IGFs) are known to stimulate both the proliferation and differentiation of neuroblastoma cells, but the role of the IGF binding proteins (IGFBPs) has not yet been established. In this study, human neuroblastoma SH-SY5Y cells have been treated with IGF-I and its potent analogue des (1–3) IGF-I alone or following preincubation with a differentiating agent such as 12-o-tetradecanoylphorbol-13-acetate (TPA). Cell proliferation and differentiation were evaluated. Conditioned medium was tested for the presence of IGFBPs by ligand blotting. The SH-SY5Y cell proliferation was maximally stimulated by des (1–3) IGF-I. The TPA-induced differentiation of SH-SY5Y, evaluated by assessment of cell morphology and GAP-43 expression as a biochemical marker of differentiation, was potentiated by nanomolar concentrations of des (1–3) IGF-I and, to a smaller extent, IGF-I. Conditioned medium showed the presence of a major IGFBP band with an approximate molecular weight of 32.5 kD and a very faint band of approximately 24 kD. The IGFBP immunoblotting results suggest that the predominant band might represent IGFBP-2. Our data represent a first demonstration of the presence of IGFBPs in conditioned medium of human neuroblastoma SH-SY5Y cells. The finding that the potent IGF-I analogue des (1–3) IGF-I with reduced affinity for IGFBPs induce major effects on cell growth and differentiation suggests that the IGFBPs may play an active role in the neuronal response to the proliferative and differentiative effects of IGF-I.

Stefano Cianfarani, Laboratory of Paediatric Endocrinology, Department of Paediatrics, "Tor Vergata" University, via di Tor Vergata 135, 00133 Rome, Italy