RSS 1.0Endocrinology
The department is a specialist referral centre and combines an active research and teaching programme with a busy clinical service based in our dedicated endocrinology unit.
Recent Submissions
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Long-term safety of growth hormone replacement after CNS irradiation.Radiotherapy is a central component in the treatment of many brain tumors, but long-term sequelae include GH deficiency and increased risk of secondary neoplasms. It is unclear whether replacement therapy with GH (GHRT) further increases this risk.
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GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways.Phosphoinositide 3-kinase (PI3K) regulates the transcription factor hypoxia-inducible factor-1 (HIF-1) in thyroid carcinoma cells. Both pathways are associated with aggressive phenotype in thyroid carcinomas.
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The Interface between thyroid and diabetes mellitus.Thyroid disease and type 1 but also type 2 diabetes mellitus are strongly associated and this has important clinical implications for insulin sensitivity and treatment requirements. The pathophysiological basis of this association has only recently been better elucidated. It rests on a complex interaction of common signalling pathways and, in the case of type 1 diabetes and autoimmune thyroid disease, on a linked genetic susceptibility. The pathophysiological mechanisms underlying this linked regulation are increasingly being unravelled. They are exemplified in the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a central target not only for the modulation of insulin sensitivity but also for the feedback of thyroid hormones on appetite and energy expenditure. The present review will discuss these concepts and their consequences for the clinical care of patients with diabetes mellitus and thyroid disorders. Moreover, it makes reference to the added effect of metformin in suppressing TSH.
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Serum regulates cortisol bioactivity by corticosteroid-binding globulin dependent and independent mechanisms, as revealed by combined bioassay and physicochemical assay approaches.Context: Corticosteroid-binding globulin (CBG) is the principal carrier of natural glucocorticoids in the circulation and we hypothesized that it modulates glucocorticoid bioactivity. Alterations in CBG, the presence of non-cortisol, naturally occurring glucocorticoids and the use of potent, synthetic glucocorticoids, all make it difficult to assess adrenal activity in-vivo; these problems can be addressed by a glucocorticoid bioassay. Design and subjects: A bioassay was developed for serum glucocorticoid bioactivity (GBA) and a physicochemical ultrafiltration-liquid chromatography-tandem mass spectrometry assay for free serum cortisol (FreeF). We studied individuals homozygous and heterozygous for a non-functioning CBG variant (CBG G237V) and healthy controls. Results: FreeF concentrations were similar in healthy controls, and those with absent functional CBG, but surprisingly we found low GBA in CBG null individuals. This may suggest that CBG delivers cortisol to target cells. However, further experiments revealed that dilution of serum in the bioassay caused release of cortisol from CBG, resulting in elevated GBA measurements in all but the CBG G237V homozygotes. Furthermore, we identified a specific and potent inhibitory effect of high concentration serum on glucocorticoid sensitivity of the recipient cells used in the bioassay. Analysis of inflammatory synovial fluid, a filtrate of serum with lower CBG concentration, revealed elevated free cortisol compared to non-inflammatory synovial fluid, a change not attributable to interconversion between cortisol and cortisone. Conclusions: Our findings reveal that dilution of CBG enhances cortisol release, and so bioactivity, and also that serum potently induces glucocorticoid resistance in target cells.
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Serum Insulin-like Growth Factor-I and its Binding Protein 3 in their Relation to Intima Media Thickness: Results of the Study of Health in Pomerania (SHIP).Objective: Previous studies detected associations between lower insulin-like growth factor I (IGF-I) levels and increased risk of congestive heart failure or ischemic heart disease. The aim of the present study was to assess the association of IGF-I and its binding protein 3 (IGFBP-3) with the carotid intima-media thickness (IMT) as marker of asymptomatic cardiovascular disease. Design and population: From the population-based Study of Health in Pomerania (SHIP), a total of 2,286 participants aged 45 years or older with readable ultrasound of the carotid arteries were available for the present analyses. Methods and measurements: Serum IGF-I and IGFBP-3 levels were categorized into three groups (low, moderate, high) according to the sex-specific 10th and 90th percentile. Analyses of variance (ANOVA) and logistic regression analyses adjusted for age, waist circumference, diabetes, hypertension, and creatinine clearance were performed. Results: After adjusting for confounding factors, IGF-I and the IGF-I/IGFBP3 ratio were positively related to IMT in analyses of variance. Logistic regression analyses confirmed these findings and showed that high IGF-I levels, a high IGF-I/IGFBP3 ratio, and low IGFBP-3 levels were associated to higher odds of increased IMT. Conclusion: In conclusion, high IGF-I or high IGF-I/IGFBP3 ratio values and low IGFBP-3 levels are associated with increased IMT. Therefore systemic levels of the IGF axis or alterations in the balance of its components are associated with subclinical atherosclerotic disease.
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Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone.The accurate measurement of cortisol by immunoassay is compromised by the potential for cross-reactivity of reagent antibodies with structurally related steroids present in serum. This susceptibility is potentiated when normal steroid metabolism is altered pharmaceutically by antisteroidogenic drugs utilized in the management of Cushing's syndrome to moderate cortisol production. The clinical implications of falsely elevated cortisol results include over-treatment and unrecognized hypoadrenalism. To investigate the effect of the 11β-hydroxylase inhibitor metyrapone on serum cortisol assay, a comparison of measurement by immunoassay versus liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted.
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Plasma bile acids are associated with energy expenditure and thyroid function in humans.Animal studies implicate a role of bile acids (BA) in thyroid-regulated energy expenditure (EE) via activation of the TGR-5/adenylate cyclase/deiodinase type 2 pathway. Here we investigated these possible associations in humans.
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Changes in arterial stiffness but not carotid intimal thickness in acromegaly.Acromegaly increases cardiovascular morbidity. We tested the hypothesis that increased arterial stiffness together with left ventricular hypertrophy may be a contributory factor.
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Neuroendocrine disturbances after acquired brain damage.Hypopituitarism is not a rare disease and its clinical signs and symptoms deserve the attention of the clinically practising neurologist. Next to the classical cause of hypopituitarism mediated by tumours of the hypothalamo-pituitary region, a number of recent articles have highlighted the high frequency of central endocrine disturbances in patients with brain damage, i. e. not only after traumatic brain injury and subarachnoid haemorrhage but also as a consequence of the treatment of childhood brain tumours. This article provides an overview of the clinical symptomatology and pathophysiology of hypopituitarism as well as the current knowledge about neuroendocrine disturbances in the adult patient suffering from the above-mentioned disorders.
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Current management practices for acromegaly: an international survey.To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.
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Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay.Thyronamines are thyronergic metabolites of thyroid hormones. Lack of reliable and sensitive detection methods for endogenous 3-iodothyronamine (3-T(1)AM) has so far hampered progress in understanding their physiological action and role in endocrine homeostasis or pathophysiology of diseases.
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Hypothyroidism following childhood cancer therapy-an under diagnosed complication.To determine the prevalence of hypothyroidism amongst most adult survivors of childhood cancer in Britain using the British Childhood Cancer Survivor Study (BCCSS). The BCCSS is a population based cohort of individuals diagnosed with childhood cancer between 1940 and 1991 and who survived at least 5 years from diagnosis (n = 17,981). 10483, 71% of those survivors aged at least 16 years, returned a completed questionnaire, which asked if hypothyroidism had been diagnosed. Of the whole cohort, 7.7% reported hypothyroidism with the highest risk among patients treated for Hodgkin's disease (HD) (19.9%), CNS neoplasms (15.3%), Non-Hodgkin's lymphoma (6.2%) and leukaemia (5.2%). Survivors were more likely to develop hypothyroidism if they had received radiotherapy for HD (p = 0.0001) or a CNS neoplasm (p < 0.00005) but not leukaemia (p = 0.3). In these three patient groups, the frequency of hypothyroidism was similar in men and women. Survivors of irradiated CNS tumours reported a prevalence of hypothyroidism, which was substantially lower if discharged to primary care compared with being on hospital follow-up and which declined substantially with increased follow-up in both primary care (p = 0.004) and hospital follow-up (p = 0.023) settings. Hypothyroidism is a common finding amongst adult survivors of childhood malignancy. The substantial differences in reported hypothyroidism prevalence after irradiated CNS neoplasms suggests substantial under-diagnosis, which increased with increased follow-up, and which increased among those followed-up in primary care compared with hospital settings.
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Proinsulin and the proinsulin/insulin ratio in overweight and obese children and adolescents: relation to clinical parameters, insulin resistance, and impaired glucose regulation.In adults with impaired glucose regulation (IGR) or type 2 diabetes mellitus (T2DM), proinsulin (PI) and its ratio to insulin (ins; PI/I ratio) are frequently elevated.
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Visualizing hormone actions in the brain.Profound and multifaceted effects of hormones on the development, maturation and function of the CNS are well documented. Recent developments in magnetic resonance imagining (MRI) and positron emission tomography (PET) permit detailed in vivo studies of cerebral structure and function in humans. Techniques to measure subtle differences in cerebral structure, regional brain activation, changes in blood flow and other physiological biomarkers allow us to translate experimental evidence of hormone effects obtained from animal models to humans. Here we review the imaging techniques available to support studies of hormone effects on the CNS, emphasizing the recent developments of MRI. In summarizing the major current studies we discuss the potential of these techniques for an emerging new field in endocrinology.
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Early diagnosis of acromegaly: computers vs clinicians.Background Early diagnosis of a number of endocrine diseases is theoretically possible by the examination of facial photographs. One of these is acromegaly. If acromegaly were found, early in the course of the disease, morbidity would be lessened and cures more likely. Objectives, design, patients, measurements Our objective was to develop a computer program which would separate 24 facial photographs, of patients with acromegaly, from those of 25 normal subjects. The key to doing this was to use a previously developed database that consisted of three-dimensional representations of 200 normal person's heads (SIGGRAPH '99 Conference Proceedings, 1999). We transformed our 49, two-dimensional photos into three-dimensional constructs and then, using the computer program, attempted to separate them into those with and without the features of acromegaly. We compared the accuracy of the computer to that of 10 generalist physicians. A second objective was to examine, by a subjective analysis, the features of acromegaly in the normal subjects of our photographic database. Results The accuracy of the computer model was 86%; the average of the 10 physicians was 26%. The worst individual physician, 16%, the best, 90%. The faces of 200 normal subjects, the original faces in the database, could be divided into four groups, averaged by computer, from those with fewer to those with more features of acromegaly. Conclusions The present computer model can sort photographs of patients with acromegaly from photographs of normal subjects and is much more accurate than the sorting by practicing generalists. Even normal subjects have some of the features of acromegaly. Screening with this approach can be improved with automation of the procedure, software development and the identification of target populations in which the prevalence of acromegaly may be increased over that in the general population.
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Serum vascular endothelial growth factor (VEGF) is elevated in GH deficient adults.GHD adults exhibit a number of adverse surrogate markers of vascular risk culminating in excess vascular morbidity and mortality. Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of a number of vascular morbidities. Furthermore, serum levels decrease following GH replacement in GHD adults, though it remains unclear if levels are significantly elevated in untreated individuals.
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Endoscopic transsphenoidal pituitary surgery: evidence of an operative learning curve.BACKGROUND: The use of the fiberoptic endoscope is a recent innovation in pituitary surgery. OBJECTIVE: To investigate the evidence of an operative learning curve after the introduction of endoscopic transsphenoidal surgery in our unit. METHODS: The first 125 patients who underwent endoscopic transnasal transsphenoidal surgery for pituitary fossa lesions between 2005 and 2007 performed by 1 surgeon were studied. Changes in a number of parameters were assessed between 2 equal 15-month time periods: period 1 (53 patients) and period 2 (72 patients). RESULTS: There were 67 patients (54%) with nonfunctioning adenomas, 22 (18%) with acromegaly, and 10 (8%) with Cushing's disease. Between study periods 1 and 2, there was a decrease in the mean duration of surgery for nonfunctioning adenomas (from 120 minutes to 91 minutes; P < .01). This learning effect was not apparent for functioning adenomas, the surgery for which also took longer to perform. The proportion of patients with an improvement in their preoperative visual field deficits increased over the study period (from 80% to 93%; P < .05). There were nonsignificant trends toward improved endocrine remission rates for patients with Cushing's disease (from 50% to 83%), but operative complications, notably the rates of hypopituitarism, did not change. Overall length of hospital stay decreased between time periods 1 and 2 (from 7 to 4 days median; P < .01). CONCLUSION: The improvements in the duration of surgery and visual outcome noted after about 50 endoscopic procedures would favor the existence of an operative learning curve for these parameters. This further highlights the benefits of subspecialization in pituitary surgery.
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Novel corticosteroid-binding globulin variant that lacks steroid binding activity.BACKGROUND: Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. PATIENTS, METHODS, AND RESULTS: In a 26-yr-old female with hypotension, fatigue, and undetectable total serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated total serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband. CONCLUSION: We describe a novel CBG variant that lacks steroid binding activity. All mutant homozygotes have very low total serum cortisol, but normal free serum cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.
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Immune function in hypopituitarism; time to reconsider?Abstract Hypopituitarism is not currently considered as a potential cause of immune disruption in humans. Accumulating data from in-vitro and animal models support a role for the pituitary gland in immune regulation. Furthermore the increased mortality risk noted in patients with adult hypopituitarism remains poorly explained and immune dysfunction could conceivably contribute to this observation. In a recent issue of Clinical & Experimental Immunology we presented new data relating to immune status in adults with treated, severe hypopituitarism. We observed humoral immune deficiency in a significant proportion, despite stable pituitary replacement, including growth hormone (GH). This was especially evident in those with low pre-treatment IGF-I levels and appeared independent of anticonvulsant use or corticosteroid replacement. These observations require substantiation with future studies. In this short review we summarise existing data relating to the effects of pituitary hormones on immune function, and discuss potential clinical implications surrounding the hypothesis of immune dysregulation in severe hypopituitarism.
