Showing papers in "European Journal of Endocrinology in 2009"
TL;DR: In patients with HO and SHO, insulin resistance was comparable and insulin-stimulated rates of glucose transport in isolated monocytes were decreased due to impaired translocation of GLUT4 glucose transporters on the plasma membrane, which could justify the increased risk for insulin resistance-associated disorders, such as cardiovascular disease, observed in patients withHO or SHO.
Abstract: Objective: Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. Design and methods: To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. Results: HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC0–300 32 190G1067 and 31 497G716 mg/dl min respectively) versus EU (27 119 G1156 mg/dl min, P!0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC0–300 11 020G985 and 9565G904 mU/l min respectively) compared with EU subjects (AUC0–300 7588G743 mU/l min, P!0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81G0.3 and 2.43G0.38 respectively) compared with EU subjects (1.27 G0.16, P!0.05), while Matsuda and Belfiore indices were decreased in HR (4.21G0.41 and 0.77G0.05 respectively, P!0.001) and SHR patients (4.47G0.33 and 0.85G0.05 respectively, P!0.05 versus EU (7.76G0.87 and 1 respectively). At 100 mU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8G7 mean fluorescence intensity (MFI)) and SHR patients (522.2G25 MFI) compared with EU subjects (407G18 MFI, P!0.01 and P!0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8G5%) versus EU subjects (61.26G10%, P!0.05). Conclusions: Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.
368 citations
TL;DR: Data from recent research suggest that TH, especially T(3), can be considered as a marker for survival in patients with kidney disease.
Abstract: Thyroid hormones (TH) are essential for an adequate growth and development of the kidney. Conversely, the kidney is not only an organ for metabolism and elimination of TH, but also a target organ of some of the iodothyronines' actions. Thyroid dysfunction causes remarkable changes in glomerular and tubular functions and electrolyte and water homeostasis. Hypothyroidism is accompanied by a decrease in glomerular filtration, hyponatremia, and an alteration of the ability for water excretion. Excessive levels of TH generate an increase in glomerular filtration rate and renal plasma flow. Renal disease, in turn, leads to significant changes in thyroid function. The association of different types of glomerulopathies with both hyper- and hypofunction of the thyroid has been reported. Less frequently, tubulointerstitial disease has been associated with functional thyroid disorders. Nephrotic syndrome is accompanied by changes in the concentrations of TH due primarily to loss of protein in the urine. Acute kidney injury and chronic kidney disease are accompanied by notable effects on the hypothalamus-pituitary-thyroid axis. The secretion of pituitary thyrotropin (TSH) is impaired in uremia. Contrary to other non-thyroidal chronic disease, in uraemic patients it is not unusual to observe the sick euthyroid syndrome with low serum triodothyronine (T(3)) without elevation of reverse T(3) (rT(3)). Some authors have reported associations between thyroid cancer and kidney tumors and each of these organs can develop metastases into the other. Finally, data from recent research suggest that TH, especially T(3), can be considered as a marker for survival in patients with kidney disease.
365 citations
TL;DR: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome, however, chemerin does not predict coronary atherosclerosis.
Abstract: Objectives: Chemerin is a recently discovered adipokine that regulates adipocyte differentiation and modulates chemotaxis and activation of dendritic cells and macrophages. Given the convergence of adipocyte and macrophage function, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis in humans. We sought to examine the relationship of i) chemerin and markers of inflammation, ii) chemerin and components of the metabolic syndrome, and iii) chemerin and coronary atherosclerotic plaque burden and morphology. Design: Serum chemerin levels were determined in 303 patients with stable typical or atypical chest pain who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed, or non-calcified. Results: Chemerin levels were highly correlated with high sensitivity C-reactive protein (rZ0.44, P!0.0001), interleukin-6 (rZ0.18, PZ0.002), tumor necrosis factor-a (rZ0.24, P!0.0001), resistin (rZ0.28, P!0.0001), and leptin (rZ0.36, P!0.0001) concentrations. Furthermore, chemerin was associated with components of the metabolic syndrome including body mass index (rZ0.23, PZ0.0002), triglycerides (rZ0.29, P!0.0001), HDL-cholesterol (rZK0.18, PZ0.003), and hypertension (P!0.0001). In bivariate analysis, chemerin levels were weakly correlated with coronary plaque burden (rZ0.16, PZ0.006) and the number of non-calcified plaques (rZ0.14, PZ0.02). These associations, however, were lost after adjusting for established cardiovascular risk factors (odds ratio, OR 1.17, 95% confidence interval (CI) 0.97–1.41, PZ0.11 for coronary plaque burden; OR 1.06, 95% CI 0.96–1.17, PZ0.22 for non-calcified plaques). Conclusions: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome. However, chemerin does not predict coronary atherosclerosis.
295 citations
TL;DR: It is demonstrated that low 25(OH)D levels are associated with features of the metabolic syndrome in PCOS women and large intervention trials are warranted to evaluate the effect of vitamin D supplementation on metabolic disturbances in PCos women.
Abstract: Objectives: Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances, in particular from insulin resistance. Accumulating evidence suggests that vitamin D deficiency may contribute to the development of metabolic syndrome (MS). Hence, the aim of our study was to investigate the association of 25(OH)D levels and the components of the MS in PCOS women. Methods: 25(OH)D levels were measured by means of ELISA in 206 women affected by PCOS. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. Results: The prevalence of insufficient 25(OH)D levels (!30 ng/ml) was 72.8% in women with PCOS. PCOS women with MS had lower 25(OH)D levels than PCOS women without these features (17.3 vs 25.8 ng/ml respectively; P!0.05). In multivariate regression analysis including 25(OH)D, season, body mass index (BMI), and age, 25(OH)D and BMI were independent predictors of homeostatic model assessment-insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI; P!0.05 for all). In binary logistic regression analyses, 25(OH)D (odds ratio, OR 0.86, PZ0.019) and BMI (OR 1.28, P!0.001) were independent predictors of MS in PCOS women. We found significantly negative correlations of 25(OH)D levels with BMI, waist circumference, waist-to-hip ratio, systolic and diastolic blood pressure, fasting and stimulated glucose, area under the glucose response curve, fasting insulin, HOMA-IR, HOMA-b, triglycerides, and quotient total cholesterol/high-density lipoprotein (HDL) and positive correlations of 25(OH)D levels with QUICKI and HDL (P!0.05 for all). Conclusion: We demonstrate that low 25(OH)D levels are associated with features of MS in PCOS women. Large intervention trials are warranted to evaluate the effect of vitamin D supplementation on metabolic disturbances in PCOS women.
292 citations
TL;DR: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates, which argues for a review of current guidelines.
Abstract: Objective: To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. Design and methods: Literature review. Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded. Results: The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (!1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma. Conclusion: Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.
261 citations
TL;DR: In a cohort of pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH, and maternal FT(4) concentrations and child loss were not associated.
Abstract: Background: To examine the relationship between maternal TSH and free thyroxine (FT4) concentrations in early pregnancy and the risk of miscarriage, fetal or neonatal death. Method: Cohort study of 2497 Dutch women. TSH, FT4, and thyroid peroxidase antibodies concentrations were determined at first booking. Child loss was operationalized as miscarriage, fetal or neonatal death. Women with overt thyroid dysfunction were excluded. Results: Twenty-seven cases of child loss were observed. The mean TSH and FT4 level in the women with child loss was 1.48 mU/l and 9.82 pmol/l compared with 1.11 mU/l and 9.58 pmol/l in women without child loss. The incidence of child loss increased by 60% (ORZ1.60 (95% confidence interval (CI): 1.04‐2.47)) for every doubling in TSH concentration. This association remained after adjustment for smoking, age, parity, diabetes mellitus, hypertension, previous preterm deliveries, and previous preterm stillbirth/miscarriage (adjusted odds ratioZ1.80 (95% CI: 1.07‐3.03)). This was not true for FT4 concentrations (ORZ1.41 (95% CI: 0.21‐9.40); PZ0.724). Conclusion: In a cohort of pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH. Maternal FT4 concentrations and child loss were not associated.
251 citations
TL;DR: Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patientsWith bone metastases, and thyroglobulin response reflected radiological responses.
Abstract: Objective: Treatment options for patients with radioactive iodine (RaI) refractory metastases of differentiated thyroid carcinoma (DTC) are limited. We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression. Design: Open, single center, single arm 26-week prospective phase II study with open-ended extension. Methods: We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d. The primary endpoint was reinduction of RaI uptake at 26 weeks. Additional endpoints were the radiological response and the influence of bone metastases. Results: At 26 weeks of sorafenib therapy, no reinduction of RaI uptake at metastatic sites was observed, but 19 patients (59%) had a clinical beneficial response, eight of whom had a partial response (25%) and 11 had stable disease (34%). Seven patients had progressive disease (22%). Sorafenib was significantly less effective in patients with bone metastases. The estimated median progression free survival was 58 weeks (95% confidence interval, CI, 47‐68). In general, thyroglobulin (Tg) response (both unstimulated and TSH stimulated) reflected radiological responses. The median time of the nadir of Tg levels was 3 months. Responses were not influenced by histological subtype, mutational status or other variables. No unusual side effects were observed. Conclusions: Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patients with bone metastases. Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake.
237 citations
TL;DR: Diagnosis of polyglandular autoimmune syndromes involves serological measurement of organ-specific autoantibodies and subsequent functional testing and management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.
Abstract: The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase non-receptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.
206 citations
TL;DR: Nutritional rickets is rare in southern Denmark and largely restricted to immigrants, but the incidence among ethnic Danish children was unexpectedly high, and nutritional rickets was most frequent among all young children.
Abstract: Objective: To estimate the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets. Design: Population-based retrospective cohort study based on a review of medical records. Methods: Patients aged 0–14.9 years referred to or discharged from hospitals in southern Denmark from 1985 to 2005 with a diagnosis of rickets were identified by register search, and their medical records were retrieved. Patients fulfilling the diagnostic criteria of primary rickets were included. Results: We identified 112 patients with nutritional rickets of whom 74% were immigrants. From 1995 to 2005, the average incidence of nutritional rickets in children aged 0–14.9 and 0–2.9 years was 2.9 and 5.8 per 100 000 per year respectively. Among immigrant children born in Denmark, the average incidence was 60 (0–14.9 years) per 100 000 per year. Ethnic Danish children were only diagnosed in early childhood and the average incidence in the age group 0–2.9 years declined from 5.0 to 2.0 per 100 000 per year during 1985–1994 to 1995–2005. Sixteen cases of hereditary rickets were diagnosed during the study period giving an average incidence of 4.3 per 100 000 (0–0.9 years) per year. The prevalence of hypophosphatemic rickets and vitamin D-dependent rickets type 1 was 4.8 and 0.4 per 100 000 (0–14.9 years) respectively. Conclusions: Nutritional rickets is rare in southern Denmark and largely restricted to immigrants, but the incidence among ethnic Danish children was unexpectedly high. Hereditary rickets is the most common cause of rickets in ethnic Danish children, but nutritional rickets is most frequent among all young children.
204 citations
TL;DR: Serum osteocalcin was closely associated with not only fat and glucose metabolism but also with lipid metabolism, and was also positively associated with homeostasis model assessment of beta-cell function.
Abstract: Objectives: Osteocalcin, a bone-derived protein, has recently been reported to affect energy metabolism. We investigated the relationship between serum osteocalcin and parameters of adiposity, glucose tolerance, and lipid profile in Chinese subjects. Methods: Serum osteocalcin was measured by electrochemiluminescence immunoassay in 254 men (128 with newly diagnosed type 2 diabetes mellitus (T2DM) and 126 with normal glucose tolerance (NGT)), 66 premenopausal women (33 with T2DM and 33 with NGT) as well as 180 postmenopausal women (92 with T2DM and 88 with NGT). Their associations with parameters of adiposity, glucose tolerance, and lipid profile were examined. Results: Serum osteocalcin concentrations in diabetic patients were significantly lower than those in NGT subjects after adjusted for age, gender, and body mass index (PZ0.003). Postmenopausal women had higher osteocalcin concentrations than premenopausal women and men (both P!0.001). Multiple stepwise regression analysis showed that age, %fat, high-density lipoprotein cholesterol, fasting plasma glucose, and fasting serum insulin were independently associated with osteocalcin in men (P!0.05). Age and HbA1c were independently correlated with osteocalcin in postmenopausal women. Besides age and HbA1c, serum triglyceride was also an independent factor influencing osteocalcin in premenopausal women. In addition, osteocalcin was also positively associated with homeostasis model assessment of b-cell function. Furthermore, multiple logistic regression analysis demonstrated that osteocalcin was independently associated with T2DM. Conclusions: Serum osteocalcin was closely associated with not only fat and glucose metabolism but also with lipid metabolism.
191 citations
TL;DR: In non-obese young subjects, new relationships between 25(OH)D and several metabolic risk factors and adiponectin are observed and are significantly inversely correlated with body mass index and systolic blood pressure.
Abstract: Objectives: Several studies suggest a link between circulating 25-hydroxyvitamin D (25(OH)D) and metabolic risk factors. However, this relation has been mainly studied in elderly and/or obese subjects. In addition, the relation between 25(OH)D and adiponectin is unclear. The purpose of this study is to look at these relations in non-obese young individuals. Design: We investigated the relation between serum 25(OH)D and adiposity, blood pressure, glucose metabolism, lipid profile, and adiponectin in 381 randomly selected university students (201 males and 180 females, mean age 23.9G3.9). Results: In the overall population, 25(OH)D is significantly inversely correlated with body mass index (BMI), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), insulin levels, and homeostasis model assessment of insulin resistance (HOMA index) and positively correlated with adiponectin and high density lipoprotein-cholesterol (P!0.01 for all variables). In males, these correlations are still significant for BMI, SBP, WC, and adiponectin (PZ0.02, PZ0.01, PZ0.04 and PZ0.01 respectively); also, 25(OH)D is inversely correlated with low density lipoprotein (LDL)cholesterol (PZ0.007). In females, 25(OH)D is only inversely correlated with FPG and HOMA index (P!0.001 and PZ0.03 respectively). In multivariate regression analysis models, after adjustment for sex and BMI, 25(OH)D is an independent predictor of FPG and SBP (PZ0.032 and PZ0.05 respectively) in the overall population, while in males 25(OH)D is a predictor of LDL-cholesterol and SBP independently of BMI (PZ0.007 and PZ0.035 respectively). Conclusion: In non-obese young subjects, we observe new relationships between 25(OH)D and several metabolic risk factors and adiponectin. Further research is needed to elucidate the gender differences and to look at the relation between 25(OH)D and adiponectin.
TL;DR: Thyroid autoimmunity is not a major cause sustaining the high rate of SH in morbid obese patients, and in these patients, the diagnosis of SH itself, as assessed by a raised TSH alone, appears questionable.
Abstract: Objective: Morbid obesity (body mass index (BMI)R40 kg/m 2 ) is associated with thyroid function disturbances, with a high rate of subclinical hypothyroidism (SH) being the most consistently reported. We evaluated the circulating thyroid function parameters in morbid obese patients and related the results to the presence of circulating thyroid antibodies (Thyr-Ab). Design and methods: Morbid obese patients were consecutively enrolled (nZ350). Two control groups were used: control group (CG)1, healthy normo-weight subjects (nZ50); CG2, normo-weight patients with SH (nZ56) matched for TSH with the obese patients with SH. Serum levels of free triiodothyronine (FT3), free thyroxine (FT4), TSH, antithyroglobulin antibodies, and antithyroperoxidase antibodies were measured in all patients. Results: i) Compared with CG1, obese patients having thyroid function parameters in the normal range and negative Thyr-Ab showed significantly higher serum TSH and lower free thyroid hormones levels, but a similar FT4/FT3 ratio; ii) SH was recorded in 13.7% obese patients; iii) compared with CG2, obese patients with untreated SH had a significantly lower rate of positive Thyr-Ab (32.1 vs 66.1%; P!0.005); iv) no gender prevalence was observed in SH obese patients with negative Thyr-Ab; and v) the comparison of the untreated SH patients (obese and normo-weight) with CG1 demonstrated that in SH obese subjects, unlike normo-weight SH patients, the FT3 levels were significantly lower. This resulted in a normal FT4/FT3 ratio in SH obese patients. Conclusion: Thyroid autoimmunity is not a major cause sustaining the high rate of SH in morbid obese patients. In these patients, the diagnosis of SH itself, as assessed by a raised TSH alone, appears questionable.
TL;DR: The data provide the first evidence that IR is an independent risk factor for nodule formation in an iodine-deficient environment and patients with MetS have significantly increased thyroid volume and nodule prevalence.
Abstract: Objective: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities with insulin resistance (IR) as a major component. It has been recently questioned whether MetS and its related components are associated with functional and morphological alterations of the thyroid gland. The aim of our study is to examine thyroid volume and nodule prevalence in a case–control study of patients with MetS in a mild-to-moderate iodine-deficient area. Design: Two hundred and seventy-eight patients with MetS were randomly matched for age, gender, and smoking habits with 261 subjects without MetS. Serum TSH, free tri-iodothyronine and thyroxine, and the level of IR, which was estimated by the homeostasis model assessment for IR, as well as other MetS parameters were evaluated. Thyroid ultrasonography was performed in all subjects. All subjects with thyroid nodules O1 cm were offered to undergo thyroid fine needle aspiration biopsy. Results: TSH was significantly positively correlated with the presence of MetS diagnosis. There was no association between free thyroid hormone levels and MetS and its related components. Mean thyroid volume was significantly higher in patients with MetS than in controls (17.5G5.5 vs 12.2G4.2 ml, P!0.0001). Also the percentage of patients with thyroid nodules was significantly higher in patients with MetS (50.4 vs 14.6%, P!0.0001). Subjects were also divided into two groups according to the presence of IR. The group of subjects with IR had increased thyroid volume and nodule formation. The odds ratio for the development of thyroid nodule in the presence of IR was 3.2. TSH as well as all MetS components were found to be independent predictors for thyroid volume increase. IR but not TSH was found to be correlated with thyroid nodule formation. Thyroid cancer was diagnosed in 3 out of 38 patients with MetS who agreed to have a biopsy (7.9%). None of the subjects in the control group was diagnosed to have thyroid cancer. Conclusions: The results suggest that patients with MetS have significantly increased thyroid volume and nodule prevalence. Multivariate regression analysis model demonstrated that the presence of IR contributed substantially to this increased risk. Our data provide the first evidence that IR is an independent risk factor for nodule formation in an iodine-deficient environment.
TL;DR: The results suggest that post receptor defects are present in the insulin signaling pathway in placenta of women with pregnancies complicated by diabetes and obesity.
Abstract: Objective: Studies in adipose tissue and skeletal muscle suggest that impaired insulin action is due to defects in the insulin signaling pathway and may play a role in the pathophysiology of insulin resistance associated with gestational diabetes mellitus (GDM) and obesity. The present study tested the hypothesis that endogenous expression levels in the human term placenta of insulin signaling components are altered in placental tissue from GDM women in comparison with normal controls and maternal obesity. Design and methods: Placental tissue was collected from normal, diet-controlled GDM, and insulincontrolled GDM in both non-obese and obese women (nZ6–7 per group). Western blotting and quantitative RT-PCR was performed to determine the level of expression in the insulin signaling pathway. Results: There was a significant increase in insulin receptor (IR) substrate (IRS)-1 protein expression with a concurrent decrease in IRS-2 protein expression in non-obese women with insulin-controlled GDM compared with diet-controlled GDM and normal controls. Furthermore, a decrease in both protein and mRNA expression of phosphatidyl-inositol-3-kinase (PI3-K) p85a and glucose transporter (GLUT)-4 was observed in non-obese and obese women with insulin controlled GDM compared with normal controls. When comparing non-obese to obese patients, significant decreases in mRNA expression of IR-b, PI3K p85a and GLUT-4 was found in obese patients. Conclusion: Our results suggest that post receptor defects are present in the insulin signaling pathway in placenta of women with pregnancies complicated by diabetes and obesity. In addition, expression studies demonstrate post receptor alterations in insulin signaling possibly under selective maternal regulation and not fetal regulation.
TL;DR: Owing to better availability and accessibility of imaging procedures, the number of incidentally discovered phaeochromocytoma is increasing and reaches nearly 30% in the study population.
Abstract: Context: Adrenal and extra-adrenal phaeochromocytoma are chromaffin cell-derived tumours that are discovered due to classical symptom triad with headache, sweating and palpitations combined with persistent or paroxysmal hypertension. However, an increasing proportion of phaeochromocytoma seems to be discovered incidentally upon abdominal imaging. Objective: To specify the exact circumstances of discovery of adrenal and extra-adrenal phaeochromocytoma. Design and patients: Four German endocrine centres participated in this retrospective study. Medical records of 201 patients with adrenal and extra-adrenal phaeochromocytoma who were diagnosed between 1973 and 2007 were analyzed. Results: The typical triad of symptoms was found only in 10% of cases. Ten percent of patients presented were without clinical symptoms and 6.1% were normotensive. Documented blood pressure peaks occurred in 44.1% of cases. In 24 patients (12.2%), phaeochromocytoma was malignant. Before 1985, !10% of cases were incidentally discovered, whereas thereafter the frequency was O25% (29.4% of the total study population). Patients with incidentally detected phaeochromocytoma were significantly older (53.1G1.9 vs 47.0G1.3 years; P!0.05) and often had less blood pressure peaks (37.0 vs 70.7%; P!0.001) than patients in whom the diagnosis was suspected on clinical grounds. Of phaeochromocytomas 94.4% were intra-adrenal tumours, of which 12.9% were bilateral. Bilateral tumours were significantly smaller than unilateral tumours (36.6G14.7 vs 52.5G34.3 mm; P!0.05), whereas extra-adrenal tumours had a mean diameter of 52.6G28.7 mm. Conclusions: Owing to better availability and accessibility of imaging procedures, the number of incidentally discovered phaeochromocytoma is increasing and reaches nearly 30% in our study population. Every adrenal incidentaloma should be investigated for the presence of phaeochromocytoma.
TL;DR: Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function.
Abstract: Graves' disease is a common autoimmune disorder in women in fertile ages. The hyperthyroidism is caused by generation of TSH-receptor activating antibodies. In pregnancy both the antibodies and the antithyroid medication given to the mother pass the placenta and affect the foetal thyroid gland. Thyroid function should be controlled not only in the mother with Graves' hyperthyroidism but also in her foetus.The review includes two cases illustrating some of the problems in managing Graves' disease in pregnancy. Major threats to optimal foetal thyroid function are inadequate or over aggressive antithyroid drug therapy of the mother. It should be taken into account that antithyroid drugs tend to block the foetal thyroid function more effectively than the maternal thyroid function, and that levothyroxin (L-T(4)) given to the mother will have only a limited effect in the foetus. Surgical thyroidectomy of patients with Graves' hyperthyroidism does not lead to immediate remission of the autoimmune abnormality, and the combination thyroidectomy+withdrawal of antithyroid medication+L-T(4) replacement of the mother involves a high risk of foetal hyperthyroidism. Conclusion Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function. Surgical thyroidectomy of a pregnant woman with active disease may lead to isolated foetal hyperthyroidism.
TL;DR: The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.
Abstract: BACKGROUND: Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy ...
TL;DR: In this article, the impact of endogenous testosterone levels in community-dwelling men on later risk for myocardial infarction (MI) and all-cause, cardiovascular disease (CVD), and ischemic heart disease (IHD) mortality was studied.
Abstract: Objective: To study the impact of endogenous testosterone levels in community-dwelling men on later risk for myocardial infarction (MI) and all-cause, cardiovascular disease (CVD), and ischemic heart disease (IHD) mortality. Design: Population-based prospective cohort study. Methods: For the analyses, we used a cohort of 1568 randomly selected men, with sex-hormone data participating in the fourth Tromso Study (1994–1995). Defined end points were first-ever MI (fatal or nonfatal), all-cause, CVD, and IHD mortality. A committee performed thorough ascertainment of end points, following a detailed protocol. Complete ascertainment of end points was until 30 September 2007 for all-cause mortality, until 31 December 2005 for CVD/IHD mortality, and until 31 December 2004 for first-ever MI. The prospective association between total and free testosterone and end points were examined using Cox proportional hazard regression, allowing for multivariate adjustment for age and cardiovascular risk factors. Results: During follow-up, there were 395 deaths from all causes, 130 deaths from CVD and 80 deaths from IHD, while 144 men experienced a first-ever MI. There was a significant increase in all-cause mortality risk for men with free testosterone in the lowest quartile (!158 pmol/l) compared with the higher quartiles after age adjustment hazard ratios (HR 1.24, 95% confidence interval, CI 1.01–1.53) and after multivariate adjustments (HR 1.24, 95% CI 1.01–1.54). Total testosterone was not associated with mortality risk. Likewise, there were no significant changes in risk for first-ever MI across different total or free testosterone levels. Conclusion: Men with free testosterone levels in the lowest quartile had a 24% increased risk of all-cause mortality.
TL;DR: This review aims to summarize reported findings concerning the role of adipocytokines in early life, while attempting to speculate mechanisms through which differential regulation of leptin, adiponectin, ghrelin, tumor necrosis factor, and visfatin may influence the risk for development of chronic diseases in later life.
Abstract: Intrauterine growth restriction (IUGR) is the failure of the fetus to achieve his/her intrinsic growth potential, due to anatomical and/or functional disorders and diseases in the feto-placental-maternal unit. IUGR results in significant perinatal and long-term complications, including the development of insulin resistance/metabolic syndrome in adulthood. The thrifty phenotype hypothesis holds that intrauterine malnutrition leads to an adaptive response that alters the fetal metabolic and hormonal milieu designed for intrauterine survival. This fetal programming predisposes to an increased susceptibility for chronic diseases. Although the mechanisms controlling intrauterine growth are poorly understood, adipose tissue may play an important role in linking poor fetal growth to the subsequent development of adult diseases. Adipose tissue secretes a number of hormones, called adipocytokines, important in modulating metabolism and recently involved in intrauterine growth. This review aims to summarize reported findings concerning the role of adipocytokines (leptin, adiponectin, ghrelin, tumor necrosis factor (TNF), interleukin-6 (IL6), visfatin, resistin, apelin) in early life, while attempting to speculate mechanisms through which differential regulation of adipocytokines in IUGR may influence the risk for development of chronic diseases in later life.
TL;DR: BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy, and lend support to the recommendations that 15-25 mg hydrocortisone daily is more appropriate than the higher conventional doses.
Abstract: Context: Patients with primary adrenal insufficiency (Addison’s disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone. Objective: To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics. Design, setting and participants: A cross-sectional study of two large Addison’s cohorts from Norway (nZ187) and from UK and New Zealand (nZ105). Main outcome measures: Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity. Results: Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean K0.28 (95% confidence intervals (CI) K0.42, K0.16); UK and New Zealand: K0.21 (95% CI K0.36, K0.06)). Lumbar spine Z-scores were reduced (Norway: K0.17 (K0.36, C0.01); UK and New Zealand: K0.57 (K0.78, K0.37)), and significantly lower in males compared with females (PZ0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CTOTT PZ0.015), with a similar trend at the hip and spine. Conclusions: BMD at the femoral neck and lumbar spine is reduced in Addison’s disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15–25mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.
TL;DR: Meta-analysed RCTs performed in type 2 diabetic patients with GLP-1 receptor agonists suggest that the efficacy and tolerability of the novel agent, liraglutide, which is adequate for once-a-day administration, are comparable with those of exenatide bis in die.
Abstract: Objective: The role of glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes is debated; many recent trials, which were not included in previous meta-analyses, could add relevant information. Design and methods: All available randomized controlled trials (RCTs), either published or unpublished, performed in type 2 diabetic patients with GLP-1 receptor agonists (exenatide and liraglutide), with a durationO12 weeks were meta-analysed for HbA1c, body mass index, hypoglycaemia and other adverse events. Results and conclusions: A total of 21 RCTs (six of which unpublished), enrolling 5429 and 3053 patients (with GLP-1 receptor agonists and active comparator or placebo respectively), was retrieved and included in the analysis. GLP-1 receptor agonists determine a significant improvement of HbA1c in comparison with placebo (K1.0 (K1.1, K0.8), P!0.001), with a low risk of hypoglycaemia. There is no evidence of increased cardiovascular risk with the use of GLP-1 receptor agonists. GLP-1 receptor agonists, which induce weight loss, are associated with gastrointestinal side effects. GLP-1 receptor agonists are effective in reducing HbA1c and postprandial glucose. In patients failing to sulphonylureas and/or metformin, GLP-1 receptor agonists are similarly effective as insulin. Available data suggest that the efficacy and tolerability of the novel agent, liraglutide, which is adequate for oncea-day administration, are comparable with those of exenatide bis in die.
TL;DR: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency.
Abstract: Objective: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing’s syndrome (CS). Design: Retrospective study of patients treated in seven European centers. Methods: Twenty patients with malignant (nZ15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (nZ5, four with Cushing’s disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200–1000). Median treatment duration was 2 months (0.25–21) for malignant CS, and 6 months (0.5–24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. Results: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. Conclusion: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.
TL;DR: The protective effect of testosterone on myocardial ischaemia is maintained throughout treatment without decrement and the potentially beneficial effects of testosteroneOn body composition were confirmed and there were no adverse effects.
Abstract: Introduction: In short-term studies, testosterone replacement therapy has been shown to protect male subjects from exercise-induced ischaemia and modify cardiovascular risk factors such as insulin resistance, fat mass and lipid profiles. Methods: This randomised parallel group controlled trial was designed to assess the treatment effect of testosterone therapy (Nebido) compared with placebo in terms of exercise-induced ischaemia, lipid profiles, carotid intima-media thickness (CIMT) and body composition during 12 months treatment in men with low testosterone levels and angina. Results: A total of 15 men were recruited but 13 (nZ13) reached adequate duration of follow-up; seven were treated with testosterone and six with placebo. Testosterone increased time to ischaemia (129G48 s versus 12G18, PZ0.02) and haemoglobin (0.4G0.6 g/dl versus K0.03G0.5, PZ0.04), and reduced body mass index (K0.3 kg/m 2 versus 1.3G1, PZ0.04) and triglycerides (K0.36 G0.4 mmol/l versus 0.3G1.2, PZ0.05). The CIMT decreased in the testosterone group more than placebo, but full between group analyses suggested this was only a statistical trend (K0.5G0.1 vs K0.09G0.06, PZ0.16). There were no significant effects on serum prostate specific antigen, total or high-density lipoprotein cholesterol; or on mood and symptom scores as assessed by Seattle Angina Score and EuroQol. Conclusion: The protective effect of testosterone on myocardial ischaemia is maintained throughout treatment without decrement. Previously noted potentially beneficial effects of testosterone on body composition were confirmed and there were no adverse effects.
TL;DR: Elevated MIC-1 levels in patients with obesity are further increased by the presence of T2DM, and it is suggested that in contrast to patients with cancer cachexia, increased MIC- 1 levels in obese patients and diabetic patients do not induce weight loss.
Abstract: Objective: Macrophage inhibitory cytokine-1 (MIC-1) is a novel regulator of energy homeostasis. We explored whether alterations in MIC-1 levels contribute to metabolic disturbances in patients with obesity and/or obesity and type 2 diabetes mellitus (T2DM). Design: We measured serum MIC-1 levels and its mRNA expression in subcutaneous and visceral adipose tissue of 17 obese nondiabetic women, 14 obese women with T2DM and 23 healthy lean women. We also explored the relationship of MIC-1 with anthropometric and biochemical parameters and studied the influence of 2-week very low calorie diet (VLCD) on serum MIC-1 levels. Methods: Serum MIC-1 levels were measured by ELISA and its mRNA expression was determined by RT-PCR. Results: Both obese and T2DM group had significantly elevated serum MIC-1 levels relative to controls. T2DM group had significantly higher serum MIC-1 levels relative to obese group. Serum MIC-1 positively correlated with body weight, body fat, and serum levels of triglycerides, glucose, HbAlc, and C-reactive protein and it was inversely related to serum high-density lipoprotein cholesterol. Fat mRNA MIC-1 expression did not significantly differ between lean and obese women but it was significantly higher in subcutaneous than in visceral fat in both groups. VLCD significantly increased serum MIC-1 levels in obese but not T2DM group. Conclusion: Elevated MIC-1 levels in patients with obesity are further increased by the presence of T2DM. We suggest that in contrast to patients with cancer cachexia, increased MIC-1 levels in obese patients and diabetic patients do not induce weight loss.
TL;DR: Most macroprolactinomas primarily treated with CAB are adequately controlled with doses < or =1.5 mg/week, and about 20% of patients, mainly men and/or those with invasive tumors will require a higher dose of CAB.
Abstract: Context: Macroprolactinomas poorly responsive to dopamine-agonists are often more aggressive and are usually termed resistant but this clinical concept has always been defined empirically Objective: To define resistance to cabergoline on the basis of a dose-response relationship established in a large series of macroprolactinoma patients and to assess the influence of gender and of tumor invasiveness on the response to treatment Design: Retrospective study Methods: 122 patients (72 women and 50 men) primarily treated with cabergoline for at least one year were included Main outcome measures were serum prolactin and tumor size Results: Normalization of prolactin was obtained in 115 of the 122 patients (94%) The majority of patients (96/115, 83%) was controlled with a cabergoline dose < 15 mg/week Most of the other patients (19/26) had only a partial resistance, responding to a further increase of the cabergoline dose Beyond the dose of 35 mg/week, there was no clear advantage in further increasing the dose instead of continuing the treatment at the same dose Most tumors (98/119 assessable cases, 82%) showed a significant shrinkage during cabergoline treatment It was more likely to occur in cases of prolactin normalization Both cavernous sinus invasion and male gender were significantly and independently associated with partial or complete resistance to treatment Conclusions: Most macroprolactinomas primarily treated with cabergoline are adequately controlled with doses < 15 mg/week About 20% of patients, mainly men and/or those with invasive tumors, will require a higher dose We suggest defining such patients as resistant to cabergoline
TL;DR: In a study design, where morning TSH levels were unaltered between groups combination therapy, (treated with T(3) 20 microg once daily) was superior to monotherapy by evaluating several QOL, depression and anxiety rating scales as well as patients own preference.
Abstract: Background: Treatment of hypothyroidism with 3,5,3 0 -triiodothyronine (T3) is controversial. A recent meta-analysis concludes that no evidence is present in favour of using T3. However, the analysis included a mixture of different patient groups and dose-regimens. Objective: To compare the effect of combination therapy with thyroxine (T4) and T3 versus T4 monotherapy in patients with hypothyroidism on stable T4 substitution. Study design: Double-blind, randomised cross-over. Fifty micrograms of the usual T4 dose was replaced with either 20 m gT 3 or 50 m gT 4 for 12 weeks, followed by cross-over for another 12 weeks. The T4 dose was regulated if needed, intending unaltered serum TSH levels. Evaluation: Tests for quality of life (QOL) and depression (SF-36, Beck Depression Inventory, and SCL90-R) at baseline and after both treatment periods. Inclusion criteria: Serum TSH between 0.1 and 5.0 mU/l on unaltered T4 substitution for 6 months. Results: A total of 59 patients (55 women); median age 46 years. When comparing scores of QOL and depression on T4 monotherapy versus T4/T3 combination therapy, significant differences were seen in 7 out of 11 scores, indicating a positive effect related to the combination therapy. Forty-nine percent preferred the combination and 15% monotherapy (PZ0.002). Serum TSH remained unaltered between the groups as intended. Conclusion: In a study design, where morning TSH levels were unaltered between groups combination therapy, (treated with T3 20 mg once daily) was superior to monotherapy by evaluating several QOL, depression and anxiety rating scales as well as patients own preference.
TL;DR: A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort, and novel strategies of P OF phenotyping are in such content mandatory to improve the rate of PTO patients for whom etiology is identified.
Abstract: Objective: Premature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis. Design and methods: We performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center. Results: Seventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turner’s syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1. Conclusion: A genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.
TL;DR: In obese children and adolescents, increased UA levels are associated with carotid atherosclerosis, and this association was significant when multivariate analysis was performed after adjusting for age, gender, pubertal stage, creatinine, and MS.
Abstract: Objective: The association between hyperuricemia, metabolic syndrome (MS), and atherosclerotic vascular disease has been reported in adults, but very little is known about this association in children. The aims of our study were to ascertain the correlates of uric acid (UA) in a sample of obese children, and to investigate whether UA is associated with carotid intima-media thickness (IMT) independently from classical risk factors including MS. Methods: We analyzed carotid IMT along with serum triglycerides, total and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), alanine aminotransferase, g-glutamyltransferase, creatinine, and UA in 120 obese children and 50 healthy control children. Results: UA concentrations were significantly higher in obese children compared with controls; moreover, they correlated with the most established cardiovascular risk factors. In the group of obese children, after adjustment for age, sex, pubertal stage, and creatinine, an independent association between UA levels and the presence of MS syndrome was observed (unstandardized coefficient, 0.044 (95% confidence intervals (CI) 0.015‐0.072); P!0.01). Carotid IMT significantly increased in the fourth quartile of UA compared with that in the first, second, and third quartile (0.49 (0.46‐0.53), 0.53 (0.49‐0.56), and 0.55 (0.52‐0.59) vs 0.61 (95% CI, 0.58‐0.64); P!0.01). When multivariate analysis was performed after adjusting for age, gender, pubertal stage, creatinine, and MS (considered as a single clinical entity), or the individual components of MS simultaneously included, the association between UA and carotid IMT was significant (P!0.01). Conclusions: In obese children and adolescents, increased UA levels are associated with carotid atherosclerosis.
TL;DR: Long-term combined treatment with SSA and twice weekly PEG-V up to more than 4 years seems to be safe and a clinical significant decrease in tumor size was observed in 14 patients during combined treatment.
Abstract: Background: We previously reported on the efficacy, safety, and quality of life (QoL) of long-acting somatostatin analogs (SSA) and (twice) weekly pegvisomant (PEG-V) in acromegaly and improvement after the addition of PEG-V to long-acting SSA. Objective: To assess the long-term safety in a larger group of acromegalic patients over a larger period of time: 29.2 (1.2‐57.4) months (mean (range)). Design: Pegvisomant was added to SSA monotherapy in 86 subjects (37 females), to normalize serum IGF1 concentrations (nZ63) or to increase the QoL. The median dosage was 60.0 (20‐200) mg weekly. Results: After a mean treatment period of 29.2 months, 23 patients showed dose-independent PEG-V related transient liver enzyme elevations (TLEE). TLEE occurred only once during the continuation of combination therapy, but discontinuation and re-challenge induced a second episode of TLEE. Ten of these patients with TLEE also suffered from diabetes mellitus (DM). In our present series, DM had a 2.28 odds ratio (CI 1.16‐9.22; pZ0.03) higher risk for developing TLEE. During the combined therapy, a clinical significant decrease in tumor size by more than 20% was observed in 14 patients. Two of these patients were previously treated by pituitary surgery, 1 with additional radiotherapy and all other patients received primary medical treatment. Conclusion: Long-term combined treatment with SSA and twice weekly PEG-V up to more than 4 years seems to be safe. Patients with both acromegaly and DM have a 2.28 higher risk of developing TLEE. Clinical significant tumor shrinkage was observed in 14 patients during combined treatment.
TL;DR: SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present.
Abstract: Objective
Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD) We hypothesized that NR5A1 mutations could be identified in boys with hypospadias