Showing papers in "Clinical Endocrinology in 2008"

Primary ovarian insufficiency : a more accurate term for premature ovarian failure

Abstract: Premature ovarian failure (POF) is a disorder with a complicated clinical presentation and course that is poorly defined by its name. A more scientifically accurate term for the disorder is primary ovarian insufficiency (POI), a term that can be appropriately modified to describe the state of ovarian function. In recent years, the known aetiologies of POI have expanded, although the cause of POI in a majority of clinical cases remains undefined. The most common aetiologies should be ruled out clinically including chromosomal abnormalities, fragile X premutations and autoimmune causes. Management should be directed at symptom resolution and bone protection, but most importantly should include psychosocial support for women facing this devastating diagnosis.

Severe hypomagnesaemia in long‐term users of proton‐pump inhibitors

Abstract: Summary Objective To explore the mechanism underlying severe hypomagnesaemia in long-term users of proton-pump inhibitors (PPIs). Patients Two cases of severe hypomagnesaemia in adult long-term users of the PPI omeprazole, presenting with hypocalcaemic seizures. Measurements We studied renal magnesium handling during an incremental intravenous magnesium infusion, and assessed total body magnesium status by the 24-h retention of the parenteral load. We also observed the effects of oral magnesium supplements whilst continuing the PPI, and the effect of withdrawal of the PPI. Results Both patients were severely magnesium-depleted and had avid renal magnesium retention, implicating a failure of intestinal magnesium absorption. There was no evidence of generalized malabsorption. The hypomagnesaemia could be partially corrected by high dose oral magnesium supplementation, and resolved on withdrawal of PPIs. Conclusions PPI use can inhibit active magnesium transport in the intestine, though it is not clear if this is an idiosyncratic effect. Long-term PPI users who are highly adherent to treatment can eventually deplete total body magnesium stores and present with severe complications of hypomagnesaemia.

Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency

Abstract: OBJECTIVES: Primary adrenocortical insufficiency is mostly caused by an autoimmune destruction of the adrenal cortex. The disease may appear isolated or as a part of an autoimmune polyendocrine syndrome (APS). APS1 is a rare hereditary disorder with a broad spectrum of clinical manifestations. In APS2, primary adrenocortical insufficiency is often combined with autoimmune thyroid disease and/or type 1 diabetes. We analysed mortality and cancer incidence in primary adrenocortical insufficiency patients during 40 years. Data were compared with the general Swedish population. DESIGN AND PATIENTS: A population based cohort study including all patients with autoimmune primary adrenocortical insufficiency (3299) admitted to Swedish hospitals 1964-2004. MEASUREMENTS: Mortality risk was calculated as the standardized mortality ratio (SMR) and cancer incidence as the standardized incidence ratio (SIR). RESULTS: A more than 2-fold increased mortality risk was observed in both women (SMR 2.9, 95% CI 2.7-3.0) and men (SMR 2.5, 95% CI 2.3-2.7). Highest risks were observed in patients diagnosed in childhood. SMR was higher in APS1 patients (SMR 4.6, 95% CI 3.5-6.0) compared with patients with APS2 (SMR 2.1, 95% CI 1.9-2.4). Cancer incidence was increased (SIR 1.3, 95% CI 1.2-1.5). When tumours observed during the first year of follow-up were excluded, only the cancer risk among APS1 patients remained increased. Cause-specific cancer incidence analysis revealed significantly higher incidences of oral cancer, nonmelanoma skin cancer, and male genital system cancer among patients. Breast cancer incidence was lower than in the general population. CONCLUSIONS: Our study shows a reduced life expectancy and altered cancer incidence pattern in patients with autoimmune primary adrenocortical insufficiency.

The GH-IGF-I axis and the cardiovascular system: clinical implications.

Abstract: Background GH and IGF-I affect cardiac structure and performance. In the general population, low IGF-I has been associated with higher prevalence of ischaemic heart disease and mortality. Both in GH deficiency (GHD) and excess life expectancy has been reported to be reduced because of cardiovascular disease. Objective To review the role of the GH-IGF-I system on the cardiovascular system. Results Recent epidemiological evidence suggests that serum IGF-I levels in the low-normal range are associated with increased risk of acute myocardial infarction, ischaemic heart disease, coronary and carotid artery atherosclerosis and stroke. This confirms previous findings in patients with acromegaly or with GH-deficiency showing cardiovascular impairment. Patients with either childhood- or adulthood-onset GHD have cardiovascular abnormalities such as reduced cardiac mass, diastolic filling and left ventricular response at peak exercise, increased intima-media thickness and endothelial dysfunction. These abnormalities can be reversed, at least partially, after GH replacement therapy. In contrast, in acromegaly chronic GH and IGF-I excess causes a specific cardiomyopathy: concentric cardiac hypertrophy (in more than two-thirds of the patients at diagnosis) associated to diastolic dysfunction is the most common finding. In later stages, impaired systolic function ending in heart failure can occur, if GH/IGF-I excess is not controlled. Abnormalities of cardiac rhythm and of cardiac valves can also occur. Successful control of acromegaly is accompanied by decrease of the left ventricular mass and improvement of cardiac function. Conclusion The cardiovascular system is a target organ for GH and IGF-I. Subtle dysfunction in the GH-IGF-I axis are correlated with increased prevalence of ischaemic heart disease. Acromegaly and GHD are associated with several abnormalities of the cardiovascular system and control of GH/IGF-I secretion reverses (or at least stops) cardiovascular abnormalities.

The incidence of autoimmune thyroid disease: A systematic review of the literature

Abstract: Summary Objective To undertake a systematic review of literature published between 1980 and 2008 on the incidence of autoimmune thyroid disease. Design All relevant papers found through searches of Medline, EMBASE and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. Results The reported incidence of autoimmune hypothyroidism varied between 2·2/100 000/year (males) and 498·4/100 000/year (females) and for autoimmune hyperthyroidism, incidence ranged from 0·70/100 000/year (Black males) to 99/100 000/year (Caucasian females). Higher incidence rates were found in women compared to men for all types of autoimmune thyroid disease. The majority of studies included in the review investigated Caucasian populations mainly from Scandinavia, Spain, the UK and the USA. It is possible that nonautoimmune cases were included in the incidence rates reported here, which would give an overestimation in the incidence rates of autoimmune disease presented. Conclusion To our knowledge this is the most comprehensive systematic review of autoimmune thyroid disease conducted in the past two decades. Studies of incidence of autoimmune thyroid disease have only been conducted in a small number of mainly western countries. Our best estimates of the incidence of hypothyroidism is 350/100 000/year in women and 80/100 000/year in men; the incidence of hyperthyroidism is 80/100 000/year in women and 8/100 000/year in men.

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas.

Abstract: Summary Objective Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age- and gender-specific standard deviations (SD) scores (Z-scores) of QoL parameters in patients treated for pituitary adenomas. Patients and methods We determined Z-scores for health-related questionnaires [the Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI)-20, Nottingham Health Profile (NHP), and Short Form Health Survey (SF-36)] in patients during long-term follow-up (13 ± 8 years) after treatment for pituitary adenomas. Z-scores were calculated by comparing the data for 403 patients with acromegaly (n = 118), Cushing's disease (CD; n = 58), prolactinoma (n = 128), and nonfunctioning macroadenoma (n = 99) with a control population (n = 440) for each subscale of the questionnaires and for total QoL score. Results All subscales of the questionnaires and the total QoL score were negatively affected in patients compared to controls. Comparing the Z-scores, patients treated for acromegaly reported more impairment in physical ability and functioning and more bodily pain compared to patients treated for nonfunctioning macroadenoma and those treated for prolactinoma. Patients with CD reported impairment in physical functioning compared to patients treated for nonfunctioning macroadenoma. Linear regression analysis, with correction for age and gender, confirmed these findings. Additionally, CD was associated with increased anxiety. Hypopituitarism negatively influenced multiple aspects of QoL. Conclusion QoL is impaired in patients during long-term follow-up after treatment of pituitary adenomas. Patients with pituitary adenomas should be informed of these persistent adverse effects of their disease on QoL to prevent inappropriate expectations with respect to the long-term results of treatment.

Increased serum advanced glycation end-products is a distinct finding in lean women with polycystic ovary syndrome (PCOS).

Abstract: Summary Background Nonenzymatic advanced glycation and oxidation end-products, advanced glycation end-products (AGEs), impart a potent impact on vessels and other tissues in diabetic state and in euglycaemic conditions with increased oxidative stress. Insulin resistant (IR) polycystic ovary syndrome (PCOS) women, have elevated serum AGEs, increased receptor (RAGE) expression, and increased deposition with differential localization in the polycystic ovarian tissue (theca and granulosa) compared to normal. Objective To determine whether the raised AGE levels in noninsulin resistant women with PCOS is a distinct finding compared with those presenting the isolated components of the syndrome and among PCOS subphenotypes. Noninsulin resistant women were selected in order to show that serum AGEs are elevated in PCOS independently of the presence of IR. Design Clinical trial. Patients One hundred and ninety-three age- and BMI-matched young lean noninsulin resistant women were studied. Among them, 100 women were diagnosed with PCOS according to Rotterdam criteria, and divided to subphenotypes (hyperandrogenaemia with or without PCO morphology and with or without anovulation). Sixty-eight women with the isolated components of the PCOS phenotype were also studied along with 25 healthy women. Measurements Serum AGE levels, metabolic, hormonal profiles and intravaginal ultrasound were determined in all subjects. Results The studied population did not differ in BMI, fasting insulin concentration, waist : hip and glucose : insulin ratios. PCOS women exhibited statistically higher AGEs levels (7·96 ± 1·87 U/ml, P < 0·001) compared with those with isolated hyperandrogenaemia (5·61 ± 0·61 U/ml), anovulation (5·53 ± 1·06 U/ml), US-PCO morphology (5·26 ± 0·25 U/ml) and controls (5·86 ± 0·89 U/ml). Conclusions In PCOS, serum AGEs are distinctly elevated compared with women having the isolated characteristics of the syndrome. No difference was observed between PCOS subphenotypes. As chronic inflammation and increased oxidant stress have been incriminated in the pathophysiology of PCOS, the role of AGEs as inflammatory and oxidant mediators, may be linked with the metabolic and reproductive abnormalities of the syndrome.

Primary hyperparathyroidism and the skeleton

Abstract: Today, primary hyperparathyroidism (PHPT) in the developed countries is typically a disease with few or no obvious clinical symptoms. However, even in the asymptomatic cases the endogenous excess of PTH increases bone turnover leading to an insidious reversible loss of cortical and trabecular bone because of an expansion of the remodelling space and an irreversible loss of cortical bone due to increased endocortical resorption. In contrast trabecular bone structure and integrity to a large extent is maintained and there may be a slight periosteal expansion. Most studies have reported decreased bone mineral density (BMD) in PHPT mainly located at cortical sites, whereas sites rich in trabecular bone only show a modest reduction or even a slight increase in BMD. The frequent occurrence of vitamin D insufficiency and deficiency in PHPT and increased plasma FGF23 levels may also contribute to the decrease in BMD. The effect of smoking is unsolved. Epidemiological studies have shown that the relative risk of spine and nonspine fractures is increased in untreated PHPT starting up to 10 years before the diagnosis is made. Successful surgery for PHPT normalizes bone turnover, increases BMD and decreases fracture risk based on larger epidemiological studies. However, 10 years after surgery fracture risk appears to increase again due to an increase in forearm fractures. There are no randomized controlled studies (RCTs) demonstrating a protective effect of medical treatment on fracture risk in PHPT. Less conclusive studies suggest that vitamin D supplementation may have a beneficial effect on plasma PTH and BMD in vitamin D deficient PHPT patients. Hormone replacement therapy (HRT) and maybe SERM appear to reduce bone turnover and increase BMD. However, their nonskeletal side-effects preclude their use for this purpose. Bisphosphonates reduce bone turnover and increase BMD in PHPT as in osteoporosis and may be a therapeutical option in selected patients with low BMD. Obviously, there is a need for larger RCTs with fractures as end-points that appraise this possibility. Calcimimetics reduce plasma calcium and PTH in PHPT but has no beneficial effect on bone turnover or BMD. In symptomatic hypercalcaemic PHPT with low BMD where curative surgery is impossible or contraindicated a combination of a calcimimetic and a bisphosphonate may be an undocumented therapeutical option that needs further evaluation.

Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review*

Abstract: Summary Background An association between radioiodine therapy (RAI) for Graves’ disease (GD) and the development or worsening of Graves’ ophthalmopathy (GO) is widely quoted but there has been no systematic review of the evidence. Aims We undertook a systematic review of randomized controlled trials (RCTs) to assess whether RAI for GD is associated with increased risk of ophthalmopathy compared with antithyroid drugs (ATDs) or surgery. We also assessed the efficacy of glucocorticoid prophylaxis in the prevention of occurrence or progression of ophthalmopathy, when used with RAI. Methods We identified RCTs regardless of language or publication status by searching six databases and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Random effects meta-analyses were used to combine the study data. Ten RCTs involving 1136 patients permitted 13 comparisons. Two RCTs compared RAI with ATD. Two RCTs compared RAI with thyroidectomy. Four RCTs compared the use of adjunctive ATD with RAI vs. RAI. Five RCTs examined the use of glucocorticoid prophylaxis with RAI. Results RAI was associated with an increased risk of ophthalmopathy compared with ATD [relative risk (RR) 4·23; 95% confidence interval (CI): 2·04 ‐8 ·77] but compared with thyroidectomy, there was no statistically significant increased risk (RR 1·59, 95% CI 0·89‐2·81). The risk of severe GO was also increased with RAI compared with ATD (RR 4·35; 95% CI 1·28‐14·73). Prednisolone prophylaxis for RAI was highly effective in preventing the progression of GO in patients with pre-existing GO (RR 0·03; 95% CI 0·00‐0·24). The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO. Conclusion RAI for GD is associated with a small but definite increased risk of development or worsening of Graves’ ophthalmopathy compared with ATDs. Steroid prophylaxis is beneficial for patients with pre-existing GO.

Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods.

Abstract: Summary Background Familial hypocalciuric hypercalcaemia (FHH) must be differentiated from primary hyperparathyroidism (PHPT) because prognosis and treatment differ. In daily practice this discrimination is often based on the renal calcium excretion or the calcium/creatinine clearance ratio (CCCR). However, the diagnostic performance of these variables is poorly documented. Aim To appraise the power of various simple biochemical variables to differentiate between FHH and PHPT using calcium sensing receptor (CASR) gene analysis and histopathological findings as gold standards. Design Follow-up approach (direct design). Materials We included 54 FHH patients (17 males and 37 females, aged 18–75 years) with clinically significant mutations in the CASR gene and 97 hypercalcaemic patients with histologically verified PHPT (17 males and 80 females, aged 19–86 years). All PHPT patients became normocalcaemic following successful neck exploration. Results Based on receiver operating characteristic (ROC) curve analysis, the CCCR was only marginally better, as judged by the area under curve (AUC = 0·923 ± 0·021 (SE)), than the 24-h calcium/creatinine excretion ratio (AUC = 0·903 ± 0·027) and the 24-h calcium excretion (AUC = 0·876 ± 0·029). However, overlap performance analysis disclosed that the CCCR included fewer patients with PHPT together with the FHH patients than the other two variables at different cut-off points. Based on the ROC curve, the optimal cut-off point for diagnosing FHH using CCCR was < 0·0115, which yielded a diagnostic specificity of 0·88 and a sensitivity of 0·80. Overlap analysis revealed that a cut-off point for CCCR at < 0·020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients. Conclusion Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two-step diagnostic procedure, where the first step is based on the CCCR with a cut-off at < 0·020, and the second step is CASR gene analysis in patients with FHH or PHPT.

Prevalence of metabolic syndrome (MS) in children and adolescents with varying degrees of obesity

Abstract: Summary Objective Childhood obesity is increasingly common and is associated with health problems; in particular, obesity plays a central role in the metabolic syndrome (MS). We estimated the prevalence of MS in Caucasian children and adolescents with varying degrees of obesity. Patients and methods We studied 191 obese [body mass index (BMI) > 97th percentile] children and adolescents. Obesity was stratified on the basis of a threshold BMI z-score and subjects were classified as moderately (z-score 2–2·5) or severely obese (z-score > 2·5). Seventy-six, nonobese subjects were recruited into a comparison group. Thirty-one of them were of normal weight (BMI < 75th percentile) and 45 overweight (BMI 75th–97th percentile). Patients were classified as having MS if they met three or more of the following criteria for age and sex: BMI > 97th percentile, triglyceride levels > 95th percentile, high density lipoprotein (HDL) cholesterol level 95th percentile and impaired glucose tolerance (blood glucose level: 7·8–11·1 mmol/l at 2 h). Insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) and impaired insulin sensitivity was defined as a HOMA-IR ≥ 2·5 in prepubertal patients and HOMA-IR > 4 in pubertal subjects. Results The overall prevalence of MS was 13·9% and was present in 12·0% of moderately obese and 31·1% of severely obese subjects; no overweight or normal weight subjects met the criteria for MS. The rate of the MS increased progressively with increasing BMI categories (P < 0·001). Severely obese patients had a threefold increased risk with respect to moderately obese patients. Conclusions The prevalence of the MS is higher in obese as opposed to nonobese subjects and increases with severity of obesity.

Radioiodine therapy (RAI) for Graves' disease (GD) and the effect on ophthalmopathy : a systematic review. Commentary

Abstract: Background An association between radioiodine therapy (RAI) for Graves' disease (GD) and the development or worsening of Graves' ophthalmopathy (GO) is widely quoted but there has been no systematic review of the evidence. Aims We undertook a systematic review of randomized controlled trials (RCTs) to assess whether RAI for GD is associated with increased risk of ophthalmopathy compared with antithyroid drugs (ATDs) or surgery. We also assessed the efficacy of glucocorticoid prophylaxis in the prevention of occurrence or progression of ophthalmopathy, when used with RAI. Methods We identified RCTs regardless of language or publication status by searching six databases and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Random effects meta-analyses were used to combine the study data. Ten RCTs involving 1136 patients permitted 13 comparisons. Two RCTs compared RAI with ATD. Two RCTs compared RAI with thyroidectomy. Four RCTs compared the use of adjunctive ATD with RAI vs. RAI. Five RCTs examined the use of glucocorticoid prophylaxis with RAI. Results RAI was associated with an increased risk of ophthalmopathy compared with ATD [relative risk (RR) 4·23; 95% confidence interval (CI): 2·04-8-77] but compared with thyroidectomy, there was no statistically significant increased risk (RR 1·59, 95% CI 0·89-2·81). The risk of severe GO was also increased with RAI compared with ATD (RR 4·35; 95% CI 1-28-14-73). Prednisolone prophylaxis for RAI was highly effective in preventing the progression of GO in patients with pre-existing GO (RR 0·03; 95% CI 0·00-0·24). The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO. Conclusion RAI for GD is associated with a small but definite increased risk of development or worsening of Graves' ophthalmopathy compared with ATDs. Steroid prophylaxis is beneficial for patients with pre-existing GO.

A systematic review examining the effects of therapeutic radioactive iodine on ovarian function and future pregnancy in female thyroid cancer survivors

Abstract: Background For women with differentiated thyroid carcinoma (DTC), the effect of radioactive iodine (RAI) therapy on gonadal and reproductive function is an important consideration. Objective and methods We systematically reviewed controlled studies examining the gonadal and reproductive effects of RAI therapy in women and adolescents surviving DTC. We searched nine electronic databases. All abstracts and papers were independently reviewed by two reviewers. Results After reviewing 349 unique citations and 61 full-text papers, 16 papers including data from 3023 women or adolescents with DTC were included. All studies were observational, with no long-term randomized control trial data. The age at first RAI treatment varied from 8 to 50 years and the cumulative activities of RAI administered for treatment varied from 30 to 1099 mCi. Transient absence of menstrual periods occurred in 8-27% of women within the first year after RAI, particularly in older women. In addition, RAI-treated women experienced menopause at a slightly younger age than women not treated with RAI. In the first year after RAI therapy, several studies reported increased rates of spontaneous and induced abortions. However, RAI treatment for DTC was generally not associated with a significantly increased risk of long-term infertility, miscarriage, induced abortions, stillbirths, or offspring neonatal mortality or congenital defects. Conclusions In female survivors of DTC, there is little observational evidence to suggest important adverse effects of RAI treatment on gonadal function, fertility or pregnancy outcomes beyond 12 months, with the exception of a possible slightly earlier age of menopause.

Molecular characteristics in papillary thyroid cancers (PTCs) with no 131I uptake

Abstract: Summary Objective Papillary thyroid cancers (PTCs) with no iodine uptake have an aggressive behaviour and a poor prognosis. The aim of our study was to characterize, at molecular level, a subset of PTC with no 131 iodine (131I) uptake. Design and methods Forty-eight cancer tissues were divided into three groups: Group 1, 28 primary cancers; Group 2, 7 recurrences capable of trapping 131I; and Group 3, 13 recurrences incapable of trapping 131I. mRNA levels of thyroid genes (sodium/iodide symporter NIS, thyroglobulin, thyroperoxidase and pendrin) and glycolytic metabolism genes (GLUT-1, hexokinase I and II) and BRAF mutations were evaluated in the different groups. Results Cancers with no 131I uptake had slightly reduced NIS, significantly reduced thyroglobulin (P < 0·01), thyroperoxidase (P = 0·01) and pendrin (P = 0·03) and significantly increased GLUT-1 (P = 0·01) gene expression levels; and a high frequency of BRAF mutations (77%). BRAFV600E mutation, in both primary and metastatic thyroid cancers, is associated with a marked drop in thyroperoxidase (29-fold) and pendrin (20-fold) expression and a considerable increase (five-fold) in GLUT-1 expression. Conclusions (1) The loss of 131I uptake in recurrences depends not only on a decrease in NIS gene, but possibly on a reduction in the molecules regulating its intracellular metabolism; (2) the high GLUT-1 gene expression supports the use of positron emission tomography with specific tracers in clinical management of such cancers; and (3) BRAFV600E point mutations may lead to less differentiated phenotypes, suggesting a worse prognosis.

Increased serum visfatin in patients with metabolic syndrome and carotid atherosclerosis

Abstract: OBJECTIVE Visfatin is a newly identified adipocytokine and recent studies indicated that visfatin may have potential proinflammatory effect. However, its pathophysiological role in the metabolic syndrome (MetS) is not fully understood. In this study we investigated whether serum visfatin levels is altered in patients with the MetS, and compared the levels of visfatin between patients with and without carotid plaques. DESIGN AND METHOD A total of 139 patients with MetS and 105 controls were included. The patients were further divided into two groups: 40 with carotid plaques and 99 without carotid plaques. Serum visfatin was measured by using enzyme immunoassay method and carotid intimal-media thickness (IMT) was measured by ultrasound in all subjects. RESULTS Serum visfatin was elevated in both MetS patients with and without carotid plaques compared to controls (log visfatin: 1.14 +/- 0.14 vs. 0.99 +/- 0.17 ng/ml vs. 0.93 +/- 0.23 ng/ml, P 1.08 ng/ml had 70% sensitivity and 67% specificity for detecting patients with carotid plaques. CONCLUSIONS/INTERPRETATION Our results showed that serum visfatin was increased in patients with MetS, especially in those with carotid plaques. Visfatin may be an inflammatory marker of MetS.

First trimester adipocytokine concentrations and risk of developing gestational diabetes later in pregnancy

Abstract: Summary Objective Adipocytokines are important regulators of insulin resistance. The aim of this study was to compare maternal adipocytokines in early pregnancy among women diagnosed with and without gestational diabetes (GDM) months later. Design A nested case-control study. Patients Adiponectin, resistin and interleukin-6 (IL-6) were measured in 59 nulliparous women (30 women with GDM and 29 controls) in plasma obtained in early pregnancy. Patients underwent routine testing for GDM in late pregnancy. Measurements Adiponectin was measured using radioimmunoassay. Resistin and IL-6 were measured by ELISA. Statistical analysis included Student's t-test, logistic regression and Pearson's correlation. Results Groups were not different by baseline descriptors or obstetric outcomes. Mean gestational age at sampling was 9·3 ± 2·6 weeks. Adiponectin was lower (P < 0·001) in women who later developed GDM compared to controls (4·3 ± 0·4 vs. 6·9 ± 0·6 µg/ml). Adiponectin was negatively associated with the development of GDM (P = 0·002; OR: 0·70, 95% CI: 0·56, 0·88) and the association persisted in multivariable analysis controlling for confounders (P = 0·01; OR: 0·69, 95% CI: 0·52, 0·92). Women with first trimester adiponectin concentrations < 25th% were 10 times more likely to be diagnosed with GDM (OR 10·2; 95% CI 1·3, 78·7). Early adiponectin concentrations negatively correlated with BMI (P = 0·01; r = –0·32) and subsequent 50 g glucose challenge (P = 0·03; r =–0·29). Mean resistin and IL-6 concentrations were not different between the two groups. Conclusions Women with GDM have evidence of altered adipocyte function as measured by adiponectin early in pregnancy, months before the clinical diagnosis of GDM is traditionally made.

Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome.

Abstract: BACKGROUND: Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited. OBJECTIVE: To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls. DESIGN/PATIENTS: Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group (n = 15) receiving 1 mg/m(2)/day GH or a non-GH-treated control group (n = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated. RESULTS: Infants in the GH group had a median age of 2.3 years [interquartile range (IQR) 1.7-3.0] and in the control group of 1.5 years (IQR 1.2-2.7) (P = 0.17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9.3% (-5.3 to 13.3) vs.-2.9% (-8.1 to 4.9) (P < 0.05) in mental development and +11.2% (-4.9 to 22.5) vs.-18.5% (-27.9 to 1.8) (P < 0.05) in motor development, respectively. CONCLUSION: One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.

BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma.

Abstract: PURPOSE BRAF(V600E) mutation represents the most common oncogenic event in sporadic papillary thyroid cancer (PTC). There are, however, significant discrepancies regarding the overall frequency, its prevalence in PTC-variants, and its relationship with clinico-pathological parameters of poor outcome. Moreover, the impact of BRAF(V600E) mutants on tumour-related patient's death has not been evaluated. DESIGN We analysed, by PCR-SSCP and/or PCR-direct sequencing, exons 8, 10, 11 and 15 of BRAF in 113 tumour samples from 49 PTC-patients. Matched lymph node metastases and/or distant metastases (DMs) were screened in 35 patients. Focal changes in the growth pattern or microscopic grade within the primary tumour (Pt) or the metastases were separately genotyped. Mutations at H-, K-, N-ras and PIK3CA exons 9 and 20 were also investigated. For comparison with PTC cases, the BRAF and Ras mutational status was evaluated in 89 specimens obtained from 24 poorly differentiated thyroid carcinomas (PDCs) and 36 anaplastic thyroid carcinomas (ATCs). RESULTS BRAF(V600E) was found in 13/16 classical PTCs (CL-PTCs), 6/17 follicular variant PTCs (FV-PTCs) and 8/16 mixed (papillary/follicular) PTCs (Mx-PTCs), being significantly associated with CL-PTCs (P = 0.015). BRAF(V600E) segregated with metastatic PTC-cells in 43% of the patients, but only one DM disclosed the mutation. PTC-tumours featuring concurrent less-differentiated foci were BRAF wild-type in both components. Noteworthy, the frequency of BRAF mutations among PDCs and ATCs resulted considerably lower (16.6% and 25%, respectively) than in PTCs (55%). The prevalence of Ras mutations among PDCs and ATCs (46% and 36%, respectively) was, however, much higher than in PTCs (14%). Five (71%) of the patients who died of PTC displayed somatic mutations. Four of them had other gene alteration associated with BRAF(V600E) and the only one that did not, BRAF(V600E) was restricted to the Pt. The occurrence of BRAF(V600E) associated with other genetic events was an independent predictor of DMs during follow-up, recurrence and tumour-related death. Remarkably, two PDCs (8.3%) and five ATCs (14%) revealed concurrent BRAF and Ras mutations. CONCLUSION BRAF(V600E)'alone' does not represent a marker for poor outcome, however, when associated with alterations in other genes identifies a subset of PTCs with increased risk of recurrence and decreased survival.

Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study.

Abstract: Summary Objective Cabergoline is a dopamine agonist used to treat hyperprolactinaemia. Because hyperprolactinaemia is a significant cause of infertility in women, cabergoline and other dopamine agonists are frequently prescribed to reduce prolactin levels and restore normal menses. They are usually discontinued shortly after the patient becomes pregnant. Although cabergoline has been used to treat hyperprolactinaemia since the mid-1990s, safety data related to maternal and foetal exposure to this agent are still limited. Design The current prospective, observational study reports on a total of 380 pregnancies. This extends by 154 pregnancies the results of a previously published interim report on the outcomes of 226 pregnancies in women treated with cabergoline up to 1994. Main outcome measures Outcomes examined include the incidence of abortions and premature delivery and the number and types of foetal malformations or abnormalities. Results Follow-up data were available for 329 pregnancies, including 258 (78%) deliveries and 71 (22%) abortions. Of the 71 reported abortions, 31 (44%) were voluntary, 30 (42%) were spontaneous miscarriages, and nine (13%) were therapeutic. Of the 258 deliveries, 250 (97%) were live deliveries, four (2%) were stillbirths, and the status of delivery was unknown for the remaining four (2%). Of the 250 live deliveries, 193 (77%) were term deliveries (gestational period > 37 weeks), 45 (18%) were preterm deliveries (gestational period ≤ 37 weeks), and 62% of the infants had normal birthweights (i.e. 3–4 kg). Neonatal abnormalities were recorded for 23 (9%) of the infants with no apparent pattern in type or severity. Conclusion The results of this study suggest that foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation.

123I-metaiodobenzylguanidine (MIBG) scintigraphy for the detection of adrenal and extra-adrenal phaeochromocytomas: CT and MRI correlation

Abstract: Context Evidence regarding the accuracy of [(123)I] metaiodobenzylguanidine (MIBG) imaging for phaeochromocytoma localization is currently limited to small series. Objective We present the largest series of primary phaeochromocytomas in which the performance of [(123)I]MIBG has been evaluated and correlated with cross-sectional imaging. Design We identified 76 patients with both preoperative [(123)I]MIBG and cross-sectional imaging for confirmed primary phaeochromocytoma between 1995 and 2005 at our institution. This comprised 60 adrenal tumours in 55 patients and 33 extra-adrenal tumours in 23 patients (2 patients had both adrenal and extra-adrenal tumours). Phaeochromocytoma metastases were not evaluated. Main outcome measure(s) [(123)I]MIBG studies were independently reviewed and correlated with CT and MRI examinations, as well as tumour functional status, to identify features that may predict a false negative [(123)I]MIBG result. Results The overall sensitivity of [(123)I]MIBG was 75%. Tumour detection was lower for extra-adrenal (58%) vs. adrenal (85%) phaeochromocytomas (P = 0.005). For extra-adrenal tumours, [(123)I]MIBG demonstrated 8 of 14 carotid body, 2 of 2 intrathoracic, 8 of 14 retroperitoneal and 2 of 3 pelvic phaeochromocytomas. Overall, MRI and CT demonstrated 68 of 68 and 72 of 74 primary phaeochromocytomas, respectively. Tumour size correlated with [(123)I]MIBG uptake for adrenal (P = 0.009) but not extra-adrenal tumours. When tumours were adjusted for size, no other imaging feature or functional status correlated with [(123)I]MIBG negativity, although two large [(123)I]MIBG negative adrenal tumours contained large areas of necrosis or haemorrhage. Conclusions Extra-adrenal and small adrenal phaeochromocytomas are more likely to result in false negatives on [(123)I]MIBG. Tumoural necrosis or haemorrhage do not consistently relate to [(123)I]MIBG uptake, although adrenal phaeochromocytomas containing minimal solid tissue due to extensive necrosis may predict a negative [(123)I]MIBG result.

Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome.

Abstract: Summary Background Prader–Willi syndrome (PWS) children have impaired growth, and abnormal body composition. Previous 1-year controlled studies showed improvement of height and body composition during GH-treatment. Objective To evaluate growth, body composition and body proportions during GH-treatment in a large group of PWS children. Design/patients We performed a randomized controlled GH trial in 91 prepubertal PWS children (42 infants, 49 children, aged 3–14 years). After stratification for age, infants were randomized to GH-treatment (GH-group; 1 mg/m2/day; n = 20), or no treatment (control group; n = 22) for 1 year. In the second year all infants were treated with GH. After stratification for BMI, children > 3 years of age were randomized to GH-treatment (GH-group; 1 mg/m2/day; n = 27) or no treatment (control group; n = 22) for 2 years. Anthropometric parameters were assessed once in every 3 months. Body composition was measured by Dual Energy X-ray Absorptiometry. Results Median (interquartile range, iqr) height SDS increased during 2 years of GH in infants from –2·3 (–2·8 to –0·7) to –0·4 (–1·1–0·0) and in prepubertal children from –2·0 (–3·1 to –1·7) to –0·6 (–1·1 to –0·1). In non-GH-treated children height SDS did not increase. Head circumference completely normalized during 1 and 2 years of GH in infants and children, respectively. Body fat percentage and body proportions improved in GH-treated children, but did not completely normalize. Lean body mass SDS improved compared to the control group. Serum IGF-I increased to levels above the normal range in most GH-treated children. Conclusions Our randomized study shows that GH-treatment in PWS children significantly improves height, BMI, head circumference, body composition and body proportions. PWS children are highly sensitive to GH, suggesting that monitoring of serum IGF-I is indicated.

The role of sex steroids in controlling pubertal growth.

Abstract: Longitudinal growth, which is primarily due to chondrocytic activity at the level of the epiphyseal growth plate, is influenced by many hormones and growth factors in an endocrine and paracrine manner. Their influence is even more complex during the accelerated growth period of puberty that accounts for about 20% of final adult height. Although abnormalities of growth during puberty are very common, the underlying mechanisms that govern the beginning and cessation of pubertal growth at the level of the growth plate are poorly understood. Sex steroids play a crucial role in pubertal growth both at the systemic level via the GH/IGF-1 axis and at the local level of the epiphyseal growth plate. In both sexes it is now accepted that oestrogen is the critical hormone in controlling growth plate acceleration and fusion. This paper reviews the mechanisms that influence pubertal growth and the problems that are associated with disorders of gonadal function.

The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma

Abstract: OBJECTIVE: Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels o ...

Utility of serum tartrate‐resistant acid phosphatase (TRACP5b) as a bone resorption marker in patients with chronic kidney disease: independence from renal dysfunction

Abstract: Summary Background Serum tartrate-resistant acid phosphatase (TRACP) 5b levels were assessed in predialysis patients with chronic kidney disease (CKD). The aim of the study was to establish the usefulness of a new assay for TRACP5b in assessing bone turnover in these patients. Methods Serum concentrations of two bone resorption markers, TRACP5b and N-terminal cross-linking telopeptide of type I collagen (NTX); two bone formation markers, bone specific alkaline phosphatase (bone ALP) and intact osteocalcin (OC[1–49]); and PTH were measured in 98 predialysis CKD patients. Results Log serum TRACP5b and other bone markers were significantly negatively correlated with glomerular filtration rate (GFR) and positively correlated with log serum PTH, suggesting an increase in serum bone markers with development of secondary hyperparathyroidism. Multiple regression analysis including age, gender, BMI, the presence of diabetes, GFR and log serum PTH showed an association of log serum PTH with log serum TRACP5b and other bone markers. GFR was associated with log serum NTX and log OC[1–49], but not with log serum TRACP5b or log bone ALP. These data show that renal dysfunction does not influence serum TRACP5b and bone ALP, but has an influence on NTX and OC[1–49]. Conclusion Serum TRACP5b may be a good marker for serum bone resorption in predialysis CKD patients, as it is not affected by renal dysfunction.

High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels.

Abstract: Summary Objective The estimated prevalence of acromegaly is 40–125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known how many subjects with increased IGF-1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF-1 levels. Design A cross-sectional, epidemiological study (the DETECT study). Patients A total of 6773 unselected adult primary care patients were included. Measurements We measured IGF-1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF-1 levels (> 2 age-dependent SDS). Results Of 125 patients with elevated IGF-1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients. Conclusions Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.

Changes in gut hormones after bariatric surgery

Abstract: Bariatric surgery is one of the most effective treatments for achieving long-term weight loss in morbidly obese patients. Bariatric surgery causes weight loss through substantial decline of hunger and increased satiety. Recently our understanding of neuroendocrine regulation of food intake and weight gain, especially regarding the role of gut hormones, has significantly increased. The changes in these hormones following bariatric surgery can partly explain the mechanism behind weight loss achieved through these procedures. In this paper, we review the effect bariatric procedures have on different gut hormone levels and how they in turn can alter the complex neuroendocrine regulation of energy homeostasis.

Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study.

Abstract: Summary Objective It has been recently demonstrated that traumatic brain injury (TBI)-mediated hypopituitarism could be more frequent than previously known However, most of the previous data were obtained from retrospective studies, and the natural history of the hypopituitarism due to TBI is still unclear So far no study has been reported in which the pituitary function of the same patients has been investigated more than 1 year after TBI Therefore, we report the results of 3 years prospective follow-up of anterior pituitary function in patients with mild, moderate and severe TBI Patients and design Thirty patients (25 males, 5 females; age 37·2 ± 2·4 years) with TBI were included in the study Pituitary function was evaluated at 1 and 3 years after TBI Results After individual evaluation of GH deficiency from 1 year to 3 years after TBI, 7 of 13 (53·8%) GH-deficient patients at 1st year recovered after 3 years of TBI, and GH deficiency detected at 3 years in one patient was new onset Additionally, five of six (83·3%) ACTH-deficient patients at 1st year recovered after 3 years of TBI, and ACTH deficiency detected at 3 years in one patient was new onset Conclusions GH deficiency is the most common pituitary deficit 1 and 3 years after TBI In patients with mild and moderate TBI, pituitary function improves over time in a considerable number of patients, but it may also worsen rarely over the 3-year period In patients with severe TBI, ACTH and GH deficiencies at 1st year evaluation persist at 3rd year

Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide.

Abstract: Summary Background Macroadenomas causing acromegaly are cured surgically in only around 50% of patients. Primary medical treatment with somatostatin analogues has been suggested to be a means of treating patients with a potentially poor surgical outcome. Previous retrospective studies have also suggested that surgical debulking of pituitary tumours causing acromegaly improves control by somatostatin analogues. No prospective study using lanreotide has been carried out thus far to assess whether this is the case. Objective We carried out a prospective study to assess whether surgical debulking of pituitary macroadenomas causing acromegaly improved the subsequent control of acromegaly by the somatostatin analogue lanreotide. Patients and methods We treated 26 consecutive patients [10 males and 16 females – median age 53·5 years (range 22–70)] with macroadenoma causing acromegaly unselected for somatostatin response for 16 weeks with lanreotide, maximizing GH and IGF-I suppression, if necessary, by incremental dosing. Surgical resection was carried out and the patients were re-assessed off medical treatment at 16 weeks following surgery. Those with nadir GH > 2 mU/l in the oral glucose tolerance test (OGTT) and a mean GH in the GH day curve (GHDC) > 5 mU/l were subsequently restarted on lanreotide and the responses were assessed at the same time points as during the preoperative lanreotide treatment. Results GH values fell on lanreotide treatment and prior to surgery they were considered ‘safe’ (mean GH in GHDC 2 mU/l in the OGTT and ‘unsafe’ GH levels (mean GH in GHDC > 5 mU/l); on re-exposure to lanreotide, GH levels fell in all patients and at the end of 16 weeks postsurgery, they were ‘safe’ in three of them (50%) (P 20% shrinkage. Conclusions In this first prospective study using lanreotide, surgical debulking of pituitary tumours causing acromegaly improved subsequent postoperative control by the somatostatin analogue lanreotide. Surgery should, therefore, be considered in patients with macroadenoma causing acromegaly, even if there is little prospect of surgical cure. Lanreotide causes significant pituitary tumour shrinkage in the majority of patients.

Polymorphisms in the brain‐specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients

Abstract: Summary Introduction Some hypothyroid patients continue to have significant impairments in psychological well-being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood–brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood–brain barrier, is considered to play a key role in delivering serum T4 to the brain. Objective To examine whether polymorphisms in OATP1C1 are determinants of well-being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3). Design and participants We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4–LT3 combination therapy. Outcome measurements Different questionnaires on well-being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1-intron3C > T, OATP1C1-Pro143Thr and OATP1C1-C3035T polymorphisms were determined. Results Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1-intron3C > T and the OATP1C1-C3035T polymorphism, but not the OATP1C1-Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4–LT3 therapy. Conclusions OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4–LT3 combination therapy. Future studies are needed to confirm these findings.

Frequency and characteristics of TBII‐seronegative patients in a population with untreated Graves’ hyperthyroidism: a prospective study

Abstract: Summary Objective It is claimed that second generation thyrotropin-binding inhibitory immunoglobulin (TBII) assays have a very high sensitivity for the diagnosis of Graves’ hyperthyroidism (GH). However, studies evaluating the accuracy of TBII have been retrospective in nature and/or GH had not been diagnosed independently of TBII. The aim of the present study, therefore, was to prospectively evaluate the frequency and characteristics of TBII-seronegative patients in a population of untreated GH diagnosed independent of serum TBII. Design Prospective multicentre observational study. Patients A total of 259 consecutive untreated patients with a first episode of GH, diagnosed independent of serum TBII. TBII levels were measured by second generation assay and correlated to thyroid function, clinical characteristics and exposure to environmental factors. Results Serum TBII was positive in 245 (94·6%) patients and negative (< 2 IU/l) in 14 (5·4%) patients. TBII-seronegative patients had lower fT4 (median 42·5 vs. 53·9 pmol/l, P = 0·02), T3 (median 3·55 vs. 4·90 nmol/l, P < 0·01) and fT3-index (median 4·30 vs. 6·27, P < 0·01) compared to TBII-seropositive patients. None of the TBII-seronegative patients had TSH-receptor activating mutations, Graves’ orbitopathy or pretibial myxedema. Serum TBII was positively correlated to free T3 (fT3)-index and free T4 (fT4)-index (P < 0·01), goitre size (P < 0·01) and the prevalence of Graves’ orbitopathy (P < 0·01). There were no significant differences between TBII-seropositive and TBII-seronegative patients in environmental factors. Conclusion The prevalence of TBII-seronegativity in untreated patients with GH is 5·4% using a second generation assay. TBII-seronegative patients have biochemically less severe thyrotoxicosis and no Graves’ orbitopathy. TBII-seronegative and TBII-seropositive patients apparently belong to the same population of GH, albeit the severity of the autoimmune attack is less in TBII-seronegative patients.