Clinical Endocrinology

Wiley Online Library : Clinical Endocrinology
  • Assessment of time to glucose peak during an oral glucose tolerance test
    We read with interest the article from Chung et al. on the association between time to glucose peak and prediabetes.1 We agree with the authors in that the morphology of the glucose curve is worth investigating as an additional indicator of prediabetes and diabetes risk. This is a rather well studied topic in the literature, and most authors agree that adding an intermediate glucose measurement (at 30 or 60 minutes) improves the ability to identify subgroups with forms of dysglycaemia not picked up by the traditional guidelines based on fasting and 2-hour values. This article is protected by copyright. All rights reserved.
  • Clinical and Genetic Features of 64 Young Male Paediatric Patients with Congenital Hypogonadotropic Hypogonadism (CHH)
    Context The diagnosis of congenital hypogonadotropic hypogonadism (CHH) in prepuberty has always been challenging. Here, we aimed at studying the clinical and genetic features of paediatric CHH, especially the phenotype of hypospadias and dual defects (patients showing hypothalamic and/or pituitary defects and testicular hypoplasia), so as to have a better understanding of CHH. Design The clinical and genetic features of CHH patients were analysed and the relationships between hypospadias, dual defects and genetics investigated. Patients Patients who visited Beijing Children's Hospital and were positively diagnosed with CHH. Measurements The collected data included sex hormones, MRI of the olfactory bulb, human chorionic gonadotropin (hCG) test and genetic testing. We analysed clinical features and genetic results, especially hypospadias and dual defects, and compared the stimulated testosterone (T) levels in patients with and without cryptorchidism. Results Sixty-four patients were positively diagnosed, and forty-seven (73.4%) had Kallmann Syndrome (KS). Four patients (6.3%) had hypospadias, including 2 KS. Micropenis combined with cryptorchidism was the most common phenotype (39%). Approximately 2/3 patients showed a poor response to hCG; 15 cases were diagnosed with dual defects, and there were no significant differences between those with and without cryptorchidism. Twenty-six cases in 51 patients (51%) were identified as having classical HH mutations, affecting 10 different genes, with oligogenic mutations in 5 cases (9.8%). The most common mutations were in PROKR2 (17.6%), FGFR1 (13.7%) and CHD7 (7.8%). The frequency of PROKR2 mutations was higher in dual HH when compared to other HH cases (6/15 vs 3/36, p=0.021). Conclusions Micropenis and/or cryptorchidism can serve as important signs for the diagnosis of HH in paediatrics and the coexistence of hypospadias, does not exclude the diagnosis of CHH, including KS or normosmic isolated HH (nIHH). Au: OK? Author: OK. Thank you!Testicular function may be impaired earlier than expected, and PROKR2 mutations need to be evaluated to identify presumed dual defects. This article is protected by copyright. All rights reserved.
  • Treatment of a thyrotropin-secreting pituitary adenoma (TSH-oma) with pasireotide LAR
  • Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome
    Objective Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). Aim To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. Design and Methods Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. Results We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001). Conclusions The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1.
  • Increased fibre and reduced trans fatty acid intake are primary predictors of metabolic improvement in overweight polycystic ovary syndrome—Substudy of randomized trial between diet, exercise and diet plus exercise for weight control
    Objective Polycystic ovary syndrome (PCOS) is commonly affected by obesity. PCOS phenotypes are prone to increased waist/hip ratio, insulin resistance and dyslipidaemia. This substudy was undertaken to evaluate the effects of lifestyle interventions on metabolic biomarkers in overweight/obese PCOS women and the interventional effects of dietary components related to metabolic outcomes. Design Randomized three-arm parallel study. Patients Fifty-seven PCOS women body mass index (BMI >27 kg/m2, age 18-40) were randomly assigned to diet (D, n = 19), exercise (E, n = 19) or diet plus exercise (DE, n = 19) in three-arm fashion over 16 weeks. The D group received nutritional counselling by a dietician to reduce their energy intake by at least 600 kcal/d. The E group received an ambulatory exercise regimen from a physiotherapist. The DE group had both interventions. Measurements Self-reported food intake over 4 days, exercise pedometers, BMI, waist/hip ratio, blood pressure, body composition and oral glucose tolerance test were performed before and at the end of intervention. Results BMI, waist circumference and total cholesterol were significantly reduced in the D and DE groups, as well as low-density lipoprotein and Homeostasis Model of Assessment index in the D group. In the E group, exercise was increased along with a decrease in BMI and waist circumference. The strongest predictor of reduced BMI was increased fibre intake (−0.44, P = .03), while a decrease in trans fatty acid intake predicted reduced insulinogenic index (0.44, P < .01). Conclusions Nutritional counselling with dieting is clearly effective to improve metabolic disturbances in overweight/obese women with PCOS. Increased fibre and reduced trans fatty acid intake are primary predictors of metabolic improvement and weight control.
  • Iron metabolism in patients with Graves’ hyperthyroidism
    Objectives Graves’ hyperthyroidism (GH) interferes with iron metabolism and elevates ferritin. The precise mechanisms remain unclear. The influence of thyroid hormones on the synthesis/regulation of hepcidin, an important regulator of iron metabolism, remains uncharacterized. Design Prospective observational study. Patients We included patients (n=31) with new-onset and untreated GH. Measurements Laboratory parameters indicative of iron metabolism (ferritin, transferrin, hepcidin), inflammatory markers/cytokines and smoking status were assessed at the diagnosis of GH (T0) and at euthyroidism (T1) in the same patients using multivariable analyses. Hepcidin was measured by mass spectrometry (hepcidinMS) and ELISA (hepcidinEL). The impact of T3 on hepatic hepcidin expression was studied in a cell culture model using HepG2 cells. Results Median ferritin levels were significantly lower and transferrin significantly higher at T1 than at T0. HepcidinMS levels were lower in males and females at T1 (statistically significant in males only). No statistically significant difference in hepcidinEL was detected between T0 and T1. Plasma levels of inflammatory markers (high-sensitive CRP, procalcitonin) and cytokines (interleukin 6, interleukin 1ß, tumor necrosis factor α) were not different between T0 and T1. Smokers tended to have lower fT3 and fT4 at T0 than non-smoking GH patients. T3 significantly induced hepcidin mRNA expression in HepG2 cells. Conclusions Iron metabolism in patients with GH undergoes dynamic changes in patients with GH that resemble an acute phase reaction. Inflammatory parameters and cytokines were unaffected by thyroid status. Gender and smoking status had an impact on ferritin, hepcidin and thyroid hormones. This article is protected by copyright. All rights reserved.
  • Serum chemerin levels are inversely associated with renal function in a general population
    Objective Chemerin has been found to be highly expressed in the kidneys of rodents and has been suggested to affect metabolic syndrome (MetS)-related phenotypes which are in turn related to kidney damage. Only few clinical studies have addressed the relation between circulating chemerin and renal function in humans and no population-based analyses have yet been performed. The potential influence of MetS-related phenotypes on the assumed association has been largely neglected. We aimed to investigate the association of serum chemerin with renal function in a general population with special regard to possible interactions between chemerin and metabolic phenotypes. Design, patients, and measurements Linear and logistic regression models were applied to analyze data from 4,082 subjects of the German Study of Health in Pomerania. Main outcomes included estimated glomerular filtration rate (eGFR), serum creatinine and cystatin C, and chronic kidney disease. Results Inverse associations of chemerin with eGFR were observed. The components of the MetS emerged as modulating factors in this relation and enhanced the association. Logistic regression models confirmed the relation between chemerin and eGFR and revealed that each increase in chemerin per 25 ng/ml was associated with an about three-fold higher odds of chronic kidney disease [odds ratio 2.72 (95% confidence interval 2.26-3.29)]. Conclusions Our results demonstrate a strong inverse association between serum chemerin levels and renal function. This association might be explained by MetS-related phenotypes, which lead to renal damage and are associated with increased chemerin levels, and/or an impaired renal elimination of chemerin by diseased kidneys. This article is protected by copyright. All rights reserved.
  • Outcomes of patients with metastatic phaeochromocytoma and paraganglioma: A systematic review and meta-analysis
    Objective The outcomes of patients with metastatic phaeochromocytoma (PHEO) and paraganglioma (PGL) are unclear. We performed a systematic review and meta-analysis of baseline characteristics and mortality rates of patients with metastatic PHEO and PGL (PPGL). Design Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, Web of Science, and references of key articles were searched from inception to 2016. Patients Studies comprised ≥20 patients with metastatic PPGL and reported baseline characteristics and follow-up data. Measurements Reviewers extracted standardized data and assessed risk of bias using a modified Newcastle-Ottawa tool. Random-effects meta-analysis was used to pool event rates across studies. Results Twenty retrospective noncomparative studies reported on 1338 patients with metastatic PHEO (685/1296, 52.9%) and PGL (611/1296, 47.1%), diagnosed at a mean age of 43.9 ± 5.2 years. Mean follow-up was 6.3 ± 3.2 years. Of 532 patients with reported data, 40.4% had synchronous metastases. Five-year (7 studies, n = 738) and 10-year (2 studies, n = 55) mortality rates for patients with metastatic PPGL were 37% (95% CI, 24%-51%) and 29% (95% CI, 17%-42%), respectively. Higher mortality was associated with male sex (RR 1.50; 95% CI, 1.11-2.02) and synchronous metastases (RR 2.43; 95% CI, 1.01-5.85). Conclusions Available low-quality evidence from heterogeneous studies suggests low mortality rates of patients with metastatic PPGL. Male sex and synchronous metastases correlated with increased mortality. The outcomes of patients with metastatic PPGL have been inadequately assessed, indicating the need for carefully planned prospective studies.
  • Thyroid disease symptoms during early pregnancy do not identify women with thyroid hypofunction that should be treated
    Objective To evaluate whether women during early pregnancy with “hypothyroidism” symptoms are at risk of biochemically defined hypothyroidism. The 2017 Guidelines of the American Thyroid Association (ATA) recommend case-finding on the basis of symptoms to identify these women during pregnancy, while evidence is lacking. Design Construct validation of a thyroid hypofunction symptom checklist during the first trimester of pregnancy comparing high scores with biochemically defined hypothyroidism. Patients A total of 2198 healthy pregnant women from an iodine-sufficient area in 2013-2014. Measurements Completion of a draft questionnaire with “classical” symptoms of hypothyroidism at 12 weeks of gestation. The 2.5th and 97.5th percentiles of TSH and fT4 during pregnancy in TPO-Ab-negative (<35 kU/L) women were used to define euthyroid women and those with overt (clinical) and subclinical hypothyroidism. The prevalence of overt (subclinical) hypothyroidism was compared between women with high symptom scores and those with low symptom scores. Results According to fT4 and TSH cut-offs (0.23-4.0 mIU/L and 11.5-18.0 pmol/L, respectively), there were 15 women with “to treat hypofunction” (overt hypothyroidism or TSH >10 mIU/L) and 68 women with subclinical hypothyroidism. Questionnaire construct validation revealed a 12-item hypothyroid checklist with normally distributed scores. The cut-off indicating high scores of OH was set at 1 SD > mean. Women with high symptom scores did not present more often with biochemically defined thyroid hypofunction. Conclusion This study does not support the ATA recommendation that pregnant women who require levothyroxine therapy can be identified by case-based screening of women with symptoms of thyroid disease.
  • Diagnostic performance of unenhanced Computed Tomography and 18F-fluorodeoxyglucose positron emission tomography in indeterminate adrenal tumors
    Objective Evidence on the diagnostic performance of adrenal imaging is limited. We aimed to assess the diagnostic performance of unenhanced computed tomography (CT) and18F-fluorodeoxyglucose(18FDG) positron emission tomography(PET)/CT imaging in a high risk population for adrenal malignancy using an optimal reference standard. Design Retrospective cohort study. Methods Imaging studies of patients with adrenal nodules who underwent adrenal biopsy and/or adrenalectomy between 1994 and 2014 were reviewed and compared to the reference standard of histology. Eighty % of patients presented with known or suspected extra-adrenal malignancy. Results Unenhanced abdominal CT was performed in 353 patients with adrenal lesions; median size was 3 (0.7-15) cm and median radiodensity was 33 (-21to78) Hounsfield units (HU). Radiodensity of >10 HU diagnosed malignancy with a sensitivity of 100%, specificity of 33%, positive predictive value (PPV) of 72%, and negative predictive value (NPV) of 100%.18FDG-PET/CT was performed in 89 patients; median tumor size was 2.1 (0.7-9.2) cm. Maximum standardized uptake (SUV max) was higher in malignant lesions when compared to benign lesions (median = 10 [2.3-29.4] vs 3.7 [1.4-24.5], respectively, P<.0001). Similarly, median SUV max lesion to SUV max liver ratio (ALR) in malignant lesions was higher than in benign lesions (median = 3 [0.74-13.4] vs. 1.2 [0.5-6.6], respectively, P<.0001).18FDG-PET/CT ALR > 1.8 diagnosed malignancy with a sensitivity of 87%, specificity of 84%, PPV of 85%, and NPV of 86%. Conclusion Noncontract CT radiodensity of ≤10 HU excludes malignancy even in a high risk population. For indeterminate adrenal lesions, given a superior specificity, 18FDG PET/CT could be considered as a second stage imaging. This article is protected by copyright. All rights reserved.
  • Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency
    Objectives There is no licensed, dose-appropriate formulation of hydrocortisone for children with adrenal insufficiency (AI) and patients rely on compounded adult medication. The aim of this study was to evaluate the absorption, palatability and safety of Infacort®, an immediate-release, granule formulation of hydrocortisone with taste masking. Study design Single site with satellites attended by a “flying” doctor from investigator site. Open-label, single-dose study in three consecutive child cohorts (n=24) with AI; Cohort 1, children aged 2 to <6 years (n=12); Cohort 2, infants aged 28 days to <2 years (n=6); Cohort 3, neonates aged 1 to <28 days (n=6). Au: the age ranges quoted are slightly different in each of the abstract, main text, Table 1 and Supplemental table. These have now been unified as shown here.. Methods Fasted children were given a single dose of Infacort® as dry granules administered directly from a capsule or spoon followed by a drink. The primary endpoint was the maximum serum cortisol concentration up to 240 minutes after Infacort® administration. Secondary endpoints were palatability and adverse events (AEs). Results All children showed an increase in cortisol above baseline after Infacort® (p<0.0001), with geometric mean ± SD cortisol concentration at 60 min of 575.8 ± 299.5 nmol/L. There was no failure in administration of Infacort®, and 95.5% of parents/carers preferred Infacort® to their child's current medication. In 6 children who completed the palatability questionnaire, 80% of responses were very good or neutral and 20% were adverse. No serious or severe treatment-emergent AEs were reported. Conclusions Infacort® is well tolerated, easy to administer to neonates, infants and children and shows good absorption, with cortisol levels at 60 minutes after administration similar to physiological cortisol levels in healthy children. This article is protected by copyright. All rights reserved.
  • Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery
  • Pregnancy in women with nonclassic congenital adrenal hyperplasia: Time to conceive and outcome
    Objective Nonclassic congenital adrenal hyperplasia (NCAH) is common among Ashkenazi Jews (1:400). It is associated with various degrees of postnatal virilization, irregular menses and infertility. Therapy of symptomatic subjects consists of physiologic doses of glucocorticoids. The objective of this study was to evaluate the effect of glucocorticoid treatment on fertility and on pregnancy outcome in women with NCAH. Design, Setting and Patients This retrospective study included 75 women diagnosed with NCAH who were followed in our clinic and sought fertility between 2008 and 2015. Results Seventy-two women succeeded in conceiving (187 pregnancies). Time to conception was 4.0 ± 7 months without and 3.3 ± 3 months with glucocorticoid therapy (P = .43). Seventeen pregnancies were achieved by glucocorticoid therapy after failure to conceive spontaneously. Time to conception before therapy initiation was 10.2 ± 11.4 months compared to 3.3 ± 3.4 months after therapy initiation (P = .02). Of 187 pregnancies, 135 (72%) resulted in live births, 38 (20.3%) ended in spontaneous miscarriages during the first trimester, seven (3.7%) were electively terminated, three (1.6%) were ectopic and four (2.1%) were ongoing during the study with similar rate in glucocorticoid treated and untreated pregnancies. Conclusions The 96% pregnancy rate among our cohort of NCAH females was similar to the 95% rate reported for the normal population. Glucocorticoid therapy may shorten the time to conceive in a subgroup of women with NCAH. Glucocorticoid therapy did not affect the rate of first trimester miscarriage. Our 77% live birth rate was similar to the 72% live birth rate in the current healthy US population.
  • A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations
    Objective Disorders of sex development (DSD) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46,XY sisters from a consanguineous family. Design We performed a whole-exome sequencing of two 46,XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (DHH) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner BOC (brother of CDO/cell adhesion molecule, downregulated by oncogenes). Patients The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH). She also had an apparent absence of intra-abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation. Results Whole-exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with BOC, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH-intein-mediated auto-processing. Conclusions This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants.
  • Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men
    Objective Patients with mutations of NKB and its receptor show hypogonadotrophic hypogonadism, but there is little evidence for the importance of this pathway in reproductive function in normal men, or its functional hierarchy with kisspeptin. Design An open label study wherein men (n=6) were administered the NK3R antagonist MLE4901 40mg orally twice a day for 7 days. Kisspeptin-10 (0.3 μg/kg iv bolus) was given before and on day 7 of NK3R antagonist treatment. Patients Subjects were healthy men. Measurements Reproductive hormones were measured before and during the NK3R antagonist administration, including frequent sampling on two occasions for analysis of pulsatile LH secretion. Results LH, FSH and testosterone secretion were decreased during NK3R antagonist administration. LH showed a biphasic response, being reduced after 24 hours of treatment (4.5±0.6 IU/l pre-treatment to 1.7±0.2 IU/l, p<0.05), with partial recovery thereafter; but it was again decreased on day 7 (2.5±0.6 IU/l, p<0.05 vs pre-treatment). FSH secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone secretion was decreased from 24 hours (18.4±1.6 pre-treatment vs 5.6±1.5 nmol/l, p<0.01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility showed that both basal and pulsatile LH secretion were markedly suppressed but there was no detected change in LH pulse frequency. Kisspeptin-10 stimulated LH secretion, with similar responses before and during NK3R antagonist administration. Conclusions These data demonstrate a central role for NKB/NK3R in the physiological regulation of reproductive function in men, and that this is functionally upstream of kisspeptin-mediated GnRH secretion. This article is protected by copyright. All rights reserved.
  • CRH stimulation tests for the infants with relative adrenal insufficiency
    Background Very low birth weight (VLBW) infants are considered to be vulnerable to relative adrenal insufficiency (RAI); however, diagnosis is difficult in some clinical settings. Considering this background, it is necessary to establish a diagnosis of RAI in preterm infants. Objective In this study, we attempted to clarify the difference in response to CRH stimulation tests for preterm infants with or without RAI. Methods Between June 2009 and December 2015, we performed CRH stimulation tests for preterm infants born at a gestational age of <30 weeks at around two weeks of age. Retrospectively, subjects were classified into two groups: infants with RAI (n=9) or without RAI (n=17) based on the clinical symptoms and responsiveness to hydrocortisone. Results We found no difference in base or peak serum cortisol levels related to CRH stimulation tests between the two groups; however delta cortisol levels and responsive ratio (peak to base ratio) were significantly reduced in infants with RAI. 140 nmol/L for delta cortisol or 1.5 times for peak to base ratio may be cut off levels in preterm infants. Conclusion This study provides evidence that base cortisol levels of preterm infants with RAI were not different from those without RAI; however, CRH stimulation tests may be a useful tool for the diagnosis of RAI in preterm infants. This article is protected by copyright. All rights reserved.
  • Dipeptidyl Peptidase 4 serum activity and concentration are increased in women with polycystic ovary syndrome
    Objective Polycystic ovary syndrome (PCOS) is a complex disease, the etiology of which is not well understood. Alterations in potential candidate genes involved in the biosynthesis and metabolism of androgens, folliculogenesis, and insulin and glucose metabolism have been suggested as possible etiologies. Dipeptidyl peptidase-4 (DPP4) plays a key role in glucose homeostasis and, thus, in the regulation of insulin secretion. The aim of our study was to analyze the DPP4 activity and concentrations in the serum of PCOS and non-PCOS patients and, additionally, study the activation of the DPP4 promoter by androgens in vitro. Design, Patients and Measurements Serum samples were obtained from 288 female patients treated at the Center for Reproductive Medicine and Andrology (154 non-PCOS and 134 PCOS patients). DPP4 activity was measured by the conversion of the DPP4 substrate Gly-Pro p-nitroanilide hydrochloride and DPP4 concentration with a commercial ELISA. Luciferase reporter assays, qPCR and Western Blot analyses were performed for the in vitro evaluation of the activation of the DPP4 promoter by androgens. Results DPP4 serum activity was increased in women with PCOS, regardless of which Rotterdam criteria led to the PCOS diagnosis. Furthermore, DPP4 serum levels were strongly correlated with the anti-Müllerian hormone (AMH) serum level. In vitro, the DPP4 promoter was stimulated by androgens in luciferase reporter assays, and DPP4 mRNA expression was increased in KGN granulosa carcinoma cells after androgen treatment. Conclusions The results suggested that a deregulation of DPP4 serum levels could be an additional characteristic of the metabolic imbalances associated with PCOS. This article is protected by copyright. All rights reserved.
  • Is primary hyperparathyroidism a cause of endothelial dysfunction?
    Objective Symptomatic primary hyperparathyroidism (PHPT) is thought to be related to increased cardiovascular morbidity and mortality. In our study, we aimed to investigate endothelial dysfunction and markers of subclinical atherosclerosis in patients with PHPT. Also we aimed to demonstrate the effect of vitamin D supplementation on these parameters. Materials and methods Twenty-nine patients followed by medical treatment (A), 25 preoperative (B) and 23 postoperative patients with PHPT (C), and 26 normocalcaemic subjects (D) were included. Groups were assessed by measurements of flow-mediated dilation (FMD), carotid intima-media thickness (CIMT), serum levels of sCD40L, high-sensitivity CRP (hs-CRP) and interleukin-8 (IL-8). Thirteen patients with low levels of 25-hydroxy-vitamin D (25OHD) in the medical treatment group were assessed before and 3 months after vitamin D replacement. Results The median FMD was 5% in group A, 5.1% in group B, 7.6% in group C and 7.7% in group D. The FMD measurement in group A was significantly lower than groups C and D (P=.02) and was similar to the FMD measurement in group B. FMD measurements of group B were not significantly lower than groups C and D. In 13 patients with low 25OHD in group A, the median FMD increased to 7.07% from 4.71% after vitamin D replacement (P=.02). Conclusion Flow-mediated dilation was impaired in patients with PHPT, particularly in the medically observed group. Vitamin D supplementation seems to provide improvements in FMD in medically observed PHPT patients with low 25OHD levels, and this was the novel observation of our study.
  • Area under the curve during OGTT in first degree relatives of diabetic patients as an efficient indicator of future risk of type 2 diabetes and pre-diabetes
    Objective To establish whether the area under the curve of an OGTT has a predictive role in identifying pre-diabetic and diabetic subjects amongst first-degree relatives (FDR) of patients with diabetes mellitus type 2 (DM). Design, patients and measurements In a population-based cohort study, 766 FDR of diabetic patients with a normal glucose tolerance test (NGT) completed a 2-h OGTT. They were followed up for 7 years and classified according to the American Diabetes Association criteria into: NGT, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and DM. Relative risk (RR) and 95% confidence intervals (95%CI) were calculated based on logistic regression. Receiver-Operator Characteristic (ROC) analysis along with AUC at different intervals and at time points during the OGTT was used to evaluate the risk of pre-diabetes and diabetes. Results Twenty-three subjects (3%) developed type 2 DM, 118 (29.3%) IFG, 81 (11.5%) IGT and 544 (71%) subjects remained NGT. AUC and mean difference of glucose in all high-risk groups demonstrated significant differences both in intervals and time points when compared with the NGT group. The cutoff values during OGTT to predict pre-diabetes and diabetes was determined as blood glucose more than 7.2 and 7.8mmol/l at 30 and 60 minutes, respectively. The time point 60 has the highest predictive role for the development of diabetes, alone, and improved the performance of a prediction model containing multiple important clinical risk factors. Conclusion The data suggests that the glycaemic response to an OGTT may predict the risk of development of diabetes in first-degree relatives of DM patients. This article is protected by copyright. All rights reserved.
  • Discordance between Imaging and Immunohistochemistry in Unilateral Primary Aldosteronism
    Objective Correct subtyping of primary aldosteronism (PA) is essential for good surgical outcomes. Adrenal vein sampling (AVS) and/or computed tomography (CT) are used for PA sub-classification. Clinical and/or biochemical improvement after surgery, however, is not always achieved in patients with presumed unilateral PA. We aimed to identify the pitfalls in PA sub-classification leading to surgical treatment failures. Patients and Design We retrospectively studied 208 patients who underwent adrenal vein sampling (AVS) for PA sub-classification in a tertiary referral centre, between January 2009 and August 2016. Simultaneous bilateral AVS was performed before and after cosyntropin administration. We implemented immunohistochemistry for aldosterone synthase (CYP11B2) and 17α-hydroxylase/17,20 lyase (CYP17A1) in adrenal glands resected from patients without improvement of PA after surgical treatment and from those with limitations in AVS interpretation. Results Of 55 patients who underwent adrenalectomy, three (5.5%) had no improvement of PA. All three patients underwent partial adrenalectomy to remove a CT-detected nodule present on the same side with AVS lateralization. Immunohistochemistry revealed a CYP11B2-negative nodule in both cases available. All patients who underwent total adrenalectomy based on AVS lateralization benefitted from surgery, including three patients with unilateral unsuccessful AVS and aldosterone suppression in the catheterized side vs. inferior vena cava. Conclusions Radiographically identified adrenal nodules are not always a source of PA, even when ipsilateral with AVS lateralization. These data caution against reliance on imaging findings, either alone or in conjunction with AVS, to guide surgery for PA. This article is protected by copyright. All rights reserved.
  • Long-term health outcomes of adults with McCune-Albright syndrome
    Context McCune-Albright syndrome (MAS) is associated with numerous health problems. Comprehensive long-term health problems of adults with MAS are less well defined in the literature. Objective Our objective is to report comprehensive health outcomes of adults with MAS (>18 years). Design Retrospective case note review of 16 adults with MAS managed by one clinician. Results expressed as median (range). Results The study included 16 adults (seven males) with MAS. Median current age is 29 years (20, 46). Twelve of 16 had craniofacial fibrous dysplasia with five of 12 (42%) with progressive facial asymmetry. Growth hormone excess was observed in six of 16 (38%) and T3-toxicosis in five of 16 (31.3%). Six of the seven men (86%) had abnormalities on testicular ultrasound with one man exhibiting marked atrophy of germ and sertoli cells with reduction in spermatogenesis. Six of the 16 (38%) had cardiorespiratory complications including high output cardiac failure (n,3), hypertension (n,2) and one man with congestive cardiac failure and restrictive lung disease. Six of eight (66%) who had screening endoscopy for upper gastrointestinal polyps show increasing numbers of polyps, with benign histology to date. One woman with a previous history of early puberty presented with early aggressive breast carcinoma, which was positive for GNAS. Two patients had GNAS-positive muscle myomas. Platelet dysfunction with bleeding tendency responsive to platelet transfusion during surgery was seen in four. Conclusion A range of complex health problems is encountered in adults with MAS. These have important implications for transition of patients with MAS and adult care. Long-term cancer risk is currently unknown but requires careful follow-up.
  • Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial
    Objective To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). Design Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). Patients Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin® SimpleXx® (0.03 mg/kg; n=2 each) for 7 days. Measurements Pharmacokinetic and pharmacodynamic profiles were assessed. Results Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between −2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. Conclusions Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified.
  • Prevalence of Treated Hypothyroidism in the Community – analysis from General Practices in North-East England with implications for the United Kingdom
    Objective Hypothyroidism is more frequently diagnosed in women and older individuals. It has been suggested that the prevalence of hypothyroidism and the number of prescriptions for thyroid hormones are increasing. However, despite hypothyroidism being a common medical condition, contemporary data on prevalence, particularly across the various age groups, is limited. Design Information regarding number of individuals diagnosed with treated hypothyroidism (defined as patients prescribed levothyroxine) across ten General Practices (total population of 66,843) in the North-East of England in 2016 was obtained in an anonymised manner. Total as well as age group specific point prevalence rates were calculated. In addition, corresponding population data for the United Kingdom was acquired and national total and age-specific hypothyroidism prevalence rates were estimated. Results The overall prevalence of hypothyroidism in this community sample was 4.5% (n=3004). Prevalence increased across the age groups from 0.1% in children aged 0 – 10 years to 15.1% in those aged more than 90 years. After adjusting for demographic differences between the North-East England and UK populations, it is estimated that the total UK wide prevalence of hypothyroidism in 2016 is 3.6%; affecting more than 2.3 million individuals including nearly 800,000 individuals aged >70 years. Conclusions Hypothyroidism affects millions of individuals in the UK and is currently a prevalent diagnosis in more than 1 in 10 individuals aged above 70 years. As the population ages this number is likely to increase. The clinical and economic effects of current management strategies for hypothyroidism, particularly in the older population, need to be evaluated. This article is protected by copyright. All rights reserved.
  • Time to glucose peak during an oral glucose tolerance test identifies prediabetes risk
    Context Morphological characteristics of the glucose curve during an oral glucose tolerance test (OGTT) (time to peak and shape) may reflect different phenotypes of insulin secretion and action, but their ability to predict diabetes risk is uncertain. Objective To compare the ability of time to glucose peak and curve shape to detect prediabetes and β-cell function. Design and participants In a cross-sectional evaluation using an OGTT, 145 adults without diabetes (age 42±9 years (mean±SD), range 24-62 years, BMI 29.2±5.3 kg/m2, range 19.9-45.2 kg/m2) were characterized by peak (30 minutes vs >30 minutes) and shape (biphasic vs monophasic). Main outcome measures Prediabetes and disposition index (DI)—a marker of β-cell function. Results Prediabetes was diagnosed in 36% (52/145) of participants. Peak>30 minutes, not monophasic curve, was associated with increased odds of prediabetes (OR: 4.0 vs 1.1; P<.001). Both monophasic curve and peak>30 minutes were associated with lower DI (P≤.01). Time to glucose peak and glucose area under the curves (AUC) were independent predictors of DI (adjR2=0.45, P<.001). Conclusion Glucose peak >30 minutes was a stronger independent indicator of prediabetes and β-cell function than the monophasic curve. Time to glucose peak may be an important tool that could enhance prediabetes risk stratification.
  • Age-stratified thresholds of anti-Müllerian hormone improve prediction of polycystic ovary syndrome over a population-based threshold
    Objective Due to its consistent elevation in polycystic ovary syndrome (PCOS) and correlation with polycystic ovarian morphology (PCOM), anti-Mullerian hormone (AMH) has been proposed as a marker of the syndrome. However, prior studies reporting thresholds of AMH for a PCOS diagnosis have been limited by small sample size, inappropriate controls, and heterogeneous AMH assays. We sought to evaluate the suitability of a standardized AMH assay as a biomarker of PCOS. Design Cross-sectional study at academic medical centres across the United States. Patients Women with PCOS were diagnosed by Rotterdam criteria and included 282 subjects from the multisite PPCOS II trial and 109 patients from a tertiary academic centre's multidisciplinary PCOS clinic. Controls included 245 participants in the ovarian ageing (OVA) study, a community-based cohort of ovulatory women not seeking treatment for fertility. Measurements Determination of AMH by a central laboratory. Receiver-operating characteristic (ROC) analyses were used to investigate the accuracy of AMH thresholds for prediction of PCOS diagnosis with stratification by age. Results The optimal threshold of AMH to distinguish PCOS from controls was 55.36 pmol/L (sensitivity: 0.82, specificity: 0.78, J: 0.60). When examining the population by age groups, the optimal AMH threshold decreased with increasing age. Conclusions AMH is an effective biomarker of PCOS. Age-stratified thresholds more accurately predicted PCOS than an overall population-based threshold.

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