International Journal of Endocrinology The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Parental Reports of Stigma Associated with Child’s Disorder of Sex Development Tue, 31 Mar 2015 14:02:25 +0000 Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. DSD-associated stigma is purported to threaten positive psychosocial adaptation. Parental perceptions of DSD-related stigma were assessed in 154 parents of 107 children (newborn–17 years) questionnaire comprising two scales, child-focused and parent-focused, and three subscales, perceived stigmatization, future worries, and feelings about the child’s condition. Medical chart excerpts identified diagnoses and clinical management details. Stigma scale scores were generally low. Parents of children with DSD reported less stigma than parents of children with epilepsy; however, a notable proportion rated individual items in the moderate to high range. Stigma was unrelated to child’s age or the number of DSD-related surgeries. Child-focused stigma scores exceeded parent-focused stigma and mothers reported more stigma than fathers, with a moderate level of agreement. Within 46,XY DSD, reported stigma was higher for children reared as girls. In conclusion, in this first quantitative study of ongoing experiences, DSD-related stigma in childhood and adolescence, while limited in the aggregate, is reported at moderate to high levels in specific areas. Because stigma threatens positive psychosocial adaptation, systematic screening for these concerns should be considered and, when reported, targeted for psychoeducational counseling. Aimee M. Rolston, Melissa Gardner, Eric Vilain, and David E. Sandberg Copyright © 2015 Aimee M. Rolston et al. All rights reserved. Prospective Analysis of Risk for Hypothyroidism after Hemithyroidectomy Mon, 30 Mar 2015 13:49:43 +0000 Objectives. To evaluate risk factors and to develop a simple scoring system to grade the risk of postoperative hypothyroidism (PH). Methods. In a controlled prospective study, 109 patients, who underwent hemithyroidectomy for a benign thyroid disease, were followed up for 12 months. The relation between clinical data and PH was analyzed for significance. A risk scoring system based on significant risk factors and clinical implications was developed. Results. The significant risk factors of PH were higher TSH (thyroid-stimulating hormone) level and lower ratio of the remaining thyroid weight to the patient’s weight (derived weight index). Based on the log of risk factor, preoperative TSH level greater than 1.4 mU/L was assigned 2 points; 1 point was for 0.8–1.4 mU/L. The derived weight index lower than 0.8 g/kg was assigned 1 point. A risk scoring system was calculated by summing the scores. The incidences of PH were 7.3%, 30.4%, and 69.2% according to the risk scores of 0-1, 2, and 3. Conclusion. Risk factors for PH are higher preoperative TSH level and lower derived weight index. Our developed risk scoring system is a valid and reliable tool to identify patients who are at risk for PH before surgery. Virgilijus Beisa, Darius Kazanavicius, Arminas Skrebunas, Gintaras Simutis, Justinas Ivaska, and Kestutis Strupas Copyright © 2015 Virgilijus Beisa et al. All rights reserved. Increased Serum Pigment Epithelium-Derived Factor in Women with Gestational Diabetes Is Associated with Type 2 Diabetes Mon, 30 Mar 2015 07:02:26 +0000 Background. Pigment epithelium-derived factor (PEDF) is demonstrated to be elevated in diabetes patients. However, no reports have emerged in pregnant women with gestational diabetes mellitus (GDM). This study was undertaken to investigate serum PEDF levels in GDM women and to evaluate PEDF as a biomarker to predict diabetes postpartum. Methods. Serum PEDF concentration and clinical characteristics were detected in the pregnant women with GDM (n = 120) and without GDM (control group, n = 120). Results. PEDF levels were elevated in subjects with GDM versus controls. Univariate correlations showed that serum PEDF levels were positively correlated with fasting glucose and fasting insulin levels, respectively, and negatively correlated with adiponectin. Receiver operating characteristic (ROC) analysis demonstrated that the AUC of serum PEDF for diabetes mellitus in women postpartum was 0.893. Conclusion. Serum PEDF was elevated in pregnant women with GDM, which is probably an early detection marker for predicting development of GDM to diabetes mellitus. Tong-Huan Li, Chun-Jian Qiu, Xiao-Juan Yu, Dan-Dan Liu, Peng-Fei Zhou, and Liang Wu Copyright © 2015 Tong-Huan Li et al. All rights reserved. Methylation of Promoter Regions of Genes of the Human Intrauterine Renin Angiotensin System and Their Expression Mon, 30 Mar 2015 06:22:08 +0000 The intrauterine renin angiotensin system (RAS) is implicated in placentation and labour onset. Here we investigate whether promoter methylation of RAS genes changes with gestation or labour and if it affects gene expression. Early gestation amnion and placenta were studied, as were term amnion, decidua, and placenta collected before labour (at elective caesarean section) or after spontaneous labour and delivery. The expression and degree of methylation of the prorenin receptor (ATP6AP2), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and two proteases that can activate prorenin (kallikrein, KLK1, and cathepsin D, CTSD) were measured by qPCR and a DNA methylation array. There was no effect of gestation or labour on the methylation of RAS genes and CTSD. Amnion and decidua displayed strong correlations between the percent hypermethylation of RAS genes and CTSD, suggestive of global methylation. There were no correlations between the degree of methylation and mRNA abundance of any genes studied. KLK1 was the most methylated gene and the proportion of hypermethylated KLK1 alleles was lower in placenta than decidua. The presence of intermediate methylated alleles of KLK1 in early gestation placenta and in amnion after labour suggests that KLK1 methylation is uniquely dynamic in these tissues. Shane D. Sykes, Carolyn Mitchell, Kirsty G. Pringle, Yu Wang, Tamas Zakar, and Eugenie R. Lumbers Copyright © 2015 Shane D. Sykes et al. All rights reserved. Subclinical Hypothyroidism in Children and Adolescents: Is It Clinically Relevant? Sun, 29 Mar 2015 12:20:01 +0000 Although subclinical hypothyroidism (SH) is a common clinical problem, its diagnosis tends to be incidental. According to the definition, it should be asymptomatic, only detectable by screening. The presence or coincidence of any symptoms leads to L-thyroxine treatment. The clinical presentation, especially in younger patients with subclinical hypothyroidism, is still under dispute. Accordingly, the aim of this paper was to review the literature from the past seven years. The literature search identified 1,594 potentially relevant articles, of which 24 met the inclusion criteria. Few studies focus on the symptomatology of subclinical hypothyroidism, and most of them analyzed a small number of subjects. A significant correlation was found by some authors between subclinical hypothyroidism and a higher risk of hypertension, dyslipidemia, and migraine. No evidence of the impact of subclinical hypothyroidism on weight, growth velocity, and puberty was revealed. As the quality of most studies is poor and no definite conclusions can be drawn, randomized, large-scale studies in children and adolescents are warranted to determine the best care for patients with SH. Aneta Gawlik, Kamila Such, Aleksandra Dejner, Agnieszka Zachurzok, Aleksandra Antosz, and Ewa Malecka-Tendera Copyright © 2015 Aneta Gawlik et al. All rights reserved. Exocrine Pancreatic Insufficiency in Diabetic Patients: Prevalence, Mechanisms, and Treatment Sun, 29 Mar 2015 11:00:51 +0000 Pancreas is a doubled-entity organ, with both an exocrine and an endocrine component, reciprocally interacting in a composed system whose function is relevant for digestion, absorption, and homeostasis of nutrients. Thus, it is not surprising that disorders of the exocrine pancreas also affect the endocrine system and vice versa. It is well-known that patients with chronic pancreatitis develop a peculiar form of diabetes (type III), caused by destruction and fibrotic injury of islet cells. However, less is known on the influence of diabetes on pancreatic exocrine function. Pancreatic exocrine insufficiency (PEI) has been reported to be common in diabetics, with a prevalence widely ranging, in different studies, in both type I (25–74%) and type II (28–54%) diabetes. A long disease duration, high insulin requirement, and poor glycemic control seem to be risk factors for PEI occurrence. The impact of pancreatic exocrine replacement therapy on glycemic, insulin, and incretins profiles has not been fully elucidated. The present paper is aimed at reviewing published studies investigating the prevalence of PEI in diabetic patients and factors associated with its occurrence. Matteo Piciucchi, Gabriele Capurso, Livia Archibugi, Martina Maria Delle Fave, Marina Capasso, and Gianfranco Delle Fave Copyright © 2015 Matteo Piciucchi et al. All rights reserved. Experimenter Effects on Pain Reporting in Women Vary across the Menstrual Cycle Sun, 29 Mar 2015 08:06:50 +0000 Background. Separate lines of research have shown that menstrual cycling and contextual factors such as the gender of research personnel influence experimental pain reporting. Objectives. This study examines how brief, procedural interactions with female and male experimenters can affect experimentally reported pain (cold pressor task, CPT) across the menstrual cycle. Methods. Based on the menstrual calendars 94 naturally cycling women and 38 women using hormonal contraceptives (  ) were assigned to low and high fertility groups. This assignment was based on estimates of their probability of conception given their current cycle day. Experimenters (12 males, 7 females) engaged in minimal procedural interactions with participants before the CPT was performed in solitude. Results. Naturally cycling women in the high fertility group showed significantly higher pain tolerance (81 sec, ) following interactions with a male but not a female experimenter. Differences were not found for women in the low fertility or contraceptive groups. Discussion. The findings illustrate that menstrual functioning moderates the effect that experimenter gender has on pain reporting in women. Conclusion. These findings have implications for standardizing pain measurement protocols and understanding how basic biopsychosocial mechanisms (e.g., person-perception systems) can modulate pain experiences. Jacob M. Vigil, Jared DiDomenico, Chance Strenth, Patrick Coulombe, Eric Kruger, Andrea A. Mueller, Diego Guevara Beltran, and Ian Adams Copyright © 2015 Jacob M. Vigil et al. All rights reserved. Shift Work and Endocrine Disorders Sun, 29 Mar 2015 06:36:46 +0000 The objective of this review was to investigate the impact of shift and night work on metabolic processes and the role of alterations in the sleep-wake cycle and feeding times and environmental changes in the occurrence of metabolic disorders. The literature review was performed by searching three electronic databases for relevant studies published in the last 10 years. The methodological quality of each study was assessed, and best-evidence synthesis was applied to draw conclusions. The literature has shown changes in concentrations of melatonin, cortisol, ghrelin, and leptin among shift workers. Melatonin has been implicated for its role in the synthesis and action of insulin. The action of this hormone also regulates the expression of transporter glucose type 4 or triggers phosphorylation of the insulin receptor. Therefore, a reduction in melatonin can be associated with an increase in insulin resistance and a propensity for the development of diabetes. Moreover, shift work can negatively affect sleep and contribute to sedentarism, unhealthy eating habits, and stress. Recent studies on metabolic processes have increasingly revealed their complexity. Physiological changes induced in workers who invert their activity-rest cycle to fulfill work hours include disruptions in metabolic processes. M. A. Ulhôa, E. C. Marqueze, L. G. A. Burgos, and C. R. C. Moreno Copyright © 2015 M. A. Ulhôa et al. All rights reserved. Type 2 Diabetes and Cardiovascular Risk in Women Thu, 26 Mar 2015 09:33:18 +0000 Giuseppina T. Russo, Giovannella Baggio, Maria Chiara Rossi, and Alexandra Kautzky-Willer Copyright © 2015 Giuseppina T. Russo et al. All rights reserved. Disease of Adrenal Glands Thu, 26 Mar 2015 09:20:03 +0000 Gianluca Iacobellis, Gian Paolo Rossi, Frederic Castinetti, and Claudio Letizia Copyright © 2015 Gianluca Iacobellis et al. All rights reserved. Profiling of Somatic Mutations in Phaeochromocytoma and Paraganglioma by Targeted Next Generation Sequencing Analysis Wed, 25 Mar 2015 14:07:50 +0000 At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse “mutation hotspots” in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); for BRAF (c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and for TP53 (c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL. Andrea Luchetti, Diana Walsh, Fay Rodger, Graeme Clark, Tom Martin, Richard Irving, Mario Sanna, Masahiro Yao, Mercedes Robledo, Hartmut P. H. Neumann, Emma R. Woodward, Farida Latif, Stephen Abbs, Howard Martin, and Eamonn R. Maher Copyright © 2015 Andrea Luchetti et al. All rights reserved. Adrenal Tumors with Unexpected Outcome: A Review of the Literature Wed, 25 Mar 2015 08:00:15 +0000 The finding of an adrenal mass should induce a diagnostic work-up aimed at assessing autonomous hormone production and differentiating between benign and (potentially) malignant lesions. The common differential diagnosis in adrenal incidentaloma consists of (non-)functioning adenoma, pheochromocytoma, myelolipoma, metastasis, and primary carcinoma. There remains a category of lesions that are hormonally inactive and display nonspecific imaging characteristics. We provide a succinct literature review regarding pathologies from this category. Imaging and histological characteristics are discussed, as well as clinical management. In conclusion, an adrenal mass may present a diagnostic challenge. After exclusion of most common diagnoses, it can be difficult to differentiate between possible pathologies based on preoperative diagnostic tests. Surgical resection of possibly harmful tumors is indicated, for example, lesions with malignant potential or risk of spontaneous hemorrhage. Resection of an obviously benign lesion is not necessary, unless problems due to tumor size are expected. Thomas M. Kerkhofs, Rudi M. Roumen, Thomas B. Demeyere, Antoine N. van der Linden, and Harm R. Haak Copyright © 2015 Thomas M. Kerkhofs et al. All rights reserved. Predictors of Subclinical Cardiovascular Disease in Women with Polycystic Ovary Syndrome: Interrelationship of Dyslipidemia and Arterial Blood Pressure Tue, 24 Mar 2015 13:50:50 +0000 Background. Women with polycystic ovary syndrome (PCOS) could develop subclinical atherosclerosis during life. Purpose. To analyze cardiovascular risk (CVR) factors and their relation to clinical markers of cardiovascular disease (CVD) in respect to their age. Material and Methods. One hundred women with PCOS ( years, BMI:  kg/m2) were compared to 50 respective controls. In all subjects, total cholesterol (TC), HDL-C, LDL-C, triglycerides, TC/HDL-C and TG/HDL-C ratios, glucose, insulin and HOMA index, waist-to-hip ratio (WHR), systolic and diastolic blood pressure (SBP and DBP, resp.), and carotid intima-media thickness (CIMT) were analyzed in respect to their age and level of androgens. Results. PCOS over 30 years had higher WHR (), SBP (), DBP (), TC (), HDL-C (), LDL-C (), triglycerides (), TC/HDL-C (), and triglycerides/HDL-C () and had more prevalent hypertension and pronounced CIMT on common carotid arteries even after adjustment for BMI ( and 0.036, resp.). TC/HDL-C and TG/HDL-C were higher in PCOS with the highest quintile of FAI in comparison to those with lower FAI ( and 0.034, resp.). Conclusions. PCOS women older than 30 years irrespective of BMI have the potential for early atherosclerosis mirrored through the elevated lipids/lipid ratios and through changes in blood pressure. Djuro Macut, Marina Bačević, Ivana Božić-Antić, Jelica Bjekić-Macut, Milorad Čivčić, Snježana Erceg, Danijela Vojnović Milutinović, Olivera Stanojlović, Zoran Andrić, Biljana Kastratović-Kotlica, and Tijana Šukilović Copyright © 2015 Djuro Macut et al. All rights reserved. Cytotoxic T Lymphocyte-Associated Antigen 4 Gene Polymorphisms and Autoimmune Thyroid Diseases: An Updated Systematic Review and Cumulative Meta-Analysis Tue, 24 Mar 2015 12:36:35 +0000 The association of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene and susceptibility to autoimmune thyroid diseases (AITDs) has been studied extensively. However, the results were not the same in different ethnic groups. We updated the meta-analysis of association of CTLA-4 gene polymorphisms with AITDs and summarized the results in specific ethnicity. The associations of A49G gene polymorphism with GD, A49G gene polymorphism with HT, CT60 gene polymorphism with GD, and CT60 gene polymorphism with HT were summarized based on the literatures published up to October 30, 2014, in English or Chinese languages. The participants involved in the studies of A49G with GD, A49G with HT, CT60 with GD, and CT60HT were 39004 subjects (in 51 studies), 13102 subjects (in 22 studies), 31446 subjects (in 22 studies), and 6948 subjects (in 8 studies), respectively. The pooled ORs of CTLA-4 gene polymorphisms with AITDs were larger than 1.00, and the 95% CIs of ORs were statistically significant among whole population analyses. However, the subgroup analysis demonstrated that pooled ORs of A49G polymorphisms with GD among Africans or Americans are less than 1.00. The accumulated evidence suggests that the G allele mutant of A49G and CT60 increased the risks of HT and GD. Hai-Feng Hou, Xu Jin, Tao Sun, Cheng Li, Bao-Fa Jiang, and Qun-Wei Li Copyright © 2015 Hai-Feng Hou et al. All rights reserved. The Endocrine Role of the Skeleton Tue, 24 Mar 2015 09:31:58 +0000 Andrea Del Fattore, Cristina Sobacchi, Martina Rauner, and Amélie Coudert Copyright © 2015 Andrea Del Fattore et al. All rights reserved. An Overview of Diabetes Management in Schizophrenia Patients: Office Based Strategies for Primary Care Practitioners and Endocrinologists Mon, 23 Mar 2015 08:26:08 +0000 Diabetes is common and seen in one in five patients with schizophrenia. It is more prevalent than in the general population and contributes to the increased morbidity and shortened lifespan seen in this population. However, screening and treatment for diabetes and other metabolic conditions remain poor for these patients. Multiple factors including genetic risk, neurobiologic mechanisms, psychotropic medications, and environmental factors contribute to the increased prevalence of diabetes. Primary care physicians should be aware of adverse effects of psychotropic medications that can cause or exacerbate diabetes and its complications. Management of diabetes requires physicians to tailor treatment recommendations to address special needs of this population. In addition to behavioral interventions, medications such as metformin have shown promise in attenuating weight loss and preventing hyperglycemia in those patients being treated with antipsychotic medications. Targeted diabetes prevention and treatment is critical in patients with schizophrenia and evidence-based interventions should be considered early in the course of treatment. This paper reviews the prevalence, etiology, and treatment of diabetes in schizophrenia and outlines office based interventions for physicians treating this vulnerable population. Aniyizhai Annamalai and Cenk Tek Copyright © 2015 Aniyizhai Annamalai and Cenk Tek. All rights reserved. The Association of Metabolic Syndrome and Urolithiasis Sun, 22 Mar 2015 12:21:19 +0000 There has been an increasing prevalence of kidney stones over the last 2 decades worldwide. Many studies have indicated a possible association between metabolic syndrome and kidney stone disease, particularly in overweight and obese patients. Many different definitions of metabolic syndrome have been suggested by various organizations, although the definition by the International Diabetes Federation (IDF) is universally considered as the most acceptable definition. The IDF definition revolves around 4 core components: obesity, dyslipidemia, hypertension, and diabetes mellitus. Several hypotheses have been proposed to explain the pathophysiology of urolithiasis resulting from metabolic syndrome, amongst which are the insulin resistance and Randall’s plaque hypothesis. Similarly the pathophysiology of calcium and uric acid stone formation has been investigated to determine a connection between the two conditions. Studies have found many factors contributing to urolithiasis in patients suffering from metabolic syndrome, out of which obesity, overweight, and sedentary lifestyles have been identified as major etiological factors. Primary and secondary prevention methods therefore tend to revolve mainly around lifestyle improvements, including dietary and other preventive measures. Yee V. Wong, Paul Cook, and Bhaskar K. Somani Copyright © 2015 Yee V. Wong et al. All rights reserved. Hidden Metabolic Disturbances in Women with Normal Glucose Tolerance Five Years after Gestational Diabetes Sun, 22 Mar 2015 08:53:40 +0000 Background. The study aimed to assess whether women with prior gestational diabetes (pGDM), despite maintenance of normal glucose tolerance (NGT) five years after delivery, display metabolic disturbances compared to healthy controls. Methods. 45 pGDM with NGT were compared to 18 women without a history of GDM (CON), matched for age (37.0 ± 4.1 versus 35.2 ± 5.3, ) and BMI (24.3 ± 3.1 versus 23.3 ± 3.3, ). Metabolic parameters were derived from oral and intravenous glucose tolerance tests; furthermore lipid profile, C-reactive protein (CRP), adiponectin, leptin, and glucagon were assessed. Results. Five years postpartum, pGDM had increased glucose concentrations during the OGTT (AUC: 1.12 ± 0.15 versus 1.0 ± 0.12 mol/L min, ) and insulin sensitivity was decreased compared to CON (OGIS: 467.2 ± 64.1 versus 510.6 ± 53.1 mL/min m2, ). pGDM had lower adiponectin (8.1 ± 2.6 versus 12.6 ± 5.3, ) but increased waist circumference and CRP compared to CON. Conclusions. Despite diagnosis of normal glucose tolerance, pGDM are characterized by hyperglycemia and insulin resistance compared to healthy controls, accompanied by decreased adiponectin and increased CRP concentrations, thus linking metabolic disturbances to an increased cardiovascular risk in pGDM. Yvonne Winhofer, Andrea Tura, Anita Thomas, Thomas Prikoszovich, Christine Winzer, Giovanni Pacini, Anton Luger, and Alexandra Kautzky-Willer Copyright © 2015 Yvonne Winhofer et al. All rights reserved. Sex Differences in Cardiovascular Mortality in Diabetics and Nondiabetic Subjects: A Population-Based Study (Italy) Sun, 22 Mar 2015 08:51:07 +0000 The objective of this study is to assess the impact of diabetes on cardiovascular mortality, focusing on sex differences. The inhabitants of Reggio Emilia province on December 31, 2009, aged 20–84 were followed up for three years for mortality. The exposure was determined using Reggio Emilia diabetes register. The age-adjusted death rates were estimated as well as the incidence rate ratios using Poisson regression model. Interaction terms for diabetes and sex were tested by the Wald test. People with diabetes had an excess of mortality, compared with nondiabetic subjects (all cause: IRR = 1.68; 95%CI 1.60–1.78; CVD: IRR = 1.61; 95%CI 1.47–1.76; AMI: IRR = 1.59; 95%CI 1.27–1.99; renal causes: IRR = 1.71; 95%CI 1.22–2.38). The impact of diabetes is greater in females than males for all causes () and for CVD, IMA, and renal causes. Further studies are needed to investigate whether the difference in cardiovascular risk profile or in the quality of care delivered justifies the higher excess of mortality in females with diabetes compared to males. Paola Ballotari, Sofia Chiatamone Ranieri, Ferdinando Luberto, Stefania Caroli, Marina Greci, Paolo Giorgi Rossi, and Valeria Manicardi Copyright © 2015 Paola Ballotari et al. All rights reserved. Liver Injury Indicating Fatty Liver but Not Serologic NASH Marker Improves under Metformin Treatment in Polycystic Ovary Syndrome Thu, 19 Mar 2015 13:21:50 +0000 Objective. Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance (IR), key features of nonalcoholic steatohepatitis (NASH). Cytokeratin 18 fragments (M30) have been established as a serum marker for NASH. The insulin sensitizer metformin improves hepatic IR. This study evaluates the influence of MF on serologic NASH (sNASH) in patients with PCOS. Patients and Methods. In 89 patients, metabolic parameters, liver injury indicating fatty liver (LIFL), and M30 were assessed at baseline and after metformin treatment. Patients with initial IR were subdivided into dissolved (PCOS-exIR) and persistent IR (PCOS-PIR) after treatment and compared to an initially insulin sensitive PCOS group (PCOS-C). Results. Improvement of LIFL prevalence could be seen in PCOS-C and PCOS-exIR compared to PCOS-PIR (−19.4, resp., −12.0% versus 7.2%, Chi2 = 29.5, ) without change in sNASH prevalence. In PCOS-PIR, ALT levels increased significantly accompanied by a nominal, nonsignificant M30 increase. Conclusions. Metformin improves LIFL in subgroups of patients with PCOS without influencing sNASH. This could either indicate a missing effect of metformin on NAFLD or slowed disease progression. Further studies are needed to elucidate NAFLD in the context of PCOS and potential therapeutic options. Susanne Tan, Nils Vollmar, Sven Benson, Jan-Peter Sowa, Lars P. Bechmann, Guido Gerken, Dagmar Fuhrer, and Ali Canbay Copyright © 2015 Susanne Tan et al. All rights reserved. Bone Regulates Glucose Metabolism as an Endocrine Organ through Osteocalcin Thu, 19 Mar 2015 13:07:39 +0000 Skeleton was considered as a dynamic connective tissue, which was essential for mobility, calcium homeostasis, and hematopoietic niche. However more and more evidences indicate that skeleton works not only as a structural scaffold but also as an endocrine organ, which regulates several metabolic processes. Besides osteoprotegerin (OPG), sclerostin (SOST), and Dickopf (DKK) which play essential roles in bone formation, modelling, remodelling, and homeostasis, bone can also secret hormones, such as osteocalcin (OCN), which promotes proliferation of β cells, insulin secretion, and insulin sensitivity. Additionally OCN can also regulate the fat cells and male gonad endocrine activity and be regulated by insulin and the neural system. In summary, skeleton has endocrine function via OCN and plays an important role in energy metabolism, especially in glucose metabolism. Jin Shao, Zhi Wang, Tieyi Yang, Hui Ying, Yan Zhang, and Shuyi Liu Copyright © 2015 Jin Shao et al. All rights reserved. Age- and Gender-Related Differences in LDL-Cholesterol Management in Outpatients with Type 2 Diabetes Mellitus Thu, 19 Mar 2015 12:52:19 +0000 Background. Dyslipidemia contribute to the excess of coronary heart disease (CHD) risk observed in women with type 2 diabetes (T2DM). Low density lipoprotein-cholesterol (LDL-C) is the major target for CHD prevention, and T2DM women seem to reach LDL-C targets less frequently than men. Aim. To explore age- and gender-related differences in LDL-C management in a large sample of outpatients with T2DM. Results. Overall, 415.294 patients (45.3% women) from 236 diabetes centers in Italy were included. Women were older and more obese, with longer diabetes duration, higher total-cholesterol, LDL-C, and HDL-C serum levels compared to men (). Lipid profile was monitored in ~75% of subjects, women being monitored less frequently than men, irrespective of age. More women did not reach the LDL-C target as compared to men, particularly in the subgroup treated with lipid-lowering medications. The between-genders gap in reaching LDL-C targets increased with age and diabetes duration, favouring men in all groups. Conclusions. LDL-C management is worst in women with T2DM, who are monitored and reach targets less frequently than T2DM men. Similarly to men, they do not receive medications despite high LDL-C. These gender discrepancies increase with age and diabetes duration, exposing older women to higher CHD risk. Giuseppina Russo, Basilio Pintaudi, Carlo Giorda, Giuseppe Lucisano, Antonio Nicolucci, Maria Rosaria Cristofaro, Concetta Suraci, Maria Franca Mulas, Angela Napoli, Maria Chiara Rossi, and Valeria Manicardi Copyright © 2015 Giuseppina Russo et al. All rights reserved. Functional Diversity of Fibroblast Growth Factors in Bone Formation Thu, 19 Mar 2015 12:48:57 +0000 The functional significance of fibroblast growth factor (FGF) signaling in bone formation has been demonstrated through genetic loss-of-function and gain-of-function approaches. FGFs, comprising 22 family members, are classified into three subfamilies: canonical, hormone-like, and intracellular. The former two subfamilies activate their signaling pathways through FGF receptors (FGFRs). Currently, intracellular FGFs appear to be primarily involved in the nervous system. Canonical FGFs such as FGF2 play significant roles in bone formation, and precise spatiotemporal control of FGFs and FGFRs at the transcriptional and posttranscriptional levels may allow for the functional diversity of FGFs during bone formation. Recently, several research groups, including ours, have shown that FGF23, a member of the hormone-like FGF subfamily, is primarily expressed in osteocytes/osteoblasts. This polypeptide decreases serum phosphate levels by inhibiting renal phosphate reabsorption and vitamin D3 activation, resulting in mineralization defects in the bone. Thus, FGFs are involved in the positive and negative regulation of bone formation. In this review, we focus on the reciprocal roles of FGFs in bone formation in relation to their local versus systemic effects. Yuichiro Takei, Tomoko Minamizaki, and Yuji Yoshiko Copyright © 2015 Yuichiro Takei et al. All rights reserved. Urinary Angiopoietin-2 Is Associated with Albuminuria in Patients with Type 2 Diabetes Mellitus Thu, 19 Mar 2015 12:38:26 +0000 Aims. To evaluate the levels of angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) in serum and urine, and their association with albuminuria in patients with type 2 diabetes mellitus. Methods. In 113 type 2 diabetic patients with normoalbuminuria, microalbuminuria, and macroalbuminuria and 30 healthy controls, the levels of Ang-1, Ang-2, and VEGF in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). Results. Urinary and serum levels of Ang-2 were significantly higher in diabetic patients with normoalbuminuria than in healthy controls. Increased urinary Ang-2 level was positively associated with the degree of albuminuria. Urinary Ang-1 levels were significantly higher in normoalbuminuria patients and lower in macroalbuminuria patients than in controls. The levels of urinary VEGF increased in the albuminuria subgroup, though serum levels of Ang-1 and VEGF did not change. Urinary Ang-2 levels were correlated positively with albuminuria and negatively with glomerular filtration rate (GFR). Stepwise multiple regression analysis identified albuminuria () and GFR () as significant predictors of urinary Ang-2. Conclusions. Our data suggest that urinary Ang-2 is stepwise increased with renal damage in patients with type 2 diabetes mellitus and is associated with albuminuria. Shan Chen, Huiqing Li, Chun Zhang, Zhenqiong Li, Qiuyuan Wang, Jinting Guo, Changqing Luo, and Yumei Wang Copyright © 2015 Shan Chen et al. All rights reserved. Iodine Supplementation: Usage “with a Grain of Salt” Thu, 19 Mar 2015 12:28:17 +0000 Iodine supplementation through salt iodization is a worldwide, effective strategy for preventing iodine deficiency-related problems. Its safety and efficacy profile has been extensively investigated, and benefits far outweigh the potential iodine-induced risks. Moreover, iodine supplementation during pregnancy in order to avoid brain damage in the newborn is considered a mainstay of preventive medicine. Exposure to high amounts of iodine is actually well tolerated in most cases and can be unrecognized. Nevertheless, at-risk individuals may develop thyroid dysfunction even when they are exposed to increases in iodine intake universally considered as safe. Iodine-induced thyroid disorders include thyroid autoimmunity, thyrotoxicosis, iodine-induced goiter, and hypothyroidism. Moreover, a relationship between iodine intake and histotype distribution of differentiated thyroid cancer has been observed, with a progressive shift from follicular to papillary thyroid cancer. To date, evaluating iodine status in a clinical setting has limitations, and assessing the actual risk for each individual can be challenging, since it is influenced by personal history, genetics, and environmental factors. In conclusion, iodine supplementation programs need to be continued and strengthened, but iodine should be used “with a grain of salt,” because a growing number of susceptible individuals will be exposed to the risk of developing iodine-induced thyroid disorders. Alessandro Prete, Rosa Maria Paragliola, and Salvatore Maria Corsello Copyright © 2015 Alessandro Prete et al. All rights reserved. A Single 60 mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women Thu, 19 Mar 2015 11:30:48 +0000 Background. The RANKL/RANK/OPG signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis. The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation. Aim. To test whether systemic blockage of RANKL by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women. Study Design. This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test. Results. A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose, insulin, or HOMA-IR at both 4 and 12 weeks. No changes could be detected in glucose response to the glucose load, Matsuda Index, or insulinogenic index. Nonetheless, 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks. Conclusions. A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients. Elena Passeri, Stefano Benedini, Elena Costa, and Sabrina Corbetta Copyright © 2015 Elena Passeri et al. All rights reserved. Sex, Prescribing Practices and Guideline Recommended, Blood Pressure, and LDL Cholesterol Targets at Baseline in the BARI 2D Trial Thu, 19 Mar 2015 09:56:15 +0000 Background. Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men. Methods. We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial. Results. Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex. Conclusions. Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia. Michelle F. Magee, Jacqueline E. Tamis-Holland, Jiang Lu, Vera A. Bittner, Maria Mori Brooks, Neuza Lopes, Alice K. Jacobs, and BARI 2D Study Group Copyright © 2015 Michelle F. Magee et al. All rights reserved. The Endocrine Role of Estrogens on Human Male Skeleton Thu, 19 Mar 2015 09:43:16 +0000 Before the characterization of human and animal models of estrogen deficiency, estrogen action was confined in the context of the female bone. These interesting models uncovered a wide spectrum of unexpected estrogen actions on bone in males, allowing the formulation of an estrogen-centric theory useful to explain how sex steroids act on bone in men. Most of the principal physiological events that take place in the developing and mature male bone are now considered to be under the control of estrogen. Estrogen determines the acceleration of bone elongation at puberty, epiphyseal closure, harmonic skeletal proportions, the achievement of peak bone mass, and the maintenance of bone mass. Furthermore, it seems to crosstalk with androgen even in the determination of bone size, a more androgen-dependent phenomenon. At puberty, epiphyseal closure and growth arrest occur when a critical number of estrogens is reached. The same mechanism based on a critical threshold of serum estradiol seems to operate in men during adulthood for bone mass maintenance via the modulation of bone formation and resorption in men. This threshold should be better identified in-between the ranges of 15 and 25 pg/mL. Future basic and clinical research will optimize strategies for the management of bone diseases related to estrogen deficiency in men. Vincenzo Rochira, Elda Kara, and Cesare Carani Copyright © 2015 Vincenzo Rochira et al. All rights reserved. Skeleton and Glucose Metabolism: A Bone-Pancreas Loop Thu, 19 Mar 2015 09:20:00 +0000 Bone has been considered a structure essential for mobility, calcium homeostasis, and hematopoietic function. Recent advances in bone biology have highlighted the importance of skeleton as an endocrine organ which regulates some metabolic pathways, in particular, insulin signaling and glucose tolerance. This review will point out the role of bone as an endocrine “gland” and, specifically, of bone-specific proteins, as the osteocalcin (Ocn), and proteins involved in bone remodeling, as osteoprotegerin, in the regulation of insulin function and glucose metabolism. Maria Felicia Faienza, Vincenza Luce, Annamaria Ventura, Graziana Colaianni, Silvia Colucci, Luciano Cavallo, Maria Grano, and Giacomina Brunetti Copyright © 2015 Maria Felicia Faienza et al. All rights reserved. Pituitary Disorders and Osteoporosis Thu, 19 Mar 2015 09:16:25 +0000 Various hormonal disorders can influence bone metabolism and cause secondary osteoporosis. The consequence of this is a significant increase of fracture risk. Among pituitary disorders such effects are observed in patients with Cushing’s disease, hyperprolactinemia, acromegaly, and hypopituitarism. Severe osteoporosis is the result of the coexistence of some of these disorders and hypogonadism at the same time, which is quite often. Marek Bolanowski, Jowita Halupczok, and Aleksandra Jawiarczyk-Przybyłowska Copyright © 2015 Marek Bolanowski et al. All rights reserved.