The Journal of clinical endocrinology and metabolism

Description

Publications in this journal

• Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials.

  Authors: Lars Rejnmark, Alison Avenell, Tahir Masud, Frazer Anderson, Haakon E Meyer, Kerrie M Sanders, Kari Salovaara, Cyrus Cooper, Helen E Smith, Elizabeth T Jacobs, David Torgerson, Rebecca D Jackson, Joann E Manson, Kim Brixen, Leif Mosekilde, John A Robbins, Roger M Francis, Bo Abrahamsen

  The Journal of clinical endocrinology and metabolism.

  Introduction:Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient dataIntroduction:Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium.Subjects and Methods:Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies.Results:The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06).Conclusion:Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

• 45,X/46,XY Mosaicism: Phenotypic Characteristics, Growth, and Reproductive Function--A Retrospective Longitudinal Study.

  Authors: Marie Lindhardt Johansen, Casper P Hagen, Ewa Rajpert-De Meyts, Susanne Kjærgaard, Bodil L Petersen, Niels E Skakkebæk, Katharina M Main, Anders Juul

  The Journal of clinical endocrinology and metabolism.

  Context:Most previous studies of 45,X/46,XY mosaicism are case reports or have described single aspects of the disease.Objective:The objective was to provide longitudinal data of patients withContext:Most previous studies of 45,X/46,XY mosaicism are case reports or have described single aspects of the disease.Objective:The objective was to provide longitudinal data of patients with 45,X/46,XY mosaicism.Design:This was a retrospective, longitudinal study conducted from June 1990 to January 2012.Setting:The study took place at a tertiary pediatric and andrological referral center.Patients or Other Participants:Twenty-five patients (18 boys, seven girls) with 45,X/46,XY mosaicism and its variants were included and were compared to healthy controls.Intervention(s):No interventions were included in the study.Main Outcome Measure(s):Phenotypes were scored using external masculinization scores. Serum LH, FSH, testosterone, estradiol, and inhibin B levels were reported in male patients. IGF-I levels and height were reported in all patients. Available biopsies/gonadectomies were histologically examined.Results:Fourteen of 18 males had external masculinization scores consistent with normal virilization. Ten of 11 male patients experienced spontaneous puberty. Median height sd score was -2.0 (range, -3 to 0.3) for males and -2.2 (range, -2.5 to -1.4) for females, both considerably below genetic potential. Median 1-yr height gain after GH treatment in seven patients was 0.5 sd (0.1 to 1.2). All tissue samples from 15 patients (eight males, seven females) revealed abnormal gonadal histology. Four patients had carcinoma in situ (CIS); two had tissue samples available from early childhood, one showing CIS.Conclusions:Gonadal function in most 45,X/46,XY males, even those with genital ambiguity, seems sufficient for spontaneous puberty. Short stature and 45,X/46,XY mosaicism seem associated, but patients appear to benefit from GH treatment. Histology from two patients with biopsies from early childhood indicates that CIS originates before puberty.

• Parental Origin of the X-Chromosome Does Not Influence Growth Hormone Treatment Effect in Turner Syndrome.

  Authors: Marie Devernay, Diana Bolca, Lamia Kerdjana, Azzedine Aboura, Bénédicte Gérard, Anne-Claude Tabet, Brigitte Benzacken, Emmanuel Ecosse, Joël Coste, Jean-Claude Carel

  The Journal of clinical endocrinology and metabolism.

  Context:The parental origin of the intact X-chromosome has been reported to affect phenotype and response to GH treatment in Turner syndrome (TS).Objective:Our objective was to evaluate the influenceContext:The parental origin of the intact X-chromosome has been reported to affect phenotype and response to GH treatment in Turner syndrome (TS).Objective:Our objective was to evaluate the influence of the parental origin of the X-chromosome on body growth and GH treatment effect in TS.Design and Setting:We conducted a population-based cohort study of TS patients previously treated with GH.Participants:Participants included patients with a nonmosaic 45,X karyotype; 556 women were identified as eligible, 233 (49%) of whom participated, together with their mothers. Data were analyzed for 180 of these patients.Main Outcome Measures:We performed fluorescence in situ hybridization analysis to exclude mosaicism and microsatellite analysis of nine polymorphic markers in DNA from the patients and their mothers. The influence on growth and effect of GH were analyzed by univariate and multivariate methods.Results:The X-chromosome was of paternal origin (X(pat)) in 52 (29%) of 180 and of maternal origin (X(mat)) in 128 (71%) of 180 patients. Height gain from the start of GH treatment to adult height was similar in X(mat) and X(pat) patients (+2.1 ± 0.9 vs. +2.2 ± 0.8 TS sd score, P = 0.45). The lack of influence of parental origin of the X-chromosome was confirmed in multivariate analysis. Parental origin of the X-chromosome also had no effect on the other growth characteristics studied, including growth velocity during the first year on GH treatment. Patient height was correlated with the heights of both parents and was not influenced by the parental origin of the X-chromosome.Conclusion:In this, the largest such study carried out to date, the parental origin of the X-chromosome did not alter the effect of GH treatment or affect any other features of growth in TS.

• Combination Treatment with T4 and T3: Toward Personalized Replacement Therapy in Hypothyroidism?

  Authors: Bernadette Biondi, Leonard Wartofsky

  The Journal of clinical endocrinology and metabolism.

  Context:Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combinedContext:Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T(3) and T(4) treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic.Evidence Acquisition:We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action.Evidence Synthesis:The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients.Conclusions:Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.

• Brown Adipose Tissue and Its Relationship to Bone Structure in Pediatric Patients.

  Authors: Skorn Ponrartana, Patricia C Aggabao, Houchun H Hu, Grace M Aldrovandi, Tishya A L Wren, Vicente Gilsanz

  The Journal of clinical endocrinology and metabolism.

  Context:Emerging evidence suggests a possible link between brown adipose tissue (BAT) and bone metabolism.Objective:The objective of this study was to examine the relationships between BAT and boneContext:Emerging evidence suggests a possible link between brown adipose tissue (BAT) and bone metabolism.Objective:The objective of this study was to examine the relationships between BAT and bone cross-sectional dimensions in children and adolescents.Design:This was a cross-sectional study.Setting:The study was conducted at a pediatric referral center.Patients:Patients included 40 children and teenagers (21 males and 19 females) successfully treated for pediatric malignancies.Interventions:There were no interventions.Main Outcome Measures:The volume of BAT was determined by fluorodeoxyglucose-positron emission tomography/computed tomography. Measures of the cross-sectional area and cortical bone area and measures of thigh musculature and sc fat were determined at the midshaft of the femur.Results:Regardless of sex, there were significant correlations seen between BAT volume and the cross-sectional dimensions of the bone (r values between 0.68 and 0.77; all P ≤ 0 .001). Multiple regression analyses indicated that the volume of BAT predicted femoral cross-sectional area and cortical bone area, even after accounting for height, weight, and gender. The addition of muscle as an independent variable increased the predictive power of the model but significantly decreased the contribution of BAT.Conclusions:The volume of BAT is positively associated with the amount of bone and the cross-sectional size of the femur in children and adolescents. This relation between BAT and bone structure could, at least in part, be mediated by muscle.

• Adolescent Fiber Consumption Is Associated with Visceral Fat and Inflammatory Markers.

  Authors: Samip Parikh, Norman K Pollock, Jigar Bhagatwala, De-Huang Guo, Bernard Gutin, Haidong Zhu, Yanbin Dong

  The Journal of clinical endocrinology and metabolism.

  Context:The link between adolescent fiber consumption, inflammation, and body fat distribution has not been investigated.Objective:This study investigated associations of dietary fiber intake withContext:The link between adolescent fiber consumption, inflammation, and body fat distribution has not been investigated.Objective:This study investigated associations of dietary fiber intake with inflammatory-related biomarkers and robust measures of total and central adiposity in a sample of 559 adolescents aged 14-18 yr (49% female, 45% Black).Methods:Fasting blood samples were measured for leptin, adiponectin, resistin, C-reactive protein, and fibrinogen. Diet was assessed with four to seven 24-h recalls, and physical activity was determined by accelerometry. Fat-free soft tissue mass and fat mass were measured by dual-energy x-ray absorptiometry. Visceral adipose tissue was assessed using magnetic resonance imaging.Results:Multiple linear regression, adjusting for age, race, Tanner stage, fat-free soft tissue mass, energy intake, and physical activity, revealed that dietary fiber intake was inversely associated with fat mass and serum leptin in males (all P < 0.03) but not in females. In both genders, dietary fiber intake was negatively associated with visceral adipose tissue, plasma C-reactive protein, and plasma fibrinogen and positively associated with plasma adiponectin (all P < 0.05). No relations were found between dietary fiber intake and plasma resistin in either males or females.Conclusion:Our adolescent data suggest that greater consumption of dietary fiber is associated with lower visceral adiposity and multiple biomarkers implicated in inflammation.

• Remarkable Cystic Expansion of Microprolactinoma Causing Diabetes Insipidus during Pregnancy.

  Authors: Eri Amano, Mitsuru Nishiyama, Yasumasa Iwasaki, Sachio Matsushima, Hiroyoshi Oguri, Noriaki Fukuhara, Hiroshi Nishioka, Shozo Yamada, Naoko Inoshita, Takao Fukaya, Yoshio Terada

  The Journal of clinical endocrinology and metabolism.

  Abstract Not Available.

• Factors Predicting Vitamin D Response Variation in Non-Hispanic White Postmenopausal Women.

  Authors: Lan-Juan Zhao, Yu Zhou, Fengxiao Bu, Dianne Travers-Gustafson, An Ye, Xiaojing Xu, Lee Hamm, Daniel Michael Gorsage, Xiang Fang, Hong-Wen Deng, Robert R Recker, Joan M Lappe

  The Journal of clinical endocrinology and metabolism.

  Objective:It is well documented that there is wide variation in the response of serum 25-hydroxyvitamin D [25(OH)D] to a given dose of vitamin D supplementation. Understanding factors affecting theObjective:It is well documented that there is wide variation in the response of serum 25-hydroxyvitamin D [25(OH)D] to a given dose of vitamin D supplementation. Understanding factors affecting the response variation is important for identifying subjects who are susceptible to vitamin D deficiency or toxicity. This study aimed to evaluate potential predictors for vitamin D response variation.Design and Participants:A total of 1179 non-Hispanic white postmenopausal women were enrolled into a 4-yr calcium and vitamin D (1100 IU/d) clinical trial. Among them, serum 25(OH)D level of 1063 subjects were measured at both baseline and after 12 months treatment. Vitamin D response was computed for these 1063 subjects as the difference in levels of serum 25(OH)D concentration at the end of a 12-month vitamin D treatment compared with baseline. Stepwise linear regression was used to identify predictors of vitamin D response variation.Results:Increase in vitamin D intake, baseline serum 25(OH)D level, baseline blood collection season, baseline serum calcium level, and baseline body mass index were predictors of vitamin D response variation. These five factors explained 46.8% of the vitamin D response variation in the 1063 subjects. The first three factors [increase in vitamin D intake, baseline serum 25(OH)D level, baseline blood collection season] remained as predictors in the 392 subjects with trial vitamin D supplementation. For the first time, our study indicated that season is an important prediction factor for vitamin D response variation. Subjects who started vitamin D treatment in a cold season (autumn and winter) achieved a significantly higher serum 25(OH)D increase than those started in a hot season (summer) (P < 0.001).Conclusion:Our study suggests that the increase in vitamin D supplementation, baseline serum 25(OH)D level, and the season when initiating the vitamin D supplementation can partially predict vitamin D response variation in non-Hispanic postmenopausal women.

• Gene Expression Profiling Identifies ESRP1 as a Potential Regulator of Epithelial Mesenchymal Transition in Somatotroph Adenomas from a Large Cohort of Patients with Acromegaly.

  Authors: Tove Lekva, Jens Petter Berg, Stine Lyngvi Fougner, Ole Kristoffer Olstad, Thor Ueland, Jens Bollerslev

  The Journal of clinical endocrinology and metabolism.

  Context:The epithelial marker E-cadherin plays a crucial role in epithelial-mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumorContext:The epithelial marker E-cadherin plays a crucial role in epithelial-mesenchymal transition (EMT). Decreased protein content in somatotroph adenomas has been associated with increased tumor size, invasion, and poor response to somatostatin analog (SA) treatment, but the potential mechanisms of EMT progression in these adenomas are lacking.Objective:We hypothesized that characterization of EMT-related transcripts in somatotroph adenomas could identify novel therapeutic targets in individuals with poor response to SA treatment and provide more knowledge of the mechanism of EMT progression.Patients:Fifty-three patients with acromegaly participated in the study.Research Design and Methods:We performed microarray analysis of 16 adenomas, eight with high expression and eight with low expression of E-cadherin, in order to identify EMT-related transcripts. Candidate transcripts were further explored in vivo in 53 adenomas and in vitro in a rat pituitary GH-producing cell (GH3) after exploring three models for reducing E-cadherin and inducing a mesenchymal phenotype.Results:In vivo E-cadherin mRNA expression in tumor tissue is associated negatively with tumor size and invasiveness and positively with GH and IGF-I levels in serum and response to SA treatment. Microarray and subsequent PCR analysis identify several EMT-related genes associated with E-cadherin expression. In vitro, few of these EMT-related genes were regulated by silencing E-cadherin or by TGF-β1 treatment in GH3 cells. In contrast, silencing Esrp1 in GH3 cells regulated many of the EMT-related transcripts.Conclusion:These results indicate that ESRP1 could be a master regulator of the EMT process in pituitary adenomas causing acromegaly.

• Metabolic and Neuroendocrine Responses to Roux-en-Y Gastric Bypass. I: Energy Balance, Metabolic Changes, and Fat Loss.

  Authors: X Liu, A Lagoy, I Discenza, G Papineau, E Lewis, G Braden, J Romanelli, B Braun, J E Silva

  The Journal of clinical endocrinology and metabolism.

  Context:Obesity is a major health problem. Effective treatment requires understanding the homeostatic responses to caloric restriction.Objective:The aim was to study Roux-en-Y gastric bypass patientsContext:Obesity is a major health problem. Effective treatment requires understanding the homeostatic responses to caloric restriction.Objective:The aim was to study Roux-en-Y gastric bypass patients longitudinally for 6 months after surgery to identify major factors modulating fat loss.Methods:We studied 13 patients (11 females and two males) aged 41.2 ± 2 yr. Mean body mass index was 44.6 ± 1.2 kg/m(2), with 50 ± 1% body fat (58.3 kg). Selection excluded patients with confounding comorbidities or treatments.Results:Caloric intake was reduced 742 ± 82 kcal/d by 1 month and 450 kcal/d between 2 and 4 months postoperatively. By 6 months, relative to baseline, body mass index decreased 24.8 ± 1.1%; percentage body fat, 37.3 ± 3.2% (21.7 kg); fat free mass (FFM), 9.7 ± 1.2%; and resting metabolic rate (RMR), 18.1 ± 4.3%. RMR correlated with FFM at all times (r = 0.71; P < 0.0001), but FFM explained no more than 50% of RMR variance. Exercise capacity (treadmill walking, 53 m/min with increasing grade) improved with time. Mean nonexercise physical activity level was low (1.2, or 20% of RMR), with considerable variance among individuals. Fat loss did not correlate with the aggregate energy deficit or its individual components. Resting or postexercise respiratory exchange ratio (RER) was lowest, whereas plasma β-OH-butyrate and glycerol were highest, between 1 and 2 months after surgery. RER increased linearly with mild exercise, and fat loss correlated positively with physical activity level and RER.Conclusions:Although the ultimate cause for weight loss is the energy deficit, the variance in fat loss correlated with glucose oxidation, suggesting that glucose partition between oxidation (muscle) and storage (adipose tissue) is an important factor affecting fat loss in individuals submitted to Roux-en-Y gastric bypass.

• Differential Gene Expression by Oxyphil and Chief Cells of Human Parathyroid Glands.

  Authors: Cynthia S Ritter, Bruce H Haughey, Brent Miller, Alex J Brown

  The Journal of clinical endocrinology and metabolism.

  Context:Parathyroid oxyphil cells, whose function is unknown, are thought to be derived from chief cells. Oxyphil cells increase in number in parathyroid glands of patients with chronic kidneyContext:Parathyroid oxyphil cells, whose function is unknown, are thought to be derived from chief cells. Oxyphil cells increase in number in parathyroid glands of patients with chronic kidney disease (CKD) and are even more abundant in patients receiving treatment for hyperparathyroidism with calcitriol and/or the calcimimetic cinacalcet.Objective:We examined oxyphil and chief cells of parathyroid glands of CKD patients for differential expression of genes important to parathyroid function.Design/Setting/Participants:Parathyroid tissue from CKD patients with refractory hyperparathyroidism was immunostained for gene expression studies.Main Outcome Measure:Immunostaining for PTH, PTHrP, calcium-sensing receptor, glial cells missing 2, vitamin D receptor, 25-hydroxyvitamin D-1α-hydroxylase, and cytochrome c was quantified and expression reported for oxyphil and chief cells.Results:Expression of all proteins analyzed, except for the vitamin D receptor, was higher in oxyphil cells than in chief cells.Conclusion:Human parathyroid oxyphil cells express parathyroid-relevant genes found in the chief cells and have the potential to produce additional autocrine/paracrine factors, such as PTHrP and calcitriol. Additional studies are warranted to define the secretory properties of these cells and clarify their role in parathyroid pathophysiology.

• Kisspeptin Administration to Women: A Window into Endogenous Kisspeptin Secretion and GnRH Responsiveness across the Menstrual Cycle.

  Authors: Yee-Ming Chan, James P Butler, Valerie F Sidhoum, Nancy E Pinnell, Stephanie B Seminara

  The Journal of clinical endocrinology and metabolism.

  Context:Kisspeptin is the most powerful known stimulus of GnRH-induced LH secretion across mammalian species. However, the effects of kisspeptin are just being explored, and the dynamics ofContext:Kisspeptin is the most powerful known stimulus of GnRH-induced LH secretion across mammalian species. However, the effects of kisspeptin are just being explored, and the dynamics of kisspeptin responsiveness across the menstrual cycle are incompletely understood.Objective:The objective of the study was to characterize the effects of kisspeptin on GnRH secretion in healthy women in different phases of the menstrual cycle.Participants and Intervention:Ten women in the early follicular phase, three women in the late follicular (preovulatory) phase, and 14 women in the midluteal phase received a bolus of kisspeptin 112-121 0.24 nmol/kg iv. An additional four women in the early to midfollicular phase received kisspeptin 112-121 0.72 nmol/kg iv.Results:The response to kisspeptin varied depending on the phase of the menstrual cycle. LH pulses were observed immediately after kisspeptin administration in all luteal and preovulatory women. However, only half the women in the early follicular phase had unambiguous kisspeptin responses. Increasing the kisspeptin dose did not increase the LH response in early to midfollicular phase women. Kisspeptin did not appear to reset the GnRH pulse generator in women as it does in men.Conclusions:Differences in responses to exogenous kisspeptin across the menstrual cycle suggest that kisspeptin tone is higher in the early follicular phase compared with other cycle phases. The mechanisms that determine the timing of GnRH pulse generation in men and women appear to be distinct.

• ZNF764 Haploinsufficiency May Explain Partial Glucocorticoid, Androgen, and Thyroid Hormone Resistance Associated with 16p11.2 Microdeletion.

  Authors: Tomoshige Kino, Maria G Pavlatou, Andreas G Moraitis, Robin L Nemery, Margarita Raygada, Constantine A Stratakis

  The Journal of clinical endocrinology and metabolism.

  Context:Nuclear hormone receptors exert their transcriptional effects through shared cofactor molecules; thus, defects in such intermediate proteins may be associated with multiple hormoneContext:Nuclear hormone receptors exert their transcriptional effects through shared cofactor molecules; thus, defects in such intermediate proteins may be associated with multiple hormone resistance. Microdeletion of small chromosomal segments results in hereditary or sporadic diseases by affecting expression of residing genes.Objectives:We describe a 7-yr-old boy with partial resistance to glucocorticoids, thyroid hormones, and possibly androgens. He was diagnosed as being in the autism spectrum disorder and had developmental delay and several facial morphological manifestations. We explored genes responsible for multiple hormone resistance of this case.Results:We found in this patient an approximately 1.1-Mb heterozygous 16p11.2 microdeletion, which included an approximately 500-kb unique deletion along with the common, previously reported approximately 600-kb 16p11.2 microdeletion. The small interfering RNA-based screening revealed that knockdown of ZNF764, which is located in the deleted segment unique to our case, significantly reduced glucocorticoid-, androgen-, and thyroid hormone-induced transcriptional activity of their responsive genes in HeLa cells, whereas its overexpression enhanced their transcriptional activity. The activities of the estrogen and progesterone receptors, cAMP response element-binding protein, and p53 were not affected in these cells. ZNF764 (zinc finger protein 764) expression was reduced in the patient's peripheral blood mononuclear cells, whereas exogenously supplemented ZNF764 recovered responsiveness to glucocorticoids in the patient's Epstein-Barr virus-transformed lymphocytes. The effect of ZNF764 on the glucocorticoid receptor transcriptional activity was mediated through cooperation with a general nuclear hormone receptor coactivator, transcriptional intermediary factor 1.Conclusions:ZNF764 haploinsufficiency caused by microdeletion may be responsible for the partial multiple hormone resistance observed in our patient. ZNF764 appears to be involved in glucocorticoid, androgen, and thyroid hormone action.

• Prestimulation with Recombinant Human Thyrotropin (rhTSH) Improves the Long-Term Outcome of Radioiodine Therapy for Multinodular Nontoxic Goiter.

  Authors: Søren Fast, Viveque Egsgaard Nielsen, Peter Grupe, Henrik Boel-Jørgensen, Lars Bastholt, Peter Bøgeskov Andersen, Steen Joop Bonnema, Laszlo Hegedüs

  The Journal of clinical endocrinology and metabolism.

  Objective:The objective of the study was to evaluate the long-term outcome of recombinant human TSH (rhTSH)-augmented radioiodine ((131)I) therapy for benign multinodular nontoxic goiter.Patients andObjective:The objective of the study was to evaluate the long-term outcome of recombinant human TSH (rhTSH)-augmented radioiodine ((131)I) therapy for benign multinodular nontoxic goiter.Patients and Methods:Between 2002 and 2005, 86 patients with a multinodular nontoxic goiter were treated with (131)I in two randomized, double-blind, placebo-controlled trials. (131)I-therapy was preceded by 0.3 mg rhTSH (n = 42) or placebo (n = 44). In 2009, 80 patients completed a follow-up (FU) visit, including determination of thyroid volume, thyroid function, and patient satisfaction by a visual analog scale.Results:In both groups, thyroid volume was further reduced from 1 yr to final FU (71 months). The mean goiter volume reductions obtained at 1 yr and final FU [59.2 ± 2.4% (sem) and 69.7 ± 3.1%, respectively] in the rhTSH group were significantly greater than those obtained in the (131)I-alone group (43.2 ± 3.7 and 56.2 ± 3.6%, respectively, P = 0.001 and P = 0.006), corresponding to a gain of 24% at final FU. At last FU the mean reduction in compression visual analog scale score was significantly greater in patients receiving rhTSH (P = 0.049). Additional therapy (thyroid surgery or (131)I) was required more often in the placebo group (nine of 44) compared with the rhTSH group (two of 42) (P = 0.05). The prevalence of hypothyroidism at 1 yr [9 and 43% in the placebo and rhTSH groups, respectively (P < 0.0001)] increased to 16 and 52%, respectively, at final FU (P = 0.001).Conclusion:Enhanced goiter volume reduction with rhTSH-augmented (131)I therapy improves the long-term reduction in goiter-related symptoms and reduces the need for additional therapy compared with plain (131)I therapy. Overall patient satisfaction is benefited, despite a higher rate of permanent hypothyroidism.

• A Reverse J-Shaped Association of All-Cause Mortality with Serum 25-Hydroxyvitamin D in General Practice, the CopD Study.

  Authors: D Durup, H L Jørgensen, J Christensen, P Schwarz, A M Heegaard, B Lind

  The Journal of clinical endocrinology and metabolism.

  Context:Optimal levels of vitamin D have been a topic of heavy debate, and the correlation between 25-hydroxyvitamin D [25(OH)D] levels and mortality still remains to be established.Objective:The aimContext:Optimal levels of vitamin D have been a topic of heavy debate, and the correlation between 25-hydroxyvitamin D [25(OH)D] levels and mortality still remains to be established.Objective:The aim of the study was to determine the association between all-cause mortality and serum levels of 25(OH)D, calcium, and PTH.Design and Setting:We conducted a retrospective, observational cohort study, the CopD Study, in a single laboratory center in Copenhagen, Denmark.Participants:Serum 25(OH)D was analyzed from 247,574 subjects from the Copenhagen general practice sector. In addition, serum levels of calcium, albumin-adjusted calcium, PTH, and creatinine were measured in 111,536; 20,512; 34,996; and 189,496 of the subjects, respectively.Main Outcome Measures:Multivariate Cox regression analysis was used to compute hazard ratios for all-cause mortality.Results:During follow-up (median, 3.07 yr), 15,198 (6.1%) subjects died. A reverse J-shaped association between serum level of 25(OH)D and mortality was observed. A serum 25(OH)D level of 50-60 nmol/liter was associated with the lowest mortality risk. Compared to 50 nmol/liter, the hazard ratios (95% confidence intervals) of all-cause mortality at very low (10 nmol/liter) and high (140 nmol/liter) serum levels of 25(OH)D were 2.13 (2.02-2.24) and 1.42 (1.31-1.53), respectively. Similarly, both high and low levels of albumin-adjusted serum calcium and serum PTH were associated with an increased mortality, and secondary hyperparathyroidism was associated with higher mortality (P < 0.0001).Conclusion:In this study from the general practice sector, a reverse J-shaped relation between the serum level of 25(OH)D and all-cause mortality was observed, indicating not only a lower limit but also an upper limit. The lowest mortality risk was at 50-60 nmol/liter. The study did not allow inference of causality, and further studies are needed to elucidate a possible causal relationship between 25(OH)D levels, especially higher levels, and mortality.

• Effects of Adding Exercise to a 16-Week Very Low-Calorie Diet in Obese, Insulin-Dependent Type 2 Diabetes Mellitus Patients.

  Authors: Marieke Snel, Amalia Gastaldelli, D Margriet Ouwens, Matthijs K C Hesselink, Gert Schaart, Emma Buzzigoli, Marijke Frölich, Johannes A Romijn, Hanno Pijl, A Edo Meinders, Ingrid M Jazet

  The Journal of clinical endocrinology and metabolism.

  Context:Reduction of 50% excess body weight, using a very low-calorie diet (VLCD; 450 kcal/d) improves insulin sensitivity in obese type 2 diabetes mellitus patients.Objective:The objective of theContext:Reduction of 50% excess body weight, using a very low-calorie diet (VLCD; 450 kcal/d) improves insulin sensitivity in obese type 2 diabetes mellitus patients.Objective:The objective of the study was to evaluate whether adding exercise to the VLCD has additional benefits.Design:This was a randomized intervention study.Setting:The study was conducted at a clinical research center in an academic medical center.Subjects:Twenty-seven obese [body mass index 37.2 ± 0.9 kg/m(2) (mean ± sem)] insulin-treated type 2 diabetes mellitus patients.Intervention:Patients followed a 16-wk VLCD. Thirteen of them simultaneously participated in an exercise program (E) consisting of 1-h, in-hospital training and four 30-min training sessions on a cycloergometer weekly.Outcome Measures:Insulin resistance was measured by a hyperinsulinemic euglycemic clamp. Insulin signaling, mitochondrial DNA (mtDNA) content, and intramyocellular lipid content was measured in skeletal muscle biopsies.Results:Baseline characteristics were identical in both groups. Substantial weight loss occurred (-23.7 ± 1.7 kg VLCD-only vs. -27.2 ± 1.9 kg VLCD+E, P = NS within groups). The exercise group lost more fat mass. Insulin-stimulated glucose disposal increased similarly in both study groups [15.0 ± 0.9 to 39.2 ± 4.7 μmol/min(-1) · kg lean body mass (LBM(-1)) VLCD-only vs. 17.0 ± 1.0 to 37.5 ± 3.5 μmol/min(-1) · kg LBM(-1) in VLCD+E], as did phosphorylation of the phosphatidylinositol 3-kinase-protein kinase B/AKT insulin signaling pathway. In contrast, skeletal muscle mtDNA content increased only in the VLCD+E group (1211 ± 185 to 2288 ± 358, arbitrary units, P = 0.016 vs. 1397 ± 240 to 1196 ± 179, P = NS, VLCD-only group). Maximum aerobic capacity also only increased significantly in the VLCD+E group (+6.6 ± 1.7 ml/min(-1) · kg LBM(-1) vs. +0.7 ± 1.5 ml/min(-1) · kg LBM(-1) VLCD-only, P = 0.017).Conclusion:Addition of exercise to a 16-wk VLCD induces more fat loss. Exercise augments maximum aerobic capacity and skeletal muscle mtDNA content. These changes are, however, not reflected in a higher insulin-stimulated glucose disposal rate.

• Epidermal Growth Factor Induces Human Oviductal Epithelial Cell Invasion by Down-Regulating E-Cadherin Expression.

  Authors: Jung-Chien Cheng, Hsun-Ming Chang, Peter C K Leung

  The Journal of clinical endocrinology and metabolism.

  Context:The loss of E-cadherin enhances cell invasiveness. There is increasing evidence that high-grade serous ovarian cancer may arise from oviductal epithelial cells rather than the ovarian surfaceContext:The loss of E-cadherin enhances cell invasiveness. There is increasing evidence that high-grade serous ovarian cancer may arise from oviductal epithelial cells rather than the ovarian surface epithelium. Despite the controversy over the cellular origins of this disease, the roles of epidermal growth factor (EGF) in human oviductal epithelial cells are largely unknown.Objective:We examined whether EGF could induce oviductal epithelial cell invasion by its down-regulation of E-cadherin.Methods:Matrigel-coated transwells were used for the invasion assay. Small interfering RNA was used to knock down the expression of EGF receptor (EGFR). Specific mRNA and protein levels were examined by quantitative RT-PCR and Western blot, respectively.Results:The expression of Pax8 confirmed the secretory type of the cultured human oviductal epithelial cell line OE-E6/E7. EGFR was expressed in OE-E6/E7 cells, and treatment with EGF down-regulated E-cadherin expression. The effect of EGF on the down-regulation of E-cadherin was abolished by small interfering RNA-mediated depletion of EGFR. EGF treatment led to the activation of ERK1/2, p38, and Akt. Snail and Slug are transcriptional repressors of E-cadherin. Interestingly, our results show that EGF induced Slug but not Snail expression. Moreover, the inhibition of EGF-induced ERK1/2, p38, and Akt activation by pharmacological inhibitors attenuated EGF-induced Slug expression and the down-regulation of E-cadherin, as well as subsequent cell invasion.Conclusions:EGF induces human oviductal epithelial cell invasion through the activation of ERK1/2, p38, and Akt, the up-regulation of Slug, and the down-regulation of E-cadherin.

• Emerging Effects of Early Environmental Factors over Genetic Background for Type 1 Diabetes Susceptibility: Evidence from a Nationwide Italian Twin Study.

  Authors: Lorenza Nisticò, Dario Iafusco, Alfonso Galderisi, Corrado Fagnani, Rodolfo Cotichini, Virgilia Toccaceli, Maria Antonietta Stazi

  The Journal of clinical endocrinology and metabolism.

  Context:The incidence of type 1 diabetes has been increasing over time.Objective:We estimated the genetic and environmental components of type 1 diabetes susceptibility in a twin cohort ofContext:The incidence of type 1 diabetes has been increasing over time.Objective:We estimated the genetic and environmental components of type 1 diabetes susceptibility in a twin cohort of recent-onset cases to explore the sources of changing disease epidemiology.Design:We linked the population-based Italian Twin Registry with 14803 type 1 diabetes records from 36 pediatric diabetes care centers throughout Italy, except Sardinia, and identified 173 diabetic twins. Patients were positive for at least one autoantibody to islet cell, glutamate decarboxylase, tyrosine phosphatase, insulin, or zinc transporter 8 and were insulin dependent since their diagnosis. Zygosity was determined by DNA genotyping or by questionnaire.Outcome Measures:We estimated proband-wise concordance, cotwin recurrence risk with Kaplan-Meier method, and genetic and environmental proportions of susceptibility variance by structural equation models.Results:We recruited 104 diabetic twins (53 males) from 88 pairs (34 monozygotic, 54 dizygotic) and one triplet. The mean age at diagnosis was 8.1 yr (range 1.1-20.5 yr), and the median year of diagnosis was 2002. Proband-wise concordances were 45.5 and 16.4% in monozygotic and dizygotic pairs (P = 0.01). Recurrence risks in monozygotic and dizygotic cotwins were 37 and 12% after 10 yr from the proband's diagnosis (P = 0.005). Genetic contribution to type 1 diabetes susceptibility was 40% (95% confidence interval 8-78), and the shared and individual-specific environmental components were 51% (14-77) and 9% (4-19), respectively.Conclusions:In addition to the moderate genetic effects on type 1 diabetes susceptibility, our results draw attention to the substantial shared environmental effects, suggesting that exposures in fetal or early postnatal life may contribute to the increasing incidence of the disease.

• DISHphagia: An Unusual Cause of Dysphagia.

  Authors: Nicola Martinelli, Fabiana Busti, Domenico Girelli, Oliviero Olivieri

  The Journal of clinical endocrinology and metabolism.

  Abstract Not Available.

• Biological Characteristics of Growth Hormone-Producing Pituitary Adenomas Are Different According to Responsiveness to Thyrotropin-Releasing Hormone.

  Authors: Hideyuki Arita, Manabu Kinoshita, Satoru Oshino, Tetsuhiro Kitamura, Michio Otsuki, Soji Kasayama, Toshio Shimokawa, Iichiro Shimomura, Toshiki Yoshimine, Youichi Saitoh

  The Journal of clinical endocrinology and metabolism.

  Objective:The paradoxical response of GH to TRH in patients with acromegaly has been previously reported. However, few reports have focused on tumor characteristics reflected by this response. ThisObjective:The paradoxical response of GH to TRH in patients with acromegaly has been previously reported. However, few reports have focused on tumor characteristics reflected by this response. This study aimed to clarify the relationship between TRH-induced GH responsiveness and other tumor characteristics.Methods:Patients with acromegaly who underwent initial surgery between 2000 and 2012 were divided into TRH-responder and nonresponder groups. Clinical features were compared between the two groups with respect to tumor size, Knosp grade, endocrinological profiles, and histopathological findings revealed by cytokeratin staining. Tumor size was quantitatively evaluated with volumetry. Cytokeratin staining patterns were categorized into three groups: sparsely granulated type, densely granulated type, and intermediate type.Results:Sixty-two patients were included in the study. TRH responders (n = 45) showed significantly smaller tumor size than nonresponders (n = 17) (2.78 ± 4.71 vs. 7.56 ± 9.00 ml, P < 0.005). In addition, TRH responders showed significantly higher preoperative basal GH per volume ratio than nonresponders (10.1 ± 8.4 vs. 7.72 ± 11.85 ng/ml(2), P < 0.05). Logarithmic regression modeling showed significant correlation between TRH responsiveness and tumor volume (r = -0.341; P < 0.01). The difference between cytokeratin staining patterns was also significant: sparsely granulated-type adenomas were found in only 13% of TRH responders but in 64% of nonresponders (P < 0.0005). TRH responders showed higher GH suppression rates in the octreotide test compared with nonresponders (86 vs. 68%, P < 0.01).Conclusion:The present data suggest that the responsiveness of serum GH level to TRH reflects significant tumor biological characteristics.

• Association between Benign Thyroid and Endocrine Disorders and Subsequent Risk of Thyroid Cancer among 4.5 Million U.S. Male Veterans.

  Authors: Sanjeeve Balasubramaniam, Elaine Ron, Gloria Gridley, Arthur B Schneider, Alina V Brenner

  The Journal of clinical endocrinology and metabolism.

  Context:Risk factors for thyroid cancer (TC) in males are poorly understood.Objectives, Setting, and Participants: Our aim was to evaluate the relationship between history of benign thyroid andContext:Risk factors for thyroid cancer (TC) in males are poorly understood.Objectives, Setting, and Participants: Our aim was to evaluate the relationship between history of benign thyroid and endocrine disorders and risk of TC among 4.5 million male veterans admitted to U.S. Veterans Affairs hospitals between July 1, 1969, and September 30, 1996.Design:We conducted a retrospective cohort study based on hospital discharge records with 1053 cases of TC.Main Outcome Measures:We estimated relative risks (RR) and computed 95% confidence intervals (CI) for TC using time-dependent Poisson regression models. To evaluate potential ascertainment bias and/or delayed diagnosis of TC, we also analyzed RR by time between diagnosis of benign disorder and TC (<5 or ≥5 yr).Results:RR for TC were significantly elevated with many disorders and were often higher less than 5 yr compared with 5 yr or more before TC diagnosis. RR (95% CI) less than 5 yr/at least 5 yr were 67.9 (42.4-108.8)/28.9 (9.2-90.2) for thyroid adenoma, 77.8 (64.5-93.1)/25.9 (17.9-38.0) for nontoxic nodular goiter, 23.9 (13.8-41.3)/12.9 (4.8-34.4) for thyroiditis, 8.8 (6.9-11.3)/6.0 (3.8-9.6) for hypothyroidism, 6.4 (4.4-9.4)/ 2.0 (0.8-4.8) for thyrotoxicosis, and 1.2 (1.0-1.4)/1.1 (0.9-1.5) for diabetes. For some disorders, RR also significantly varied by attained age and race with younger patients and Blacks having higher RR than older patients and Whites.Conclusions:We found strong associations for a history of thyroid adenoma, nodular goiter, thyroiditis, or hypothyroidism with TC in males allowing for increased surveillance/delayed diagnosis and evidence that some of these associations are modified by age and race.

• Hyperandrogenism Sensitizes Leukocytes to Hyperglycemia to Promote Oxidative Stress in Lean Reproductive-Age Women.

  Authors: Frank González, K Sreekumaran Nair, Janice K Daniels, Eati Basal, Jill M Schimke, Hilary E Blair

  The Journal of clinical endocrinology and metabolism.

  Context:Hyperandrogenism and oxidative stress are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate oxidative stress.Objective:The purpose of thisContext:Hyperandrogenism and oxidative stress are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate oxidative stress.Objective:The purpose of this study was to determine the effect of oral androgen administration on fasting and glucose-stimulated leukocytic reactive oxygen species (ROS) generation, reduced nicotinamide adenine dinucleotide phosphate oxidase p47(phox) subunit gene expression, and plasma thiobarbituric acid-reactive substances (TBARS) in lean healthy reproductive-age women.Participants, Design, and Setting:Sixteen lean healthy ovulatory reproductive-age women were treated with 130 mg dehydroepiandrosterone (DHEA) or placebo (n = 8 each) for 5 d in this randomized, controlled, double-blind study that was performed at an an academic medical center.Main Outcome Measures:Leukocytic ROS generation, p47(phox) gene expression, and plasma TBARS were quantified in the fasting state and 2 h after glucose ingestion, before and after treatment.Results:Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any prooxidant markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-sulfate, increased the percent change in glucose-challenged p47(phox) RNA content, and increased the percent change in fasting and glucose-challenged ROS generation from mononuclear cells and polymorphonuclear cells, p47(phox) protein content, and plasma TBARS.Conclusion:Elevation of circulating androgens comparable to what is present in PCOS increases leukocytic ROS generation, p47(phox) gene expression, and plasma TBARS to promote oxidative stress in lean healthy reproductive-age women. Thus, hyperandrogenemia activates and sensitizes leukocytes to glucose in this population.

• Monoamine Oxidase A Down-Regulation Contributes to High Metanephrine Concentration in Pheochromocytoma.

  Authors: Eric Grouzmann, Maurice Matter, Stefan Bilz, Adeline Herren, Frédéric Triponez, Christophe Henzen, Kwang-Soo Kim, Henryk Zulewski, Thierry Buclin, Noureddine Brakch, Karim Abid

  The Journal of clinical endocrinology and metabolism.

  Context:The high diagnostic performance of plasma-free metanephrines (metanephrine and normetanephrine) (MN) for pheochromocytoma (PHEO) results from the tumoral expression ofContext:The high diagnostic performance of plasma-free metanephrines (metanephrine and normetanephrine) (MN) for pheochromocytoma (PHEO) results from the tumoral expression of catechol-O-methyltransferase (COMT), the enzyme involved in O-methylation of catecholamines (CAT). Intriguingly, metanephrine, in contrast to epinephrine, is not remarkably secreted during a stress in hypertensive or normotensive subjects, whereas in PHEO patients CAT and MN are both raised to high levels. Because epinephrine and metanephrine are almost exclusively produced by the adrenal medulla, this suggests distinct CAT metabolism in chromaffin cells and pheochromocytes.Objective:The objective of the study was to compare CAT metabolism between adrenal medulla and PHEO tissue regarding related enzyme expression including monoamine oxidases (MAO) and COMT.Design:A multicenter comparative study was conducted.Study Participants:The study included 21 patients with a histologically confirmed PHEO and eight adrenal glands as control.Main Outcome Measures:CAT, dihydroxyphenol-glycol, 3,4-dihydroxyphenylacetic acid, and MN were measured in adrenal medulla and PHEO tissue. Western blot, quantitative RT-PCR and immunofluorescence studies for MAOA, MAOB, tyrosine hydroxylase, dopamine β-hydroxylase, l-amino acid decarboxylase, and COMT were applied on tissue homogenates and cell preparations.Results:At both the protein and mRNA levels, MAOA and COMT are detected less often in PHEO compared with adrenal medulla, conversely to tyrosine hydroxylase, l-amino acid decarboxylase, and dopamine β-hydroxylase, much more expressed in tumor tissue. MAOB protein is detected less often in tumor but not differently expressed at the mRNA level. Dihydroxyphenol-glycol is virtually absent from tumor, whereas MN, produced by COMT, rises to 4.6-fold compared with adrenal medulla tissue. MAOA down-regulation was observed in 100% of tumors studied, irrespectively of genetic alteration identified; on the other hand, MAOA was strongly expressed in all adrenal medulla collected independently of age, gender, or late sympathetic activation of the deceased donor.Conclusion:High concentrations of MN in tumor do not only arise from CAT overproduction but also from low MAOA expression, resulting in higher substrate availability for COMT.

• Skeletal-Related Events due to Bone Metastases from Differentiated Thyroid Cancer.

  Authors: Azeez Farooki, Vivien Leung, Hernan Tala, R Michael Tuttle

  The Journal of clinical endocrinology and metabolism.

  Background:In oncology, the clinical impact of metastatic bone disease is conveyed via a composite end point termed skeletal-related events (SRE), which encompasses spinal cord compression,Background:In oncology, the clinical impact of metastatic bone disease is conveyed via a composite end point termed skeletal-related events (SRE), which encompasses spinal cord compression, pathological fracture, a need for external beam radiation or surgery to bone, and hypercalcemia of malignancy. An appreciation for the high incidence of SRE in other advanced cancers involving the bone has led to the approval of potent antiresorptive agents because they delay the time to the first SRE and decrease the incidence of SRE. The risk and rate of SRE after diagnosis of bone metastasis have not been described in thyroid cancer; antiresorptive agents are not routinely used.Methods:This was a retrospective review of 245 differentiated thyroid cancer patients with bone metastases identified as part of routine clinical care at Memorial Sloan-Kettering Cancer Center between 1960 and 2011. The occurrence of SRE was recorded from the initial diagnosis of bone metastasis until final follow-up or death.Results:Seventy-eight percent of patients (192 of 245) either presented with or developed at least one SRE after the diagnosis of metastatic bone disease. The median time from identification of bone metastasis to first SRE was 5 months (excluding the 97 patients in whom first SRE occurred at the time of the bone metastasis diagnosis). Of the patients who sustained an initial SRE, 65% (120 of 192) went on to sustain a second SRE at a median of 10.7 months after the first event. SRE were frequently multiple; 39% (74 of 192) sustained three or more discrete SRE.Conclusion:Thyroid cancer bone metastases identified as part of routine clinical follow-up frequently cause significant and recurrent morbidity. The incidence of SRE and median time to first SRE in metastatic thyroid cancer to bone are similar to those reported in other solid tumors. Prospective clinical trials to assess the efficacy of antiresorptive agents in this population are needed.

• Altered MicroRNA Expression Profile in Human Pituitary GH Adenomas: Down-Regulation of miRNA Targeting HMGA1, HMGA2, and E2F1.

  Authors: Daniela D'Angelo, Dario Palmieri, Paula Mussnich, Magali Roche, Anne Wierinckx, Gerald Raverot, Monica Fedele, Carlo Maria Croce, Jacqueline Trouillas, Alfredo Fusco

  The Journal of clinical endocrinology and metabolism.

  Context:MicroRNA (miRNA) are an important class of regulators of gene expression. Altered miRNA expression has been constantly found in human neoplasias and plays an important role in the process ofContext:MicroRNA (miRNA) are an important class of regulators of gene expression. Altered miRNA expression has been constantly found in human neoplasias and plays an important role in the process of carcinogenesis.Objective:The aim of this study was to identify specific miRNA whose expression is altered in GH-secreting pituitary adenomas.Design:Using a miRNACHIP microarray, we have analyzed the miRNA expression profile of human GH adenomas vs. normal pituitary gland.Results:We report the identification of a set of miRNA, including miR-34b, miR-326, miR-432, miR-548c-3p, miR-570, and miR-603, drastically and constantly down-regulated in GH adenomas. We demonstrate that these miRNA target genes such as high-mobility group A1 (HMGA1), HMGA2, and E2F1, whose overexpression and/or activation plays a critical role in pituitary tumorigenesis. We also show that the enforced expression of the down-regulated miRNA has a negative role on the growth regulation of pituitary adenoma cells. Finally, an inverse correlation is found between the expression of these miRNA and HMGA1 and HMGA2 protein levels in GH adenomas.Conclusion:Our study identifies a specific subset of miRNA, whose down-regulation might contribute to pituitary tumorigenesis.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.