bluuebunny/crossref_metadata_2025 huggingface dataset:
RAPID COMMUNICATION: Human Ovarian Cancers Express Somatostatin Receptors
Authors: Halmos Gabor , Sun Baodong , Schally Andrew V. , Hebert Francine , Nagy Attila
Published: January 2014

ABSTRACT. Characteristics of receptors for somatostatin (SST) analog RC-160 on 17 surgical specimens of human epithelial ovarian cancer and two human ovarian cancer lins were determined by ligand competition assays. The expression of mRNA for four SST receptor subrypes (sst1, sst3, sst2A, sst5) was investigated by RT-PCR. Thirteen of 17 specimens (76%) exhibited high affinity binding sites for RC-160 with Kd = 6.55 nmol/L and a Bmax = 575.4 fmol/mg membrane protein. Specific receptors for RC-160 were also found in xenografts of OV-1063 and UCI-107 human ovarian cancer lines. The mRNA for sst1 was detected in 65% of the ovarian cancer specimens, while the incidence ov sst2A, sst3, and sst5 was 65%, 41% and 24%, respectively. Both ovarian cancer cell lines also expressed mRNA for these four subtypes. The presence of these SST receptor subtypes in human ovarian cancers allows the use of SST analogs and their radionuclide and cytoxic derivatives for the diagnosis and treatment of this malignancy.
Angiogenesis in the Human Corpus Luteum: Localization and Changes in Angiopoietins, Tie-2, and Vascular Endothelial Growth Factor Messenger Ribonucleic Acid1
Authors: Wulff Christine , Wilson Helen , Largue Pawlina , Duncan W. Colin , Armstrong David G. , Fraser Hamish M.
Published: January 2014

In the menstrual cycle, extensive angiogenesis accompanies luteinization. During luteolysis, endothelial cells die, whereas in a conceptual cycle, the corpus luteum (CL) persists, and endothelial cell survival is extended. A main stimulator for angiogenesis is vascular endothelial growth factor (VEGF), while the angiopoietins (Ang-1 and Ang-2) may be important modulators. The aim of this study was to investigate the localization of Ang-1, Ang-2, their common receptor Tie-2, and VEGF messenger ribonucleic acid (mRNA) at the different stages of the functional luteal phase and after rescue by hCG. Ang-1 mRNA was uniformly expressed at a low level throughout the CL. The signal was highest during the early luteal phase. In contrast, Ang-2 mRNA expression was localized strongly to individual granulosa and thecal luteal and endothelial cells. Administration of hCG was associated with an increase in the Ang-2 mRNA area of expression and grain density in individual luteal and endothelial cells. The Tie-2 receptor mRNA was localized in endothelial cells, and the area of expression was highest during the early luteal phase and during luteal rescue. VEGF mRNA was found exclusively in granulosa luteal cells, and the area of expression was highest in corpora lutea during simulated pregnancy. These results begin to characterize the molecular regulation of the divergent processes involved in luteal angiogenesis during luteinization, luteolysis, and rescue in the human and imply that the angiopoietins are involved during the initial angiogenic phase and in luteal rescue.
Vitamin D Insufficiency and Hyperparathyroidism in a Low Income, Multiracial, Elderly Population1
Authors: Harris Susan S. , Soteriades Elpidoforos , Coolidge Jo Anna Stina , Mudgal Sharmilla , Dawson-Hughes Bess
Published: January 2014

This report examines the wintertime vitamin D and PTH status of 308 participants in the Boston Low Income Elderly Osteoporosis Study of noninstitutionalized low income elderly men and women (age, 64–100 yr) living in subsidized housing in Boston, MA. Twenty-one percent of the 136 black subjects and 11% of the 110 whites had very low plasma 25-hydroxyvitamin D (25OHD) concentrations (<25 nmol/L), and 73% of the blacks and 35% of the whites had 25OHD concentrations less than 50 nmol/L. The mean 25OHD levels of the smaller Hispanic and Asian subsets were generally similar to those of the white subjects. In addition to race, significant predictors of 25OHD included vitamin D intake (positive association) and smoking (inverse association), but not sex or age. Low 25OHD concentrations were associated with increased PTH and reduced serum calcium. The PTH level in the black subjects was substantially higher than that in the white subjects, and this difference was only partially explained by the racial difference in 25OHD. Elderly individuals who live in northern areas, particularly African-Americans, should be strongly encouraged to increase their vitamin D intake, especially in winter.
Growth and Insulin-Like Growth Factors (IGFs) in Children with Insulin-Dependent Diabetes Mellitus at the Onset of Disease: Evidence for Normal Growth, Age Dependency of the IGF System Alterations, and Presence of a Small (Approximately 18-Kilodalton) IGF-Binding Protein-3 Fragment in Serum
Authors: Cianfarani Stefano , Bonfanti Riccardo , Bitti Maria Luisa Manca , Germani Daniela , Boemi Sergio , Chiumello Giuseppe , Boscherini Brunetto
Published: January 2014

Data on growth of children with insulin-dependent diabetes mellitus (IDDM) before the onset of disease are conflicting, and although the insulin-like growth factor (IGF) system has almost invariably been found altered at diagnosis, most of previous studies are affected by the small number of patients investigated. We studied 60 IDDM children at the onset of disease, comparing their stature with target height, normal growth standards, and height of 102 sex- and age-matched controls. Furthermore, we assessed serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and IGFBP-3 circulating forms. IDDM children were subdivided into 2 groups according to an age above (n = 26) or below (n = 34) 6 yr. The values of endocrine variables of diabetics older than 6 yr were compared with those of 34 age-matched controls. Although the height of diabetics was higher than growth reference values (mean height ± sd, 0.64 ± 1.4 z-score) and their target height (mean target height ± sd, 0.1 ± 0.84 z-score; P < 0.005), no significant difference in height was found between IDDM children and controls (mean height ± sd, 0.64 ± 0.95 z-score) even analyzing the 2 age groups separately. Overall, IDDM children showed reduced levels of IGF-I (mean ± sd,− 0.65 ± 1.9 z-score) and normal levels of IGF-II (mean ± sd, −0.05 ± 1.2 z-score) and IGFBP-3 (mean ± sd, −0.06 ± 1.2 z-score). However, whereas patients younger than 6 yr showed normal values of IGF-I, IGF-II, and IGFBP-3, these peptides were significantly reduced in older subjects compared with either younger IDDM children or controls (P < 0.01). IGFBP-3 immunoblot analysis revealed the presence of an approximately 18-kDa fragment of IGFBP-3 in addition to the major approximately 29-kDa fragment and the intact form (∼42–39 kDa) in 46 of 60 IDDM patients, whereas the approximately 18-kDa band was absent in all 34 control sera. No relationship was found between the endocrine variables and stature at diagnosis. In conclusion, our results indicate that IDDM children at the onset of disease are not taller than healthy peers and have increased IGFBP-3 proteolytic activity. Finally, although the IGF system is normal in younger IDDM children, older patients have reduced IGF levels.
Effect of Estrogen Replacement Therapy on Insulin Sensitivity of Glucose Metabolism and Preresistance and Resistance Vessel Function in Healthy Postmenopausal Women1
Authors: Vehkavaara Satu , Westerbacka Jukka , Hakala-Ala-Pietilä Tiina , Virkamäki Antti , Hovatta Outi , Yki-Järvinen Hannele
Published: January 2014

In the present study, we hypothesized that estradiol, via its ability to vasodilate in an endothelium-dependent manner, might enhance vascular effects of insulin. Basal and insulin-stimulated peripheral blood flow and resistance, arterial stiffness, and glucose metabolism were determined in 27 healthy postmenopausal women before and after 12 weeks of treatment with either transdermal or oral estradiol or corresponding placebo preparations. Whole body insulin sensitivity was determined using the euglycemic insulin clamp technique (rate of continuous insulin infusion 1 mU/kg·min), forearm blood flow with a strain-gauge plethysmography, and arterial stiffness using pulse wave analysis. Estradiol therapy increased basal peripheral blood flow (1.5 ± 0.1 vs. 1.9 ± 0.1 mL/dL·min, 0 vs. 12 weeks; P < 0.01), decreased peripheral vascular resistance (65 ± 3 vs. 52± 3 mm Hg/mL/dL·min, respectively; P < 0.01), and diastolic blood pressure (78 ± 2 vs. 75± 2 mm Hg, respectively; P < 0.05) but had no effect on large artery stiffness. Infusion of insulin did not acutely alter peripheral blood flow but diminished large artery stiffness significantly both before and after the 12-week period of estradiol therapy. No measure of acute insulin action (glucose metabolism, blood flow, or large artery stiffness) was altered by estradiol or placebo treatment. These data demonstrate that insulin and estradiol have distinct hemodynamic effects. Physiological doses of estradiol increase peripheral blood flow but have no effects on large artery stiffness, whereas physiological concentrations of insulin acutely decrease stiffness without changing peripheral blood flow. Putative vasculoprotection by estradiol is, thus, not mediated via alterations in arterial stiffness or insulin sensitivity.
Energy Economy Hampers Body Weight Loss after Gastric Bypass
Authors: Bobbioni-Harsch E. , Morel P. , Huber O. , Assimacopoulos-Jeannet F. , Chassot G. , Lehmann T. , Volery M. , Golay A.
Published: January 2014

The impact of energy economy on body weight loss was investigated in 20 obese women, submitted to Roux-en-Y gastric bypass. Resting energy expenditure (REE), substrate oxidation rates, plasma glucose, free fatty acid, and insulin and leptin levels were measured before and 3, 6, and 12 months after surgery. Predicted REE was obtained from linear regression analysis of REE and fat free mass, in a group of 85 women, whose body mass index ranged between 20 and 60 kg/m2. The deviation from predicted REE, calculated as area under the curve (AUC) over the 12-month period for each patient, was considered as the expression of energy economy. Energy economy AUC was significantly (P < 0.005) negatively related to the weight lost during 12 months after surgery.

Energy intake, calculated from self-reported food consumption, was also expressed as AUC. Energy intake AUC showed a significant (P < 0.002) positive correlation with weight loss.

Lipid oxidation rate, also calculated as AUC, significantly correlated, negatively, with energy economy (P < 0.001) and, positively, with energy intake (P < 0.002). Preoperative leptin values were significantly (P < 0.01) linked to individual energy economy capacity.

In conclusion, after Roux-en-Y gastric bypass, energy economy hampers the weight loss process, probably through a low fat oxidation rate.
Detection of Minimal Levels of Serum Anti-Müllerian Hormone during Follow-Up of Patients with Ovarian Granulosa Cell Tumor by Means of a Highly Sensitive Enzyme-Linked Immunosorbent Assay
Authors: Long Wen-Qing , Ranchin Valérie , Pautier Patricia , Belville Corinne , Denizot Philippe , Cailla Hélène , Lhommé Catherine , Picard Jean-Yves , Bidart Jean-Michel , Rey Rodolfo
Published: January 2014

Granulosa cell tumors (GCT) are ovarian neoplasms that tend to recur and spread in the pelvis and the abdomen several years after the initial treatment. Anti-Müllerian hormone (AMH) is a reliable serum marker of these tumors. To enhance the availability and the sensitivity of serum AMH determination, we developed an ultrasensitive enzyme-linked immunosorbent assay. In this work we compare the results of serum AMH levels, obtained using the ultrasensitive and the traditional assays, in 31 patients with ovarian GCT followed up for up to 7 yr.

The ultrasensitive enzyme-linked immunosorbent assay has a significantly higher sensitivity than the traditional one. This resulted in the detection of low serum AMH levels, which were undetectable with the traditional assay, in several cases including one patient in whom a recurrence of a GCT had developed and two patients in whom the treatment had not been completely successful. These cases highlight the importance of the availability of a highly sensitive assay allowing evaluation with high precision of the results of treatment and to detect the recurrences of GCT at an early, preclinical stage.
Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany
Authors: Krone Nils , Braun Andreas , Roscher Adelbert Anton , Knorr Dietrich , Schwarz Hans Peter
Published: January 2014

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppvnull) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppvA to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppvB was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppvC was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.
Gender Difference in Insulin-Like Growth Factor I Response to Growth Hormone (GH) Treatment in GH-Deficient Adults: Role of Sex Hormone Replacement
Authors: Span J. P. T. , Pieters G. F. F. M. , Sweep C. G. J. , Hermus A. R. M. M. , Smals A. G. H.
Published: January 2014

GH production in healthy women is about thrice that in men. Yet insulin-like growth factor I (IGF-I) levels are similar, suggesting a lower responsivity to GH in women. In untreated GH-deficient adults, basal IGF-I levels are reportedly lower in females than in males, and the therapeutic recombinant human GH (rhGH) dose required to achieve optimal IGF-I levels is higher in the former, suggesting a pivotal role of estrogens on rhGH requirement in GH-deficient patients. We, therefore, analyzed our 2-yr data on the effect of rhGH on serum IGF-I in 77 GH-deficient patients (33 men, mean ± sd age, 37.2 ± 13.8 yr; 44 women, mean ± sd age, 36.9 ± 11.9 yr) with due attention to gender differences and to the effects of sex hormone replacement. Of the 44 women, 33 had estrogen substitution. Of the 33 men, 23 were on androgen replacement. Patients (11 premenopausal women and 10 men) not on hormonal replacement were eugonadal.

Basal IGF-I levels in untreated GH-deficient women were significantly lower than in men (8.8 ± 0.7 nmol/L vs. 12.2 ± 0.9 nmol/L; P < 0.01), despite similar basal GH levels. The daily rhGH dose per kg body weight required to normalize IGF-I in women was higher than in men, the difference being statistically significant at all time points (P < 0.05–0.01). The IGF-I increase (Δ) per IU GH/day·kg over the 24-month period was about twice higher in men than in women. Also calculated on a weight basis, rhGH responsivity (rhGH responsivity = (ΔIGF1(nmol/L)/dose (IU/day/kg)) was higher in men than in women at all time intervals (P < 0.05–0.01).

Estrogen replacement in women significantly increased rhGH requirement. The rhGH dose per kg body weight required in estrogen-substituted women was significantly higher than in nonestrogen-substituted women (P < 0.01 at t = 18 and 24 months, respectively). In women on estrogen substitution, rhGH responsivity plateaued from 6 months on, whereas in eugonadal women without estrogen substitution the responsivity for rhGH increased over time. In men, the reverse was true; rhGH responsivity increased over time in men on androgen substitution, but plateaued in men without androgen substitution.

The mechanisms underlying this gender difference are not known. Differential influences of estrogens and androgens on the expression of the GH receptor gene and IGF-I messenger RNA may be operative.

The present study confirms short-term data published in the literature on a sex difference in rhGH dose requirement in GH-deficient patients. It furthers extends the data by demonstrating that this sex difference in GH responsivity persists and changes during the 24 months of the study. Moreover, it shows that estrogen replacement blunts the IGF-I response to rhGH in women, whereas in men with androgen substitution the responsivity increases over time, thus bearing a risk of undertreatment in women and overtreatment in men.
Withdrawal of Long-Term Physiological Growth Hormone (GH) Administration: Differential Effects on Bone Density and Body Composition in Men with Adult-Onset GH Deficiency*
Authors: Biller Beverly M. K. , Sesmilo Gemma , Baum Howard B. A. , Hayden Douglas , Schoenfeld David , Klibanski Anne
Published: January 2014

Adults with acquired GH deficiency (GHD) have been shown to have osteopenia associated with a 3-fold increase in fracture risk and exhibit increased body fat and decreased lean mass. Replacement of GH results in decreased fat mass, increased lean mass, and increased bone mineral density (BMD). The possible differential effect of withdrawal of GH replacement on body composition compartments and regional bone mass is not known. We performed a randomized, single blind, placebo-controlled 36-month cross-over study of GH vs. placebo (PL) in adults with GHD and now report the effect of withdrawal of GH on percent body fat, lean mass, and bone density, as measured by dual energy x-ray absorptiometry. Forty men (median age, 51 yr; range, 24–64 yr) with pituitary disease and peak serum GH levels under 5μ g/L in response to two pharmacological stimuli were randomized to GH therapy (starting dose, 10 μg/kg·day, final dose 4 μg/kg·day) vs. PL for 18 months. Replacement was provided in a physiological range by adjusting GH doses according to serum insulin-like growth factor I levels. After discontinuation of GH, body fat increased significantly (mean ± sem, 3.18 ± 0.44%; P = 0.0001) and returned to baseline. Lean mass decreased significantly (mean loss, 2133 ± 539 g; P = 0.0016), but remained slightly higher (1276 ± 502 g above baseline;P = 0.0258) than at study initiation.

In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 ± 0.00042, g/cm2·month; P = 0.005) between months 18–36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.
Sleep Apnea and Daytime Sleepiness and Fatigue: Relation to Visceral Obesity, Insulin Resistance, and Hypercytokinemia
Authors: Vgontzas Alexandros N. , Papanicolaou Dimitris A. , Bixler Edward O. , Hopper Kenneth , Lotsikas Angela , Lin Huong-Mo , Kales Anthony , Chrousos George P.
Published: January 2014

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure. The purpose of this study was to test three separate, albeit closely related, hypotheses. 1) Does sleep apnea contribute to the previously reported changes of plasma cytokine (tumor necrosis factor-α and interleukin-6) and leptin levels independently of obesity? 2) Among obese patients, is it generalized or visceral obesity that predisposes to sleep apnea? 3) Is apnea a factor independent from obesity in the development of insulin resistance? Obese middle-aged men with sleep apnea were first compared with nonapneic age- and body mass index (BMI)-matched obese and age-matched lean men. All subjects were monitored in the sleep laboratory for 4 consecutive nights. We obtained simultaneous indexes of sleep, sleep stages, and sleep apnea, including apnea/hypopnea index and percent minimum oxygen saturation. The sleep apneic men had higher plasma concentrations of the adipose tissue-derived hormone, leptin, and of the inflammatory, fatigue-causing, and insulin resistance-producing cytokines tumor necrosis factor-α and interleukin-6 than nonapneic obese men, who had intermediate values, or lean men, who had the lowest values. Because these findings suggested that sleep apneics might have a higher degree of insulin resistance than the BMI-matched controls, we studied groups of sleep-apneic obese and age- and BMI-matched nonapneic controls in whom we obtained computed tomographic scan measures of total, sc, and visceral abdominal fat, and additional biochemical indexes of insulin resistance, including fasting plasma glucose and insulin. The sleep apnea patients had a significantly greater amount of visceral fat compared to obese controls (<0.05) and indexes of sleep disordered breathing were positively correlated with visceral fat, but not with BMI or total or sc fat. Furthermore, the biochemical data confirmed a higher degree of insulin resistance in the group of apneics than in BMI-matched nonapneic controls. We conclude that there is a strong independent association among sleep apnea, visceral obesity, insulin resistance and hypercytokinemia, which may contribute to the pathological manifestations and somatic sequelae of this condition.
Studies of the Variability of the Genes Encoding the Insulin-Like Growth Factor I Receptor and Its Ligand in Relation to Type 2 Diabetes Mellitus1
Authors: Rasmussen Søren K. , Lautier Corinne , Hansen Lars , Echwald Søren M. , Hansen Torben , Ekstrøm Claus T. , Urhammer Søren A. , Borch-Johnsen Knut , Grigorescu Florin , Smith Robert J. , Pedersen Oluf
Published: January 2014

Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of growth, differentiation, and development, and as low birth weight has been associated with impaired glucose tolerance and overt type 2 diabetes in adult life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR) as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here we report the mutational analysis of the coding regions of the IGF-I and IGF-IR performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR genes were detected, but several silent and intronic polymorphisms were found. The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was evaluated in a population-based sample of 349 young healthy subjects, where the variant had an allele frequency of 0.44 (95% confidence interval, 0.40–0.48). No significant relationships between this variant and birth weight, birth length, or insulin sensitivity index were detected. In addition, we did not observe any significant differences in allelic frequencies of the codon 1013 variant between 395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval, 0.49–0.55) and 238 matched glucose-tolerant control subjects (allelic frequency, 0.47; 95% confidence interval, 0.43–0.50). In conclusion, variability in the coding regions of IGF-I and the IGF-IR does not associate with reduced birth weight, insulin sensitivity index, or type 2 diabetes in the Danish population.
Insulin, Androgen, and Gonadotropin Concentrations, Body Mass Index, and Waist to Hip Ratio in the First Years after Menarche in Girls with Regular Menstrual Cycles, Irregular Menstrual Cycles, or Oligomenorrhea1
Authors: van Hooff M. H. A. , Voorhorst F. J. , Kaptein M. B. H. , Hirasing R. A. , Koppenaal C. , Schoemaker J.
Published: January 2014

Data on changes in hormone concentrations during the first years after menarche are scarce. We studied the relation between gynecological age (age minus age at menarche), hormone concentrations, and body measurements from the 1st to the 6th yr after menarche in 229 observations of girls with regular menstrual cycles, 157 observations of girls with irregular menstrual cycles, and 104 observations of girls with oligomenorrhea.

Body Mass Index, waist circumference, hip circumference, LH, androstenedione, testosterone, and dehydro-epiandrosterone sulphate increased significantly (linear regression, P < 0.05) by gynecological age in all menstrual cycle pattern groups. For PRL and estradiol a significant increase with gynecological age was only documented in the regular menstrual cycle group and for waist to hip ratio only in the irregular menstrual cycle group. No significant correlation could be documented between gynecological age and overnight fasting insulin concentrations or glucose to insulin ratio.

We found no significant correlation between insulin concentrations or glucose to insulin ratio and androgen concentrations. Significant positive correlations were found between LH and androgens.

LH and androgen levels increase during the first years after menarche, and reference values should be adjusted for gynecological age. In these years, no significant correlation between hyperinsulinemia and hyperandrogenemia could be documented.
Detection of Binding and Blocking Autoantibodies to the Human Sodium-Iodide Symporter in Patients with Autoimmune Thyroid Disease*
Authors: Ajjan Ramzi A. , Kemp E. Helen , Waterman Elizabeth A. , Watson Philip F. , Endo Toyoshi , Onaya Toshimasa , Weetman Anthony P.
Published: January 2014

The sodium iodide symporter (NIS) is a novel autoantigen in autoimmune thyroid disease (ATD). A recent study has described the development of a bioassay for human (h) NIS antibody detection, but this will not detect antibodies that bind the symporter without modulating its activity. Therefore, the establishment of a binding assay is of importance to determine the overall prevalence of hNIS antibodies in ATD patients. An in vitro transcription and translation system was used to produce [35S]-labeled hNIS. The radiolabeled ligand reacted specifically in immunoprecipitation experiments with rabbit antiserum raised against a peptide fragment of hNIS. Subsequently, the reactivity of control and ATD sera to translated [35S]hNIS was determined using RIAs.

A significant difference in the frequency of hNIS antibody-positive sera was found when patients with either Graves’ disease (GD) or autoimmune hypothyroidism (AH) were compared with normal controls (P = 0.01 and P = 0.03, respectively). Of 49 GD and 29 AH sera tested, 11 (22%) and 7 (24%), respectively, were found to contain hNIS antibodies. Differences were also significant when the antibody-binding indices of the control group of sera were compared with those of both the GD and the AH patient sera (P < 0.0001 and P = 0.001, respectively). In contrast, sera from 10 patients with Addison’s disease and 10 patients with vitiligo (without associated ATD) were all negative for antibody reactivity to the symporter. No differences were detected when the antibody binding indices of either the Addison’s disease or the vitiligo sera were compared with those of the normal sera group (P = 0.9 and P = 0.6, respectively).

Eight of the 11 (73%) GD and 3 of the 7 (43%) AH sera, which were positive for hNIS antibodies in the immunoprecipitation assay, were also found to inhibit iodide uptake in hNIS-transfected CHO-K1 cells, suggesting the existence of antibodies in some serum samples that bind to the symporter without modulating its function. Overall, a significant correlation was found between the iodide uptake inhibition and the binding assays for hNIS antibody detection (r = 0.49, P < 0.0001).

In summary, we have developed a specific and quantitative assay for the detection of hNIS binding antibodies in sera of patients with ATD. This system offers the advantage of studying antibody reactivity against conformational epitopes and will be useful in understanding the role of NIS autoreactivity in the pathogenesis of ATD.
Estrogen Replacement Therapy in a Man with Congenital Aromatase Deficiency: Effects of Different Doses of Transdermal Estradiol on Bone Mineral Density and Hormonal Parameters
Authors: Rochira Vincenzo , Faustini-Fustini Marco , Balestrieri Antonio , Carani Cesare
Published: January 2014

The effects of different doses of transdermal estradiol (TE) on bone mineral density (BMD) in a man with aromatase deficiency were evaluated. The study protocol was divided in the following four phases: phase 1, before estradiol treatment; phase 2, 50 μg TE twice weekly for 6 months; phase 3, 25 μg TE twice weekly for 9 months; and phase 4, 12.5 μg TE twice weekly for 9 months. X-rays of hands, legs, and pelvis were performed, and BMD of the lumbar spine, hormonal parameters (LH, FSH, testosterone, and estradiol), and markers of bone turnover were determined during each phase.

BMD in phase 1 was 0.933 g/cm2 and increased to 1.051 and 1.173 g/cm2 after 4 and 7 months of TE, respectively. In phase 3, BMD reached the maximum value (1.275 g/cm2). In phase 4, BMD decreased to 1.180 g/cm2 and was 1.029 g/cm2 at the end of the study protocol. A bilateral necrosis of femoral heads was also detected by x-ray films.

In phase 1 serum testosterone was in the normal range, whereas serum estradiol was undetectable. During the 24-month period of treatment with TE (phases 2–4), estradiol was directly related to the amount of TE, whereas LH was inversely related to estradiol serum levels. Estradiol and gonadotropins reached optimal values only in phase 3, when FSH also was near normal; serum testosterone concentrations were normal in phases 3 and 4.

This study confirms the role of estrogens in achieving and maintaining bone mineral content in the human male, providing further clinical tools useful in the management of bone loss in aromatase deficiency in the male. We suggest that the adequate substitutive dose of TE for maintaining both bone mass and normal estradiol serum levels in adult men with aromatase deficiency may be 25 μg twice weekly (0.47 μg/kg weekly).
Signal Transduction Characteristics of the Corticotropin-Releasing Hormone Receptors in the Feto-Placental Unit
Authors: Karteris E. , Grammatopoulos D. , Randeva H. , Hillhouse E. W.
Published: January 2014

Placentally derived CRH plays a major role in the mechanisms controlling human pregnancy and parturition. In this study, we sought to investigate the signal transduction mechanisms of CRH Type-1 receptors in the feto-placental unit. To clarify the signal transduction components in placenta and fetal membranes, we investigated the expression of G proteins and adenylate cyclase.

Using the nonhydrolysable photoreactive analog [α-32P] GTP-azidoanilide and peptide antisera raised against G proteinα -subunits, we studied coupling of CRH receptors to G proteins in both placental and fetal membranes. Treatment of placental membranes with human CRH (100 nm) increased the labeling of Gq, Go, and Gz but not Gi and Gs. Treatment of fetal membranes with human CRH (100 nm) increased the labeling of Go and Gq but not Gi, Gs, and Gz. These results were supported by experiments that showed that CRH failed to activate adenylate cyclase in these tissues, but induced an increase in inositol phosphates instead. These findings provide new insights into the components of the signal transduction machinery in both fetal and placental membranes and suggest that CRH Type-1 receptors can couple to different G proteins in different tissues. The physiological significance of these observations remains to be elucidated.
Comparison of Alendronate and Intranasal Calcitonin for Treatment of Osteoporosis in Postmenopausal Women*
Authors: Downs Jr. Robert W. , Bell Norman H. , Ettinger Mark P. , Walsh Brian W. , Favus Murray J. , Mako Barbara , Wang Lixia , Smith Mary E. , Gormley Glenn J. , Melton Mary E.
Published: January 2014

This study compared the effects of oral alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Women at least 5 yr postmenopause (n = 299) were randomized to either 10 mg alendronate, matching alendronate placebo, or open-label intranasal calcitonin 200 IU daily for 12 months. Hip and spine bone mineral density (BMD) and markers of bone turnover were measured, and safety and tolerability were assessed. Alendronate produced greater increases in BMD than calcitonin at 12 months at the lumbar spine (5.16% vs. 1.18%; P < 0.001), trochanter (4.73% vs. 0.47%; P < 0.001), and femoral neck (2.78% vs. 0.58%; P< 0.001). Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. Greater decreases in bone turnover were seen with alendronate than with calcitonin (serum bone-specific alkaline phosphatase, 43% vs. 9%, P < 0.001; urinary N-telopeptide, 62% vs. 11%, P < 0.001). Similar percentages of patients in each group reported an adverse experience during the study. We conclude that, in postmenopausal women with osteoporosis, 12 months of therapy with alendronate produced significantly greater increases in BMD of the hip and spine and greater decreases in bone turnover than intranasal calcitonin.
Peroxisome Proliferator-Activated Receptor-γ2 P12A and Type 2 Diabetes in Canadian Oji-Cree*
Authors: Hegele Robert A. , Cao Henian , Harris Stewart B. , Zinman Bernard , Hanley Anthony J. G. , Anderson Carol M.
Published: January 2014

Among the Oji-Cree of northern Ontario, we previously identified a novel variant in the HNF1A gene, namely G319S, that was strongly associated with type 2 diabetes. However, the majority of subjects with diabetes did not have the HNF1A S319 variant, suggesting that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, we found that some of them had the PPARG A12 variant. After genotyping PPARG in the entire adult Oji-Cree population, we found that: 1) PPARG A12 was strongly associated with type 2 diabetes in women, but not men; 2) among women, the odds of being affected for carriers of PPARG A12 compared with noncarriers was 2.3 (95% confidence interval, 1.4–3.8); and 3) among women, affected carriers of PPARG A12 had a significantly earlier age-of-onset and/or age-at-diagnosis compared with noncarriers. When taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least two genes are involved in determining susceptibility to the disease in these people.
Continuation of Growth Hormone (GH) Therapy in GH-Deficient Patients during Transition from Childhood to Adulthood: Impact on Insulin Sensitivity and Substrate Metabolism
Authors: Nørrelund Helene , Vahl Nina , Juul Anders , Møller Niels , Alberti K. G. M. M. , Skakkebæk Niels E. , Christiansen Jens Sandahl , Jørgensen Jens Otto Lunde
Published: January 2014

The appropriate management of GH-deficient patients during transition from childhood to adulthood has not been reported in controlled trials, even though there is evidence to suggest that this phase is associated with specific problems in relation to GH sensitivity. An issue of particular interest is the impact of GH substitution on insulin sensitivity, which normally declines during puberty.

We, therefore, evaluated insulin sensitivity (euglycemic glucose clamp) and substrate metabolism in 18 GH-deficient patients (6 females and 12 males; age, 20 ± 1 yr; body mass index, 25 ± 1 kg/m2) in a placebo-controlled, parallel study. Measurements were made at baseline, where all patients were on their regular GH replacement, after 12 months of either continued GH (0.018 ± 0.001 mg/kg·day) or placebo, and finally after 12 months of open phase GH therapy (0.016 mg/kg·day). Before study entry GH deficiency was reconfirmed by a stimulation test. During the double-blind phase, insulin sensitivity and fat mass tended to increase in the placebo group [ΔM-value (mg/kg·min), −0.7 ± 1.1 (GH) vs. 1.3 ± 0.8 (placebo), P = 0.18; ΔTBF (kg), 0.9 ± 1.2 (GH) vs. 4.4 ± 1.6 (placebo), P = 0.1]. Rates of lipid oxidation decreased [Δlipid oxidation (mg/kg·min), 0.02 ± 0.14 (GH) vs. −0.32 ± 0.13 (placebo), P< 0.05], whereas glucose oxidation increased in the placebo-treated group (P < 0.05). In the open phase, a decrease in insulin sensitivity was found in the former placebo group, although they lost body fat and increased fat-free mass [M-value (mg/kg·min), 5.1 ± 0.7 (placebo) vs. 3.4 ± 1.0 (open), P = 0.09]. In the group randomized to continued GH treatment almost all hormonal and metabolic parameters remained unchanged during the study.

In conclusion, 1) discontinuation of GH therapy for 1 yr in adolescent patients induces fat accumulation without compromising insulin sensitivity; and 2) the beneficial effects of continued GH treatment on body composition in terms of decrease in fat mass and increase in fat-free mass does not fully balance the direct insulin antagonistic effects.
Blood Micronutrient and Thyroid Hormone Concentrations in the Oldest-Old
Authors: Ravaglia Giovanni , Forti Paola , Maioli Fabiola , Nesi Barbara , Pratelli Loredana , Savarino Lucia , Cucinotta Domenico , Cavalli Giancarlo
Published: January 2014

Several micronutrients are involved in thyroid hormone metabolism, but it is unclear whether their marginal deficits may contribute to the alterations in thyroid function observed in extreme aging. The relationships among blood concentrations of thyroid hormones and selenium, zinc, retinol, and α-tocopherol were studied in 44 healthy Northern Italian oldest-old subjects (age range, 90–107 yr), selected by the criteria of the SENIEUR protocol. Control groups included 44 healthy adult (age range, 20–65 yr) and 44 SENIEUR elderly (age range, 65–89 yr) subjects. Oldest-old subjects had higher TSH (P < 0.01) and lower free T3 (FT3)/freeT4 (FT4) ratio, zinc, and selenium serum values (P < 0.001) than adult and elderly control subjects. No significant difference was found for plasma retinol and α-tocopherol values. The associations between micronutrients and thyroid hormones were evaluated by multivariate analysis. In oldest-old subjects, plasma retinol was negatively associated with FT4 (P = 0.019) and TSH serum levels (P = 0.040), whereas serum zinc was positively associated with serum FT3 (P = 0.010) and FT3/FT4 ratio (P = 0.011). In younger subjects, no significant association was found among thyroid variables and micronutrients. In conclusion, blood levels of specific micronutrients are associated with serum iodothyronine levels in extreme aging.
Gender-Related Differences in Counterregulatory Responses to Antecedent Hypoglycemia in Normal Humans1
Authors: Davis S. N. , Shavers C. , Costa F.
Published: January 2014

Compared to men, inherent counterregulatory responses are reduced in healthy and type 1 diabetic women. Despite this, the prevalence of hypoglycemia in patients with type 1 diabetes (type 1 DM) is gender neutral. The aim of this study was to determine the in vivo mechanism(s) responsible for this apparent clinical paradox. The central importance of antecedent hypoglycemia in causing subsequent counterregulatory failure is now established. We, therefore, hypothesized that a gender-related difference to the blunting effects of prior hypoglycemia may exist, and this could explain why type 1 DM women do not have an increased prevalence of hypoglycemia despite reduced counterregulatory responses. Fifteen healthy male and female individuals (eight men and seven women) underwent four separate 2-day experimental protocols in a randomized fashion. Day 1 involved identical morning and afternoon 2-h hyperinsulinemic (9 pmol/kg·min) glucose clamp studies with 5.1 ± 0.1, 3.9 ± 0.1, 3.3± 0.1, or 2.9 ± 0.1 mmol/L. Day 2 consisted of a single 2-h hypoglycemic clamp of 2.9 ± 0.1 mmol/L. Insulin levels were similar on both days of each protocol in men and women. After day 1 euglycemia (5.1 ± 0.1 mmol/L), day 2 counterregulatory responses were significantly increased (P < 0.01) in men relative to women. In women, counterregulatory responses were resistant to the effects of day 1 hypoglycemia. Antecedent hypoglycemia of 3.9, 3.3, and 2.9 ± 0.1 mmol/L produced 3 ± 2%, 5 ± 2%, and 25 ± 4% aggregate reductions in day 2 neuroendocrine, muscle sympathetic nerve activity, and metabolic counterregulatory responses. In marked contrast, identical day 1 hypoglycemia of 3.9, 3.3, and 2.9 ± 0.1 mmol/L in men produced significantly greater reductions in day 2 counterregulatory responses of 30 ± 6%, 39 ± 6%, and 52 ± 6%, respectively. The net effect of the differential gender effects of antecedent hypoglycemia was to overcome the usually increased (50%) sympathetic nervous system (SNS) counterregulatory responses to hypoglycemia found in men. We conclude that 1) antecedent hypoglycemia produces less blunting of counterregulatory responses to subsequent hypoglycemia in women relative to men; 2) two episodes of antecedent hypoglycemia can overcome the greater SNS response to hypoglycemia usually found in men; and 3) the reduced susceptibility of women to the blunting effects of antecedent hypoglycemia may be the mechanism explaining why, despite inherently reduced SNS counterregulatory responses, female type 1 DM patients have a similar prevalence of hypoglycemia compared to men.
Visceral Adipose Tissue Is an Independent Correlate of Glucose Disposal in Older Obese Postmenopausal Women1
Authors: Brochu Martin , Starling Raymond D. , Tchernof André , Matthews Dwight E. , Garcia-Rubi Ernesto , Poehlman Eric T.
Published: January 2014

Older obese postmenopausal women have an increased risk for type 2 diabetes and cardiovascular disease. Increased abdominal obesity may contribute to these comorbidities. There is considerable controversy, however, regarding the effects of visceral adipose tissue as a singular predictor of insulin resistance compared to the other constituents of adiposity. To address this issue, we examined the independent association of regional adiposity and total fat mass with glucose disposal in obese older postmenopausal women. A secondary objective examined the association between glucose disposal with markers of skeletal muscle fat content (muscle attenuation) and physical activity levels.

We studied 44 healthy obese postmenopausal women between 50 and 71 yr of age (mean ± sd, 56.5 ± 5.3 yr). The rate of glucose disposal was measured using the euglycemic/hyperinsulinemic clamp technique. Visceral and sc adipose tissue areas and midthigh muscle attenuation were measured from computed tomography. Fat mass and lean body mass were estimated from dual energy x-ray absorptiometry. Peak VO2 was measured from a treadmill test to volitional fatigue. Physical activity energy expenditure was measured from indirect calorimetry and doubly labeled water.

Pearson correlations indicated that glucose disposal was inversely related to visceral adipose tissue area (r = −0.40; P < 0.01), but not to sc adipose tissue area (r = 0.17), total fat mass (r = 0.05), midthigh muscle attenuation (r = 0.01), peak VO2 (r = −0.22), or physical activity energy expenditure (r = −0.01). The significant association persisted after adjusting visceral adipose tissue for fat mass and abdominal sc adipose tissue levels (r = −0.45; P < 0.005; in both cases). Additional analyses matched two groups of women for fat mass, but with different visceral adipose tissue levels. Results showed that obese women with high visceral adipose tissue levels (283 ± 59 vs. 137 ± 24 cm2; P < 0.0001) had a lower glucose disposal per kg lean body mass compared to those with low visceral adipose tissue levels (0.44 ± 0.14 vs. 0.66 ± 0.28 mmol/kg·min; P < 0.05).

Visceral adipose tissue is an important and independent predictor of glucose disposal, whereas markers of skeletal muscle fat content or physical activity exhibit little association in obese postmenopausal women.
Effects of Resistance Training and Endurance Training on Insulin Sensitivity in Nonobese, Young Women: A Controlled Randomized Trial1
Authors: Poehlman Eric T. , Dvorak Roman V. , DeNino Walter F. , Brochu Martin , Ades Philip A.
Published: January 2014

We examined the effects of a 6-month randomized program of endurance training (n = 14), resistance training (n = 17), or control conditions (n = 20) on insulin sensitivity in nonobese, younger women (18–35 yr). To examine the possible mechanism(s) related to alterations in insulin sensitivity, we measured body composition, regional adiposity, and skeletal muscle characteristics with computed tomography. We observed no changes in total body fat, sc abdominal adipose tissue, or visceral adipose tissue with endurance or resistance training. Insulin sensitivity, however, increased with endurance training (pre, 421 ± 107; post, 490 ± 133 mg/min; P < 0.05) and resistance training (pre, 382± 87; post, 417 ± 89 mg/min; P = 0.06). When the glucose disposal rate was expressed per kg fat-free mass (FFM), the improved insulin sensitivity persisted in endurance-trained (pre, 10.5 ± 2.7; post, 12.1 ± 3.3 mg/min·kg FFM; P < 0.05), but not in resistance-trained (pre, 9.7 ± 1.9; post, 10.2 ± 1.8 mg/min·kg FFM; P = NS) women. Muscle attenuation ratios increased (P < 0.05) in both endurance- and resistance-trained individuals, but this was not related to changes in insulin sensitivity. Moreover, the change in insulin sensitivity was not related to the increased maximum aerobic capacity in endurance-trained women (r = 0.24; P = NS). We suggest that both endurance and resistance training improve glucose disposal, although by different mechanisms, in young women. An increase in the amount of FFM from resistance training contributes to increased glucose disposal probably from a mass effect, without altering the intrinsic capacity of the muscle to respond to insulin. On the other hand, endurance training enhances glucose disposal independent of changes in FFM or maximum aerobic capacity, suggestive of an intrinsic change in the muscle to metabolize glucose. We conclude that enhanced glucose uptake after physical training in young women occurs with and without changes in FFM and body composition.