bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Aromatase Excess Syndrome Is Associated with Feminization of Both Sexes and Autosomal Dominant Transmission of Aberrant P450 Aromatase Gene Transcription1
Authors: Stratakis Constantine A. , Vottero Alessandra , Brodie Angela , Kirschner Lawrence S. , DeAtkine David , Lu Qing , Yue Wei , Mitsiades Constantine S. , Flor Armando W. , Chrousos George P. 
Published: January 2014

Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or gynecomastia, and affected females had isosexual precocity and/or macromastia.The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old sister had precocious puberty, and their father and paternal grandmother had peripubertal gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adrenal steroid hormones were determined before and after the administration of corticotropin and/or hCG. Aromatase activity was determined by[ 3H]Δ4-androstenedione to[ 3H]estrone conversion by cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphocytes and was detected by immunohistochemistry and/or Western analysis. Linkage was examined with a polymorphism of the aromatase (P450arom) gene. The P450arom messenger ribonucleic acid was analyzed by rapid amplification of complementary DNA (cDNA) ends, ribonuclease protection assay, and RT-PCR.hCG testing demonstrated a high rate of conversion ofΔ 4-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a GnRH analog, which successfully delayed skeletal and pubertal development in both children. Markedly increased aromatase activity was found in the patients’ fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom polymorphism segregated with the disease in the family. A new 5′-splice variant was present in the patients’ P450arom messenger ribonucleic acid, thus identifying yet another first exon of this gene, which appears to be aberrantly expressed in this family.In conclusion, a family with the aromatase excess syndrome is described, in which the condition was inherited in an autosomal dominant manner, led to feminizing manifestations in both sexes, and was associated with the aberrant utilization of a novel transcript of the P450arom gene.
The Impact of Reversible Gonadal Sex Steroid Suppression on Serum Leptin Concentrations in Children with Central Precocious Puberty1
Authors: Palmert Mark R. , Radovick Sally , Boepple Paul A. 
Published: January 2014

Serum leptin concentrations increase during childhood in both sexes. During sexual maturation, levels rise further in girls, but decrease in boys. These data suggest that testosterone either directly suppresses leptin levels or induces changes in body composition that result in lower leptin concentrations.To examine further the relationship between sex steroids and leptin, we performed a longitudinal study in children with central precocious puberty (28 girls and 12 boys) before, during, and after discontinuation of GnRH agonist-induced pituitary-gonadal suppression. Nighttime and daytime leptin levels were measured to determine whether the activity of the pituitary-gonadal axis affects their diurnal variation.In the boys, suppression of testosterone increased leptin levels, whereas resumption of puberty was associated with decreased leptin levels [3.5 ± 0.8 vs. 9.5 ± 3.1 ng/dL (P = 0.005) and 12.2 ± 4.5 vs. 7.0 ± 2.6 ng/dL (P = 0.012), respectively]. Serum leptin levels did not change in the girls with alteration of the pituitary-ovarian axis and consistently exceeded those in boys. Nighttime levels were consistently greater than daytime values by an average of 38.3% in the girls and 29.4% in the boys.These serial observations during reversible pituitary-gonadal suppression suggest that testosterone decreases leptin concentrations, but that estrogen, at least in this childhood model, has no discernible effect. In addition, our data indicate that the presence of the diurnal rhythm in leptin concentrations is independent of the state of the reproductive axis.
Decline in Insulin-Like Growth Factor I Levels after Clomiphene Citrate Does Not Correct Hyperandrogenemia in Polycystic Ovary Syndrome
Authors: Fiad Tarek M. , Smith Thomas P. , Cunningham Sean K. , McKenna T. Joseph 
Published: January 2014

It is widely accepted that the action of clomiphene citrate (CC) is mediated through its antiestrogenic properties on the hypothalamic-pituitary axis. Although insulin-like growth factor I (IGF-I) enhances the thecal cell response to LH, and estrogen treatment is associated with a reduction in IGF-I levels, CC is known to decrease circulatory IGF-I levels in polycystic ovary syndrome (PCOS) patients. The impact of lowering IGF-I levels on androgen levels in PCOS is unknown. This study was designed to examine the impact of CC treatment on the interrelationships of IGF-I, androgens, and estrogens in normal subjects and patients with PCOS. IGF-I, gonadotropin, androgen, estrogen, and sex hormone-binding globulin levels were measured in 8 PCOS patients and 10 normal subjects before and after treatment with the antiestrogen CC. Studies were performed in the early follicular phase, days 4–6 of the menstrual cycle in normal subjects. In normal subjects, CC treatment led to a significant increase in estradiol (84 ± 10 to 234 ± 62 pmol/L, untreated and CC treated; P &lt; 0.05) and estrone (125 ± 14 to 257± 29 pmol/L; P &lt; 0.05) levels with a significant lowering of IGF-I levels (297 ± 25 to 230 ± 17 μg/L; P &lt; 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 ± 11 to 245 ± 58 pmol/L; P &lt; 0.05) and estrone (301 ± 32 to 401 ± 90 pmol/L; P &lt; 0.05) levels and a significant lowering of IGF-I levels (330 ± 43 to 214 ± 27μ g/L; P &lt; 0.05) were observed after CC treatment. However, no significant correlation was observed between changes in IGF-I and changes in estradiol in either group. Compared to pretreatment levels, no significant changes in the following parameters were observed after 5 days of CC treatment in either study group: testosterone, testosterone/sex hormone-binding globulin ratio, and androstenedione.
The relationship among CC treatment, gonadotropin, estrogen, and IGF-I levels is complex. Changes in blood IGF-I levels are not associated with changes in androgen levels, although paracrine and or autocrine effects cannot be excluded.
Concentration of Insulin-Like Growth Factor (IGF)-I and -II in Iliac Crest Bone Matrix from Pre- and Postmenopausal Women: Relationship to Age, Menopause, Bone Turnover, Bone Volume, and Circulating IGFs1
Authors: Seck Thomas , Scheppach Beate , Scharla Stefan , Diel Ingo , Blum Werner F. , Bismar Hanadi , Schmid Gerald , Krempien Burkhard , Ziegler Reinhard , Pfeilschifter Johannes 
Published: January 2014

Insulin-like growth factor-I (IGF-I) and -II are important local regulators of bone metabolism, but their role as determinants of human bone mass is still unclear. In the present study, we analyzed the concentration of IGF-I and -II in the bone matrix of 533 human biopsies from the iliac crest that were obtained during surgery for early breast cancer. There was an inverse association of bone matrix IGF-I concentration with age that was unaffected by menopause. Bone matrix IGF-I was positively associated with histomorphometric and biochemical parameters of bone formation and bone resorption and with cancellous bone volume. Based on the estimates of the linear regression analysis, women with a bone matrix IGF-I concentration 2 sd above the mean had a 20% higher bone volume than women with a bone matrix IGF-I concentration 2 sd below the mean. In contrast, serum IGF-I was neither correlated with bone turnover nor with bone volume and was only weakly associated with bone matrix IGF-I when adjusted for the serum concentration of IGF binding protein-3. Bone matrix IGF-II was positively associated with the osteoblast surface, but in contrast to IGF-I, tended to be positively associated with age and was unrelated to cancellous bone volume.In summary, our study suggests the following. 1) The concentration of IGF-I in cancellous bone undergoes age-related decreases that are similar to those of circulating IGF-I. 2) Menopause has no effect on this age-related decline. 3) Physiological differences in bone matrix IGF-I are associated with differences in iliac crest cancellous bone volume. 4) Bone matrix IGF-I is a better predictor of cancellous bone volume than circulating IGF-I. 5) The role of IGF-II in human bone tissue is clearly distinct from that of IGF-I.
Molecular Screening of Uncoupling Protein 2 Gene in Patients with Noninsulin-Dependent Diabetes Mellitus or Obesity1
Authors: Kubota Takanori , Mori Hiroyuki , Tamori Yoshikazu , Okazawa Hideki , Fukuda Tsuneo , Miki Masatoshi , Ito Chikako , Fleury Christophe , Bouillaud Frédéric , Kasuga Masato 
Published: January 2014

abstract
Uncoupling protein 2 (UCP2), a member of the family of mitochondrial carrier proteins, has been implicated in the control of whole-body energy balance. The coding region of the human UCP2 gene has now been shown to comprise six exons, and the sequences of the exon-intron boundaries were determined. With the use of this sequence information, 25 Japanese patients with obesity and noninsulin-dependent diabetes mellitus (NIDDM) and 25 subjects with simple obesity were screened for mutations in the entire coding region of UCP2 by PCR and single-strand conformation polymorphism analysis. Two nucleotide polymorphisms resulting in Ala55 → Val and Ala232 → Thr substitutions were detected. With the use of PCR and restriction fragment length polymorphism analysis, the allele frequencies for each of these polymorphisms were determined in 210 Japanese patients with NIDDM, 42 obese individuals, and 218 normal control subjects. The frequency of the Val55 allele did not differ significantly among the NIDDM group (46.0%), the obesity group (48.8%), and the normal control group (48.4%). The Thr232 allele was detected in only three subjects, who were heterozygotes and in the NIDDM group (allele frequency, 0.7%). However, expression in yeast of the human wild-type UCP2 protein and UCP2 containing Thr232 revealed no difference in functional activity. These results indicate that the Ala55 → Val and Ala232 → Thr variants of UCP2 do not play an important role in the pathogenesis of NIDDM or obesity in the Japanese population.
Mechanisms of Whole-Body Glycogen Deposition after Oral Glucose in Normal Subjects. Influence of the Nutritional Status1
Authors: Féry F. , Plat L. , Balasse E. O. 
Published: January 2014

abstractIt is known that prior fasting enhances whole-body glycogen retention after glucose ingestion. To identify the involved mechanisms, 33 normal volunteers underwent a total fast, varying between 14 h and 4 days, and ingested thereafter 75 g glucose labeled with[ 14C]-glucose. Measurements of oral glucose oxidation (expired 14CO2, corrected for incomplete recovery) and total carbohydrate (CHO) oxidation (indirect calorimetry) were performed over the following 5 h. These data allowed us to calculate oral glucose storage (uptake − oxidation), glycogen oxidation (CHO oxidation − oral glucose oxidation), and net CHO balance (oral glucose uptake − CHO oxidation). As compared with an overnight fast, prolonged fasting (4 days) inhibited the uptake (64.8 vs. 70.3 g/5 h; P &lt; 0.01) and the oxidation (10.9 vs. 20.0 g/5h; P&lt; 0.001) of oral glucose and stimulated slightly its conversion to glycogen (53.9 vs. 50.3 g/5 h; P &lt; 0.05). The latter effect played only a minor role in the marked increase in net CHO balance (52.3 vs. 25.2 g/5 h; P &lt; 0.001), which was almost entirely related to a decrease in glycogen oxidation (1.6 vs. 25.1 g/5 h; P &lt; 0.001). Considering the whole series of data, including intermediate durations of fast, it was observed that the modifications in postprandial CHO metabolism, induced by fasting, correlated strongly with basal CHO oxidation, suggesting that the degree of initial glycogen depletion is a major determinant of glycogen oxidation and net CHO storage. Thus, prior fasting stimulates postprandial glycogen retention, mainly through an inhibition of the glycogen turnover that exists in overnight-fasted subjects, during the absorptive period.
Congenital Adrenal Hypoplasia: Clinical Spectrum, Experience with Hormonal Diagnosis, and Report on New Point Mutations of the DAX-1 Gene
Authors: Peter Michael , Viemann Matthias , Partsch Carl-Joachim , Sippell Wolfgang G. 
Published: January 2014

abstract
X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne’s muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne’s muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates’ persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.
Recovery of Growth Hormone Release from Suppression by Exogenous Insulin-Like Growth Factor I (IGF-I): Evidence for a Suppressive Action of Free Rather Than Bound IGF-I1
Authors: Chapman Ian M. , Hartman Mark L. , Pieper Karen S. , Skiles Emily H. , Pezzoli Suzan S. , Hintz Raymond L. , Thorner Michael O. 
Published: January 2014

abstract
To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18–29 yr) received, in randomized order, 4-h iv infusions of recombinant human IGF-I (rhIGF-I; 3 μg/kg·h) or saline (control) from 25.5–29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4–4.0) vs. 4.8 (2.8–7.9) μg/L; P &lt; 0.05]. A rebound increase in GH concentrations occurred 5–7 h after the end of rhIGF-I infusion [7.6 (4.6–11.7) vs. 4.3 (2.5–6.0) μg/L; P &lt; 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 ± 43 vs. 263 ± 44 μg/L; P &lt; 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 ± 36 vs. 202 ± 23 μg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 ± 0.4 vs. 0.88 ± 0.3 μg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.
Vitamin K Status and Bone Health: An Analysis of Methods for Determination of Undercarboxylated Osteocalcin1
Authors: Gundberg Caren M. , Nieman Sherril D. , Abrams Steven , Rosen Harold 
Published: January 2014

Recent studies suggest that fracture risk is associated with increased undercarboxylated osteocalcin. Methods use differences in binding of undercarboxylated and fully carboxylated osteocalcin to hydroxyapatite or barium sulfate. We evaluated these methods and found that results varied with the amount and preparation of the salts. Furthermore, patient samples with differing amounts of total osteocalcin could not be directly compared. Errors in the determination of undercarboxylated osteocalcin were minimized by expressing data as the percent of the total osteocalcin in the sample, and correcting for the basal level of osteocalcin using a polynomial equation derived from multiple binding curves. Errors from 5–15% in estimation of undercarboxylated osteocalcin were observed without both of these corrections. When differing types of assays were employed (RIA, intact, N-terminal), results also were affected. In normal adults and children and in patients on long-term warfarin therapy, the percent osteocalcin not bound to hydroxyapatite was lower when measured with an intact assay than by a polyclonal RIA. Differences were related to the amount of N-terminal osteocalcin fragments, which had low affinity for hydroxyapatite and resulted in variable overestimation of undercarboxylated osteocalcin.In a kit specific for uncarboxylated osteocalcin, we found good discrimination between carboxylated and uncarboxylated intact osteocalcin. However, the assay detected large osteocalcin fragments and overestimated their concentration by up to 350%. Values for uncarboxylated osteocalcin were not different in patients on coumadin compared with normal adults with this kit, but when normalized to the total intact osteocalcin, percent uncarboxylated osteocalcin was greater in patients on coumadin than in controls, as would be expected. Kit values for uncarboxylated osteocalcin in normal children were higher than intact values in the same subject, because of the increased reactivity of the kit toward circulating fragments that were elevated in children.Thus, for estimation of undercarboxylated osteocalcin, care must be taken to standardize the hydroxyapatite or barium sulfite used for binding, to correct for the basal level of osteocalcin in the sample, to use immunoassays that do not detect small fragments, and to express the results as the percent of the total osteocalcin in the sample. Without these precautions, the assessment of undercarboxylated osteocalcin is not reliable.
Microsatellite Polymorphism of the MHC Class I Chain-Related (MIC-A and MIC-B) Genes Marks the Risk for Autoimmune Addison’s Disease
Authors: Gambelunghe Giovanni , Falorni Alberto , Ghaderi Mehran , Laureti Stefano , Tortoioli Cristina , Santeusanio Fausto , Brunetti Paolo , Sanjeevi Carani B. 
Published: January 2014

Abstract
The major histocompatibility complex class I chain-related MIC-A and MIC-B genes are located on chromosome 6 between the histocompatibility leucocyte antigen (HLA)-B and the B-associated transcript genes. The presence of 21-hydroxylase autoantibodies is a sensitive and specific marker of autoimmune Addison’s disease. We studied the polymorphism of exon 5 of the MIC-A gene, of intron 1 of the MIC-B gene, and of HLA-DRB1, -DQA1, and -DQB1 genes in 28 autoimmune (21-hydroxylase autoantibody positive) Addison’s disease patients and in 75 healthy subjects from central Italy. The MIC-A5.1 allele was significantly more frequent in Addison’s disease patients (79%) than in healthy subjects (36%) [odds ratio (OR) = 6.52, corrected P (Pc) = 0.0015], whereas MIC-A6 was significantly reduced in affected subjects (15% vs. 56%, OR = 0.13, Pc = 0.002). The A5.1/A5.1 genotype had an OR for autoimmune Addison’s disease as high as 18.0 and an absolute risk of 1 per 1131. In the presence of MIC-A5.1, MICB-CA-25 was significantly increased in Addison’s disease patients (25% vs. 4%, OR = 8.0, P = 0.0039, Pc = 0.047). The MICB-CA-17 allele was absent in Addison’s disease patients, but present in more than 25% healthy individuals (OR = 0.10, P = 0.0025, Pc = 0.03). Among HLA-DR and -DQ haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3/DQ2) was significantly more frequent in Addison’s disease patients than in healthy subjects, but only in the presence of MIC-A5.1. The frequency of MIC-A5.1 was significantly increased in Addison’s disease patients only in the presence of HLA-DR3-DQ2. Our study demonstrates that susceptibility to autoimmune Addison’s disease is linked to the MIC-A microsatellite allele 5.1 and that both MIC-A5.1 and HLA-DR3/DQ2 are necessary to confer increased genetic risk for Addison’s disease.
The Interaction of TSH Receptor Autoantibodies with 125I-Labelled TSH Receptor
Authors: Sanders Jane , Oda Yasuo , Roberts Sara , Kiddie Angela , Richards Tonya , Bolton Jane , McGrath Vivienne , Walters Susannah , Jaskólski Donat , Furmaniak Jadwiga , Smith Bernard Rees 
Published: January 2014

Abstract
Detergent-solubilized porcine TSH receptor (TSHR) has been labeled with 125I using a monoclonal antibody to the C-terminal domain of the receptor. The ability of sera containing TSHR autoantibody to immunoprecipitate the labeled receptor was then investigated. Sera negative for TSHR autoantibody (as judged by assays based on inhibition of labeled TSH binding to detergent-solubilized porcine TSHR) immunoprecipitated about 4% of the labeled receptor, whereas sera with high levels of receptor autoantibody immunoprecipitated more than 25% of the labeled receptor. The ability to immunoprecipitate labeled TSHR correlated well with ability of the sera to inhibit labeled TSH binding to the receptor (r = 0.92; n = 63), and this is consistent with TSHR autoantibodies in these samples being directed principally to a region of the receptor closely related to the TSH binding site. Preincubation of labeled TSHR with unlabeled TSH before reaction with test sera inhibited the immunoprecipitation reaction, providing further evidence for a close relationship between the TSHR autoantibody binding site(s) and the TSH binding site. This was the case whether the sera had TSH agonist (i.e., thyroid stimulating) or TSH antagonist (i.e., blocking) activities, thus, providing no clear evidence for different regions of the TSHR being involved in forming the binding site(s) for TSHR autoantibodies with stimulating and with blocking activities. The ability of TSHR autoantibodies to stimulate cyclic AMP production in isolated porcine thyroid cells was compared with their ability to immunoprecipitate labeled porcine TSHR. A significant correlation was observed (r = 0.58; n = 50; P &lt; 0.001) and the correlation was improved when stimulation of cyclic AMP production was compared with inhibition of labeled TSH binding to porcine TSHR (r = 0.76). Overall, our results indicate that TSHR autoantibodies bind principally to a region on the TSHR closely related to the TSH binding site, and this seems to be the case whether the autoantibodies act as TSH agonists or antagonists.