bluuebunny/crossref_metadata_2025_split huggingface dataset:
Congenital Hypothyroidism with Impaired Thyroid Response to Thyrotropin (TSH) and Absent Circulating Thyroglobulin: Evidence for a New Inactivating Mutation of the TSH Receptor Gene*
Authors: Tonacchera Massimo , Agretti Patrizia , Pinchera Aldo , Rosellini Veronica , Perri Anna , Collecchi Paola , Vitti Paolo , Chiovato Luca 
Published: January 2014

AbstractCongenital hypothyroidism due to impaired thyroid response to TSH was originally described by Stanbury. A diagnosis of congenital hypothyroidism with thyroid unresponsiveness to TSH is accepted if the patient has congenital hypothyroidism, the thyroid gland is in the normal position in the neck, the size of the thyroid is either normal or atrophic, the serum TSH level is increased, the bioactivity of TSH is intact, and the response of the thyroid gland to TSH stimulation is decreased. In all originally described cases serum thyroglobulin was undetectable. We describe a 22-yr-old female patient who was severely hypothyroid and mentally retarded. Serum T4 and T3 concentrations were below the sensitivity of the methods, with elevated serum TSH levels. Serum thyroglobulin was undetectable. A normally shaped hypoplastic gland located in the appropriate anatomical position in the neck was found at scintiscan. The gland did not respond after administration of bovine TSH in terms of 131I uptake, serum thyroid hormones, and thyroglobulin secretion. A diagnosis of congenital hypothyroidism due to TSH unresponsiveness was formulated.Genetic analysis in the propositus showed a homozygous inactivating mutation of the TSH receptor that had not been previously described. The mutation consisted of the substitution of an isoleucine in place of a highly conserved threonine at position 477 in the first extracellular loop of the receptor (T477I). The brother, one sister of the father (whose DNA was not available), the mother of the propositus, one sister, and the brother were heterozygous for T477I. All the heterozygous persons were unaffected.After transfection in COS-7 cells, the mutant receptor displayed an extremely low expression at cell surface. At variance with cells transfected with the wild-type TSH receptor, cells transfected with the mutant T477I did not show constitutive activity for the adenylyl cyclase pathway. A dramatic reduction in the amount of cAMP accumulation after bovine TSH challenge was observed in cells transfected with the mutant T477I receptor. A structural defect in the mutant TSH receptor protein was probably responsible for the poor routing of the receptor to the cell membrane. This is the first time that a loss of function mutation of the TSH receptor is described in a patient with severe congenital hypothyroidism and absent circulating thyroglobulin due to TSH unresponsiveness and the first time that an inactivating mutation of the TSH receptor is described in the first extracellular loop.
Identification of Novel Human GH-1 Gene Polymorphisms that Are Associated with Growth Hormone Secretion and Height*
Authors: Hasegawa Yukihiro , Fujii Katsura , Yamada Makoto , Igarashi Yutaka , Tachibana Katsuhiko , Tanaka Toshiaki , Onigata Kazumichi , Nishi Yoshikazu , Kato Shigeaki , Hasegawa Tomonobu 
Published: January 2014

AbstractHeight, which is partially determined by GH secretion, is genetically influenced. The purpose of this study was to identify polymorphisms in the GH-1 gene, which are associated with altered GH production. The subjects included prepubertal short children with GH insufficiency without gross pituitary abnormalities (n = 43), short children with normal GH secretion (n = 46), and normal adults (n = 294). A polymorphism in intron 4 (P-1, A or T at base 1663) was identified. Two additional polymorphic sites (P-2, T or G at base 218, and P-3, G or T at base 439) in the promoter region of the GH-1 gene were also identified and matched with the P-1 polymorphism (A or T, respectively) in more than 90% of the subjects. P-1, P-2, and P-3 were considered to be associated with GH production, and the results of P-2 are explained as a representative in this abstract. For example, the allele frequency of T at P-2 in prepubertal short children with GH insufficiency without gross pituitary abnormalities (58.1%) was significantly different from that in short children with normal GH secretion and normal adults (37.0% and 43.5%, respectively; P &lt; 0.001). Furthermore, significant differences were observed in maximal GH peaks in provocative tests (11.1 vs. 18.2 ng/mL, P = 0.006), insulin-like growth factor I sd scores (SDS) (−2.4 vs. −0.8, P &lt; 0.0001), and height (Ht) SDS (−3.7 vs. −3.0, P = 0/001) in children with the T/T or G/G genotypes at P-2, respectively. In the entire study group, significant differences in insulin-like growth factor SDS (T/T,− 0.9; G/G, −0.2; P = 0.0009) and Ht SDS (T/T,− 1.0; G/G, −0.4; P = 0.022) were observed between the T/T and G/G genotypes at P-2. These data indicate that GH secretion is partially determined by polymorphisms in the GH-1 gene, which explain some of the variations in GH secretion and Ht.
Adenovirus-Mediated Herpes Simplex Virus Type-1 Thymidine Kinase Gene Therapy Suppresses Oestrogen-Induced Pituitary Prolactinomas*
Authors: Windeatt S. , Southgate T. D. , Dewey R. A. , Bolognani F. , Perone M. J. , Larregina A. T. , Maleniak T. C. , Morris I. D. , Goya R. G. , Klatzmann D. , Löwenstein P. R. , Castro M. G. 
Published: January 2014

AbstractWe tested the hypothesis that gene transfer using recombinant adenovirus vectors (RAds) expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) might offer an alternative therapeutic approach for the treatment of pituitary prolactinomas that do not respond to classical treatment strategies. HSV1-TK converts the prodrug ganciclovir (GCV) to GCV monophosphate, which is in turn further phosphorylated by cellular kinases to GCV triphosphate, which is toxic to proliferating cells. One attractive feature of this system is the bystander effect, whereby untransduced cells are also killed. Our results show that RAd/HSV1-TK in the presence of GCV is nontoxic for the normal anterior pituitary (AP) gland in vitro, but causes cell death in the pituitary tumor cell lines GH3, a PRL/GH-secreting cell line, and AtT20, a corticotrophic cell line. We have used sulpiride- and oestrogen-induced lactotroph hyperplasia within the rat AP gland as an in vivo animal model. Intrapituitary infection of rats bearing oestrogen-induced lactotroph hyperplasia, with RAd/HSV1-TK and subsequent treatment with GCV, decreases plasma PRL levels and reduces the mass of the pituitary gland. More so, there were no deleterious effects on circulating levels of other AP hormones, suggesting that the treatment was nontoxic to the AP gland in situ. In summary, our results show that suicide gene therapy using the HSV1-TK transgene could be further developed as a useful treatment to complement current therapies for prolactinomas.
Prediction of Bone Mass Change after Parathyroidectomy in Patients with Primary Hyperparathyroidism*
Authors: Nakaoka Daiki , Sugimoto Toshitsugu , Kobayashi Tatsuya , Yamaguchi Toru , Kobayashi Akira , Chihara Kazuo 
Published: January 2014

Abstract
A major challenge in the management of primary hyperparathyroidism (pHPT) is the decision regarding which patients should undergo parathyroidectomy (PTX), although the Consensus Development Conference of the NIH has proposed guidelines for the indication of surgery. In the present study, changes in bone mineral density (BMD) after PTX were compared between pHPT patients who did and did not meet the NIH criteria, and we further tried to predict the BMD change after PTX from preoperative parameters. The subjects were 44 pHPT patients (30 women and 14 men) who had had successful PTX. Lumbar and radial BMD were measured before and 1 yr after PTX by dual energy x-ray absorptiometry and single photon absorptiometry, respectively. Average annual percent increases in lumbar and radial BMD after PTX were 12.2 ± 1.4% and 11.6 ± 1.6% (mean ± sem), respectively, and those net increases were 0.0803 ± 0.0008 and 0.0484 ± 0.0006 g/cm2, respectively. There were no significant differences in percent or net changes in either radial or lumbar BMD after PTX between the groups divided according to each of the NIH criteria, such as age (≥50 and &lt;50 yr), serum calcium level (≥12 and&lt;12 mg/dL) or the existence of urinary stones (presence and absence). On the other hand, when the subjects were divided on the basis of radial BMD (above and below a z-score of −2), the annual percent and net increases in lumbar BMD and percent increase in radial BMD after PTX were significantly higher in the group with the lower z-score. Next, patients were divided into two groups with and without the indication of PTX based on NIH guidelines. Twenty-nine patients had the surgical indication by meeting one or more of these criteria and 15 patients had no indication without meeting any of the criteria. There were no significant differences between the two groups in annual percent or net changes in radial or lumbar BMD after PTX. A stepwise multiple regression analysis revealed that serum alkaline phosphatase level and the severity of cortical bone mass reduction were the best predictors of both percentage and net changes in lumbar BMD, with high determination coefficients (r2 &gt; 0.7). In conclusion, a considerable increase in BMD could be obtained after PTX even in patients without surgical indication from the NIH. Alkaline phosphatase and the severity of cortical bone mass reduction are clinically useful for predicting the changes in lumbar BMD after PTX. The present findings provide a useful clue for the indication of surgery in pHPT.
Uniparental Disomy in Steroid 5α-Reductase 2 Deficiency
Authors: Chávez Bertha , Valdez Evangelina , Vilchis Felipe 
Published: January 2014

Abstract
Steroid 5α-reductase 2 deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the SRD5A2 gene. In this study, we performed DNA analyses in two unrelated subjects bearing the enzyme deficiency and found differences in the mode of transmission for the disease. The data showed that in both families the fathers were carriers for an E197D mutation, whereas the mothers were carriers for a P212R mutation. Patient 1 was identified as compound heterozygote because he had both alterations (E197D/P212R). On the contrary, patient 2 was found to be homozygous, but only for the paternal mutation. Because this finding could not be explained on the basis of nonpaternity or a chromosomal abnormality, the presence of uniparental disomy was suggested. The reduction to homozygosity for the E197D mutation, as confirmed by restriction analysis, supported this view. The results of our study give evidence of the first case of 5α-reductase deficiency resulting from uniparental disomy and also disclose an alternate mechanism whereby this enzymatic disorder can derive from a single parent.
Treatment of Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism in Nonobese, Adolescent Girls: Effect of Flutamide*
Authors: Ibáñez Lourdes , Potau Neus , Marcos Maria Victoria , de Zegher Francis 
Published: January 2014

Abstract
Functional ovarian hyperandrogenism, a variant of polycystic ovary syndrome, is often associated with hyperinsulinism and dyslipidemia. The mechanisms interlinking this triad are poorly understood; both hyperandrogenism and hyperinsulinism have been proposed as factors involved in the pathogenesis of the dyslipidemia. Precocious pubarche (PP) in girls is a risk factor for subsequent anovulation, ovarian and adrenal hyperandrogenism, hyperinsulinism and dyslipidemia.
Flutamide, a nonsteroidal antiandrogen, is known to be effective in reducing hirsutism in patients with ovarian hyperandrogenism. However, the effects of flutamide on the endocrine-metabolic correlates of hyperandrogenism are uncertain. We assessed the effects of low dose flutamide treatment (250 mg daily for 18 months) on hormonal and metabolic variables in 18 nonobese adolescent girls (age, 16.8 ± 0.3 yr) with functional ovarian hyperandrogenism (diagnosis by GnRH agonist test) after PP.
Flutamide treatment was accompanied by a marked decrease in the hirsutism score, free androgen index, and testosterone, androstenedione, and dehydroepiandrosterone levels and by an increase in sex hormone-binding globulin concentrations. However, there were no substantial changes in the pattern of menstrual cycles, gonadotropin, estradiol, or dehydroepiandrosterone sulfate concentrations, and there was no detectable effect on the 17-hydroxyprogesterone response to GnRH agonist. Serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels decreased markedly during flutamide therapy, whereas high-density lipoprotein cholesterol, fasting glycemia/insulinemia, and the insulin response to a glucose load remained unchanged. Flutamide was well tolerated.
In conclusion, low dose flutamide treatment was found to be an effective and safe approach to reduce hirsutism and circulating androgen, low-density lipoprotein cholesterol, and triglyceride levels in girls with functional ovarian hyperandrogenism after PP. However, flutamide failed to increase high-density lipoprotein cholesterol levels or decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease.
Novel Point Mutation in the Splice Donor Site of Exon-Intron Junction 6 of the Androgen Receptor Gene in a Patient with Partial Androgen Insensitivity Syndrome*
Authors: Sammarco Innocenzo , Grimaldi Paola , Rossi Pellegrino , Cappa Marco , Moretti Costanzo , Frajese Gaetano , Geremia Raffaele 
Published: January 2014

AbstractAndrogen receptor (AR) gene mutations have been shown to cause androgen insensitivity syndrome with altered sexual differentiation in XY individuals, ranging from a partial insensitivity with male phenotype and azoospermia to a complete insensitivity with female phenotype and the absence of pubic and axillary sexual hair after puberty.In this study we present an 11-yr-old XY girl, with clinical manifestations peculiar for impaired androgen biological action, including female phenotype, blind-ending vagina, small degree of posterior labial fusion, and absence of uterus, fallopian tubes, and ovaries. At the time of the diagnosis the patient had a FSH/LH ratio according to the puberal stage, undetectable 17β-estradiol, and high levels of testosterone (80.1 ng/mL). After bilateral gonadectomy, performed at the age of 11 yr, histological examination showed small embryonic seminiferous tubules containing prevalently Sertoli cells and occasional spermatogonia together with abundant fibrous tissue. Molecular study of the patient showed a guanine to thymine transversion in position +5 of the donor splice site in the junction between exon 6 and intron 6 of the AR gene. The result of RT-PCR amplification of the AR messenger ribonucleic acid from cultured genital skin fibroblasts of the patient suggests that splicing is defective, and intron 6 is retained in most of the receptor messenger ribonucleic acid molecules. We show by immunoblotting that most of the expressed protein lacks part of the C-terminal hormone-binding domain, and a small amount of normal receptor is observed. This is probably responsible for the reduced binding capacity in genital skin fibroblasts of the patient.The molecular basis of the alteration in this case is a novel, uncommon mutation, leading to a phenotype indicative of a partial androgen insensitivity syndrome, Quigley’s grade 5.
Treatment of Familial Hyperaldosteronism Type I: Only Partial Suppression of Adrenocorticotropin Required to Correct Hypertension
Authors: Stowasser Michael , Bachmann Anthony W. , Huggard Phillip R. , Rossetti Tony R. , Gordon Richard D. 
Published: January 2014

AbstractIn familial hyperaldosteronism type I, inheritance of a hybrid 11β-hydroxylase/aldosterone synthase gene leads to ACTH-regulated overproduction of aldosterone (causing hypertension) and of“ hybrid” steroids, 18-hydroxy- and 18-oxo-cortisol. To determine whether complete suppression of the hybrid gene is necessary to normalize blood pressure, we sought evidence of persisting expression in eight patients who were rendered normotensive for 1.3–4.5 yr by glucocorticoid treatment. At the time of the study, six patients were receiving dexamethasone (0.125–0.25 mg/day) and two patients were taking prednisolone (2.5 or 5 mg/day). Urinary 18-oxo-cortisol levels during treatment demonstrated close correlation with mean “day curve” (blood collected every 2 h for 24 h) cortisol (r = 0.74), consistent with regulation by ACTH. Although urinary 18-oxo-cortisol levels were lower during than before treatment (mean 12.6 ± 2.4 semvs. 35.0 ± 5.6 nmol/mmol creatinine; P &lt; 0.01), they remained above normal (0.8–5.2 nmol/mmol creatinine) in all eight patients. Although mean upright plasma potassium levels during treatment were higher, aldosterone levels lower, PRA levels higher, and aldosterone to PRA ratios lower than before treatment, PRA levels were uncorrected (&lt;13 pmol/L·min) and aldosterone to PRA ratios were uncorrected (&gt;65) during treatment in four patients. For each of the eight patients, day curve aldosterone levels during treatment correlated more tightly with cortisol (mean r for the eight patients, 0.87 ± 0.05 sem) than with PRA (mean r = 0.36 ± 0.10 sem). Hence, control of hypertension by glucocorticoid treatment was associated, in all patients, with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production is not a requisite for hypertension control and, if used as a treatment goal, may unnecessarily increase the risk of Cushingoid side effects.
Evidence for the Presence of Angiogenin in Human Follicular Fluid and the Up-Regulation of Its Production by Human Chorionic Gonadotropin and Hypoxia*
Authors: Koga Kaori , Osuga Yutaka , Tsutsumi Osamu , Momoeda Mikio , Suenaga Akihiko , Kugu Koji , Fujiwara Toshihiro , Takai Yasushi , Yano Tetsu , Taketani Yuji 
Published: January 2014

Abstract
Angiogenesis is an essential event during the development of the ovarian follicle and ensuing formation of the corpus luteum. We investigated the presence of angiogenin, a potent inducer of angiogenesis, and the regulatory mechanisms of its production in the human ovary. Follicular fluid (FF) and granulosa cells (GCs) were collected from women undergoing in vitro fertilization and embryo transfer. The presence of angiogenin in FF and GCs was demonstrated by Western blot analysis. The production of angiogenin by cultured GCs was stimulated with the addition of human CG or cAMP or under the hypoxic milieu. Concentrations of angiogenin in FF from an individual follicle were positively correlated with those of progesterone, but not estradiol and testosterone. Given the presence of angiogenin in FF and up-regulation of its production by human CG and hypoxia, it seems logical to assume that angiogenin may play a role as a local angiogenic factor in the human ovary.
A Novel Mutation in the Calcium-Sensing Receptor Gene in a Chinese Subject with Persistent Hypercalcemia and Hypocalciuria1
Authors: Jap Tjin-Shing , Wu Yi-Chi , Jenq Shwu-Fen , Won Gin-Sing 
Published: January 2014

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder characterized by high penetrance of relatively benign, lifelong persistent hypercalcemia and hypocalciuria. By contrast, neonatal severe hyperparathyroidism represents a life-threatening form of hypercalcemia that can cause the early newborn mortality if immediate intervention is not undertaken. Both disorders are due to inactivation mutation of the human calcium-sensing receptor (CaSR) gene on chromosome 3q21-24. Up to now, more than 30 mutations in the CaSR gene associated with FHH have been described. In this study, we analyzed one 79-yr-old male with hypocalciuric hypercalcemia without siblings or children to compare with an additional group of 50 normal Chinese subjects in Taiwan. DNA sequence analysis of the CaSR gene was performed. The result showed that the proband had a heterozygous nonsense mutation in exon 7 of the CaSR gene at codon 648 (CGA→TGA/Arg→Ter). This mutation, located in the COOH-terminal of the first intracellular loop of the CaSR, predicts a markedly truncated protein.
We have identified a novel R648X mutation in the CaSR gene in one patient with FHH in Taiwan
Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing’s Syndrome
Authors: Bourdeau Isabelle , D’Amour Pierre , Hamet Pavel , Boutin Jean-Marie , Lacroix André 
Published: January 2014

Cortisol secretion in adrenal Cushing’s syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin.
Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing’s syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH.
A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 μg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female.
This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.