bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Lipids, Lipoproteins, and Lipid Metabolizing Enzymes in Identical Twins Discordant for Obesity
Authors: Rönnemaa Tapani , Marniemi Jukka , Savolainen Markku J. , Kesäniemi Y. Antero , Ehnholm Christian , Bouchard Claude , Koskenvuo Markku
Published: January 2014

abstract

Obesity is associated with adverse changes in plasma lipoprotein metabolism, but it is not known completely how this association is modified by genetic factors. We assessed the contribution of obesity to serum lipid and lipoprotein levels and lipid metabolizing enzyme activities by examining 23 identical twin pairs (9 male, 14 female) who had, on the average, an 18-kg intrapair difference in BW. Compared with lean co-twins, obese co-twins had approximately 20% higher low-density lipoprotein (LDL) cholesterol (P < 0.01), 20% lower high-density lipoprotein2 cholesterol (P = 0.010), and 90% (men) or 35% (women) higher (P ≤ 0.06) total, very-low-density lipoprotein and LDL triglycerides. The pairs were divided into subgroups by the gender-specific median value of abdominal visceral fat (AVF) area in the obese co-twin and by apolipoprotein E 4 phenotype. The intrapair differences in serum cholesterol fractions were similar in twin pairs with high or low AVF, whereas only high AVF pairs showed significant differences in triglyceride fractions. The greatest intrapair differences in total, very-low-density lipoprotein and LDL triglycerides were observed in apolipoprotein E 4-positive pairs expressing high AVF. Compared with lean co-twins, lecithin cholesterol acyltransferase activity was 18% higher (P < 0.001) and hepatic lipase activity was 38% higher (P = 0.016) in obese co-twins with high AVF. When genetic factors are identical, obesity is associated with an atherogenic lipid profile, especially in subjects with high visceral fat accumulation.
Gene Transcription of Receptors for Growth Hormone-Releasing Peptide and Somatostatin in Human Pituitary Adenomas1
Authors: Nielsen Steen , Mellemkjær Søren , Rasmussen Lars M. , Ledet Thomas , Astrup Jens , Weeke Jørgen , Jørgensen Jens O. L.
Published: January 2014

abstract

Growth hormone (GH)-releasing peptides (GHRP) or secretagogs (GHS) constitute a family of synthetic compounds with potent and specific GH releasing activity. The receptor (GHS-R) has recently been cloned even though the endogenous ligand remains to be identified. GHRPs act both at the hypothalamic and the pituitary level through mechanisms involving amplification of GH-releasing hormone activity and functional somatostatin antagonism. In the present study we examined the co-expression of messenger RNA (mRNA) for GHS-R and all 5 somatostatin receptor subtypes (sstr 1–5) in 28 human pituitary tumors by RT-PCR. GHS-R transcription was detected in 11 out of 12 somatotroph adenomas and in 2 out of 2 prolactinomas, whereas GHS-R expression was detected in only 2 out of 14 clinically nonfunctioning adenomas (NFPA), and no expression was seen in the only ACTH secreting adenoma. Almost all tumors expressed sstr 2 mRNA (n = 24), whereas only 1 tumor expressed sstr 4 mRNA. The expression of sstr 3 mRNA was inversely associated with GHS-R expression (P < 0.001), which could be attributed to a high prevalence of sstr 3 expression in NFPA.

This study suggests that GHS-R expression is predominantly observed in somatotroph adenomas and much less so in NFPA. Moreover, the presence of a distinct pattern of somatostatin receptor subtype co-expression is suggested, which may provide a molecular basis for the complex interaction between GHRPs and somatostatin.
Identification of New Sequence Variants in the Leptin Gene
Authors: Karvonen Matti K. , Pesonen Ullamari , Heinonen Paula , Laakso Markku , Rissanen Aila , Naukkarinen Hannu , Valve Raisa , Uusitupa Matti I. J. , Koulu Markku
Published: January 2014

The leptin gene (LEP) has been linked to extreme obesity. However, no common obesity-related gene variants have been found to exist in the LEP. The present study was designed to investigate the LEP for variants by screening both the putative promoter and the coding region of this gene in obese Finnish subjects (n = 200; body mass index, >27 kg/m2). PCR-amplified DNA samples were subjected to single strand conformation analysis. A G144A substitution in codon 48 and a G328A substitution in codon 110 were identified in two obese subjects, both of whom had very low serum leptin levels. A rare silent C538T polymorphism was detected 33 bp downstream of the translation stop codon (TGA). A common polymorphism A19G was identified in the untranslated exon 1. This polymorphism was not associated with traits of obesity; in agreement, the allele frequencies were similar between 64 normal weight and 141 obese Finns. In summary, this study failed to find a common gene variant in the LEP associated with obesity, but introduces 2 rare mutations associated with very low serum leptin concentrations in 2 obese subjects.
Steroid Regulation of Prostaglandin Dehydrogenase Activity and Expression in Human Term Placenta and Chorio-Decidua in Relation to Labor1
Authors: Patel Falguni A. , Clifton Vicki L. , Chwalisz K. , Challis John R. G.
Published: January 2014

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is the key catabolic enzyme controlling levels of biologically active PGs. PGDH is localized to syncytiotrophoblast in placenta, and to trophoblast cells in chorion. To examine the regulation of PGDH by steroids and to determine any changes with labor, we obtained placenta and chorion from term elective cesarean section or spontaneous delivery and isolated trophoblast cells using a Percoll density gradient. Cells were treated with varying concentrations of cortisol, progesterone, the synthetic progestins R5020, and medroxyprogesterone acetate with or without RU486 or the specific progesterone receptor antagonist, onapristone, and the 3β-hydroxysteroid dehydrogenase inhibitor, trilostane. The activity of PGDH was assessed by measurement of 13,14-dihydro-15-keto-PGF2α. PGDH messenger ribonucleic acid was quantified by in situ hybridization and computerized image analysis.

The basal output of 13,14-dihydro-15-keto-PGF2α was lower in placenta or chorion collected at spontaneous labor than in that obtained at elective cesarean section. Cortisol had a significant dose-dependent inhibitory effect on PGDH activity in both placental and chorion trophoblast cells and significantly decreased levels of PGDH messenger ribonucleic acid. Responses were similar between tissues from laboring and nonlaboring women. PGDH activity was increased by R5020 and medroxyprogesterone acetate and was inhibited by RU486, onapristone, and trilostane. We conclude that cortisol inhibits PGDH activity and expression and that progestagens increase PGDH activity in human chorion and placenta.
Serum Free Insulin-Like Growth Factor I (IGF-I), Total IGF-I, and IGF-Binding Protein-3 Concentrations in Normal Children and Children with Growth Hormone Deficiency1
Authors: Kawai Nobuyasu , Kanzaki Susumu , Takano-Watou Syouko , Tada Chiaki , Yamanaka Yoshitaka , Miyata Tsuyoshi , Oka Masanori , Seino Yoshiki
Published: January 2014

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0–40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay.

We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy (<1 yr of age; males, 0.71± 0.26 μg/L, mean ± sd; females, 1.05 ± 0.49μ g/L), increased during puberty (males, 5.84 ± 2.18 μg/L; females, 5.80 ± 1.49 μg/L), and declined thereafter. 2) Free IGF-I in the serum occupied about 0.95–2.02% of the total IGF-I values, with the highest ratio occurring in infancy (males, 1.77± 0.60%; females, 2.02 ± 0.87%). 3) The sd scores of serum free IGF-I in the 21 GHD children ranged from −3.30 to 0.30, and the 5 complete GHD children had free IGF-I values more than −2 sd below those of age-matched normal subjects. 4) There was a significant correlation between the sd scores of free IGF-I and those of total IGF-I (r = 0.715; P< 0.0005) in the GHD children. 5) In the 16 partial GHD children receiving GH treatment, the serum free IGF-I levels were elevated to 209% of pretreatment levels after 1 month of GH treatment and remained high during GH therapy. The GH-induced increase in the serum free IGF-I levels was significantly higher than those of the total IGF-I and IGF binding protein-3 levels. 6) The percent increase in the serum free IGF-I level after 1 month of GH treatment showed a significant positive correlation with that of the GH-induced improvement in the percent increase in the height velocity during 1 yr of GH therapy (r = 0.526; P < 0.05).

These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.
Lack of Effect of GnRH Agonists on Final Height in Girls with Advanced Puberty: A Randomized Long-Term Pilot Study
Authors: Bouvattier C. , Coste J. , Rodrigue D. , Teinturier C. , Carel J. C. , Chaussain J. L. , Bougnères P. F.
Published: January 2014

GnRH agonists improve final height in girls with “true” precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 ± 0.1 yr), a variant of normal called “advanced” puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 ± 4.3 cm (+0.6 sds) in group I, 136.1 ± 4.2 cm (+0.8 sds ) in group II, with target height 157.6 ± 4.3 cm (group I) and 157.8 ± 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 ± 3.9 cm and 155.2 ± 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 ± 4.0 cm) and untreated girls (156.1 ± 5.3 cm) (NS).
A Frame-Shift Mutation in the Type I Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Causing Blomstrand Lethal Osteochondrodysplasia
Authors: Karperien Marcel , van der Harten Hans J. , van Schooten Ron , Farih-Sips Hetty , den Hollander Nicolette S. , Kneppers Sander L. J. , Nijweide Peter , Papapoulos Socrates E. , Löwik Clemens W. G. M.
Published: January 2014

Blomstrand osteochondrodysplasia (BOCD) is a rare lethal skeletal dysplasia characterized by accelerated endochondral and intramembranous ossification. Comparison of the characteristics of BOCD with type I PTH/PTH-related peptide (PTHrP) receptor-ablated mice reveals striking similarities that are most prominent in the growth plate. In both cases, the growth plate is reduced in size due to a strongly diminished zone of resting cartilage and the near absence of columnar arrangement of proliferating chondrocytes. This overall similarity suggested that an inactivating mutation of the PTH/PTHrP receptor might be the underlying genetic defect causing BOCD. Indeed, inactivating mutations of the PTH/PTHrP receptor have been recently identified in two cases of BOCD.

We describe here a novel inactivating mutation in the PTH/PTHrP receptor. Sequence analysis of all coding exons of the type I PTH/PTHrP receptor gene and complementary DNA of a case with BOCD identified a homozygous point mutation in exon EL2 in which one nucleotide (G at position 1122) was absent. The mutation was inherited from both parents, supporting the autosomal recessive nature of the disease. The missense mutation resulted in a shift in the open reading frame, leading to a truncated protein that completely diverged from the wild-type sequence after amino acid 364. The mutant receptor, therefore, lacked transmembrane domains 5, 6, and 7; the connecting intra- and extracellular loops; and the cytoplasmic tail. Functional analysis of the mutant receptor in COS-7 cells and of dermal fibroblasts obtained from the case proved that the mutation was indeed inactivating. Neither the transiently transfected COS-7 cells nor the dermal fibroblasts responded to a challenge with PTH or PTHrP with a rise in intracellular cAMP levels, in sharp contrast to control cells. Our results provide further evidence that BOCD is caused by inactivating mutations of the type I PTH/PTHrP receptor and underscore the importance of this receptor in mammalian skeletal development
Cerebrospinal Fluid and Plasma Leptin Measurements: Covariability with Dopamine and Cortisol in Fasting Humans*
Authors: Hagan Mary M. , Havel Peter J. , Seeley Randy J. , Woods Stephen C. , Ekhator Nosa N. , Baker Dewleen G. , Hill Kelly K. , Wortman Matthew D. , Miller Andrew H. , Gingerich Ronald L. , Geracioti Thomas D.
Published: January 2014

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites,β -lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.
The Feasibility of High Dose Iodine 131 Treatment as an Alternative to Surgery in Patients with a Very Large Goiter: Effect on Thyroid Function and Size and Pulmonary Function*
Authors: Bonnema Steen J. , Bertelsen Henrik , Mortensen Jesper , Andersen Peter B. , Knudsen Dorthe U. , Bastholt Lars , Hegedüs Laszlo
Published: January 2014

Some patients with very large goiters (>150 mL) are not candidates for surgery. We evaluated the feasibility of high dose 131I in such patients. Twenty-three patients (2 men and 21 women; median age, 67 yr; range, 42–86 yr) with very large goiter (8 toxic) were treated with calculated high dose 131I [median, 2281 megabecquerels (61.6 mCi); range, 988-4620 megabecquerels (26.7–124.9 mCi)]. During the 12-month observation period, goiter reduction and tracheal anatomy were monitored by magnetic resonance imaging, and the respiratory capacity was monitored by pulmonary function tests.

Five patients (22%) developed hypothyroidism. Thyroid volumes were at baseline, after 1 week, and after 1 yr [mean ± sem, 311 ± 28, 314 ± 26 (P = NS), and 215 ± 26 (P < 0.01) mL]. The relative changes 1 week after therapy ranged from −14.1% to 15.3%. After 1 yr the mean size was reduced by 33.9% (range, 13.5–61.4%). Only the initial goiter size showed a significant negative correlation to the percent reduction. The smallest cross-sectional area of the trachea decreased 9.2% within 1 week after treatment, but eventually emerged with a 17.9% larger area [mean ± sem, 84.3 ± 4.8, 75.5 ± 5.1 (P < 0.01), and 98.2 ± 6.0 (P < 0.01) mm2]. The inspiratory parameter, FIF50%, improved after an initial insignificant decline[ baseline therapy, after 1 week, after 3 months, and after 1 yr (mean ± sem), 2.37 ± 0.24, 2.20 ± 0.21 (P = NS), 2.51 ± 0.23 (P= NS), and 2.76 ± 0.25 (P = 0.01) L/s]. FIF50% correlated significantly with the smallest cross-sectional tracheal area (baseline, 1 week, and 1 yr: r = 0.74; P < 0.001, r = 0.63; P < 0.005, and r = 0.46; P < 0.05). Changes in tracheal anatomy did not correlate with changes in either lung dynamics or goiter size. In conclusion, very large goiters can be reduced by a third, on the average, with high dose 131I therapy without any initial clinically significant tracheal compression. Tracheal cross-sectional area as well as pulmonary inspiratory capacity improve. No serious adverse effects are seen.
A Novel Mutation of the Signal Peptide of the Preproparathyroid Hormone Gene Associated with Autosomal Recessive Familial Isolated Hypoparathyroidism*
Authors: Sunthornthepvarakul Thongkum , Churesigaew Sunchai , Ngowngarmratana Supunnee
Published: January 2014

We report a novel mutation of the signal peptide of the prepro-PTH gene associated with autosomal recessive familial isolated hypoparathyroidism. The proposita presented with neonatal hypocalcemic seizures. Serum calcium was 1.5 mmol/L (normal, 2.0–2.5); phosphate was 3.6 mmol/L (normal, 0.9–1.5). She was born to consanguineous parents. A few years later, 2 younger sisters and her niece presented with neonatal hypocalcemic seizures. Their intact PTH levels were undetectable during severe hypocalcemia. Genomic DNA from the proposita was sequenced all exons of the prepro-PTH gene. A replacement of thymine with a cytosine was found in the first nucleotide of position 23 in the 25-amino acid signal peptide. This results in the replacement of the normal Ser (TCG) with a Pro (CCG). Genotyping of family members was carried out by identification of a new MspI site created by the mutation. Only affected family members were homozygous for the mutant allele, whereas the parents were heterozygous, supporting autosomal recessive inheritance. As this mutation is at the− 3 position in the signal peptide of the prepro-PTH gene, we hypothesized that the prepro-PTH mutant might not be cleaved by signal peptidase at the normal position, and it might be degraded in rough endoplasmic reticulum.
A Comparison of Recombinant Human Thyrotropin and Thyroid Hormone Withdrawal for the Detection of Thyroid Remnant or Cancer1
Authors: Haugen Bryan R. , Pacini Furio , Reiners Christoph , Schlumberger Martin , Ladenson Paul W. , Sherman Steven I. , Cooper David S. , Graham Kathryn E. , Braverman Lewis E. , Skarulis Monica C. , Davies Terry F. , DeGroot Leslie J. , Mazzaferri Ernest L. , Daniels Gilbert H. , Ross Douglas S. , Luster Markus , Samuels Mary H. , Becker David V. , Maxon Harry R. , Cavalieri Ralph R. , Spencer Carole A. , McEllin Kevin , Weintraub Bruce D. , Ridgway E. Chester
Published: January 2014

Recombinant human TSH has been developed to facilitate monitoring for thyroid carcinoma recurrence or persistence without the attendant morbidity of hypothyroidism seen after thyroid hormone withdrawal. The objectives of this study were to compare the effect of administered recombinant human TSH with thyroid hormone withdrawal on the results of radioiodine whole body scanning (WBS) and serum thyroglobulin (Tg) levels. Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS were studied. Radioiodine WBS and serum Tg measurements were performed after administration of recombinant human TSH and again after thyroid hormone withdrawal in each patient. Radioiodine whole body scans were concordant between the recombinant TSH-stimulated and thyroid hormone withdrawal phases in 195 of 220 (89%) patients. Of the discordant scans, 8 (4%) had superior scans after recombinant human TSH administration, and 17 (8%) had superior scans after thyroid hormone withdrawal (P = 0.108). Based on a serum Tg level of 2 ng/mL or more, thyroid tissue or cancer was detected during thyroid hormone therapy in 22%, after recombinant human TSH stimulation in 52%, and after thyroid hormone withdrawal in 56% of patients with disease or tissue limited to the thyroid bed and in 80%, 100%, and 100% of patients, respectively, with metastatic disease. A combination of radioiodine WBS and serum Tg after recombinant human TSH stimulation detected thyroid tissue or cancer in 93% of patients with disease or tissue limited to the thyroid bed and 100% of patients with metastatic disease. In conclusion, recombinant human TSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer persistence and recurrence.
Intrauterine Growth Retardation Predisposes to Insulin Resistance But Not to Hyperandrogenism in Young Women
Authors: Jaquet D. , Leger J. , Chevenne D. , Czernichow P. , Levy-Marchal C.
Published: January 2014

It was recently suggested that precocious pubarche associated with subsequent functional ovarian hyperandrogenism and hyperinsulinemia could have a common origin in reduced fetal growth. We previously reported that young women born with intrauterine growth retardation (IUGR: birth weight less than the third percentile) were hyperinsulinemic and less insulin sensitive than women born with normal birth weight. The aim of the present study was to investigate whether these IUGR-born women demonstrated hyperandrogenism compared with controls. Our study population was composed of 130 IUGR-born women and 150 controls, of similar age (20.6 ± 3.2 vs. 20.4 ± 2.0 yr). Hormonal contraception in terms of frequency and medication, including antiandrogenic therapy, was identical in the 2 groups. After adjustment for hormonal contraception, being born with IUGR had no independent effect on serum androgen concentrations. In women who were not receiving hormonal contraception, no statistical differences were found between IUGR-born women (n = 67) and controls (n = 64) for Δ4-androstenedione (2.26 ± 0.68 vs. 2.24 ± 0.55 ng/mL; P = 0.76), dehydroepiandrosterone sulfate (2294 ± 1117 vs. 2489 ± 1235 ng/mL; P = 0.24), testosterone (0.82 ± 0.85 vs. 0.70 + 0.26 ng/mL; P = 0.80), or serum sex hormone-binding protein concentrations (45.5 ± 28.2 vs. 53.1 ± 30.3 nmol/L; P = 0.27). In both IUGR and control groups, sex hormone-binding protein correlated negatively with fasting insulin (r = −0.23; P = 0.03 and r = −0.26; P= 0.05), but serum androgen levels did not correlate with insulin. In summary, hyperinsulinemia observed in young women born with IUGR is not associated with hyperandrogenism. Consequently, our results do not support the hypothesis of a common in utero programming of hyperandrogenism and hyperinsulinemia.
Functioning and Nonfunctioning Thyroid Adenomas Involve Different Molecular Pathogenetic Mechanisms1
Authors: Tonacchera Massimo , Vitti Paolo , Agretti Patrizia , Ceccarini Giovanni , Perri Anna , Cavaliere Rossana , Mazzi Barbara , Naccarato Antonio Giuseppe , Viacava Paolo , Miccoli Paolo , Pinchera Aldo , Chiovato Luca
Published: January 2014

The molecular biology of follicular cell growth in thyroid nodules is still poorly understood. Because gain-of-function (activating) mutations of the thyroid-stimulating hormone receptor (TShR) and/or Gsα genes may confer TSh-independent growth advantage to neoplastic thyroid cells, we searched for somatic mutations of these genes in a series of hyperfunctioning and nonfunctioning follicular thyroid adenomas specifically selected for their homogeneous gross anatomy (single nodule in an otherwise normal thyroid gland). TShR gene mutations were identified by direct sequencing of exons 9 and 10 of the TShR gene in genomic DNA obtained from surgical specimens. Codons 201 and 227 of the Gsα gene were also analyzed. At histology, all hyperfunctioning nodules and 13 of 15 nonfunctioning nodules were diagnosed as follicular adenomas. Two nonfunctioning thyroid nodules, although showing a prevalent microfollicular pattern of growth, had histological features indicating malignant transformation (a minimally invasive follicular carcinoma and a focal papillary carcinoma). Activating mutations of the TShR gene were found in 12 of 15 hyperfunctioning follicular thyroid adenomas. In one hyperfunctioning adenoma, which was negative for TShR mutations, a mutation in codon 227 of the Gsα gene was identified. At variance with hyperfunctioning thyroid adenomas, no mutation of the TShR or Gsα genes was detected in nonfunctioning thyroid nodules. In conclusion, our findings clearly define a different molecular pathogenetic mechanism in hyperfunctioning and nonfunctioning follicular thyroid adenomas. Activation of the cAMP cascade, which leads to proliferation but maintains differentiation of follicular thyroid cells, typically occurs in hyperfunctioning thyroid adenomas. Oncogenes other than the TShR and Gsα genes are probably involved in nonfunctioning follicular adenomas.
Skeletal Features and Growth Patterns in 14 Patients with Haploinsufficiency of SHOX: Implications for the Development of Turner Syndrome
Authors: Kosho Tomoki , Muroya Koji , Nagai Toshiro , Fujimoto Masatoshi , Yokoya Susumu , Sakamoto Hiromi , Hirano Takeki , Terasaki Hiroshi , Ohashi Hirofumi , Nishimura Gen , Sato Seiji , Matsuo Nobutake , Ogata Tsutomu
Published: January 2014

We report on clinical features in 14 Japanese patients (4 males and 10 females) with partial monosomy of the short arm pseudoautosomal region involving SHOX (n = 11) or total monosomy of the pseudoautosomal region with no involvement of disease genes on the sex-differential regions (n = 3). Skeletal assessment showed that three patients had no discernible skeletal abnormalities, one patient exhibited short 4th metacarpals and borderline cubitus valgus, and the remaining 10 patients had Madelung deformity and/or mesomelia characteristic of Léri-Weill dyschondrosteosis (LWD), together with short 4th metacarpals and/or cubitus valgus. Skeletal lesions were more severe in females and became obvious with age. Growth evaluation revealed that patients without LWD grew along by the −2 sd growth curve before puberty and showed a normal or exaggerated pubertal growth spurt, whereas those with LWD grew along by the standard growth curves before puberty but exhibited an attenuated pubertal growth spurt and resultant short stature. Maturational assessment indicated a tendency of relatively early maturation in patients with LWD. There was no correlation between the clinical phenotype and the deletion size.

These findings suggest that haploinsufficiency of SHOX causes not only short stature but also Turner skeletal anomalies (such as short 4th metacarpals, cubitus valgus, and LWD) and that growth pattern is primarily dependent on the presence or absence of LWD. Because skeletal lesions have occurred in a female-dominant and age-influenced fashion, it is inferred that estrogens exert a maturational effect on skeletal tissues that are susceptible to premature fusion of growth plates because of haploinsufficiency of SHOX, facilitating the development of skeletal lesions.
Prevalence of Mild Apparent Mineralocorticoid Excess in Mennonites
Authors: Ugrasbul Figen , Wiens Timothy , Rubinstein Pablo , New Maria I. , Wilson Robert C.
Published: January 2014

We have studied an unusual patient with mild low-renin hypertension due to a homozygous mutation in the HSD11B2 gene (PNAS 95:10200–10205, 1998). The patient came from an inbred Mennonite family, and though the mutation identified her as an AME patient, she had a normal birth weight and did not demonstrate the typical features of AME, such as hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. Biochemically, typical patients with AME have abnormal cortisol metabolites and an exceedingly diminished ability to convert [11-3H] cortisol to cortisone. In this patient with mild AME, the conversion of cortisol to cortisone was 58% compared to 0 to 6% in typical AME patients, while the normal conversion is 90 to 95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous mutation in codon 227 (P227L).

We studied this Mennonite population for the prevalence of the P227L mutation. Our hypothesis was that this mild form of AME would be prevalent in the somewhat inbred Mennonite population to which the patient belongs. Our proposed study was 1) to determine if there are other cases of this mild form of AME, and 2) to establish the heterozygote frequency of the mutation in the Mennonites. Results: We did not detect any additional cases of mild AME. We detected 15 carriers of the P227L mutation out of 445 Mennonites, resulting in a heterozygote frequency of 0.03. Conclusion: Since this is an inbred population, the chance of two heterozygotes marrying would be 0.001, which is 1 in 1000 people. This population is known to have large families and therefore the possibility of having an affected child is high. The population consists of 2000 members and we have discovered one affected patient. Thus, there might be one other patient in this population.
Adult Height in Girls with Central Precocious Puberty Treated with Gonadotropin-Releasing Hormone Analogues and Growth Hormone
Authors: Pasquino Anna Maria , Pucarelli Ida , Segni Maria , Matrunola Marco , Cerrone Fabio
Published: January 2014

GnRH analogues (GnRHa) represent the treatment of choice in central precocious puberty (CPP), because arresting pubertal development and reducing either growth velocity (GV) or bone maturation (BA) should improve adult height. However, in some patients, GV decrease is so remarkable that it impairs predicted adult height (PAH); and therefore, the addition of GH is suggested. Out of twenty subjects with idiopathic CPP (treated with GnRHa depot-triptorelin, at a dose of 100 μg/kg im every 21 days, for at least 2–3 yr), whose GV fall below the 25th percentile for chronological age, 10 received, in addition to GnRHa, GH at a dose of 0.3 mg/kg·week sc, 6 days weekly, for 2–4 yr; and 10 matched for BA, chronological age, and duration of GnRHa treatment, who showed the same growth pattern but refused GH treatment, served to evaluate the efficacy of GH addition. No patient showed classical GH deficiency. Both groups discontinued treatment at a comparable BA (mean ± sem): 13.2 ± 0.2 in GnRHa plus GH vs. 13.0 ± 0.1 yr in the control group. At the conclusion of the study, all the patients had achieved adult height. Adult height was considered to be attained when the growth during the preceding year was less than 1 cm, with a BA of over 15 yr. Patients of the group treated with GH plus GnRHa showed an adult height significantly higher (P < 0.001) than pretreatment PAH (160.6 ± 1.3 vs. 152.7 ± 1.7 cm). Target height (TH) was significantly exceeded. The group treated with GnRH alone reached an adult height not significantly higher than pretreatment PAH (157.1 ± 2.5 vs. 155.5 ± 1.9 cm). TH was just reached but not significantly exceeded. The gain in centimeters obtained, calculated between pretreatment PAH and final height, was 7.9 ± 1.1 cm in patients treated with GH combined with GnRHa; whereas in patients treated with GnRHa alone, the gain was just 1.6 ± 1.2 cm (P = 0.001). Furthermore, no side effects have been observed either on bone age progression or ovarian cyst appearance and the gynecological follow-up in the GH-treated patients (in comparison with those treated with GnRHa alone). In conclusion, a gain of 7.9 cm in adult height represents a significant improvement, which justifies the addition of GH for 2–3 yr during the conventional treatment with GnRHa, especially in patients with CPP, and a decrease in GV so marked as to impair PAH, not allowing it to reach even the third centile.
Apoptosis, Proliferation, and Sex Hormone Receptors in Superficial Parts of Human Endometrium at the End of the Secretory Phase1
Authors: Dahmoun M. , Boman K. , Cajander S. , Westin P. , Bäckström T.
Published: January 2014

Apoptosis with one regulator, Bcl-2, and proliferation with the marker Ki-67 were studied in 75 endometrial biopsies representing superficial parts of endometrium from 35 regularly menstruating women premenstrually and menstrually. Hormonal withdrawal was studied in serum samples and potentiated in epithelium by the decreasing 17β-estradiol and progesterone receptor scores 4 days premenstrually. The apoptotic index increased 2 days before the onset of menstruation and peaked on the second menstrual day. The high apoptotic index together with low proliferation in endometrial epithelium at the end of the menstrual cycle are similar to the involution process seen in other hormone-dependent organs. In stroma, the apo-ptotic index increased later, at the onset of menstruation, and the increase was lower than that in epithelium. The Ki-67 index increased during the last 3 days of the secretory phase, parallel with an increasing progesterone receptor score and decreasing Bcl-2 staining, and peaked at the onset of menstruation. The findings in stroma concur with high proliferation at the end of the menstrual cycle and high cell turnover during menstruation, suggesting the participation of stroma in the renewal process of endometrium.
High Serum Leptin Concentrations during Catch-Up Growth of Children Born with Intrauterine Growth Retardation1
Authors: Jaquet D. , Leger J. , Tabone M. D. , Czernichow P. , Levy-Marchal C.
Published: January 2014

The aim of the study was to investigate how leptin could be involved in catch-up growth of children born with intrauterine growth retardation (IUGR). The study population was made up of 70 newborns with IUGR longitudinally studied during the first 2 yr of life and 35 newborns and 32, 66, and 61 children with normal birth weight aged 3 days, 12 months, and 24 months, respectively. Postnatal patterns of body mass index (BMI) were similar in the 2 groups, but BMI remained significantly lower in IUGR over the study period. In contrast, children born with IUGR aged 1 yr had significantly higher serum leptin levels than normal children (P < 0.0001) independently of BMI. The correlation observed between BMI and serum leptin at birth in both groups and in the control group thereafter disappeared in children born with IUGR. Similarly, sexual dimorphism observed in normal children over the study period was not observed in the IUGR group during the first 2 yr of life. In summary, serum leptin is effective and regulated during the first years of life as it is in older children. Children born with IUGR demonstrate high serum leptin values during the first year of life, with a loss of the regulatory effect of BMI and gender. We suggest that these children develop an adaptative leptin resistance beneficial for their catch-up growth. An alternative hypothesis is that these observations could reflect an adipocyte dysfunction, a consequence of the special time course of adipose tissue development in children born with IUGR.
Biotransformation of Oral Dehydroepiandrosterone in Elderly Men: Significant Increase in Circulating Estrogens
Authors: Arlt Wiebke , Haas Joachim , Callies Frank , Reincke Martin , Hübler Doris , Oettel Michael , Ernst Michael , Schulte Heinrich Maria , Allolio Bruno
Published: January 2014

The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 ± 5.1 yr; mean body mass index, 25.5 ± 1.5 kg/m2) with serum DHEAS concentrations below 4.1 μmol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0–12 h (mean ± sd) for DHEA, 108 ± 22 vs. 252 ± 45 vs. 349 ± 72 nmol/L·h; AUC 0–12 h for DHEAS, 33 ± 9 vs. 114 ±. 19 vs. 164± 36 μmol/L·h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17β-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men[ placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0–12 h for 17β-estradiol, 510 ± 198 vs. 635 ± 156 vs. 700 ± 209 pmol/L·h (P < 0.0001); AUC 0–12 h for estrone, 1443 ± 269 vs. 2537 ± 434 vs. 3254 ± 671 pmol/L·h (P< 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.
Endogenous Androgens and Carotid Intimal-Medial Thickness in Women
Authors: Bernini G.P. , Sgro’ M. , Moretti A. , Argenio G.F. , Barlascini C.O. , Cristofani R. , Salvetti A.
Published: January 2014

The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and postmenopausal females, we evaluated the relationship between serum androgen levels and both carotid artery intimal-medial thickness (IMT) and major cardiovascular risk factors. In addition to evaluation of blood pressure, body mass index, and waist-to-hip ratio, serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), total testosterone (TTS), free testosterone (FTS), insulin, cholesterol (total and high density lipoproteins), triglycerides, and glucose were measured. All women underwent carotid ultrasonography. Spearman correlation coefficients showed that serum DHEA-S and A levels were negatively related (P < 0.03–0.0004) to several IMT measures. Higher tertiles of DHEA-S, A, and FTS corresponded to significantly lower measures of carotid thickness. DHEA-S, and all androgens were inversely related to age (P < 0.03 or less), showing no unfavorable association with major cardiovascular risk factors. In contrast, serum DHEA-S was negatively associated with WHR (P < 0.02), while A was negatively associated with body mass index (P < 0.02). Stepwise multiple regression analysis indicated that A and FTS showed an inverse association with IMT measures (P< 0.05–0.001).

In conclusion, our data indicate that in women serum DHEA-S and androgens decline with age and that normal hormonal levels are not associated with major cardiovascular risk factors. They also show that higher DHEA-S and androgen concentrations are related to lower carotid wall thickness; for A this association is independent of cardiovascular risk factors. Our results suggest that, in the physiological range, DHEA-S and androgens in women are correlated with lower risk of carotid artery atherosclerosis.
Sulfation of Thyroid Hormone by Estrogen Sulfotransferase
Authors: Kester M. H. A. , van Dijk C. H. , Tibboel D. , Hood A. M. , Rose N. J. M. , Meinl W. , Pabel U. , Glatt H. , Falany C. N. , Coughtrie M. W. H. , Visser T. J.
Published: January 2014

Sulfation is one of the pathways by which thyroid hormone is inactivated. Iodothyronine sulfate concentrations are very high in human fetal blood and amniotic fluid, suggesting important production of these conjugates in utero. Human estrogen sulfotransferase (SULT1E1) is expressed among other tissues in the uterus. Here we demonstrate for the first time that SULT1E1 catalyzes the facile sulfation of the prohormone T4, the active hormone T3 and the metabolites rT3 and 3,3′-diiodothyronine (3,3′-T2) with preference for rT3 ≈ 3,3′-T2 > T3 ≈ T4. Thus, a single enzyme is capable of sulfating two such different hormones as the female sex hormone and thyroid hormone. The potential role of SULT1E1 in fetal thyroid hormone metabolism needs to be considered.
A Sexually Dimorphic Pattern of Growth Hormone Secretion in the Elderly
Authors: Hindmarsh P. C. , Dennison E. , Pincus S. M. , Cooper C. , Fall C. H. D. , Matthews D. R. , Pringle P. J. , Brook C. G. D.
Published: January 2014

In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4–73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio.

Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn).

There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = −0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = −0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = −0.40; P = 0.006; females: r = −0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = −0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.
The Midnight to Morning Urinary Cortisol Increment Is an Accurate, Noninvasive Method for Assessment of the Hypothalamic-Pituitary-Adrenal Axis
Authors: Kong W. M. , Alaghband-Zadeh J. , Jones J. , Carter G. , O’Shea D.
Published: January 2014

The optimal method for assessing the hypothalamic-pituitary-adrenal axis (HPA) remains controversial. The insulin tolerance test (ITT) is considered the gold standard, but is invasive and potentially dangerous. The short Synacthen test (SST) is the most commonly used alternative, but its concordance with the ITT is poor. Using sleep as a reliable stimulus to ACTH release, we proposed that the increment in urinary cortisol levels between midnight and waking could provide a noninvasive, physiological means for the assessment of the HPA axis. Double voided urine samples were collected at home at midnight and waking in 40 patients with pituitary disease and 40 controls. Cortisol and creatinine levels were measured, and the cortisol/creatinine (Cort/Cr) ratio was calculated. The Cort/Cr increment was defined as the morning Cort/Cr ratio minus the midnight Cort/Cr ratio. The Cort/Cr increment of the patients was compared to the results of their ITT or SST. Using the results from the 40 controls, a normal Cort/Cr increment was defined as greater then 9. The positive predictive value of a Cort/Cr increment for the diagnosis of HPA insufficiency was 95%. These findings suggest that the midnight to morning Cort/Cr increment is a reliable, noninvasive alternative to the ITT/SST for assessment of the HPA.
Oral Glibenclamide Suppresses Glucagon Secretion during Insulin-Induced Hypoglycemia in Patients with Type 2 Diabetes1
Authors: Landstedt-Hallin Lena , Adamson Ulf , Lins Per-Eric
Published: January 2014

Intensifying pharmacological therapy in patients with type 2 diabetes increases the risk of hypoglycemia and often requires the simultaneous use of more than one agent. Combining insulin and sulfonylurea is an effective and frequently used therapy in such patients. However, sulfonylurea derivatives have been shown to affect the release of glucagon, indicating a possible effect of such therapy on hormonal counterregulation to hypoglycemia. Thirteen patients receiving combined therapy were studied on two occasions: 1) after a wash-out period of glibenclamide (−GLIB), and 2) after resuming combined treatment for 6 months (+GLIB). We performed nonstepwise, hyperinsulinemic hypoglycemic clamps using a constant iv insulin infusion and clamping blood glucose at 2.7 mmol/L (48 mg/dL) for 60 min. C Peptide levels were significantly higher during +GLIB, but no significant differences were seen in peripheral plasma insulin levels (+GLIB mean ± sd, 70 ± 17 mU/L vs. −GLIB, 75 ± 14; P = 0.26). Epinephrine responses were similar in the two tests, but when glibenclamide was present the glucagon response was smaller, both the peak value (P = 0.016) and the incremental area under the curve (P = 0.011) as well as the total area under the curve (P = 0.016). These results suggest that intraislet insulin secretion is of importance for the α-cell responsiveness to hypoglycemia in these patients.
Normocortisolemic Cushing’s Syndrome Initially Presenting with Increased Glucocorticoid Receptor Numbers1
Authors: Newfield Ron S. , Kalaitzoglou George , Licholai Teresa , Chilton David , Ashraf Javed , Thompson E. Brad , New Maria I.
Published: January 2014

A girl who developed Cushingoid features in peripuberty, but was eucortisolemic, was previously reported to have markedly elevated lymphocyte glucocorticoid receptor sites per cell with normal binding affinity as a potential cause of her phenotype. Her circadian rhythm of cortisol and pituitary-adrenal axis were initially intact, but later proved to be dysregulated. The patient presented at age 10.8 yr with centripetal obesity, moon facies, buffalo hump, and purple striae, but no statural stunting, which is a cardinal sign of Cushing’s syndrome. At 11.5 yr she suffered a compression fracture of the L1 vertebra. That prompted treatment with the antiprogestin drug mifepristone (RU486), which was administered at high dose to achieve an antiglucocorticoid effect. From ages 13.75 yr through 15.5 yr, RU486 was administered in various intervals to suppress her Cushingoid features. Once RU486 was introduced, however, a consistent correlation over time between the Cushingoid features and glucocorticoid receptor sites per cell was no longer observed. However, the number of glucocorticoid receptor sites per cell tended to decrease in response to administering RU486. Ultimately, her Cushingoid phenotype proved to be transient.