bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing GH Therapy in Adults and Children
Authors: Drake W. M. , Howell S. J. , Monson J. P. , Shalet S. M. 
Published: January 2014

AbstractUntil the advent of modern neuroradiological imaging techniques in 1989, a diagnosis of GH deficiency in adults carried little significance other than as a marker of hypothalamo-pituitary disease. The relatively recent recognition of a characteristic clinical syndrome associated with failure of spontaneous GH secretion and the potential reversal of many of its features with recombinant human GH has prompted a closer examination of the physiological role of GH after linear growth is complete. The safe clinical practice of GH replacement demands a method of judging overall GH status, but there is no biological marker in adults that is the equivalent of linear growth in a child by which to judge the efficacy of GH replacement. Assessment of optimal GH replacement is made difficult by the apparent diverse actions of GH in health, concern about the avoidance of iatrogenic acromegaly, and the growing realization that an individual’s risk of developing certain cancers may, at least in part, be influenced by cumulative exposure to the chief mediator of GH action, IGF-I. As in all areas of clinical practice, strategies and protocols vary between centers, but most physicians experienced in the management of pituitary disease agree that GH is most appropriately begun at low doses, building up slowly to the final maintenance dose. This, in turn, is best determined by a combination of clinical response and measurement of serum IGF-I, avoiding supraphysiological levels of this GH-dependent peptide. Numerous studies have helped define the optimum management of GH replacement during childhood. The recent requirement to measure and monitor GH status in adult life has called into question the appropriateness of simplistic weight- and surface area-based dosing regimens for the management of GH deficiency in childhood, with reliance on linear growth as the sole marker of GH action. It is clear that the monitoring of parameters other than linear growth to help refine GH therapy should now be incorporated into childhood GH treatment protocols. Further research will be required to define the optimal management of the transition from pediatric to adult GH replacement; this transition will only be possible once the benefits of GH in mature adults are defined and accepted by pediatric and adult endocrinologists alike.
Changes in Proinflammatory Cytokine Activity after Menopause
Authors: Pfeilschifter Johannes , Köditz Roland , Pfohl Martin , Schatz Helmut 
Published: January 2014

AbstractThere is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in proinflammatory cytokines. The cytokines that have obtained the most attention are IL-1, IL-6, and TNF-α. The exact mechanisms by which estrogen interferes with cytokine activity are still incompletely known but may potentially include interactions of the ER with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and changes in immune cell function. Experimental and clinical studies strongly support a link between the increased state of proinflammatory cytokine activity and postmenopausal bone loss. Preliminary evidence suggests that these changes also might be relevant to vascular homeostasis and the development of atherosclerosis. Better knowledge of the mechanisms and the time course of these interactions may open new avenues for the prevention and treatment of some of the most prevalent and important disorders in postmenopausal women.
Turner’s Syndrome in Adulthood
Authors: Elsheikh M. , Dunger D. B. , Conway G. S. , Wass J. A. H. 
Published: January 2014

AbstractTurner’s syndrome is the most common chromosomal abnormality in females, affecting 1:2,500 live female births. It is a result of absence of an X chromosome or the presence of a structurally abnormal X chromosome. Its most consistent clinical features are short stature and ovarian failure. However, it is becoming increasingly evident that adults with Turner’s syndrome are also susceptible to a range of disorders, including osteoporosis, hypothyroidism, and renal and gastrointestinal disease. Women with Turner’s syndrome have a reduced life expectancy, and recent evidence suggests that this is due to an increased risk of aortic dissection and ischemic heart disease. Up until recently, women with Turner’s syndrome did not have access to focused health care, and thus quality of life was reduced in a significant number of women. All adults with Turner’s syndrome should therefore be followed up by a multidisciplinary team to improve life expectancy and reduce morbidity.
Sex Steroids and the Construction and Conservation of the Adult Skeleton
Authors: Riggs B. Lawrence , Khosla Sundeep , Melton L. Joseph 
Published: January 2014

AbstractHere we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4–8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.
Infants of Women with Polycystic Ovary Syndrome have Lower Cord Blood Androstenedione and Estradiol Levels
Authors: Anderson Helen , Fogel Naomi , Grebe Stefan K. , Singh Ravinder J. , Taylor Robert L. , Dunaif Andrea 
Published: January 2014

ABSTRACT

Context
Prenatal androgen excess can cause a phenocopy of polycystic ovary syndrome (PCOS) in mammals. Retrospective studies have suggested that girls at risk for PCOS have low birth weight and prospective studies have suggested an increased prevalence of small for gestational age offspring in women with PCOS.

Objective
To determine whether infants of women with PCOS have reduced birth weight or increased intrauterine androgen levels.

Design
Prospective case-control study.

Participants
Thirty-nine PCOS and 31 control women and their infants.

Main outcome measures
Birth weight and mixed cord blood testosterone, androstenedione (A), dehydroepiandrosterone, 17-hydroxyprogesterone, estradiol (E2), and dihydrotestosterone levels.

Results
Mean birth weight did not differ but there was a significant increase in the prevalence of large for gestational age infants in the PCOS group. Cord blood E2 and A levels were lower (p &lt; 0.05) but testosterone:E2 ratios did not differ in female PCOS compared to control offspring. There was no difference in E2 and A levels in the male PCOS and control offspring. There was no difference in 17-hydroxyprogesterone or in other androgen levels in either male or female PCOS offspring compared to their respective control group.

Conclusion
Infants of women with PCOS were more likely to be large for gestational age. Female offspring of affected women have lower cord blood A levels; other cord blood androgen levels do not differ compared to female control offspring. Cord blood E2 levels are also significantly decreased in PCOS, without any difference in the testosterone:E2 ratio, suggesting decreased fetal or placental production of steroids.
Endocrine and Physiological Changes in Response to Chronic Corticosterone: A Potential Model of the Metabolic Syndrome in Mouse
Authors: Karatsoreos Ilia N. , Bhagat Sarah M. , Bowles Nicole P. , Weil Zachary M. , Pfaff Donald W. , McEwen Bruce S. 
Published: January 2014

ABSTRACT
Numerous clinical and experimental studies have linked stress to changes in risk factors associated with the development of physiological syndromes, including metabolic disorders. How different mediators of the stress response, such as corticosterone (CORT), influence these changes in risk remains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure can result in damage to the physiological systems it protects acutely. Disruption of this important physiologic signal is observed in numerous disparate disorders, ranging from depression to Cushing’s syndrome. Thus, understanding the effects of chronic high CORT on metabolism and physiology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in the drinking water on the physiology and behavior of male mice. We used this approach as a noninvasive way of altering plasma CORT levels, whereas retaining some integrity in the diurnal rhythm present in normal animals. This approach has advantages over methods involving constant CORT pellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 μg/ml) result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and decreased home-cage locomotion. A lower dose of CORT (25 μg/ml) resulted in an intermediate phenotype in some of these measures, whereas having no effect on others. We propose that the physiological changes observed in the high-CORT animals approximate changes observed in individuals suffering from the metabolic syndrome and that they potentially serve as a model for hypercortisolemia and stress-related obesity.
Lower Brain-Derived Neurotrophic Factor in Patients with Prader-Willi Syndrome Compared to Obese and Lean Control Subjects
Authors: Han Joan C. , Muehlbauer Michael J. , Cui Huaxia N. , Newgard Christopher B. , Haqq Andrea M. 
Published: January 2014

ABSTRACT

Context
Brain-derived neurotrophic factor (BDNF) haploinsufficiency is associated with hyperphagia and obesity in both animals and humans. BDNF appears to function downstream of the leptin-melanocortin signaling pathway to control energy balance. The potential role of BDNF in the etiology of the severe hyperphagia associated with PWS has not been previously explored.

Objective
The aim was to compare BDNF concentrations in subjects with PWS and obese controls (OC) and lean controls (LC).

Design and Setting
We conducted a cross-sectional study at an outpatient clinical research center.

Participants
We studied 13 subjects with PWS [five males and eight females; mean ± sd: age, 11.0 ± 4.1 yr; body mass index (BMI)-Z, 2.05 ± 0.78], 13 OC (eight females, five males; age, 12.3 ± 2.7 yr; BMI-Z, 2.18 ± 0.61), and 13 LC (six females, seven males; age, 12.4 ± 2.6 yr; BMI-Z, −0.57 ± 0.73).

Main Outcome Measure
BDNF was measured in serum and plasma by ELISA. Analysis of covariance adjusted for age, sex, and BMI-Z.

Results
All groups were comparable for age (P = 0.50) and sex distribution (P = 0.49). BMI-Z was comparable between PWS and OC (P = 0.89) and lower in LC (P &lt; 0.001). Adjusted serum BDNF was comparable (P = 0.35) in OC (mean ± sem: 13.5 ± 1.2 ng/ml) and LC (19.2 ± 1.3 ng/ml), but lower in PWS (8.3 ± 1.2 ng/ml; P = 0.01 vs. OC; P = 0.03 vs. LC). Adjusted plasma BDNF in PWS (217 ± 130 pg/ml) was lower than OC (422 ± 126 pg/ml; P = 0.02), but statistically comparable with LC (540 ± 143 pg/ml; P = 0.10).

Conclusions
Lower BDNF in PWS suggests insufficient central BDNF production because BDNF in peripheral circulation is believed to reflect cerebral BDNF output. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. Further studies are needed to confirm this preliminary pilot study in a larger cohort of patients with PWS.
A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone Receptor
Authors: Neumann Susanne , Huang Wenwei , Eliseeva Elena , Titus Steve , Thomas Craig J. , Gershengorn Marvin C. 
Published: January 2014

ABSTRACT
Small molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1, 2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of principle that small, drug-like molecules can inhibit basal signaling by TSHR. We suggest that this small molecule is a lead compound for the development of higher-potency inverse agonists that can be used as probes of TSHR biology with therapeutic potential.
Polymorphism in Vitamin D-Binding Protein as a Genetic Risk Factor in the Pathogenesis of Endometriosis
Authors: Faserl Klaus , Golderer Georg , Kremser Leopold , Lindner Herbert , Sarg Bettina , Wildt Ludwig , Seeber Beata 
Published: January 2014

Context
Previous studies have implicated a deficiency in the inflammatory response in women who develop endometriosis. The specific immunological deficits have not been completely elucidated.

Objective
Our objective was to identify differences in protein expression in serum that might shed light on the pathophysiology of endometriosis.

Design and Setting
This cross-sectional study of women undergoing laparoscopy between 2003 and 2005 took place at a university medical center.

Patients
Patients included consenting women age 18-49 yr undergoing surgery for pain and/or infertility or elective tubal ligation. Women with acute or chronic medical conditions were excluded.

Intervention
Blood was collected preoperatively.

Main Outcome Measure
Proteomic analysis of serum was done using two-dimensional difference gel electrophoresis.

Results
We found 25 protein spots with a significant difference in abundance between women with endometriosis and controls, including acute-phase proteins and complement components. The abundance of vitamin D-binding protein was higher in all endometriosis pools by a factor of approximately 3 compared with the control pool (P &lt; 0.02). Analysis of specific allele products using nano-LC-ESI-MS indicated that it was the GC*2 allele product that was in greater concentration in serum pools, as well as in single validation samples, in women with endometriosis (P = 0.006). In contrast to the GC*1 allele product, which is readily converted to a potent macrophage factor (Gc protein-derived macrophage-activating factor), the GC*2 allele product undergoes practically no such conversion.

Conclusions
We speculate that the inability to sufficiently activate macrophages’ phagocytotic function in those carrying the GC*2 polymorphism (more prevalent in endometriosis) may allow endometriotic tissues to implant in the peritoneal cavity. Future studies evaluating specific vitamin D-binding protein polymorphisms as a risk factor for endometriosis in larger populations of women are warranted.
Fibroblast Growth Factor-2 Supports ex Vivo Expansion and Maintenance of Osteogenic Precursors from Human Bone Marrow*
Authors: Martin Ivan , Muraglia Anita , Campanile Giuliano , Cancedda Ranieri , Quarto Rodolfo 
Published: January 2014

AbstractWe have investigated the effects of different growth factors on the proliferation and osteogenic potential of primary cultures of human bone marrow stromal cells (BMSC). Fibroblast growth factor (FGF)-2 was the most effective in promoting growth of these cells in vitro. The size of colonies formed in clonal conditions was approximately 2.5 times larger in presence of FGF-2. Also the morphology of BMSC was affected: cells cultured in 10% FCS alone became flattened, whereas FGF-2 expanded cells maintained a fibroblast-like elongated phenotype. Levels of alkaline phosphatase activity in BMSC expanded with FGF-2 were significantly lower (56%) than control and, after stimulation with ascorbic acid,β Glycerophosphate and dexamethasone, FGF-2 expanded BMSC deposited approximately 3-fold more mineralized matrix than control cells. We have assessed osteogenicity of BMSC on hydroxyapatite porous scaffolds (bioceramics) by an ectopic bone formation assay. FGF-2 expanded BMSC yielded a higher bone formation (&gt;20-fold) than control cells. We conclude that FGF-2, promoting BMSC proliferation, maintains cells in a more immature state allowing in vitro expansion of human osteo-progenitors which, associated with bioceramics, can differentiate in vivo and form bone tissue.
Hepatocyte Growth Factor Regulates Ovarian Theca-Interstitial Cell Differentiation and Androgen Production*
Authors: Zachow Rob J. , Weitsman Stacy R. , Magoffin Denis A. 
Published: January 2014

AbstractDuring ovarian follicle growth, precise regulation of the onset of androgen production by ovarian theca-interstitial cells (TIC) is necessary for maintaining follicle viability. Thus, temporary suppression of TIC androgen production in preantral follicles is the key to promoting follicle development. Evidence indicates that this process is coordinated via intraovarian growth factors. Hepatocyte growth factor (HGF) can induce granulosa cell (GC) proliferation and suppress follicular atresia, indicating a role for HGF in promoting follicle growth and viability. To determine whether HGF could reversibly suppress androgen production, this study investigated the effect of HGF on TIC differentiation and steroid production. Twenty-six-day-old rats were used in all studies. HGF messenger RNA (mRNA) expression in TIC and GC was determined by reverse transcription-PCR. Agarose gel electrophoresis of the PCR products yielded a single band corresponding to the 290-bp HGF product for both TIC and GC. HGF expression in cultured TIC and GC was not blocked by gonadotropins or HGF. To investigate the effects of HGF on TIC steroidogenesis, TIC were isolated from the ovaries of hypophysectomized rats. TIC (3.0 × 104 cells/well) were cultured with LH (0–3 ng/ml) and/or HGF (0–100 ng/ml) for 48 h, and androsterone levels were measured by RIA. HGF did not alter androsterone levels in the absence of LH; however, HGF reversibly impaired LH-dependent androsterone production by as much as 57% (IC50 = 1.5 ± 0.01 ng/ml). LH (0.3 ng/ml) stimulated progesterone (P4) synthesis by TIC (1201 ± 190 pg/ml) compared to that by control cells (210 ± 30 pg/ml). HGF stimulated basal P4 production, and LH-dependent P4 synthesis was augmented 2.6-fold by HGF (ED50 = 0.3 ± 0.01 ng/ml). The DNA content and cell viability in TIC cultures were not affected by HGF. The effect of HGF on steroidogenic enzyme gene expression in TIC was also investigated via PCR. HGF did not alter the level of basal or LH-induced P450 side-chain cleavage and 3β-hydroxysteroid dehydrogenase mRNAs; however, LH-dependent P45017α hydroxylase/C17,20 lyase mRNA content was reduced 4.5-fold in the presence of HGF. Thus, HGF is expressed in both TIC and GC obtained from the immature rat ovary, suggesting its presence in growing follicles. In TIC, HGF stimulated P4 synthesis, but impaired androgen production, concurrent with a down-regulatory effect on P45017α hydroxylase/C17,20 lyase gene expression. Collectively, these results indicate that HGF reversibly impairs LH-stimulated androgen production in TIC. Such effects may help promote folliculogenesis.
Inhibition by Interleukin-1β and Tumor Necrosis Factor-α of the Insulin-Like Growth Factor I Messenger Ribonucleic Acid Response to Growth Hormone in Rat Hepatocyte Primary Culture*
Authors: Thissen Jean-Paul , Verniers Josiane 
Published: January 2014

AbstractThe cytokines are the putative mediators of the catabolic reaction that accompanies infection and trauma. Evidence suggests that their catabolic actions are indirect and potentially mediated through changes in hormonal axis such as the hypothalamo-pituitary-adrenal axis. Insulin-like growth factor I (IGF-I) is a GH-dependent growth factor that regulates the protein metabolism. To determine whether cytokines can directly inhibit the production of IGF-I by the liver, we investigated the regulation of IGF-I gene expression by interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (10 ng/ml) in a model of rat primary cultured hepatocytes. Hepatocytes were isolated by liver collagenase perfusion and cultured on Matrigel 48 h before experiments. Each experiment was performed in at least three different animals. In the absence of GH, IL-1β and TNF-α did not affect the IGF-I messenger RNA (mRNA) basal levels, whereas IL-6 increased it by a factor of 2.5 after 24 h (P &lt; 0.05). GH (500 ng/ml) alone stimulated the IGF-I gene expression markedly (5- to 10-fold increase) after 24 h (P &lt; 0.001). IL-1β, and TNF-α to a lesser extent, dramatically inhibited the IGF-I mRNA response to GH (IL-1β: −82%, P &lt; 0.001 and TNF-α: −47%, P &lt; 0.01). The half-maximal inhibition of the IGF-I mRNA response to GH was observed for a concentration of IL-1β between 0.1 and 1 ng/ml. Moreover, IL-1β abolished the IL-6-induced IGF-I mRNA response. In contrast, IL-6 did not impair the IGF-I mRNA response to GH. To determine the potential role of the GH receptor (GHR) and the GH-binding protein (GHBP) in this GH resistance, we assessed the GHR and GHBP mRNAs response to these cytokines. GH alone did not affect the GHR/GHBP mRNA levels. IL-1β markedly decreased the GHR and GHBP mRNA levels (respectively, −68% and −60%, P &lt; 0.05). Neither TNF-α nor IL-6 affected the GHR/GHBP gene expression. In conclusion, our results show that IL-1β, and TNF-α to a lesser extent, blunt the IGF-I mRNA response to GH. The resistance to GH induced by IL-1β might be mediated by a decrease of GH receptors, as suggested by the marked reduction of GHR mRNA. These findings suggest that decreased circulating IGF-I, in response to infection and trauma, may be caused by a direct effect of cytokines at the hepatocyte level.