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Permanent Endocrinology Job in Easton Pennsylvania with Community Health Systems
Strong opportunity for Endocrinologist Easton Hospital is searching for an Endocrinologist to develop a private practice with support from the hospital, or, to join an existing practice in the area.
Permanent Endocrinology Job in Coatesville Pennsylvania with Community Health Systems
Coatesville, PA, located west of Philadelphia Seeking BC/BE Endocrinologist to join an exisitng multi-specialty group with two other endocrinologists. Coatesville is located just 35 miles west of Philadelphia
Permanent Endocrinology Job in San Angelo Texas with Community Health Systems
Excellent opportunity to offer a new service to the community! San Angelo Community Medical Center is searching for a BC/BE endocrinologist to start a practice in the community. With a population of
Current Opinion in Endocrinology, Diabetes and Obesity - Current Table Of Contents
Editorial introductions.
Page: viiDOI: 10.1097/MED.0b013e32831c7004
Pharmacogenetics of osteoporosis and the prospect of individualized prognosis and individualized therapy.
Page: 481DOI: 10.1097/MED.0b013e32831a46beAuthors: Nguyen, Tuan V; Center, Jacqueline R; Eisman, John A
Assessment of vitamin D status and definition of a normal circulating range of 25-hydroxyvitamin D.
Page: 489DOI: 10.1097/MED.0b013e328317ca6cAuthors: Hollis, Bruce W
PubMed: 0013-7227
The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques.
Nguyen AD, Corbin CJ, Pattison JC, Bird IM, Conley AJ Related Articles The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques. Endocrinology. 2008 Nov 26; Authors: Nguyen AD, Corbin CJ, Pattison JC, Bird IM, Conley AJ Adrenarche is thought to be experienced only by humans and some Old World primates despite observed regression of an adrenal fetal zone (FZ) and establishment of a functional zona reticularis (ZR) in other species like rhesus macaques. Adrenal differentiation remains poorly defined biochemically in non-human primates. The present studies defined ZR development in the neonatal rhesus by examining androgen synthetic capacity and factors affecting it in rhesus and marmoset adrenals. Western immunoblots examined expression of 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3beta-hydroxysteroid dehydrogenase (3betaHSD), among other key enzymes. 17,20-lyase activity was quantified in adrenal microsomes, as was the contribution of b5 to 17,20-lyase activity in microsomes and cell transfection experiments with rhesus and marmoset P450c17. Expression of b5 increased from birth to 3 months and was positively correlated with age and 17,20-lyase activity in the rhesus. Recombinant b5 addition stimulated 17,20-lyase activity to an extent inversely proportional to endogenous levels in adrenal microsomes. Although 3betaHSD expression also increased with age, P450c17, 21-hydroxylase cytochrome P450 and the redox partner, NADPH-cytochrome P450 oxidoreductase (CPR) did not; nor did recombinant CPR augment 17,20-lyase activity. Co-transfection with b5 induced a dose-dependent increase in DHEA synthesis by both non-human primate P450c17 enzymes. We conclude that the increase in 17,20-lyase activity characteristic of an adrenarche in rhesus macaques is driven primarily by increased b5 expression, without the need for a decrease in 3betaHSD, as suggested from human studies. The rhesus macaque is a relevant and accessible model for human ZR development and adrenal function. PMID: 19036885 [PubMed - as supplied by publisher]
An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues.
Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, Nguyen V, Lazarus JE, Nilsson O, Baron J Related Articles An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues. Endocrinology. 2008 Nov 26; Authors: Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, Nguyen V, Lazarus JE, Nilsson O, Baron J Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified >1600 genes that were regulated with age (1 versus 4 weeks) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly downregulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and that the decreasing expression with age was due to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0-5 weeks of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size. PMID: 19036884 [PubMed - as supplied by publisher]
Type 2 deiodinase expression is induced by PPAR-{gamma} agonists in skeletal myocytes.
Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW Related Articles Type 2 deiodinase expression is induced by PPAR-{gamma} agonists in skeletal myocytes. Endocrinology. 2008 Nov 26; Authors: Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW The thyroid hormone activating type 2 deiodinase (D2) is known to play a role in brown adipose tissue mediated adaptive thermogenesis in rodents, but the finding of D2 in skeletal muscle raises the possibility of a broader metabolic role. In the current study, we examined the regulation of the D2 pathway in primary skeletal muscle myoblasts taken from both humans and mice. We found that pioglitazone treatment led to a 1.6 to 1.9-fold increase in primary human skeletal myocyte D2 activity; this effect was seen with other PPAR-gamma agonists. D2 activity in primary murine skeletal myotubes increased 2.8 fold in response to 5uM pioglitazone and 1.6 fold in response to 5nM insulin, and increased in a dose-dependent manner in response to lithocholic acid (maximum response at 25microM was approximately 3.8 fold). We compared Akt phosphorylation in primary myotubes derived from wild type and D2 knock-out mice: phospho-Akt was reduced by 50% in the D2KO muscle following 1nM insulin exposure. Expression of T3-responsive muscle genes via RT-qPCR suggests that D2KO cells have decreased thyroid hormone signaling, which could contribute to the abnormalities in insulin signaling. D2 activity in skeletal muscle fragments from both murine and human sources was low, on the order of approximately 0.01 fmol/min/mg of muscle protein. The phenotypic changes seen with D2KO cells support a metabolic role for D2 in muscle, hinting at a D2-mediated linkage between thyroid hormone and insulin signaling, but the low activity calls into question whether skeletal muscle D2 is a major source of plasma T3. PMID: 19036883 [PubMed - as supplied by publisher]
Prolactin receptor is required for normal glucose homeostasis and modulation of {beta}-cell mass during pregnancy.
Huang C, Snider F, Cross JC Related Articles Prolactin receptor is required for normal glucose homeostasis and modulation of {beta}-cell mass during pregnancy. Endocrinology. 2008 Nov 26; Authors: Huang C, Snider F, Cross JC Increased islet mass is an adaptive mechanism which occurs to combat insulin resistance during pregnancy. Prolactin (PRL) can enhance beta-cell proliferation and insulin secretion in vitro yet whether it is PRL or other pregnancy-related factors that mediate these adaptive changes during pregnancy is unknown. The objective of this study was to determine whether prolactin receptor (Prlr) is required for normal maternal glucose homeostasis during pregnancy. Intraperitoneal glucose tolerance test was performed on timed-pregnant Prlr(+/+) and heterozygous null Prlr(+/-) mice on days 0, 15, and 18 of pregnancy. Compared with Prlr(+/+) mice, Prlr(+/-) mice had impaired glucose clearance, decreased glucose-stimulated insulin release, higher non-fasted blood glucose and lower insulin levels during but not before pregnancy. There was no difference in their insulin tolerance. Prlr(+/+) mice show a significant incremental increase in islet density, beta-cell number and mass throughout pregnancy, which was attenuated in the Prlr(+/-) mice. Prlr(+/+) mice also had a more robust beta-cell proliferation rate during pregnancy, while there was no difference in apoptosis rate between the Prlr(+/+) and Prlr(+/-) mice before, during, or after pregnancy. Interestingly, genotype of the mothers had a significant impact on the offspring's phenotype, such that daughters derived from Prlr(+/-) mothers had a more severe phenotype than those derived from Prlr(+/+) mothers. In conclusion, this is the first in vivo demonstration that the action of pregnancy hormones, acting through Prlr, is required for normal maternal glucose tolerance during pregnancy by increasing beta-cell mass. PMID: 19036882 [PubMed - as supplied by publisher]
Role of c-Myb during PRL-induced Stat5a signaling in breast cancer cells.
Fang F, Rycyzyn MA, Clevenger CV Related Articles Role of c-Myb during PRL-induced Stat5a signaling in breast cancer cells. Endocrinology. 2008 Nov 26; Authors: Fang F, Rycyzyn MA, Clevenger CV Implicated in the pathogenesis of breast cancer, prolactin (PRL) mediates its function in part through the prolactin receptor (PRLr)-associated Jak2/Stat5 signaling complex. To delineate the mechanisms of Stat5a regulation in breast cancer, transcription factor-transcription factor (TF-TF) array analysis was employed to identify associated transcriptional regulators. These analyses revealed a PRL-inducible association of Stat5a with the transcription factor and proto-oncogene c-Myb. Confirmatory co-immunoprecipitation studies using lysates from both T47D and MCF7 breast cancer cells revealed an PRL-inducible association between these transcription factors. Ectopic expression of c-Myb enhanced the PRL-induced expression from both composite and synthetic Stat5a-responsive luciferase reporters. Chromatin immunoprecipitation (ChIP) assays also revealed a PRL-inducible association between c-Myb and endogenous Stat5a-responsive CISH promoter, which was associated with an enhanced expression of CISH gene product at the RNA and protein levels. SiRNA-mediated c-Myb knockdown impaired the PRL-induced mRNA expression of five Stat5-responsive genes. DNA binding-defective mutants of c-Myb, incapable of activating expression from a c-Myb-responsive reporter, maintained their ability to enhance a Stat5a-responsive reporter. At a cellular level, ectopic expression of c-Myb resulted in an increase in T47D proliferation. Taken together, these results indicate that c-Myb potentiates Stat5a-driven gene expression, possibly functioning as a Stat5a co-activator, in human breast cancer. PMID: 19036881 [PubMed - as supplied by publisher]
HEXOSAMINE BIOSYNTHESIS PATHWAY FLUX CONTRIBUTES TO INSULIN RESISTANCE VIA ALTERING MEMBRANE PIP2 AND CORTICAL F-ACTIN.
Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS Related Articles HEXOSAMINE BIOSYNTHESIS PATHWAY FLUX CONTRIBUTES TO INSULIN RESISTANCE VIA ALTERING MEMBRANE PIP2 AND CORTICAL F-ACTIN. Endocrinology. 2008 Nov 26; Authors: Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS We recently found that plasma membrane (PM) phosphatidylinositol 4,5 bisphosphate (PIP2)-regulated filamentous actin (F-actin) polymerization was diminished in hyperinsulinemic cell culture models of insulin resistance. Here we delineated if increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes the PIP2/F-actin dysregulation and insulin resistance induced by hyperinsulinemia. Increased HBP activity was detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nM Ins; 12 h) and in cells where HBP activity was amplified by 2 mM glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP2 and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP2 corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP2/F-actin structure, inhibition of the rate-limiting HBP enzyme (GFAT, glutamine:fructose-6-phosphate amidotransferase) restored PIP2-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of GFAT was associated with a loss of detectable PM PIP2 and insulin sensitivity. A slight decrease in intracellular ATP resulted from amplifying HBP by hyperinsulinemia and GlcN. However, experimental maintenance of the intracellular ATP pool under both conditions with inosine did not reverse the PIP2/F-actin-based insulin-resistant state. Furthermore, less invasive challenges with glucose, in the absence of insulin, also led to PIP2/F-actin dysregulation. Accordingly, we suggest that the functionality of cell systems dependent on PIP2 and/or F-actin status, such as the glucose transport system, can be critically compromised by inappropriate HBP activity. PMID: 19036880 [PubMed - as supplied by publisher]
Conditional inactivation of glucocorticoid receptor gene in dopamine-b-hydroxylase cells impairs chromaffin cell survival.
Parlato R, Otto C, Tuckermann J, Stotz S, Kaden S, Gröne HJ, Unsicker K, Schütz G Related Articles Conditional inactivation of glucocorticoid receptor gene in dopamine-b-hydroxylase cells impairs chromaffin cell survival. Endocrinology. 2008 Nov 26; Authors: Parlato R, Otto C, Tuckermann J, Stotz S, Kaden S, Gröne HJ, Unsicker K, Schütz G Glucocorticoid hormones (GCs) have been thought to determine the fate of chromaffin cells from sympathoadrenal progenitor cells. The analysis of mice carrying a germline deletion of the glucocorticoid receptor (GR) gene has challenged these previous results since the embryonic development of adrenal chromaffin cells is largely unaltered. In the present study, we have analyzed the role of GC-dependent signaling in postnatal development of adrenal chromaffin cells by conditional inactivation of the GR gene in cells expressing dopamine-beta-hydroxylase, an enzyme required for the synthesis of noradrenaline and adrenaline. These mutant mice are viable, allowing to study whether in absence of GC signaling further development of the adrenal medulla is affected. Our analysis shows that loss of GR leads not only to loss of phenylethanolamine-N-methyl-transferase (PNMT) expression and therefore to inhibition of adrenaline synthesis, but also to a dramatic reduction in the number of adrenal chromaffin cells. We provide evidence that increased apoptotic cell death is the main consequence of GR loss. These findings define the essential role of GCs for survival of chromaffin cells and underscore the specific requirement of GCs for adrenergic chromaffin cell differentiation and maintenance. PMID: 19036879 [PubMed - as supplied by publisher]
Impaired bacterial clearance in type 3 deiodinase deficient mice infected with Streptococcus pneumoniae.
Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A Related Articles Impaired bacterial clearance in type 3 deiodinase deficient mice infected with Streptococcus pneumoniae. Endocrinology. 2008 Nov 26; Authors: Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A The activation of type 3 deiodinase (D3) has been postulated to play a role in the reduction of thyroid hormone levels during illness. Using a mouse model of acute bacterial infection, we have recently demonstrated marked D3 immunostaining in neutrophils infiltrating infected organs. These observations suggest a possible additional role for this enzyme in the innate immune response. To further assess the role of D3 in the response to acute bacterial infection, we used null D3 (D3KO) and wild type (WT) mice and infected them with Streptococcus (S). pneumoniae. Marked reductions in serum thyroid hormone levels were observed both in D3KO and WT mice. Infection resulted also in a decrease in liver D1 activity in WT, but not in infected D3KO mice. Upon infection, pulmonary neutrophilic influx (measured by MPO levels), IL-6 and TNF concentrations increased equally in D3KO and WT mice and histological examination of infected mice showed similar pulmonary inflammation in both strains. However, D3KO animals demonstrated significantly higher bacterial load in blood, lung and spleen compared to WT mice. We conclude that: 1) D3 is not required to generate the systemic manifestations of the nonthyroidal illness (NTI) syndrome in this model. 2) The lack of D3 does not affect the extent of pulmonary inflammation and 3) Bacterial outgrowth in blood, spleen and lung of D3KO mice is significantly higher than in WT mice. Our results suggest a protective role for D3 in the defence against acute bacterial infection probably by reinforcing the microbial killing capacity of neutrophils. PMID: 19036878 [PubMed - as supplied by publisher]
Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption.
Keay J, Thornton JW Related Articles Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption. Endocrinology. 2008 Nov 26; Authors: Keay J, Thornton JW As the primary mediators of estrogen signaling in vertebrates, estrogen receptors (ERs) play crucial roles in reproduction, development, and behavior. They are also the major mediators of endocrine disruption - health impairment by xenobiotic pollutants that mimic or block estrogen action. ERs that are sensitive to estrogen and endocrine disrupters have long been thought to be restricted to vertebrates: although there is evidence for estrogen signaling in invertebrates, the only ERs studied to date - from mollusks and cephalochordates - have been insensitive to estrogen and therefore incapable of mediating estrogen signaling or disruption. To determine whether estrogen-sensitivity is ancestral or a unique characteristic of vertebrate ERs, we isolated and characterized ERs from two annelids, Platynereis dumerilii and Capitella capitata, because annelids are the sister phylum to mollusks and have been shown to produce and respond to estrogens. Functional assays show that annelid ERs specifically activate transcription in response to low estrogen concentrations and bind estrogen with high affinity. Further, numerous known endocrine-disrupting chemicals activate or antagonize the annelid ER. This is the first report of a hormone-activated invertebrate estrogen receptor. Our results indicate that estrogen signaling via the ER is as ancient as the ancestral bilaterian animal and corroborate the estrogen-sensitivity of the ancestral steroid receptor. They suggest that the taxonomic scope of endocrine disruption by xenoestrogens may be very broad and reveal how functional diversity evolved in a gene family central to animal endocrinology. PMID: 19036877 [PubMed - as supplied by publisher]
PubMed: 0804-4643
Glycodelin in reproductive endocrinology and hormone-related cancer.
Seppala M, Koistinen H, Koistinen R, Hautala L, Chiu P, Yeung W Related Articles Glycodelin in reproductive endocrinology and hormone-related cancer. Eur J Endocrinol. 2008 Nov 27; Authors: Seppala M, Koistinen H, Koistinen R, Hautala L, Chiu P, Yeung W ABSTRACT Glycodelin is an endocrine-regulated glycoprotein that has significant effects on immune cells, apoptosis, reproduction, cell adhesion, differentiation and cancer. In reproduction, glycodelin contributes to capacitation and immunoprotection of spermatozoa, and it modulates sperm-oocyte binding, acrosome reaction and implantation. In endocrine-related cancer, the differentiation inducing effects of glycodelin are accompanied by growth restriction of malignant cells, decreased expression of oncogenes, increased expression of tumor suppressor genes, and morphological reversion of the malignant phenotype. This review features these properties and clinical connections, highlighting the role of glycosylation in biological actions. PMID: 19039086 [PubMed - as supplied by publisher]
Growth response to an individualized versus fixed dose growth hormone (GH) treatment in short children born small for gestational age (SGA): the OPTIMA study.
Jung H, Land C, Nicolay C, De Schepper J, Blum W, Schoenau E Related Articles Growth response to an individualized versus fixed dose growth hormone (GH) treatment in short children born small for gestational age (SGA): the OPTIMA study. Eur J Endocrinol. 2008 Nov 27; Authors: Jung H, Land C, Nicolay C, De Schepper J, Blum W, Schoenau E Objective: Initial GH-induced catch-up growth is highly variable in short children born SGA and mainly influenced by age at start of therapy and GH dose. This study compared the first-year growth-promoting effect of an individually adjusted GH dose (IAD) versus a fixed high GH dose (FHD) in pre-pubertal children born SGA with severe short stature. Design: This was a randomized, open-label, multi-centre study. Methods: The FHD group received GH at 0.067mg/kg/day throughout the 12-month study. The IAD group initially received 0.035mg/kg/day GH; at 3 months the Cologne growth-prediction model for first-year change in height SDS was applied; if predicted change was <0.75, GH was increased to 0.067mg/kg/day for the remaining 9 months, otherwise the initial dose was continued. Results: In the IAD group, 38 of 80 patients required the higher GH dose from month 3. From an ANCOVA for non-inferiority, mean difference in change in height SDS between IAD and FHD groups was -0.24 (95%CI -0.35: -0.12), the CI for height SDS being above the pre-defined non-inferiority margin of -0.5. GH dose reductions due to IGF-I SDS >0.5 and IGFBP-3 SDS < -0.5 were performed in 4/99 FHD patients, but none of the IAD group patients. Safety data were similar between groups. Conclusion: With a mean treatment group difference of 1cm in 12-month growth response, although statistically significant, the IAD group was considered non-inferior compared to the FHD group. Early growth-prediction can be used to tailor the dose to the individual patient's needs resulting in lower overall GH dose. PMID: 19039085 [PubMed - as supplied by publisher]
Adiponectin is associated with low bone mineral density in elderly men.
Maria Lourdes B, Galvan R, Cordova N, Saucedo R, Vargas C, Campos S, Halley E, Avelar F, Zarate A Related Articles Adiponectin is associated with low bone mineral density in elderly men. Eur J Endocrinol. 2008 Nov 27; Authors: Maria Lourdes B, Galvan R, Cordova N, Saucedo R, Vargas C, Campos S, Halley E, Avelar F, Zarate A Objective. Recent evidence suggest that adiponectin may play a role in bone metabolism. Previous studies demonstrated that adiponectin levels had a negative correlation with bone mineral density (BMD) in women. However, little is known about the relationship between adiponectin and BMD in men. The aim of this study was to determinate the relationship between adiponectin levels and BMD in elderly men. Design. Cross-sectional study including 92 healthy men aged 60 to 80 years. Methods. Main outcome measures were adiponectin levels estimated by radioimmunoassay and bone mineral density (BMD) at lumbar spine and femoral neck using dual energy X-ray absorptiometry. Results. The negative correlation between adiponectin and BMD at the spine was r= -0.209, (p <0.05) and at the femoral neck was r= -0.237, (p <0.001). These correlations disappeared after adjustment for BMI. When stratified by BMI, the relationship between BMD and adiponectin remained significant in the subgroup of participants with BMI >27 kg/m2, but disappeared in men with BMI <27 kg/m2. In multiple regression analysis, adiponectin was a significant determinant of BMD at the spine, not at femoral neck, in those with BMI >27. Conclusion. BMD is negatively associated with adiponectin levels in men older than 60 years and this relationship is greater in those men with BMI above 27, which suggests a plausible connection between bone and fat tissue. PMID: 19039084 [PubMed - as supplied by publisher]
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Permanent Endocrinology Job in Easton Pennsylvania with Community Health Systems
Strong opportunity for Endocrinologist Easton Hospital is searching for an Endocrinologist to develop a private practice with support from the hospital, or, to join an existing practice in the area.
Permanent Endocrinology Job in Coatesville Pennsylvania with Community Health Systems
Coatesville, PA, located west of Philadelphia Seeking BC/BE Endocrinologist to join an exisitng multi-specialty group with two other endocrinologists. Coatesville is located just 35 miles west of Philadelphia
Permanent Endocrinology Job in San Angelo Texas with Community Health Systems
Excellent opportunity to offer a new service to the community! San Angelo Community Medical Center is searching for a BC/BE endocrinologist to start a practice in the community. With a population of
Current Opinion in Endocrinology, Diabetes and Obesity - Current Table Of Contents
Editorial introductions.
Page: viiDOI: 10.1097/MED.0b013e32831c7004
Pharmacogenetics of osteoporosis and the prospect of individualized prognosis and individualized therapy.
Page: 481DOI: 10.1097/MED.0b013e32831a46beAuthors: Nguyen, Tuan V; Center, Jacqueline R; Eisman, John A
Assessment of vitamin D status and definition of a normal circulating range of 25-hydroxyvitamin D.
Page: 489DOI: 10.1097/MED.0b013e328317ca6cAuthors: Hollis, Bruce W
PubMed: 0013-7227
The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques.
Nguyen AD, Corbin CJ, Pattison JC, Bird IM, Conley AJ Related Articles The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques. Endocrinology. 2008 Nov 26; Authors: Nguyen AD, Corbin CJ, Pattison JC, Bird IM, Conley AJ Adrenarche is thought to be experienced only by humans and some Old World primates despite observed regression of an adrenal fetal zone (FZ) and establishment of a functional zona reticularis (ZR) in other species like rhesus macaques. Adrenal differentiation remains poorly defined biochemically in non-human primates. The present studies defined ZR development in the neonatal rhesus by examining androgen synthetic capacity and factors affecting it in rhesus and marmoset adrenals. Western immunoblots examined expression of 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3beta-hydroxysteroid dehydrogenase (3betaHSD), among other key enzymes. 17,20-lyase activity was quantified in adrenal microsomes, as was the contribution of b5 to 17,20-lyase activity in microsomes and cell transfection experiments with rhesus and marmoset P450c17. Expression of b5 increased from birth to 3 months and was positively correlated with age and 17,20-lyase activity in the rhesus. Recombinant b5 addition stimulated 17,20-lyase activity to an extent inversely proportional to endogenous levels in adrenal microsomes. Although 3betaHSD expression also increased with age, P450c17, 21-hydroxylase cytochrome P450 and the redox partner, NADPH-cytochrome P450 oxidoreductase (CPR) did not; nor did recombinant CPR augment 17,20-lyase activity. Co-transfection with b5 induced a dose-dependent increase in DHEA synthesis by both non-human primate P450c17 enzymes. We conclude that the increase in 17,20-lyase activity characteristic of an adrenarche in rhesus macaques is driven primarily by increased b5 expression, without the need for a decrease in 3betaHSD, as suggested from human studies. The rhesus macaque is a relevant and accessible model for human ZR development and adrenal function. PMID: 19036885 [PubMed - as supplied by publisher]
An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues.
Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, Nguyen V, Lazarus JE, Nilsson O, Baron J Related Articles An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues. Endocrinology. 2008 Nov 26; Authors: Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, Nguyen V, Lazarus JE, Nilsson O, Baron J Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified >1600 genes that were regulated with age (1 versus 4 weeks) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly downregulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and that the decreasing expression with age was due to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0-5 weeks of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size. PMID: 19036884 [PubMed - as supplied by publisher]
Type 2 deiodinase expression is induced by PPAR-{gamma} agonists in skeletal myocytes.
Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW Related Articles Type 2 deiodinase expression is induced by PPAR-{gamma} agonists in skeletal myocytes. Endocrinology. 2008 Nov 26; Authors: Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW The thyroid hormone activating type 2 deiodinase (D2) is known to play a role in brown adipose tissue mediated adaptive thermogenesis in rodents, but the finding of D2 in skeletal muscle raises the possibility of a broader metabolic role. In the current study, we examined the regulation of the D2 pathway in primary skeletal muscle myoblasts taken from both humans and mice. We found that pioglitazone treatment led to a 1.6 to 1.9-fold increase in primary human skeletal myocyte D2 activity; this effect was seen with other PPAR-gamma agonists. D2 activity in primary murine skeletal myotubes increased 2.8 fold in response to 5uM pioglitazone and 1.6 fold in response to 5nM insulin, and increased in a dose-dependent manner in response to lithocholic acid (maximum response at 25microM was approximately 3.8 fold). We compared Akt phosphorylation in primary myotubes derived from wild type and D2 knock-out mice: phospho-Akt was reduced by 50% in the D2KO muscle following 1nM insulin exposure. Expression of T3-responsive muscle genes via RT-qPCR suggests that D2KO cells have decreased thyroid hormone signaling, which could contribute to the abnormalities in insulin signaling. D2 activity in skeletal muscle fragments from both murine and human sources was low, on the order of approximately 0.01 fmol/min/mg of muscle protein. The phenotypic changes seen with D2KO cells support a metabolic role for D2 in muscle, hinting at a D2-mediated linkage between thyroid hormone and insulin signaling, but the low activity calls into question whether skeletal muscle D2 is a major source of plasma T3. PMID: 19036883 [PubMed - as supplied by publisher]
Prolactin receptor is required for normal glucose homeostasis and modulation of {beta}-cell mass during pregnancy.
Huang C, Snider F, Cross JC Related Articles Prolactin receptor is required for normal glucose homeostasis and modulation of {beta}-cell mass during pregnancy. Endocrinology. 2008 Nov 26; Authors: Huang C, Snider F, Cross JC Increased islet mass is an adaptive mechanism which occurs to combat insulin resistance during pregnancy. Prolactin (PRL) can enhance beta-cell proliferation and insulin secretion in vitro yet whether it is PRL or other pregnancy-related factors that mediate these adaptive changes during pregnancy is unknown. The objective of this study was to determine whether prolactin receptor (Prlr) is required for normal maternal glucose homeostasis during pregnancy. Intraperitoneal glucose tolerance test was performed on timed-pregnant Prlr(+/+) and heterozygous null Prlr(+/-) mice on days 0, 15, and 18 of pregnancy. Compared with Prlr(+/+) mice, Prlr(+/-) mice had impaired glucose clearance, decreased glucose-stimulated insulin release, higher non-fasted blood glucose and lower insulin levels during but not before pregnancy. There was no difference in their insulin tolerance. Prlr(+/+) mice show a significant incremental increase in islet density, beta-cell number and mass throughout pregnancy, which was attenuated in the Prlr(+/-) mice. Prlr(+/+) mice also had a more robust beta-cell proliferation rate during pregnancy, while there was no difference in apoptosis rate between the Prlr(+/+) and Prlr(+/-) mice before, during, or after pregnancy. Interestingly, genotype of the mothers had a significant impact on the offspring's phenotype, such that daughters derived from Prlr(+/-) mothers had a more severe phenotype than those derived from Prlr(+/+) mothers. In conclusion, this is the first in vivo demonstration that the action of pregnancy hormones, acting through Prlr, is required for normal maternal glucose tolerance during pregnancy by increasing beta-cell mass. PMID: 19036882 [PubMed - as supplied by publisher]
Role of c-Myb during PRL-induced Stat5a signaling in breast cancer cells.
Fang F, Rycyzyn MA, Clevenger CV Related Articles Role of c-Myb during PRL-induced Stat5a signaling in breast cancer cells. Endocrinology. 2008 Nov 26; Authors: Fang F, Rycyzyn MA, Clevenger CV Implicated in the pathogenesis of breast cancer, prolactin (PRL) mediates its function in part through the prolactin receptor (PRLr)-associated Jak2/Stat5 signaling complex. To delineate the mechanisms of Stat5a regulation in breast cancer, transcription factor-transcription factor (TF-TF) array analysis was employed to identify associated transcriptional regulators. These analyses revealed a PRL-inducible association of Stat5a with the transcription factor and proto-oncogene c-Myb. Confirmatory co-immunoprecipitation studies using lysates from both T47D and MCF7 breast cancer cells revealed an PRL-inducible association between these transcription factors. Ectopic expression of c-Myb enhanced the PRL-induced expression from both composite and synthetic Stat5a-responsive luciferase reporters. Chromatin immunoprecipitation (ChIP) assays also revealed a PRL-inducible association between c-Myb and endogenous Stat5a-responsive CISH promoter, which was associated with an enhanced expression of CISH gene product at the RNA and protein levels. SiRNA-mediated c-Myb knockdown impaired the PRL-induced mRNA expression of five Stat5-responsive genes. DNA binding-defective mutants of c-Myb, incapable of activating expression from a c-Myb-responsive reporter, maintained their ability to enhance a Stat5a-responsive reporter. At a cellular level, ectopic expression of c-Myb resulted in an increase in T47D proliferation. Taken together, these results indicate that c-Myb potentiates Stat5a-driven gene expression, possibly functioning as a Stat5a co-activator, in human breast cancer. PMID: 19036881 [PubMed - as supplied by publisher]
HEXOSAMINE BIOSYNTHESIS PATHWAY FLUX CONTRIBUTES TO INSULIN RESISTANCE VIA ALTERING MEMBRANE PIP2 AND CORTICAL F-ACTIN.
Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS Related Articles HEXOSAMINE BIOSYNTHESIS PATHWAY FLUX CONTRIBUTES TO INSULIN RESISTANCE VIA ALTERING MEMBRANE PIP2 AND CORTICAL F-ACTIN. Endocrinology. 2008 Nov 26; Authors: Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS We recently found that plasma membrane (PM) phosphatidylinositol 4,5 bisphosphate (PIP2)-regulated filamentous actin (F-actin) polymerization was diminished in hyperinsulinemic cell culture models of insulin resistance. Here we delineated if increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes the PIP2/F-actin dysregulation and insulin resistance induced by hyperinsulinemia. Increased HBP activity was detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nM Ins; 12 h) and in cells where HBP activity was amplified by 2 mM glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP2 and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP2 corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP2/F-actin structure, inhibition of the rate-limiting HBP enzyme (GFAT, glutamine:fructose-6-phosphate amidotransferase) restored PIP2-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of GFAT was associated with a loss of detectable PM PIP2 and insulin sensitivity. A slight decrease in intracellular ATP resulted from amplifying HBP by hyperinsulinemia and GlcN. However, experimental maintenance of the intracellular ATP pool under both conditions with inosine did not reverse the PIP2/F-actin-based insulin-resistant state. Furthermore, less invasive challenges with glucose, in the absence of insulin, also led to PIP2/F-actin dysregulation. Accordingly, we suggest that the functionality of cell systems dependent on PIP2 and/or F-actin status, such as the glucose transport system, can be critically compromised by inappropriate HBP activity. PMID: 19036880 [PubMed - as supplied by publisher]
Conditional inactivation of glucocorticoid receptor gene in dopamine-b-hydroxylase cells impairs chromaffin cell survival.
Parlato R, Otto C, Tuckermann J, Stotz S, Kaden S, Gröne HJ, Unsicker K, Schütz G Related Articles Conditional inactivation of glucocorticoid receptor gene in dopamine-b-hydroxylase cells impairs chromaffin cell survival. Endocrinology. 2008 Nov 26; Authors: Parlato R, Otto C, Tuckermann J, Stotz S, Kaden S, Gröne HJ, Unsicker K, Schütz G Glucocorticoid hormones (GCs) have been thought to determine the fate of chromaffin cells from sympathoadrenal progenitor cells. The analysis of mice carrying a germline deletion of the glucocorticoid receptor (GR) gene has challenged these previous results since the embryonic development of adrenal chromaffin cells is largely unaltered. In the present study, we have analyzed the role of GC-dependent signaling in postnatal development of adrenal chromaffin cells by conditional inactivation of the GR gene in cells expressing dopamine-beta-hydroxylase, an enzyme required for the synthesis of noradrenaline and adrenaline. These mutant mice are viable, allowing to study whether in absence of GC signaling further development of the adrenal medulla is affected. Our analysis shows that loss of GR leads not only to loss of phenylethanolamine-N-methyl-transferase (PNMT) expression and therefore to inhibition of adrenaline synthesis, but also to a dramatic reduction in the number of adrenal chromaffin cells. We provide evidence that increased apoptotic cell death is the main consequence of GR loss. These findings define the essential role of GCs for survival of chromaffin cells and underscore the specific requirement of GCs for adrenergic chromaffin cell differentiation and maintenance. PMID: 19036879 [PubMed - as supplied by publisher]
Impaired bacterial clearance in type 3 deiodinase deficient mice infected with Streptococcus pneumoniae.
Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A Related Articles Impaired bacterial clearance in type 3 deiodinase deficient mice infected with Streptococcus pneumoniae. Endocrinology. 2008 Nov 26; Authors: Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A The activation of type 3 deiodinase (D3) has been postulated to play a role in the reduction of thyroid hormone levels during illness. Using a mouse model of acute bacterial infection, we have recently demonstrated marked D3 immunostaining in neutrophils infiltrating infected organs. These observations suggest a possible additional role for this enzyme in the innate immune response. To further assess the role of D3 in the response to acute bacterial infection, we used null D3 (D3KO) and wild type (WT) mice and infected them with Streptococcus (S). pneumoniae. Marked reductions in serum thyroid hormone levels were observed both in D3KO and WT mice. Infection resulted also in a decrease in liver D1 activity in WT, but not in infected D3KO mice. Upon infection, pulmonary neutrophilic influx (measured by MPO levels), IL-6 and TNF concentrations increased equally in D3KO and WT mice and histological examination of infected mice showed similar pulmonary inflammation in both strains. However, D3KO animals demonstrated significantly higher bacterial load in blood, lung and spleen compared to WT mice. We conclude that: 1) D3 is not required to generate the systemic manifestations of the nonthyroidal illness (NTI) syndrome in this model. 2) The lack of D3 does not affect the extent of pulmonary inflammation and 3) Bacterial outgrowth in blood, spleen and lung of D3KO mice is significantly higher than in WT mice. Our results suggest a protective role for D3 in the defence against acute bacterial infection probably by reinforcing the microbial killing capacity of neutrophils. PMID: 19036878 [PubMed - as supplied by publisher]
Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption.
Keay J, Thornton JW Related Articles Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption. Endocrinology. 2008 Nov 26; Authors: Keay J, Thornton JW As the primary mediators of estrogen signaling in vertebrates, estrogen receptors (ERs) play crucial roles in reproduction, development, and behavior. They are also the major mediators of endocrine disruption - health impairment by xenobiotic pollutants that mimic or block estrogen action. ERs that are sensitive to estrogen and endocrine disrupters have long been thought to be restricted to vertebrates: although there is evidence for estrogen signaling in invertebrates, the only ERs studied to date - from mollusks and cephalochordates - have been insensitive to estrogen and therefore incapable of mediating estrogen signaling or disruption. To determine whether estrogen-sensitivity is ancestral or a unique characteristic of vertebrate ERs, we isolated and characterized ERs from two annelids, Platynereis dumerilii and Capitella capitata, because annelids are the sister phylum to mollusks and have been shown to produce and respond to estrogens. Functional assays show that annelid ERs specifically activate transcription in response to low estrogen concentrations and bind estrogen with high affinity. Further, numerous known endocrine-disrupting chemicals activate or antagonize the annelid ER. This is the first report of a hormone-activated invertebrate estrogen receptor. Our results indicate that estrogen signaling via the ER is as ancient as the ancestral bilaterian animal and corroborate the estrogen-sensitivity of the ancestral steroid receptor. They suggest that the taxonomic scope of endocrine disruption by xenoestrogens may be very broad and reveal how functional diversity evolved in a gene family central to animal endocrinology. PMID: 19036877 [PubMed - as supplied by publisher]
PubMed: 0804-4643
Glycodelin in reproductive endocrinology and hormone-related cancer.
Seppala M, Koistinen H, Koistinen R, Hautala L, Chiu P, Yeung W Related Articles Glycodelin in reproductive endocrinology and hormone-related cancer. Eur J Endocrinol. 2008 Nov 27; Authors: Seppala M, Koistinen H, Koistinen R, Hautala L, Chiu P, Yeung W ABSTRACT Glycodelin is an endocrine-regulated glycoprotein that has significant effects on immune cells, apoptosis, reproduction, cell adhesion, differentiation and cancer. In reproduction, glycodelin contributes to capacitation and immunoprotection of spermatozoa, and it modulates sperm-oocyte binding, acrosome reaction and implantation. In endocrine-related cancer, the differentiation inducing effects of glycodelin are accompanied by growth restriction of malignant cells, decreased expression of oncogenes, increased expression of tumor suppressor genes, and morphological reversion of the malignant phenotype. This review features these properties and clinical connections, highlighting the role of glycosylation in biological actions. PMID: 19039086 [PubMed - as supplied by publisher]
Growth response to an individualized versus fixed dose growth hormone (GH) treatment in short children born small for gestational age (SGA): the OPTIMA study.
Jung H, Land C, Nicolay C, De Schepper J, Blum W, Schoenau E Related Articles Growth response to an individualized versus fixed dose growth hormone (GH) treatment in short children born small for gestational age (SGA): the OPTIMA study. Eur J Endocrinol. 2008 Nov 27; Authors: Jung H, Land C, Nicolay C, De Schepper J, Blum W, Schoenau E Objective: Initial GH-induced catch-up growth is highly variable in short children born SGA and mainly influenced by age at start of therapy and GH dose. This study compared the first-year growth-promoting effect of an individually adjusted GH dose (IAD) versus a fixed high GH dose (FHD) in pre-pubertal children born SGA with severe short stature. Design: This was a randomized, open-label, multi-centre study. Methods: The FHD group received GH at 0.067mg/kg/day throughout the 12-month study. The IAD group initially received 0.035mg/kg/day GH; at 3 months the Cologne growth-prediction model for first-year change in height SDS was applied; if predicted change was <0.75, GH was increased to 0.067mg/kg/day for the remaining 9 months, otherwise the initial dose was continued. Results: In the IAD group, 38 of 80 patients required the higher GH dose from month 3. From an ANCOVA for non-inferiority, mean difference in change in height SDS between IAD and FHD groups was -0.24 (95%CI -0.35: -0.12), the CI for height SDS being above the pre-defined non-inferiority margin of -0.5. GH dose reductions due to IGF-I SDS >0.5 and IGFBP-3 SDS < -0.5 were performed in 4/99 FHD patients, but none of the IAD group patients. Safety data were similar between groups. Conclusion: With a mean treatment group difference of 1cm in 12-month growth response, although statistically significant, the IAD group was considered non-inferior compared to the FHD group. Early growth-prediction can be used to tailor the dose to the individual patient's needs resulting in lower overall GH dose. PMID: 19039085 [PubMed - as supplied by publisher]
Adiponectin is associated with low bone mineral density in elderly men.
Maria Lourdes B, Galvan R, Cordova N, Saucedo R, Vargas C, Campos S, Halley E, Avelar F, Zarate A Related Articles Adiponectin is associated with low bone mineral density in elderly men. Eur J Endocrinol. 2008 Nov 27; Authors: Maria Lourdes B, Galvan R, Cordova N, Saucedo R, Vargas C, Campos S, Halley E, Avelar F, Zarate A Objective. Recent evidence suggest that adiponectin may play a role in bone metabolism. Previous studies demonstrated that adiponectin levels had a negative correlation with bone mineral density (BMD) in women. However, little is known about the relationship between adiponectin and BMD in men. The aim of this study was to determinate the relationship between adiponectin levels and BMD in elderly men. Design. Cross-sectional study including 92 healthy men aged 60 to 80 years. Methods. Main outcome measures were adiponectin levels estimated by radioimmunoassay and bone mineral density (BMD) at lumbar spine and femoral neck using dual energy X-ray absorptiometry. Results. The negative correlation between adiponectin and BMD at the spine was r= -0.209, (p <0.05) and at the femoral neck was r= -0.237, (p <0.001). These correlations disappeared after adjustment for BMI. When stratified by BMI, the relationship between BMD and adiponectin remained significant in the subgroup of participants with BMI >27 kg/m2, but disappeared in men with BMI <27 kg/m2. In multiple regression analysis, adiponectin was a significant determinant of BMD at the spine, not at femoral neck, in those with BMI >27. Conclusion. BMD is negatively associated with adiponectin levels in men older than 60 years and this relationship is greater in those men with BMI above 27, which suggests a plausible connection between bone and fat tissue. PMID: 19039084 [PubMed - as supplied by publisher]
Sites:
American Society for Reproductive Medicine: ASRM is devoted to advancing knowledge and expertise in reproductive medicine, including reproduction, male and female infertility, andrology, menopausal medicine, infertility diagnosis, treatment, and researchBerlex Foundation: A nonprofit organization dedicated to fostering education and encouraging research in reproductive medicine. Includes foundation information, awards and educational programs.
Human Reproduction: Clinical, Pathologic and Pharmacologic Correlations: Educational information from the University of Utah's Division of Reproductive Endocrinology and Infertility.
Inhibins and Activins- Research, Applications, Products: Forum for new discoveries in clinical research, and Resources related to Inhibins and Activins. Current research areas include IVF, Ovarian Cancer, Male infertility, Ovarian Reserve, Pre-Eclampsia
Society for Reproductive Endocrinology and Infertility: SREI is a professional organization for physicians certified in both obstetrics/gynecology and reproductive endocrinology. Its aim is to promote excellence in reproductive healthcare through research, education and patient care.
The advantage of hormone pellets discussed by Dr. Gambrell: A gynecologist and endocrinologist discusses menopause, mid-life changes, hormones, Hormone Replacement Therapy, preventative health, male menopause, and diseases of the uterus.
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