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Sample records for rapidly increase androgen

  1. Dihydrotestostenone increase the gene expression of androgen ...

    African Journals Online (AJOL)

    The actions of androgens are mediated through an androgen receptor (AR), and AR activity is modulated by coregulators. The aim of this study was to assess the action of androgens in the expression of AR and the coregulators FHL-2 and SHP-1 in human non-transformed epithelial prostatic cells (HNTEP) treated with ...

  2. A teleost androgen promotes development of primary ovarian follicles in coho salmon and rapidly alters the ovarian transcriptome.

    Science.gov (United States)

    Monson, Christopher; Forsgren, Kristy; Goetz, Giles; Harding, Louisa; Swanson, Penny; Young, Graham

    2017-11-01

    Recent studies using several teleost models have revealed that androgens increase the size of previtellogenic (primary and/or early secondary) ovarian follicles. To explore our hypothesis that androgens drive the development of primary follicles into early secondary follicles, and to determine the mechanisms underlying these androgenic effects, we exposed juvenile coho salmon to near-physiological and relatively sustained levels of the nonaromatizable androgen 11-ketotestosterone (11-KT). This resulted in significant growth of primary ovarian follicles after 10 and 20 days, with follicles after 20 days displaying a morphological phenotype characteristic of early secondary follicles (presence of cortical alveoli). Utilizing the same experimental approach, we then analyzed how 11-KT rapidly altered the ovarian transcriptome after 1 and 3 days of treatment. RNA-Seq analysis revealed that 69 (day 1) and 1,022 (day 3) contiguous sequences (contigs) were differentially expressed relative to controls. The differentially expressed contigs mapped to genes including those encoding proteins involved in gonadotropin, steroid hormone, and growth factor signaling, and in cell and ovarian development, including genes with putative androgen-response elements. Biological functions and canonical pathways identified as potentially altered by 11-KT include those involved in ovarian development, tissue differentiation and remodeling, and lipid metabolism. We conclude that androgens play a major role in stimulating primary ovarian follicle development and the transition into secondary growth. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Selection for rapid embryo development correlates with embryo exposure to maternal androgens among passerine birds

    Science.gov (United States)

    Schwabl, H.; Palacios, M.G.; Martin, T.E.

    2007-01-01

    Greater offspring predation favors evolution of faster development among species. We hypothesized that greater offspring predation exerts selection on mothers to increase levels of anabolic androgens in egg yolks to achieve faster development. Here, we tested whether (1) concentrations of yolk androgens in passerine species were associated with offspring predation and (2) embryo and nestling development rates were associated with yolk androgen concentrations. We examined three androgens that increase in potency along the synthesis pathway: androstenedione (A4) to testosterone (T) to 5??- dihydrotestosterone (5??-DHT). Concentrations of none of these steroids were related to clutch size; only A4 was allometrically related to egg volume. Species that experience greater predation showed higher yolk concentrations of T and 5??-DHT. Higher concentrations of T and particularly 5??-DHT were strongly correlated with faster development during the embryo period and less so during the nestling period. Development rates were most strongly correlated with 5??-DHT, suggesting that potency increases along the androgen synthesis pathway and that effects are mediated by the androgen receptor pathway. These results are consistent with the hypothesis that selection for faster development by time-dependent offspring mortality may be achieved epigenetically by varying embryo exposure to maternal anabolic steroids. ?? 2007 by The University of Chicago. All rights reserved.

  4. Non-Genomic Action of Androgens is Mediated by Rapid Phosphorylation and Regulation of Androgen Receptor Trafficking

    Directory of Open Access Journals (Sweden)

    Qiong Deng

    2017-08-01

    Full Text Available Background: Testosterone is critical for maintaining spermatogenesis and male fertility. The accomplishment of these processes requires the synergistic actions of the classical and non-classical signaling pathways of androgens. Methods: A murine testicular Sertoli cell line, TM4 cell was used to examine androgen actions in Sertoli cells. Western blot analysis and immunofluorescence assay were employed to study the testosterone-induced Androgen receptor (AR translocation. Protein phosphorylation antibody array was applied to identify the phosphorylation sites under testosterone treatment, and these findings were verified by Western blot analysis. Results: We found that a physiological dose of testosterone induced fast membrane association of AR. By using a phosphorylation antibody array, several phosphorylation sites, such as MEK1/2 (Ser217/221, Akt (Ser473, and Erk1/2 (Thr202/Tyr204 were rapidly phosphorylated within 5 min of testosterone treatment. Inhibition of the MEK and Akt signaling pathways prevented AR trafficking. Blocking of AR by flutamide eliminated the stimulation effect of testosterone on kinase phosphorylation. Testosterone induced kinase Src phosphorylation, and inhibition of Src restricted AR translocation to the membrane and the nucleus. Conclusion: Findings suggested that the membrane association of AR was mediated by the MEK and Akt phosphorylation signaling pathways, which resulted in Src activation and was initiated by testosterone binding to the membrane-localized AR. This study provides new insights into the testosterone signaling pathway in Sertoli cells, which mediate spermatogenesis. In addition, the study can be used in the diagnosis and treatment of male infertility caused by disorders in spermatogenesis.

  5. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate...... epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT......-qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 µM sarcosine for 24 h resulted in a 58% increase of the HER2/neu m...

  6. Manipulation of male attractiveness induces rapid changes in avian maternal yolk androgen deposition

    NARCIS (Netherlands)

    Kingma, Sjouke A.; Komdeur, Jan; Vedder, Oscar; Engelhardt, Nikolaus von; Korsten, Peter; Groothuis, Ton G.G.

    2009-01-01

    Avian eggs contain maternal androgens that may adjust offspring development to environmental conditions. We review evidence and functional explanations for the relationship between androgen concentrations in avian eggs and male attractiveness. Experimental studies in captive birds show generally

  7. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela

    2011-01-01

    -qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 μM sarcosine for 24 h resulted in a 58% increase of the HER2/neu m...... epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT...

  8. TBT-induced imposex in marine neogastropods is mediated by an increasing androgen level

    Science.gov (United States)

    Bettin, C.; Oehlmann, J.; Stroben, E.

    1996-09-01

    Tributyltin (TBT) exposure at different concentrations (5, 60, and 100 ng TBT as Sn/l) induces a concentration- and time-dependent imposex (=pseudohermaphroditism) development in female Nucella lapillus and Hinia reticulata. In both species the average imposex stage, termed as vas deferens sequence (VDS) index, and the average female penis length increases with increasing TBT concentration and duration of TBT exposure. Testosterone added at a concentration of 500 ng/l induces a faster and more intensive imposex development compared to that induced by the TBT concentrations used in the present experiments. Radioimmunological determination of endogenous steroid content reveals increasing testosterone titres in female gastropods exposed to TBT which correlate with the TBT concentration used and the duration of the experiment. The most marked and highest increase of the endogenous testosterone level is exhibited by females, of both species exposed to testosterone. Simulataneous exposure to TBT and to the antiandrogen cyproterone acetate which suppresses imposex development completely in N. lapillus and reduces imposex development strongly in H. reticulata proves that the imposex-inducing effects of TBT are mediated by an increasing androgen level and are not caused directly by the organotin compound itself. Further-more, TBT-induced imposex development can be suppressed in both snails by adding estrogens to the aqueous medium. These observations suggest that TBT causes an inhibition of the cytochrome P-450 dependent aromatase system which catalyses the aromatization of androgens to estrogens. The increase of the androgen content or the shift of the androgen-estrogen balance in favour of androgens induces the development of pseudohermaphroditism in marine prosobranchs. Artificial inhibition of the cytochrome P-450 dependent aromatase system using SH 489 (1-methyl-1,4-androstadiene-3,17-dione) as a steroidal aromatase inhibitor and flavone as a nonsteroidal aromatase

  9. Androgen Restored Contraception

    NARCIS (Netherlands)

    Zimmerman, X.Y.

    2014-01-01

    Combined oral contraceptives (COCs) reduce androgen levels, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Possible consequences of this androgen loss are diminished sexual function and mood

  10. Nrdp1-Mediated ErbB3 Increase during Androgen Ablation and its Contribution to Androgen-Independence

    Science.gov (United States)

    2013-04-01

    T. G., and Kung, H. J. (2002) Cancer Res. 62, 6606–6614 22. Libertini, S. J., Robinson, B. S., Dhillon, N. K., Glick , D., George, M., Dandekar, S...Davis, for critical reading of the manuscript; Dr. Thomas G. Pretlow (Case Western Reserve School of Medicine, Cleveland, OH) for generously providing the...study that identified androgen-responsive elements in the 3′-UTR of the NKX3.1 gene ( Thomas et al. 2010). AR binding in the 5′-UTR (two sites: 6382

  11. In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

    Directory of Open Access Journals (Sweden)

    Alison K. Heather

    2013-02-01

    Full Text Available Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

  12. In vitro androgen bioassays as a detection method for designer androgens.

    Science.gov (United States)

    Cooper, Elliot R; McGrath, Kristine C Y; Heather, Alison K

    2013-02-06

    Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

  13. Increased Intimal Hyperplasia After Vascular Injury in Male Androgen Receptor-Deficient Mice

    DEFF Research Database (Denmark)

    Wilhelmson, Anna S; Fagman, Johan B; Johansson, Inger

    2016-01-01

    replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells....... evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury......, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular...

  14. Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway.

    Science.gov (United States)

    Hsu, Shih-Che; Huang, Shih-Ming; Lin, Shih-Hua; Ka, Shuk-Man; Chen, Ann; Shih, Meng-Fu; Hsu, Yu-Juei

    2014-12-01

    Gender is known to be associated with longevity and oestrogen administration induced longevity-associated gene expression is one of the potential mechanisms underlying the benefits of oestrogen on lifespan, whereas the role of testosterone in the regulation of longevity-associated gene expressions remains largely unclear. The klotho gene, predominantly expressed in the kidney, has recently been discovered to be an aging suppressor gene. In the present study, we investigated the regulatory effects of testosterone on renal klotho gene expression in vivo and in vitro. In testosterone-administered mouse kidney and NRK-52E cells, increased klotho expression was accompanied by the up-regulation of the nuclear androgen receptor (AR). Overexpression of AR enhanced the expression of klotho mRNA and protein. Conversely, testosterone-induced klotho expression was attenuated in the presence of flutamide, an AR antagonist. A reporter assay and a chromatin immunoprecipitation (ChIP) assay demonstrated that AR directly binds to the klotho promoter via androgen response elements (AREs) which reconfirmed its importance for AR binding via the element mutation. In summary, our study demonstrates that testosterone up-regulates anti-aging klotho together with AR expression in the kidney in vivo and in vitro by recruiting AR on to the AREs of the klotho promoter.

  15. Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.

    Science.gov (United States)

    Ryan, Christopher W; Huo, Dezheng; Demers, Laurence M; Beer, Tomasz M; Lacerna, Leo V

    2006-09-01

    Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.

  16. Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Scholze, M.; Petersen, Marta Axelstad

    2008-01-01

    The incidence of hypospadias is increasing in young boys, but it remains unclear whether human exposure to endocrine disrupting chemicals plays a role. Risk assessment is based on estimation of no-observed-adverse-effect levels for single compounds, although humans are exposed to combinations...... reproductive organs were assessed on PND 47 using a score from 0 to 3 (normal to marked) for hypospadias. Markedly increased frequencies were observed after exposure to a MIX of the three chemicals compared to administration of the three chemicals alone. Anogenital distance at PND 1, nipple retention at PND 13......, and dysgenesis score at PND 16 were highly correlated with the occurrence of hypospadias, and MIX effects were seen at doses where each of the individual chemicals caused no observable effects. Therefore, the results indicate that doses of anti-androgens, which appear to induce no hypospadias when judged...

  17. Designer steroids - over-the-counter supplements and their androgenic component: review of an increasing problem.

    Science.gov (United States)

    Rahnema, C D; Crosnoe, L E; Kim, E D

    2015-03-01

    Colloquially referred to by various misleading monikers ('pro-hormones', 'natural steroids', 'testosterone boosters', etc.) designer anabolic steroids have been popular now for over a decade as a way to achieve classic anabolic steroid-like results from products sold in the legal marketplace. Recent evidence suggests that anabolic steroid use may be the most common cause of hypogonadism in men of reproductive age. Despite recent regulatory efforts that have banned specific compounds, many anabolic-androgenic steroids (AAS) remain available in over-the-counter dietary supplements that are legally sold in the United States. Severe side effects including hepatotoxicity, cholestasis, renal failure, hypogonadism, gynecomastia, and infertility have been reported secondary to the use of these products. While some of these side effects may be reversible, more aggressive use may result in more permanent end-organ damage as has been previously described for the case of aggressive AAS users (Rahnema et al., Fertil Steril, 2014). Designer AAS remain easily available for purchase in over-the-counter bodybuilding supplements and these products appear to be increasingly popular, despite the known health risks associated with their use. We conducted a systematic search to identify the designer steroids that are most commonly sold in dietary supplements as of April 2014 and review what is known regarding their potency and toxicity. We propose that the impact of AAS use on the reproductive and hormonal health of men is underestimated in the literature owing to previous studies' failure to account for designer steroid use. Lastly, we make clinical recommendations to help physicians steer patients away from potentially harmful supplements, and summarize key regulatory obstacles that have allowed potent androgens to remain unregulated in the legal marketplace. © 2015 American Society of Andrology and European Academy of Andrology.

  18. Rapid changes in plasma androgens during insulin withdrawal in male type 1 (insulin-dependent) diabetics

    DEFF Research Database (Denmark)

    Madsbad, S; Gluud, C; Bennett, Patrick

    1986-01-01

    Plasma concentrations of testosterone, androstenedione and dihydrotestosterone were measured in 15 Type 1 (insulin-dependent) diabetics with (n = 8) and without (n = 7) B-cell function during 12 h of insulin withdrawal and compared with those of 8 normal subjects. Before insulin withdrawal...... the patients without B-cell function were more metabolically decompensated from after 4 h of insulin withdrawal compared with patients with B-cell function, no significant differences were found in androgen concentrations between the two groups although a tendency to lower concentrations were seen in the group...... without B-cell function....

  19. Rapid bursts of androgen-binding protein (Abp) gene duplication occurred independently in diverse mammals.

    Science.gov (United States)

    Laukaitis, Christina M; Heger, Andreas; Blakley, Tyler D; Munclinger, Pavel; Ponting, Chris P; Karn, Robert C

    2008-02-12

    The draft mouse (Mus musculus) genome sequence revealed an unexpected proliferation of gene duplicates encoding a family of secretoglobin proteins including the androgen-binding protein (ABP) alpha, beta and gamma subunits. Further investigation of 14 alpha-like (Abpa) and 13 beta- or gamma-like (Abpbg) undisrupted gene sequences revealed a rich diversity of developmental stage-, sex- and tissue-specific expression. Despite these studies, our understanding of the evolution of this gene family remains incomplete. Questions arise from imperfections in the initial mouse genome assembly and a dearth of information about the gene family structure in other rodents and mammals. Here, we interrogate the latest 'finished' mouse (Mus musculus) genome sequence assembly to show that the Abp gene repertoire is, in fact, twice as large as reported previously, with 30 Abpa and 34 Abpbg genes and pseudogenes. All of these have arisen since the last common ancestor with rat (Rattus norvegicus). We then demonstrate, by sequencing homologs from species within the Mus genus, that this burst of gene duplication occurred very recently, within the past seven million years. Finally, we survey Abp orthologs in genomes from across the mammalian clade and show that bursts of Abp gene duplications are not specific to the murid rodents; they also occurred recently in the lagomorph (rabbit, Oryctolagus cuniculus) and ruminant (cattle, Bos taurus) lineages, although not in other mammalian taxa. We conclude that Abp genes have undergone repeated bursts of gene duplication and adaptive sequence diversification driven by these genes' participation in chemosensation and/or sexual identification.

  20. Increased blood pressure and aortic stiffness among abusers of anabolic androgenic steroids

    DEFF Research Database (Denmark)

    Rasmussen, Jon J; Schou, Morten; Madsen, Per L

    2018-01-01

    BACKGROUND: Abuse of anabolic androgenic steroids (AAS) is prevalent among recreational athletes and adverse effects on blood pressure (BP) and arterial stiffness could be substantial. Testosterone decreases natriuretic peptides which are key components in BP-regulation and may impair BP...

  1. Increased psychiatric morbidity in women with complete androgen insensitivity syndrome or complete gonadal dysgenesis.

    Science.gov (United States)

    Engberg, Hedvig; Strandqvist, Anna; Nordenström, Anna; Butwicka, Agnieszka; Nordenskjöld, Agneta; Hirschberg, Angelica Lindén; Frisén, Louise

    2017-10-01

    Knowledge concerning mental health outcomes is important to optimize the health of individuals with disorders or differences of sex development (DSD). Thus, the aim of this study was to estimate if the prevalence of psychiatric morbidity in adult women diagnosed with complete androgen insensitivity syndrome (CAIS) or complete gonadal dysgenesis (46,XY GD and 46,XX GD) differs from that in women with premature ovarian insufficiency (POI) or age-matched population controls. This cross-sectional study was conducted at the Karolinska University Hospital, Stockholm, Sweden, and included 33 women with different DSDs: 20 CAIS, 6 46,XY GD, 7 46,XX GD, 21 women with POI and 61 population-derived controls. Psychiatric morbidity was assessed using the Mini International Neuropsychiatric Interview plus (MINI+). To complement the MINI+, three self-report questions were used to evaluate current and previous psychiatric history. Results are presented as p values and estimated risks (odds ratio [OR], 95% confidence intervals [CI]) of psychiatric conditions among women with CAIS or GD in comparison with women with POI and age-matched population-derived controls. Twenty-eight of the 33 women (85%) with CAIS or GD met the criteria for at least one psychiatric disorder according to the MINI+, with depression and anxiety disorders being most common. This was significantly higher compared with population controls (52%) (OR 5.1, 95% CI 1.7-14.9), but not compared to women with POI, who had a high frequency of psychiatric diagnoses (76%). The increased psychiatric morbidity in women with CAIS and GD highlights the need for clinical awareness of the psychiatric vulnerability in these patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Androgen excess is associated with the increased carotid intima-media thickness observed in young women with polycystic ovary syndrome.

    Science.gov (United States)

    Luque-Ramírez, Manuel; Mendieta-Azcona, Covadonga; Alvarez-Blasco, Francisco; Escobar-Morreale, Héctor F

    2007-12-01

    We evaluated carotid intima-media thickness (CIMT) as an early marker of atherosclerosis, as well as its main determinants among androgen excess, obesity and insulin resistance, in patients with polycystic ovary syndrome (PCOS). We selected 40 PCOS patients and 20 non-hyperandrogenic women who were similar in terms of age and grade of obesity. Complete clinical, metabolic and hormonal profiles and left common CIMT measurements were obtained. Patients with PCOS presented with increased mean CIMT values when compared with controls (F = 8.575; P = 0.005), and this was independent of obesity. Five PCOS patients but no controls had increased CIMT values. CIMT correlated directly with serum total and free testosterone, androstenedione and dehydroepiandrosterone-sulfate levels and mean 24-h heart rate (HR), and inversely with the insulin sensitivity index (ISI), but no correlation was observed with the body mass index (BMI). Multiple stepwise linear regression models showed that in PCOS patients, the main determinants of CIMT were serum total testosterone or androstenedione concentrations, with no influence of ISI or the mean 24-h HR. Compared with control women, PCOS patients present with an increased CIMT, independent of obesity and related directly to androgen excess; this suggests that hyperandrogenism is associated with atherosclerosis and cardiovascular risk in these women.

  3. Rapid reduction in blood flow to the rat ventral prostate gland after castration: preliminary evidence that androgens influence prostate size by regulating blood flow to the prostate gland and prostatic endothelial cell survival.

    Science.gov (United States)

    Shabsigh, A; Chang, D T; Heitjan, D F; Kiss, A; Olsson, C A; Puchner, P J; Buttyan, R

    1998-08-01

    Androgenic steroids regulate the development and size of the mammalian prostate gland. The mechanism(s) for this growth control might involve a direct effect on prostate cell proliferation and survival as well as more complex effects on the tissue environment supporting nourishment and oxygenation. In this study, we evaluated an animal model of androgen action on the prostate, the rat ventral prostate gland, to determine whether acute androgen withdrawal, by means of castration, might alter the primary blood flow to the prostate gland and for the effects of castration on prostatic endothelial cell viability. Groups of rats studied included intact control males, males that had been surgically castrated, or males that received a sham-surgical castration. Relative blood flow (RBF) to the rat ventral prostate glands and rat bladders were measured at 18 and 24 hr after castration or sham castration using a fluorescent microsphere infusion technique. Thin sections from fixed and embedded rat ventral prostate glands obtained from unoperated or 12-hr castrated rats were analyzed by the TUNEL immunostaining technique to microscopically identify and quantify apoptotic epithelial, stromal, and endothelial cells. RBF to the rat ventral prostate was reduced by 38%, at 18 hr after castration when compared with intact or sham-operated rats and by 45% at 24 hr after castration (P=0.038 unoperated/0.025 sham operated). In contrast, RBF to the bladder was not significantly different between any of the groups in the 24-hr castrate experiment. TUNEL staining analysis of ventral prostate tissues obtained from 12-hr castrated rats showed only rare TUNEL-positive epithelial cells similar to the control tissue but significantly increased TUNEL labeling for endothelial and other ventral prostate stromal cells. Castration resulted in a rapid and significant reduction of blood flow to the mature rat ventral prostate gland that was not seen in the bladder. This reduction precedes the

  4. Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression

    DEFF Research Database (Denmark)

    Wang, Qian; Bailey, Charles G; Ng, Cynthia

    2011-01-01

    L-Type amino acid transporters such as LAT1 and LAT3 mediate the uptake of essential amino acids. Here, we report that prostate cancer cells coordinate the expression of LAT1 and LAT3 to maintain sufficient levels of leucine needed for mTORC1 signaling and cell growth. Inhibiting LAT function...... was sufficient to decrease cell growth and mTORC1 signaling in prostate cancer cells. These cells maintained levels of amino acid influx through androgen receptor-mediated regulation of LAT3 expression and ATF4 regulation of LAT1 expression after amino acid deprivation. These responses remained intact in primary...... prostate cancer, as indicated by high levels of LAT3 in primary disease, and by increased levels of LAT1 after hormone ablation and in metastatic lesions. Taken together, our results show how prostate cancer cells respond to demands for increased essential amino acids by coordinately activating amino acid...

  5. Aggression Is Associated With Increased Anabolic-Androgenic Steroid Use Contemplation Among Adolescents.

    Science.gov (United States)

    Sagoe, Dominic; Mentzoni, Rune A; Hanss, Daniel; Pallesen, Ståle

    2016-09-18

    We investigated the relationship between aggression and anabolic-androgenic steroid (AAS) use intent among adolescents. A nationally representative sample of Norwegian 18-year-olds (N = 1,334, females = 58.7%) took part in a survey in 2013 (response rate = 64.9%). Participants completed the physical and verbal subscales of the Short-Form Buss-Perry Aggression Questionnaire, the Intent to use AAS Scale, the Alcohol Use Disorders Identification Test-Consumption, and the Hospital Anxiety and Depression Scale. They also provided demographic information and answered questions about AAS use, gambling participation, as well as cigarette and snus use. Descriptive statistics and multinomial logistic regression were used to analyze the data. Lifetime and past year prevalence of AAS use was 0.1%. Between 0.4% and 1.7% of participants disclosed intent to use while between 1.1% and 2.5% expressed neutral intent to initiate AAS use. Compared to persons low on aggression, individuals high on aggression were more likely to report intent and curiosity towards initiating AAS use. Our findings indicate that aggression is a risk factor for AAS use contemplation among adolescents.

  6. Combined exposure to dissimilarly acting anti-androgens causes markedly increased frequency of hypospadias in the rat

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Petersen, Marta Axelstad; Kortenkamp, Andreas

    2007-01-01

    The incidence of hypospadias is increasing, but it is unclear whether human exposure to endocrine disrupting chemicals is related to this. Risk assessment based on no observed adverse effect levels (NOAELs) for single compounds indicates that human tissue levels are too low levels to cause concern...... organs were scored on PND 47/48 using a score from 0 to 3 (normal-marked) for the endpoints hypospadia and vaginal opening. Animals with scores 2 or 3 were only found in the two highest mixture groups and the highest dose of vinclozolin, and score 3 was only observed in the highest mixture group. Also......, a combination of doses of each chemical that on its own did not produce clear sign of hypospadias (DEHP, finasteride and prochloraz) or a frequency around 14% (vinclozolin) induced a 100% frequency of hypospadias. In conclusion, doses of anti-androgens, which appear to induce only low frequencies of hypospadias...

  7. Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines.

    DEFF Research Database (Denmark)

    Tørring, Niels; Sørensen, Boe Sandahl; Nexø, Ebba

    2000-01-01

    RNA for the ligands TGF alpha, amphiregulin, HB-EGF and epiregulin were increased 10 to 100 fold in androgen-independent cells, as compared to LNCaP and PNT1A cells. Expression of mRNA for the ligands EGF and betacellulin and of the receptors HER1 and HER2 were similar in all lines investigated, except LNCaP cells...... which exhibit low expression of HER1. Similar results were obtained by ELISA. CONCLUSIONS: The data indicates a selective up-regulation of a subclass of ligands of the EGF-system in androgen-independent prostate cancer cell lines. We suggest this could be a mechanism to escape androgen dependence...

  8. Increase in healthcare facilities and rapid environmental degradation

    African Journals Online (AJOL)

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    Increase in healthcare facilities and rapid environmental degradation: A technological paradox in. Nigeria's urban centres. Akinwale Coker1* and Mynepalli K. C. Sridhar2. 1Department of Civil Engineering, Faculty of Technology, University of Ibadan, Oyo State, Nigeria. 2Division of Environmental Health, Department of ...

  9. Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

    DEFF Research Database (Denmark)

    Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun

    2014-01-01

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conse......Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...... in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls...

  10. Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.

    Science.gov (United States)

    Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun; Jakobsen, Marianne Antonius; Brusgaard, Klaus; Tan, Qihua; Gaster, Michael

    2014-09-05

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Rapid increase in contact allergy to Kathon CG in Finland.

    Science.gov (United States)

    Hannuksela, M

    1986-10-01

    In unselected eczema patients subjected to routine patch testing, the number with positive reactions to Kathon CG 100 ppm increased from none in 1983 to 0.7% in January-August 1985, and to 4.6% in September 1985 to March 1986. Repeated open application tests (ROAT) with creams containing 7-15 ppm of the isothiazolinones were positive in 12 of 24 patients tested. 2 of the ROAT-positive cases had negative patch tests to 100 ppm Kathon CG, but 1 was positive with 200 ppm. Atopic dermatitis, chronic hand dermatitis and lower leg dermatitis were the most common disorders in the positive patients. The cause of the rapid increase of Kathon CG allergy in Finland during the winter of 1985-1986 was the use of a popular moisturizing cream containing first 19 ppm, then 7 ppm of a mixture of 2 isothiazolinones (Euxyl K 100).

  12. Metabolic syndrome in androgenic alopecia.

    Science.gov (United States)

    Gopinath, Hima; Upadya, Gatha M

    2016-01-01

    Androgenic alopecia has been associated with an increased risk of coronary heart disease in various studies. The relationship between androgenic alopecia and metabolic syndrome, a known risk factor for atherosclerotic cardiovascular disease, is still poorly understood. To study the association between metabolic syndrome and early-onset androgenic alopecia. A hospital-based analytical cross-sectional study was done on men in the age group of 18-55 years. Eighty five clinically diagnosed cases with early-onset (alopecia of Norwood grade III or above, and 85 controls without androgenic alopecia were included. Data collected included anthropometric measurements, arterial blood pressure and history of chronic diseases. Fasting blood and lipid profile were determined. Metabolic syndrome was diagnosed as per the new International Diabetes Federation criteria. Chi-square and Student's t-test were used for statistical analysis using Statistical Package for the Social Sciences (SPSS) version 17.00. Metabolic syndrome was seen in 19 (22.4%) patients with androgenic alopecia and 8 (9.4%) controls (P = 0.021). Abdominal obesity, hypertension and lowered high-density lipoprotein were significantly higher in patients with androgenic alopecia versus their respective controls. The limitations of our study include small sample size in subgroups and the lack of evidence of a temporal relationship between metabolic syndrome and androgenic alopecia. A higher prevalence of metabolic syndrome is seen in men with early-onset androgenic alopecia. Early screening for metabolic syndrome and its components is beneficial in patients with early-onset androgenic alopecia.

  13. Rapid increases in tropospheric ozone production and export from China

    Science.gov (United States)

    Verstraeten, Willem W.; Neu, Jessica L.; Williams, Jason E.; Bowman, Kevin W.; Worden, John R.; Boersma, K. Folkert

    2015-09-01

    Rapid population growth and industrialization have driven substantial increases in Asian ozone precursor emissions over the past decade, with highly uncertain impacts on regional and global tropospheric ozone levels. According to ozonesonde measurements, tropospheric ozone concentrations at two Asian sites have increased by 1 to 3% per year since 2000, an increase thought to contribute to positive trends in the ozone levels observed at North America’s West Coast. However, model estimates of the Asian contribution to North American ozone levels are not well-constrained by observations. Here we interpret Aura satellite measurements of tropospheric concentrations of ozone and its precursor NO2, along with its largest natural source, stratospheric ozone, using the TM5 global chemistry-transport model. We show that tropospheric ozone concentrations over China have increased by about 7% between 2005 and 2010 in response to two factors: a rise in Chinese emissions by about 21% and increased downward transport of stratospheric ozone. Furthermore, we find that transport from China of ozone and its precursors has offset about 43% of the 0.42 DU reduction in free-tropospheric ozone over the western United States that was expected between 2005 and 2010 as a result of emissions reductions associated with federal, state and local air quality policies. We conclude that global efforts may be required to address regional air quality and climate change.

  14. Androgens Regulate Ovarian Gene Expression Through Modulation of Ezh2 Expression and Activity.

    Science.gov (United States)

    Ma, Xiaoting; Hayes, Emily; Biswas, Anindita; Seger, Christina; Prizant, Hen; Hammes, Stephen R; Sen, Aritro

    2017-09-01

    A substantial amount of evidence suggests that androgen signaling through classical androgen receptors is critical for both normal and pathologic ovarian physiology. Specifically, we and others have shown that, in mouse granulosa cells, androgen actions through both extranuclear and nuclear androgen receptor signaling are critical for normal follicle development and ovulation. Here, we show that androgens through the PI3K/Akt pathway rapidly (within minutes) phosphorylate and inhibit activity of the Polycomb group protein enhancer of zeste homolog 2 (Ezh2). Over the course of 24 to 48 hours, androgens then induce expression of the microRNA miR-101, which targets Ezh2 messenger RNA (mRNA), leading to a nearly complete loss of Ezh2 protein expression. This long-term androgen-induced loss of Ezh2 actions ultimately results in sustained reduction of the H3K27me3-repressive mark in the promoter region of the Runt-related transcription factor-1 (Runx1) gene, a luteinizing hormone (LH)-induced transcription factor essential for ovulation, leading to increased Runx1 mRNA expression. Accordingly, blocking androgen-induced inhibition of Ezh2 in vivo adversely affects LH-induced Runx1 mRNA expression and subsequent ovulation. Importantly, although estrogen treatment of granulosa cells similarly causes rapid activation of the PI3K/Akt pathway and short-term phosphorylation of Ezh2, it does not induce miR-101 expression and thereby does not reduce overall Ezh2 expression, demonstrating the androgen specificity of long-term Ezh2 suppression. Thus, this study provides insight regarding how androgen-induced extranuclear kinase signaling and intranuclear transcription through Ezh2 modifications may influence the expression pattern of genes, ultimately affecting various downstream physiological processes. Copyright © 2017 Endocrine Society.

  15. Humans copy rapidly increasing choices in a multiarmed bandit problem

    NARCIS (Netherlands)

    Toelch, U.; Bruce, M.J.; Meeus, M.T.H.; Reader, S.M.

    2010-01-01

    Conformist social learning, the tendency to acquire the most common trait in a group, allows individuals to rapidly acquire established beneficial traits from a multitude of options. However, conformist strategies hinder acquisition of novel advantageous behavior patterns, because such innovations

  16. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  17. The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

    Directory of Open Access Journals (Sweden)

    Kirsten Hogg

    Full Text Available Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS. We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5 or testosterone propionate (TP; n = 9 twice weekly (100 mg; i.m from d62-102 (gestation 147 days. In a novel treatment paradigm, a second cohort received a direct C (n = 4 or TP (20 mg; n = 7 fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05 and the histological presence of fatty liver (P<0.05 independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05, glucocorticoid receptor (GR; P<0.05, UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05 and IGF1 (P<0.01 expression were upregulated. The direct fetal intervention (C and TP led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK was up-regulated in the fetal controls (P<0.05 and this was opposed by fetal TP (P<0.05. Hepatic estrogen receptor (ERα; P<0.05 and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05 were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

  18. Increased production of azadirachtin from an improved method of androgenic cultures of a medicinal tree Azadirachta indica A. Juss

    Science.gov (United States)

    Srivastava, Priyanka

    2011-01-01

    Present report is the first direct evidence of azadirachtin production in androgenic haploid cultures of Azadirachta indica, a woody medicinal tree. Anther cultures at early-late-uninucleate stage of microspores were established on MS medium with BAP (5 µM), 2,4-D (1 µM) and NAA (1 µM) containing 12% sucrose. The calli, induced, were further multiplied on 2,4-D and Kinetin media. Shoots, differentiated on BAP (2.2 µM) + NAA (0.05 µM) medium, were elongated on MS + BAP (0.5 µM) and multiplied on MS + BAP (1 µM) + CH (250 mg/l). Thereafter, the shoots were rooted on ¼ MS + IBA (0.5 µM). Cytological analysis of the calli and regenerants have confirmed their haploid status with the chromosome number as 2n = x = 12. The haploid cell lines and leaves from in vitro grown plantlets were analyzed for azadirachtin by RP-HPLC and mass spectroscopy. Maximum azadirachtin (728.41 µg/g DW) was detected in calli supporting best shoot proliferation while least (49 µg/g DW) was observed in an undifferentiated line from maintenance medium. This study has brought us a step closer to develop genetically pure lines that could serve as new and attractive alternative ways of homogeneous controlled production of high value compounds, round the year, independent of geographical and climatic barrier. PMID:21701249

  19. Rapid determination of the hypoxanthine increase in ischemic exercise tests

    NARCIS (Netherlands)

    Bolhuis, P. A.; Zwart, R.; Bär, P. R.; de Visser, M.; van der Helm, H. J.

    1988-01-01

    After ischemic exercise tests, performed to detect glycogenoses or myoadenylate deaminase (EC 3.5.4.6) deficiency, the increases in serum lactate and ammonia usually are measured. Determination of hypoxanthine instead of ammonia can also be used to show myoadenylate deaminase deficiency, but HPLC of

  20. The rapidly increasing usefulness of social media in urogynecology.

    Science.gov (United States)

    Alas, Alexandriah; Sajadi, Kamran P; Goldman, Howard B; Anger, Jennifer T

    2013-01-01

    We assessed the availability and quality of urinary incontinence and pelvic organ prolapse information in social medias and the growth of such information in the past 13 months. We focused on the most popular social medias (Facebook, Twitter, and YouTube) to evaluate the key words "urogynecology," "pelvic organ prolapse," "stress incontinence," "urge incontinence," and "incontinence." Initial evaluation included top 30 search results for key word "incontinence" to compare with our study in 2010, followed by a secondary search using the top 100 items. Results were classified as useful or not useful and then further categorized by health care providers, others, commercial, or humorous in intent. Results with the intent of providing information were presumed to be informative. Comparative search over a 13-month period showed a stable amount of useful information, 40% to 39%, but an increase in the number of health professionals (22% vs 13%). However, of the 817 search results, 406 (50%) were medically useful. Only 28% were written by health professionals, but of the informative results, 56% were written by health professionals. Finally, specific search terms provided the highest relevant and useful information, but also limited the number of search items found. Over 13 months, there was an increase in useful information presented from health professionals. These changes may reflect the medical community's growing awareness of the usefulness of social media. If these trends continue, we predict the use of these medias for medical purposes will continue to increase among medical professionals.

  1. The rapidly increasing trend of cannabis use in burn injury.

    Science.gov (United States)

    Jehle, Charles Christopher; Nazir, Niaman; Bhavsar, Dhaval

    2015-01-01

    The use of cannabis is currently increasing according to U.S. Department of Health and Human Services (HHS). Surprisingly, cannabis use among burn patients is poorly reported in literature. In this study, rates of cannabis use in burn patients are compared with general population. Data from the National Burn Repository (NBR) were used to investigate incidence, demographics, and outcomes in relation to use of cannabis as evidenced by urine drug screen (UDS). Thousands of patients from the NBR from 2002 to 2011 were included in this retrospective study. Inclusion criteria were patients older than 12 years of age who received a drug screen. Data points analyzed were patients' age, sex, UDS status, mechanism of burn injury, total body surface area, length of stay, ICU days, and insurance characteristics. Incidence of cannabis use in burn patients from the NBR was compared against national general population rates (gathered by Health and Human Services) using chi-square tests. Additionally, the burn patient population was analyzed using bivariate analysis and t-tests to find differences in the characteristics of these patients as well as differences in outcomes. Seventeen thousand eighty out of over 112,000 patients from NBR had information available for UDS. The incidence of cannabis use is increasing among the general population, but the rate is increasing more quickly among patients in the burn patient population (P = .0022). In 2002, 6.0% of patients in burn units had cannabis+ UDS, which was comparable with national incidence of 6.2%. By 2011, 27.0% of burn patients tested cannabis+ while national incidence of cannabis use was 7.0%. Patients who test cannabis+ are generally men (80.1%, P 60% of injuries, followed by scalds that are >15%. In comparing cannabis+/- patients, cannabis+ patients are more likely to be uninsured (25.2% vs 17.26%, P burns (TBSA% of 12.94 vs 10.98, P burn units is growing quickly. These patients are younger and are less likely to be insured

  2. Rapid population increase in an introduced muskox population, West Greenland

    Directory of Open Access Journals (Sweden)

    Carsten Riis Olesen

    1993-10-01

    Full Text Available In 1962 and 1965, 27 (13 and 14 muskox yearlings were translocated from East Greenland (71°N to the Angujaartorfiup Nunaa range in West Greenland (67°N. Angujaartorfiup Nunaa is a 6600 km2 icefree, continental area where caribou are indigenous. The climate is strictly continental with a minimum of precipitation but with abundant vegetation. Aerial surveys in 1990 documented that the muskox population has increased to 2600 heads despite quota-based harvesting since 1988. The annual quota was 200, 300 and 400 for 1988, 1989 and 1990, respectively. Distribution of muskoxen shows a significant preference for low altitude habitats southeast of Kangerlussuaq Airport and around Arnangarnup Qoorua (Paradise valley. Annual population increment averages 30% and the calf crop is around 24% of the population. Yearling recruitment in the population reveals that calf mortality during winter is very limited. About half of the 1-year-old females are served and they eventually give birth to their first calf when they turn 2 years old. With half of the 2-year-old females reproducing, the calf/cow ration ranges between 0.9 and 1.0.

  3. Plasma androgens in autism.

    Science.gov (United States)

    Tordjman, S; Anderson, G M; McBride, P A; Hertzig, M E; Snow, M E; Hall, L M; Ferrari, P; Cohen, D J

    1995-06-01

    Plasma levels of testosterone and the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) were measured in male autistic subjects (31 prepubertal, 8 postpubertal), mentally retarded/cognitively impaired subjects (MR, 12 prepubertal), and normal control subjects (NC, 10 prepubertal, 11 postpubertal). Mean levels of plasma testosterone were similar in the postpubertal autistic (4.54 +/- 1.12 ng/ml) and postpubertal NC (5.02 +/- 1.87 ng/ml) groups. Plasma DHEA-S levels in postpubertal autistic (2170 +/- 1020 ng/ml) and postpubertal NC (1850 +/- 777 ng/ml) groups also were not significantly different. Similarly, no significant group differences were seen for testosterone or DHEA-S in the prepubertal autistic, MR, or NC individuals, although prepubertal MR individuals with cerebral palsy did have increased plasma DHEA-S levels compared to age-matched MR or NC individuals. Significant negative correlations were found between testosterone and whole blood serotonin (5-HT) levels in the combined (all subjects, all ages) groups and in the autistic group, suggesting that the effect of puberty on whole blood 5-HT may deserve further study. Data indicate that altered secretion of the androgens is not a common feature of autism. However, abnormalities of adrenal androgen secretion may be present in individuals with cerebral palsy.

  4. Androgen insensitivity syndrome.

    Science.gov (United States)

    Hughes, Ieuan A; Davies, John D; Bunch, Trevor I; Pasterski, Vickie; Mastroyannopoulou, Kiki; MacDougall, Jane

    2012-10-20

    Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells.

    Science.gov (United States)

    Moon, Jong-Seok; Jin, Won-Ji; Kwak, Jin-Hye; Kim, Hyo-Jeong; Yun, Mi-Jin; Kim, Jae-Woo; Park, Sahng Wook; Kim, Kyung-Sup

    2011-01-01

    Up-regulation of lipogenesis by androgen is one of the most characteristic metabolic features of LNCaP prostate cancer cells. The present study revealed that androgen increases glucose utilization for de novo lipogenesis in LNCaP cells through the activation of HK2 (hexokinase 2) and activation of the cardiac isoform of PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). Activation of PKA (cAMP-dependent protein kinase) by androgen increased phosphorylation of CREB [CRE (cAMP-response element)-binding protein], which in turn bound to CRE on the promoter of the HK2 gene resulting in transcriptional activation of the HK2 gene. Up-regulation of PFKFB2 expression was mediated by the direct binding of ligand-activated androgen receptor to the PFKFB2 promoter. The activated PI3K (phosphoinositide 3-kinase)/Akt signalling pathway in LNCaP cells contributes to the phosphorylation of PFKFB2 at Ser466 and Ser483, resulting in the constitutive activation of PFK-2 (6-phosphofructo-2-kinase) activity. Glucose uptake and lipogenesis were severely blocked by knocking-down of PFKFB2 using siRNA (small interfering RNA) or by inhibition of PFK-2 activity with LY294002 treatment. Taken together, our results suggest that the induction of de novo lipid synthesis by androgen requires the transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signalling pathway to supply the source for lipogenesis from glucose in prostate cancer cells.

  6. Androgen therapy in women.

    Science.gov (United States)

    Arlt, Wiebke

    2006-01-01

    Androgens in women either derive from direct ovarian production or from peripheral conversion of the adrenal sex steroid precursor, dehydroepiandrosterone, towards active androgens. Therefore, loss of adrenal or ovarian function, caused by Addison's disease or consequent to bilateral oophorectomy, results in severe androgen deficiency, clinically often associated with a loss of libido and energy. Importantly, physiological menopause does not necessarily lead to androgen deficiency, as androgen synthesis in the ovaries may persist despite the decline in estrogen production. However, the definition of female androgen deficiency, as recently provided by the Princeton consensus statement, is not precise enough and may lead to over-diagnosis due to the high prevalence of its diagnostic criteria: androgen levels below or within the lower quartile of the normal range and concurrent sexual dysfunction. Importantly, physiological menopause is not necessarily associated with androgen deficiency and therefore does not routinely require androgen therapy. Current replacement options include transdermal testosterone administration or dehydroepiandrosterone treatment, both of which have been shown to result in significant improvements, in particular in libido and mood, while effects on body composition and muscular function are not well documented. It is important to keep in mind that the number of randomized controlled trials is still limited and that currently none of the available preparations is officially approved for use in women. Currently, androgen replacement should be reserved for women with severe androgen deficiency due to an established cause and matching clinical signs and symptoms.

  7. Insight into the Physical and Dynamical Processes that Control Rapid Increases in Total Flash Rate

    Science.gov (United States)

    Schultz, Christopher J.; Carey, Lawrence D.; Schultz, Elise V.; Blakeslee, Richard J.; Goodman, Steven J.

    2015-01-01

    Rapid increases in total lightning (also termed "lightning jumps") have been observed for many decades. Lightning jumps have been well correlated to severe and hazardous weather occurrence. The main focus of lightning jump work has been on the development of lightning algorithms to be used in real-time assessment of storm intensity. However, in these studies it is typically assumed that the updraft "increases" without direct measurements of the vertical motion, or specification of which updraft characteristic actually increases (e.g., average speed, maximum speed, or convective updraft volume). Therefore, an end-to-end physical and dynamical basis for coupling rapid increases in total flash rate to increases in updraft speed and volume must be understood in order to ultimately relate lightning occurrence to severe storm metrics. Herein, we use polarimetric, multi-Doppler, and lightning mapping array measurements to provide physical context as to why rapid increases in total lightning are closely tied to severe and hazardous weather.

  8. Androgen deprivation-induced senescence promotes outgrowth of androgen-refractory prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Dominick G A Burton

    Full Text Available Androgen deprivation (AD is an effective method for initially suppressing prostate cancer (PC progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.

  9. Androgen-induced cell migration: role of androgen receptor/filamin A association.

    Directory of Open Access Journals (Sweden)

    Gabriella Castoria

    Full Text Available BACKGROUND: Androgen receptor (AR controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK, paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. CONCLUSIONS/SIGNIFICANCE: The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development

  10. Androgens in pregnancy: roles in parturition

    Science.gov (United States)

    Makieva, Sofia; Saunders, Philippa T.K.; Norman, Jane E.

    2014-01-01

    BACKGROUND Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (i) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (ii) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggests that actions of local steroid hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogen at the time of parturition, the bio-availability and effects of androgens during pregnancy have received less scrutiny. The aim of this review is to highlight potential roles of androgens in the biology of pregnancy and parturition. METHODS A review of published literature was performed to address (i) androgen concentrations, including biosynthesis and clearance, in maternal and fetal compartments throughout gestation, (ii) associations of androgen concentrations with adverse pregnancy outcomes, (iii) the role of androgens in the physiology of cervical remodelling and finally (iv) the role of androgens in the physiology of myometrial function including any impact on contractility. RESULTS Some, but not all, androgens increase throughout gestation in maternal circulation. The effects of this increase are not fully understood; however, evidence suggests that increased androgens might regulate key processes during pregnancy and parturition. For example, androgens are believed to be critical for cervical remodelling at term, in particular cervical ripening, via regulation of cervical collagen fibril organization. Additionally, a number of studies highlight

  11. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of

  12. Adaptive Auto-Regulation of Androgen Receptor Provides a Paradigm Shifting Rationale for Bipolar Androgen Therapy (BAT) for Castrate Resistant Human Prostate Cancer

    OpenAIRE

    Isaacs, John T.; D’Antonio, Jason M; Chen, Shuangling; Antony, Lizamma; Dalrymple, Susan P.; Ndikuyeze, Georges H.; Luo, Jun; Denmeade, Samuel R.

    2012-01-01

    Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in > 25 fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts; however, when supraphysiologic androgen is acutely replaced. Cell synchronization/anti-androgen response document this is due ...

  13. Increased corrosion resistance of the AZ80 magnesium alloy by rapid solidification.

    Science.gov (United States)

    Aghion, E; Jan, L; Meshi, L; Goldman, J

    2015-11-01

    Magnesium (Mg) and Mg-alloys are being considered as implantable biometals. Despite their excellent biocompatibility and good mechanical properties, their rapid corrosion is a major impediment precluding their widespread acceptance as implantable biomaterials. Here, we investigate the potential for rapid solidification to increase the corrosion resistance of Mg alloys. To this end, the effect of rapid solidification on the environmental and stress corrosion behavior of the AZ80 Mg alloy vs. its conventionally cast counterpart was evaluated in simulated physiological electrolytes. The microstructural characteristics were examined by optical microscopy, SEM, TEM, and X-ray diffraction analysis. The corrosion behavior was evaluated by immersion, salt spraying, and potentiodynamic polarization. Stress corrosion resistance was assessed by Slow Strain Rate Testing. The results indicate that the corrosion resistance of rapidly solidified ribbons is significantly improved relative to the conventional cast alloy due to the increased Al content dissolved in the α-Mg matrix and the correspondingly reduced presence of the β-phase (Mg17 Al12 ). Unfortunately, extrusion consolidated solidified ribbons exhibited a substantial reduction in the environmental performance and stress corrosion resistance. This was mainly attributed to the detrimental effect of the extrusion process, which enriched the iron impurities and increased the internal stresses by imposing a higher dislocation density. In terms of immersion tests, the average corrosion rate of the rapidly solidified ribbons was <0.4 mm/year compared with ∼2 mm/year for the conventionally cast alloy and 26 mm/year for the rapidly solidified extruded ribbons. © 2014 Wiley Periodicals, Inc.

  14. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

    OpenAIRE

    Abbas Yavari

    2009-01-01

    According to the International Olympic Committee, the abuse of anabolic androgenic steroids (AASS) is found in over 50% of positive doping tests. AASS abuse is not restricted to the organized sports and widespread use. It remains as an unsolved public-health problem. Lower black market price, easier access to AASS, bodybuilding clubs and internet advertising are factors of this increasingly misuse. There is not real data about the prevalence of AASS abuse in various populations or countries, ...

  15. Accessible surfaces of beta proteins increase with increasing protein molecular mass more rapidly than those of other proteins.

    Directory of Open Access Journals (Sweden)

    Anna V Glyakina

    Full Text Available Here we present a systematic analysis of accessible surface areas and hydrogen bonds of 2554 globular proteins from four structural classes (all-α, all-β, α/β and α+β proteins that is aimed to learn in which structural class the accessible surface area increases with increasing protein molecular mass more rapidly than in other classes, and what structural peculiarities are responsible for this effect. The beta structural class of proteins was found to be the leader, with the following possible explanations of this fact. First, in beta structural proteins, the fraction of residues not included in the regular secondary structure is the largest, and second, the accessible surface area of packaged elements of the beta-structure increases more rapidly with increasing molecular mass in comparison with the alpha-structure. Moreover, in the beta structure, the probability of formation of backbone hydrogen bonds is higher than that in the alpha helix for all residues of α+β proteins (the average probability is 0.73±0.01 for the beta-structure and 0.60±0.01 for the alpha-structure without proline and α/β proteins, except for asparagine, aspartic acid, glycine, threonine, and serine (0.70±0.01 for the beta-structure and 0.60±0.01 for the alpha-structure without the proline residue. There is a linear relationship between the number of hydrogen bonds and the number of amino acid residues in the protein (Number of hydrogen bonds=0.678·number of residues-3.350.

  16. Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women.

    Science.gov (United States)

    Proctor, Erica; Kidwell, Kelley M; Jiagge, Evelyn; Bensenhaver, Jessica; Awuah, Baffour; Gyan, Kofi; Toy, Kathy; Oppong, Joseph Kwaku; Kyei, Ishmael; Aitpillah, Francis; Osei-Bonsu, Ernest; Adjei, Ernest; Ohene-Yeboah, Michael; Brewer, Robert Newman; Fondjo, Linda Ahenkorah; Owusu-Afriyie, Osei; Wicha, Max; Merajver, Sofia; Kleer, Celina; Newman, Lisa

    2015-11-01

    The androgen receptor (AR) is a commonly-expressed hormone receptor in breast cancer and may be a marker of response to targeted anti-androgen therapy, a particularly attractive option for triple-negative breast cancer (TNBC). Gene expression studies suggest that ARs may distinguish a luminal/AR TNBC subtype from stem cell-like subtypes. TNBC frequency is two to three times higher in African American and African breast cancers compared with White American and European breast cancers, yet little is known regarding TNBC subtypes in high-frequency African-ancestry populations. We evaluated ARs and the mammary stem cell marker aldehyde dehydrogenase 1 (ALDH1) among breast cancers from Ghana, Africa. Overall, 147 formalin-fixed, paraffin-embedded invasive breast cancers from the Komfo Anoyke Teaching Hospital in Ghana were studied at the University of Michigan, and analyzed immunohistochemically for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, ALDH1, and AR expression. The median age of patients was 45 years. Only 31 cases (21 %) were ER-positive, and 14 (10 %) were HER2-positive; 89 (61 %) were TNBCs. For the entire group, 44 % were AR-positive and 45 % were ALDH1-positive. ER/PR-positive tumors were more likely to be AR-positive compared with ER/PR-negative tumors (87 vs. 26 %; p Africa. Surprisingly, ALDH1 was found to correlate with AR expression among TNBC, suggesting that novel TNBC subtypes may exist among populations with African ancestry.

  17. Androgen levels and female social dominance in Lemur catta.

    Science.gov (United States)

    von Engelhardt, N; Kappeler, P M; Heistermann, M

    2000-01-01

    Morphological and behavioural traits which improve agonistic power are subject to intrasexual selection and, at the proximate level, are influenced by circulating androgens. Because intrasexual selection in mammals is more intense among males, they typically dominate females. Female social dominance is therefore unexpected and, indeed, rare. Ring-tailed lemurs (Lemur catta) are sexually monomorphic primates in which all adult females dominate all males. The goal of our study was to test the prediction that female dominance in this species is associated with high androgen levels. Using two captive groups, we collected data on agonistic behaviour and non-invasively assessed their androgen concentrations in faeces and saliva by enzyme immunoassay. We found that adult female L. catta do not have higher androgen levels than males. However, during the mating season there was a twofold increase in both the androgen levels and conflict rates among females. This seasonal increase in their androgen levels was probably not due to a general increase in ovarian hormone production because those females showing the strongest signs of follicular development tended to have low androgen concentrations. At the individual level neither the individual aggression rates nor the proportion of same-sexed individuals dominated were correlated with their androgen levels. We conclude that female dominance in ring-tailed lemurs is neither based on physical superiority nor on high androgen levels and that it is equally important to study male subordination and prenatal brain priming effects for a complete understanding of this phenomenon. PMID:11007329

  18. Androgens and the ageing male

    DEFF Research Database (Denmark)

    Juul, Anders; Skakkebaek, Niels E

    2002-01-01

    Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men...... 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do...... not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial...

  19. Additive effects of dietary glycotoxins and androgen excess on the kidney of a female rat model

    Directory of Open Access Journals (Sweden)

    Sotiria Palimeri

    2016-06-01

    Conclusions: The above mentioned data suggest that dietary glycotoxins, in combination with increased androgen exposure, exert a more profound negative impact on the kidney of an androgenized female rat model that mimics the metabolic characteristics of polycystic ovary syndrome.

  20. The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer

    NARCIS (Netherlands)

    Jongen, VHWM; Sluijmer, AV; Heineman, MJ

    2002-01-01

    Postmenopausal estrogens originate from the peripheral conversion of androgens, which are produced by the adrenal glands and the ovaries. Estrogens are considered to contribute to the neoplastic development of endometrium. Hyperplasia of ovarian stroma is associated with an increased androgen

  1. Explaining the Rapid Increase in Nigeria's Sex Ratio at Birth: Factors ...

    African Journals Online (AJOL)

    AJRH Managing Editor

    This paper examines the rapid increase in Nigeria's sex ratio at birth from 1.03 boys born for every 1 girl born in each year from. 1996-2008 to 1.06 in each year from 2009-2014, second only to Tunisia in Africa at 1.07. The average sex ratio at birth in the world in 2014 was 1.07. In most Black African nations or Black majority ...

  2. Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

    Science.gov (United States)

    Díaz, P; Cardenas, H; Orihuela, P A

    2016-10-01

    We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells. © 2016 Blackwell Verlag GmbH.

  3. Rapid Adjustments Cause Weak Surface Temperature Response to Increased Black Carbon Concentrations

    Science.gov (United States)

    Stjern, Camilla Weum; Samset, Bjørn Hallvard; Myhre, Gunnar; Forster, Piers M.; Hodnebrog, Øivind; Andrews, Timothy; Boucher, Olivier; Faluvegi, Gregory; Iversen, Trond; Kasoar, Matthew; Kharin, Viatcheslav; Kirkevâg, Alf; Lamarque, Jean-François; Olivié, Dirk; Richardson, Thomas; Shawki, Dilshad; Shindell, Drew; Smith, Christopher J.; Takemura, Toshihiko; Voulgarakis, Apostolos

    2017-11-01

    We investigate the climate response to increased concentrations of black carbon (BC), as part of the Precipitation Driver Response Model Intercomparison Project (PDRMIP). A tenfold increase in BC is simulated by nine global coupled-climate models, producing a model median effective radiative forcing of 0.82 (ranging from 0.41 to 2.91) W m-2, and a warming of 0.67 (0.16 to 1.66) K globally and 1.24 (0.26 to 4.31) K in the Arctic. A strong positive instantaneous radiative forcing (median of 2.10 W m-2 based on five of the models) is countered by negative rapid adjustments (-0.64 W m-2 for the same five models), which dampen the total surface temperature signal. Unlike other drivers of climate change, the response of temperature and cloud profiles to the BC forcing is dominated by rapid adjustments. Low-level cloud amounts increase for all models, while higher-level clouds are diminished. The rapid temperature response is particularly strong above 400 hPa, where increased atmospheric stabilization and reduced cloud cover contrast the response pattern of the other drivers. In conclusion, we find that this substantial increase in BC concentrations does have considerable impacts on important aspects of the climate system. However, some of these effects tend to offset one another, leaving a relatively small median global warming of 0.47 K per W m-2—about 20% lower than the response to a doubling of CO2. Translating the tenfold increase in BC to the present-day impact of anthropogenic BC (given the emissions used in this work) would leave a warming of merely 0.07 K.

  4. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses.

    Science.gov (United States)

    Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian; Banasr, Mounira; Li, Nanxin; Terwilliger, Rose; Sanacora, Gerard; Eid, Tore; Aghajanian, George; Duman, Ronald S

    2013-11-15

    Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of N-methyl-D-aspartate receptor antagonists. The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and two-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and glutamate receptor inhibitors. The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist. Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to N-methyl-D-aspartate receptor antagonists. These findings provide novel targets for safer and more efficacious rapid-acting antidepressant agents. © 2013 Society of Biological Psychiatry.

  5. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Shtutman Michael

    2010-04-01

    Full Text Available Abstract Background Castration resistant prostate cancer (CRPC develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI prostate cancer cells. Results Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881 restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to

  6. Androgen therapy with dehydroepiandrosterone.

    Science.gov (United States)

    Buvat, Jacques

    2003-11-01

    The physiological role of dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) is poorly understood. It depends in a large part on their transformation into testosterone and estradiol. The capacity of DHEA as a neurosteroid, the recent discovery of putative specific DHEA receptors on endothelial and vascular smooth muscle cells, the steady decrease of DHEA production from the 40s on, together with certain human epidemiologic data as well as various beneficial effects of DHA supplementation in rodents have suggested the possibility that this steroid is involved in cognitive and memory, metabolic and vascular, immune and sexual functions and in their aging. However, epidemiologic studies are conflicting, and no well-designed clinical trials have definitely substantiated the role of DHEA in these functions in humans, or the utility and safety of DHEA supplementation. However, beneficial effects seem plausible in women with several conditions according to the results of double-blind placebo-controlled trials: the dose of 30 to 50 mg seems beneficial to the mood, sense of well being and sexual desire and activity of women with adrenal insufficiency. The only long-term trial of supplementation devoted to women over 60 reported significant increases in bone mineral density and, in the 70-79-year-old subgroup, in sexual desire, arousal, activity and satisfaction. The dose of 200 mg also proved to decrease disease activity in systemic lupus erythematosus. Lastly, high DHEA doses have improved mood in various groups of patients of any age and gender with depressive symptoms. The use of DHEA therapy may also be discussed in women of any age when a trial of androgen supplementation seems justified because of the existence of an inhibited sexual desire or a sexual arousal disorder associated with documented androgen deficiency. The rather weak conversion of DHEA into testosterone protects from the risk of overdosing associated with testosterone preparations. However, it must

  7. Additive effects of dietary glycotoxins and androgen excess on the ...

    African Journals Online (AJOL)

    ... not significantly differ among the two groups. Conclusions: The above mentioned data suggest that dietary glycotoxins, in combination with increased androgen exposure, exert a more profound negative impact on the kidney of an androgenized female rat model that mimics the metabolic characteristics of polycystic ovary ...

  8. In the mood for sex : The value of androgens

    NARCIS (Netherlands)

    Apperloo, MJA; Van der Stege, JG; Hoek, A; Schultz, WCMW

    2003-01-01

    Androgen substitution is increasingly being employed to enhance sexual desire in women based on the assumption that low androgen levels cause low sexual desire, Sexual functioning in women is complex; therefore, decreased sexual interest can have various causes. An adequate female sexual

  9. Rapid increases in training load affects markers of skeletal muscle damage and mechanical performance

    DEFF Research Database (Denmark)

    Kamandulis, Sigitas; Snieckus, Audrius; Venckunas, Tomas

    2012-01-01

    a program involving a rapid stepwise increase in the number of jumps, drop height, and squat depth, and the addition of weight. Concentric, isometric maximal voluntary contraction (MVC), and stimulated knee extension torque were measured before and 10 min after each session. Muscle soreness and plasma...... creatine kinase activity were assessed after each session. Steep increments in stretch-shortening exercise load in sessions 4 and 7 amplified the postexercise decrease in stimulated muscle torque and slightly increased muscle soreness but had a minimal effect on the recovery of MVC and stimulated torque......The aim of the present study was to monitor the changes in indirect markers of muscle damage during 3 weeks (nine training sessions) of stretch-shortening (drop jump) exercise with constant load alternated with steep increases in load. Physically active men (n = 9, mean age 19.1 years) performed...

  10. Biochemical characterization of a membrane androgen receptor in the ovary of the atlantic croaker (Micropogonias undulatus).

    Science.gov (United States)

    Braun, Alyssa M; Thomas, Peter

    2004-07-01

    Membrane androgen receptors have been biochemically characterized in only a few vertebrate species to date. Therefore, the purpose of the current study was to comprehensively investigate the binding characteristics of a putative membrane androgen receptor in the ovary of the teleost, Atlantic croaker (Micropogonias undulatus). Specific androgen binding to an ovarian plasma membrane fraction was demonstrated using a radioreceptor assay protocol consisting of a short-term incubation with [(3)H]testosterone (T) and subsequent filtration of bound steroid from free steroid. Saturation and Scatchard analyses of T binding to an ovarian plasma membrane fraction indicated the presence of a single, high-affinity (K(d) = 15.32 +/- 2.68 nM [mean +/- SEM]), low-capacity (B(max) = 2.81 +/- 0.31 pmol/mg protein), androgen-binding site. Specific androgen binding to the receptor was readily displaceable, and the association and dissociation kinetics were rapid (half-time = 3.7 +/- 1.7 and 4.7 +/- 0.2 min, respectively). Competitive binding assays showed that 5alpha-dihydrotestosterone, T, and 11-ketotestosterone had relative binding affinities (RBAs) of 193%, 100%, and 13%, respectively, whereas none of the C(18) or C(21) steroids tested bound with high affinity except for progesterone (RBA = 191%). This androgen-binding moiety with high affinity for progesterone is unlikely to mediate the physiological actions of progestins in croaker, because it has low binding affinity for fish progestin hormones. Androgen-binding sites were also detected in membrane fractions of the brain, liver, kidney, and drumming muscle, whereas little or no binding was detected in the trunk muscle, heart, gills, or intestine. Receptor levels increased 10-fold during ovarian recrudescence, reaching maximum levels in fully mature ovaries, which suggests a likely physiological role for this receptor during the reproductive cycle of female croaker. It is concluded that the androgen-binding moiety identified in

  11. Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein.

    Science.gov (United States)

    Gao, Shuai; Gao, Yanfei; He, Housheng Hansen; Han, Dong; Han, Wanting; Avery, Amy; Macoska, Jill A; Liu, Xiaming; Chen, Sen; Ma, Fen; Chen, Shaoyong; Balk, Steven P; Cai, Changmeng

    2016-10-18

    Although well characterized as a transcriptional activator that drives prostate cancer (PCa) growth, androgen receptor (AR) can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb). Significantly, AR also indirectly increases the expression of DNA replication genes through stimulatory effects on other metabolic genes with subsequent CDK activation and Rb hyperphosphorylation. In castration-resistant PCa cells, which are dependent on high-level AR expression, this anti-proliferative repression function might be exploited through treatment with androgen in combination with agents that suppress AR-driven metabolic functions or cell cycle progression. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Androgen Receptor Tumor Suppressor Function Is Mediated by Recruitment of Retinoblastoma Protein

    Directory of Open Access Journals (Sweden)

    Shuai Gao

    2016-10-01

    Full Text Available Although well characterized as a transcriptional activator that drives prostate cancer (PCa growth, androgen receptor (AR can function as a transcriptional repressor, and high-level androgens can suppress PCa proliferation. The molecular basis for this repression activity remains to be determined. Genes required for DNA replication are highly enriched among androgen-repressed genes, and AR is recruited to the majority of these genes, where it rapidly represses their transcription. This activity is enhanced in PCa cells expressing high AR levels and is mediated by recruitment of hypophosphorylated retinoblastoma protein (Rb. Significantly, AR also indirectly increases the expression of DNA replication genes through stimulatory effects on other metabolic genes with subsequent CDK activation and Rb hyperphosphorylation. In castration-resistant PCa cells, which are dependent on high-level AR expression, this anti-proliferative repression function might be exploited through treatment with androgen in combination with agents that suppress AR-driven metabolic functions or cell cycle progression.

  13. Androgen therapy and atherosclerotic cardiovascular disease

    Directory of Open Access Journals (Sweden)

    K-CY McGrath

    2008-02-01

    Full Text Available K-CY McGrath1, LS McRobb1,2, AK Heather1,21Heart Research Institute, Camperdown, NSW, Australia; 2Discipline of Medicine, University of Sydney, Sydney, NSW, AustraliaAbstract: Cardiovascular disease (CVD remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie.

  14. Changing arctic ecosystems—What is causing the rapid increase of snow geese in northern Alaska?

    Science.gov (United States)

    Hupp, Jerry W.; Ward, David H.; Whalen, Mary E.; Pearce, John M.

    2015-09-10

    Through the Changing Arctic Ecosystems (CAE) initiative, the U.S. Geological Survey (USGS) informs key resource management decisions for Arctic Alaska by providing scientific information on current and future ecosystem response to a warming climate. The Arctic Coastal Plain (ACP) of northern Alaska is a key study area within the USGS CAE initiative. This region has experienced a warming trend over the past decades, leading to decreased sea ice, permafrost thaw, and an advancement of spring phenology. The number of birds on the ACP also is changing, marked by increased populations of the four species of geese that nest in the region. The Snow Goose (Chen caerulescens) is the most rapidly increasing of these species. USGS CAE research is quantifying these changes and their implications for management agencies.

  15. Rapid Environmental Change Drives Increased Land Use by an Arctic Marine Predator.

    Directory of Open Access Journals (Sweden)

    Todd C Atwood

    Full Text Available In the Arctic Ocean's southern Beaufort Sea (SB, the length of the sea ice melt season (i.e., period between the onset of sea ice break-up in summer and freeze-up in fall has increased substantially since the late 1990s. Historically, polar bears (Ursus maritimus of the SB have mostly remained on the sea ice year-round (except for those that came ashore to den, but recent changes in the extent and phenology of sea ice habitat have coincided with evidence that use of terrestrial habitat is increasing. We characterized the spatial behavior of polar bears spending summer and fall on land along Alaska's north coast to better understand the nexus between rapid environmental change and increased use of terrestrial habitat. We found that the percentage of radiocollared adult females from the SB subpopulation coming ashore has tripled over 15 years. Moreover, we detected trends of earlier arrival on shore, increased length of stay, and later departure back to sea ice, all of which were related to declines in the availability of sea ice habitat over the continental shelf and changes to sea ice phenology. Since the late 1990s, the mean duration of the open-water season in the SB increased by 36 days, and the mean length of stay on shore increased by 31 days. While on shore, the distribution of polar bears was influenced by the availability of scavenge subsidies in the form of subsistence-harvested bowhead whale (Balaena mysticetus remains aggregated at sites along the coast. The declining spatio-temporal availability of sea ice habitat and increased availability of human-provisioned resources are likely to result in increased use of land. Increased residency on land is cause for concern given that, while there, bears may be exposed to a greater array of risk factors including those associated with increased human activities.

  16. Methamphetamine induces a rapid increase of intracellular Ca(++) levels in neurons overexpressing GCaMP5.

    Science.gov (United States)

    Yu, Seong-Jin; Wu, Kou-Jen; Bae, Eun K; Hsu, Man-Jung; Richie, Christopher T; Harvey, Brandon K; Wang, Yun

    2016-03-01

    In this study, methamphetamine (Meth)- and glutamate (Glu)-mediated intracellular Ca(++) (Ca(++) i) signals were examined in real time in primary cortical neurons overexpressing an intracellular Ca(++) probe, GCaMP5, by adeno-associated viral (AAV) serotype 1. Binding of Ca(++) to GCaMP increased green fluorescence intensity in cells. Both Meth and Glu induced a rapid increase in Ca(++) i, which was blocked by MK801, suggesting that Meth enhanced Ca(++) i through Glu receptor in neurons. The Meth-mediated Ca(++) signal was also blocked by Mg(++) , low Ca(++) or the L-type Ca(++) channel inhibitor nifedipine. The ryanodine receptor inhibitor dantrolene did not alter the initial Ca(++) influx but partially reduced the peak of Ca(++) i. These data suggest that Meth enhanced Ca(++) influx through membrane Ca(++) channels, which then triggered the release of Ca(++) from the endoplasmic reticulum in the cytosol. AAV-GCaMP5 was also injected to the parietal cortex of adult rats. Administration of Meth enhanced fluorescence in the ipsilateral cortex. Using immunohistochemistry, Meth-induced green fluorescence was found in the NeuN-containing cells in the cortex, suggesting that Meth increased Ca(++) in neurons in vivo. In conclusion, we have used in vitro and in vivo techniques to demonstrate a rapid increase of Ca(++) i by Meth in cortical neurons through overexpression of GCaMP5. As Meth induces behavioral responses and neurotoxicity through Ca(++) i, modulation of Ca(++) i may be useful to reduce Meth-related reactions. © 2014 Society for the Study of Addiction.

  17. A clinical syndrome of mild androgen insensitivity.

    Science.gov (United States)

    Migeon, C J; Brown, T R; Lanes, R; Palacios, A; Amrhein, J A; Schoen, E J

    1984-10-01

    We studied four patients from three kindreds who had normal male body habitus and external genitalia except for short penile length and gynecomastia. Prostate size was small in all patients and spermatogenesis was decreased markedly in one and absent in three. Testicular biopsies in two patients revealed normal histology but evidence of spermatogenic arrest at the spermatocyte stage. Circulating levels of testosterone and LH were increased and the testosterone-dihydrotestosterone ratios were normal. Plasma estradiol was elevated in three of the four patients. Serum FSH levels were significantly elevated in only one patient. The response of LH and FSH to LHRH stimulation was normal in the two patients who were tested. Despite the normal male phenotype, the laboratory studies suggested the diagnosis of androgen insensitivity. This was confirmed in two patients by finding decreased dihydrotestosterone-binding capacity in genital skin fibroblasts. Two of the patients had normal levels of androgen receptor binding, suggesting that their defect represented a mild form of androgen insensitivity with normal receptor activity. These results demonstrated that mild forms of androgen insensitivity exist in which the only obvious clinical manifestations may be the presence of reduced penile length, gynecomastia, and/or infertility. The incidence of androgen insensitivity among men with these subtle phenotypic abnormalities, including infertility, remains to be determined.

  18. Total daily activity declines more rapidly with increasing age in older adults.

    Science.gov (United States)

    Buchman, Aron S; Wilson, Robert S; Yu, Lei; James, Bryan D; Boyle, Patricia A; Bennett, David A

    2014-01-01

    Longitudinal studies of objectively measured physical activity are lacking in older adults. We tested whether objective measures of total daily activity decline more rapidly in older adults. This prospective, observational cohort study included 519 community-dwelling older persons from across metropolitan Chicago participating in the Rush Memory and Aging Project. Repeated total daily activity measures (leisure and non-leisure physical activity) were derived from actigraphic recordings for up to 10 days. Generalized estimating equation models which controlled for demographics measures were employed. At baseline, age was inversely related with the level of total daily activity (estimate, -0.014, S.E. 0.002, pdaily activity declined by about 0.070 × 10(5) activity counts/day/yr (estimate -0.065, S.E. 0.005, pdaily activity declined 3% more rapidly for each additional year of age at baseline (estimate -0.002, S.E. 0.001, p=0.027). Thus, total daily activity declined almost twice as fast in an individual 91 years old at baseline versus an individual 71 years old. A higher level of education was associated with a slower rate of decline (estimate 0.004, S.E. 0.002, pdaily activity were unchanged when controlling for baseline level of motor and cognitive function, other late-life activities and chronic health conditions. These data suggest that total daily activity in very old adults declines more rapidly with increasing age. Thus, physical inactivity is likely to become a larger problem in our aging population. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Androgens and Hypertension in Men and Women: a Unifying View.

    Science.gov (United States)

    Moretti, Costanzo; Lanzolla, Giulia; Moretti, Marta; Gnessi, Lucio; Carmina, Enrico

    2017-05-01

    This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be

  20. Small Projects Rapid Integration and Test Environment (SPRITE): Application for Increasing Robutness

    Science.gov (United States)

    Lee, Ashley; Rakoczy, John; Heather, Daniel; Sanders, Devon

    2013-01-01

    Over the past few years interest in the development and use of small satellites has rapidly gained momentum with universities, commercial, and government organizations. In a few years we may see networked clusters of dozens or even hundreds of small, cheap, easily replaceable satellites working together in place of the large, expensive and difficult-to-replace satellites now in orbit. Standards based satellite buses and deployment mechanisms, such as the CubeSat and Poly Pico-satellite Orbital Deployer (P-POD), have stimulated growth in this area. The use of small satellites is also proving to be a cost effective capability in many areas traditionally dominated by large satellites, though many challenges remain. Currently many of these small satellites undergo very little testing prior to flight. As these small satellites move from technology demonstration and student projects toward more complex operational assets, it is expected that the standards for verification and validation will increase.

  1. Illicit use of androgens and other hormones: recent advances.

    Science.gov (United States)

    Kanayama, Gen; Pope, Harrison G

    2012-06-01

    To summarize recent advances in studies of illicit use of androgens and other hormones. Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

  2. Integrated omics approaches provide strategies for rapid erythromycin yield increase in Saccharopolyspora erythraea.

    Science.gov (United States)

    Karničar, Katarina; Drobnak, Igor; Petek, Marko; Magdevska, Vasilka; Horvat, Jaka; Vidmar, Robert; Baebler, Špela; Rotter, Ana; Jamnik, Polona; Fujs, Štefan; Turk, Boris; Fonovič, Marko; Gruden, Kristina; Kosec, Gregor; Petković, Hrvoje

    2016-06-03

    Omics approaches have significantly increased our understanding of biological systems. However, they have had limited success in explaining the dramatically increased productivity of commercially important natural products by industrial high-producing strains, such as the erythromycin-producing actinomycete Saccharopolyspora erythraea. Further yield increase is of great importance but requires a better understanding of the underlying physiological processes. To reveal the mechanisms related to erythromycin yield increase, we have undertaken an integrated study of the genomic, transcriptomic, and proteomic differences between the wild type strain NRRL2338 (WT) and the industrial high-producing strain ABE1441 (HP) of S. erythraea at multiple time points of a simulated industrial bioprocess. 165 observed mutations lead to differences in gene expression profiles and protein abundance between the two strains, which were most prominent in the initial stages of erythromycin production. Enzymes involved in erythromycin biosynthesis, metabolism of branched chain amino acids and proteolysis were most strongly upregulated in the HP strain. Interestingly, genes related to TCA cycle and DNA-repair were downregulated. Additionally, comprehensive data analysis uncovered significant correlations in expression profiles of the erythromycin-biosynthetic genes, other biosynthetic gene clusters and previously unidentified putative regulatory genes. Based on this information, we demonstrated that overexpression of several genes involved in amino acid metabolism can contribute to increased yield of erythromycin, confirming the validity of our systems biology approach. Our comprehensive omics approach, carried out in industrially relevant conditions, enabled the identification of key pathways affecting erythromycin yield and suggests strategies for rapid increase in the production of secondary metabolites in industrial environment.

  3. Rapid Maxillary Expansion Increases Internal Nasal Dimensions of Children With Bilateral Cleft Lip and Palate.

    Science.gov (United States)

    Trindade-Suedam, Ivy Kiemle; Castilho, Ricardo Leão; Sampaio-Teixeira, Ana Claudia Martins; Araújo, Bruna Mara Adorno Marmotel; Fukushiro, Ana Paula; Campos, Letícia Dominguez; Trindade, Inge Elly Kiemle

    2016-05-01

    The transverse maxillary deficiency frequently observed in patients with cleft lip and palate (CLP) is usually treated by rapid maxillary expansion (RME). Considering that RME causes a significant increase of the internal nasal dimensions in children with unilateral CLP (UCLP), this study aimed to characterize the internal nasal geometry of children with bilateral CLP (BCLP) and transverse maxillary deficiency using acoustic rhinometry. The study also aimed to analyze changes caused by RME. Cross-sectional prospective study. Laboratory of Physiology, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, SP, Brazil. Fifteen children with repaired BCLP of both genders, aged 8 to 15 years, referred for RME, were prospectively analyzed. Subjects underwent acoustic rhinometry before the expander installation and after the active phase of expansion. Cross-sectional areas (CSA) and volumes (V) of the nasal valve regions (CSA1 and V1) and turbinates (CSA2, CSA3, and V2), were measured after nasal decongestion. In the majority of the subjects, an increase of internal nasal dimensions was observed. Percent changes of CSA1, CSA2, CSA3, V1, and V2 were: +25%, +11%, +9%, 20%, and +12%, respectively. Differences were significant for all variables studied, except CSA3 (P < .05). RME promotes an increase in the internal nasal dimensions of children with BCLP, suggesting that RME is capable of substantially improving nasal patency in this population.

  4. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects

    OpenAIRE

    Chowdhury, Golam M.I.; Zhang, Jie; Thomas, Monique; Banasr, Mounira; Ma, Xiaoxian; Pittman, Brian; Bristow, Linda; Schaeffer, Eric; Duman, Ronald; Rothman, Douglas; Behar, Kevin; Sanacora, Gerard

    2016-01-01

    Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in medial prefronal cortex (mPFC) of awak...

  5. Effects of 17β-Estradiol and Androgen on Glucose Metabolism in Skeletal Muscle.

    Science.gov (United States)

    Inada, Akari; Fujii, Nobuharu L; Inada, Oogi; Higaki, Yasuki; Furuichi, Yasuro; Nabeshima, Yo-Ichi

    2016-12-01

    Diabetes develops predominantly in males in experimental models, and extensive evidence suggests that 17β-estradiol (E2) modulates progression of diabetes in humans. We previously developed a severely diabetic transgenic (Tg) mouse model by β-cell-specific overexpression of inducible cAMP early repressor (ICER) and found that male ICER-Tg mice exhibit sustained severe hyperglycemia, but female ICER-Tg mice gradually became normoglycemic with aging. This implies that differences in circulating androgen and E2 levels might influence skeletal muscle glucose uptake and glycemic status. Here we examined whether a decrease of androgen or E2 excess can improve muscle glucose uptake in hyperglycemic male ICER-Tg mice and, conversely, whether a decrease of E2 or androgen excess can elevate blood glucose levels and impair muscle glucose uptake in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX) or ORX+E2 pellet implantation and normoglycemic female ICER-Tg mice with ovariectomy (OVX) or OVX+5α-DHT pellet implantation to alter the androgen to E2 ratio. ORX+E2 treatment of male ICER-Tg mice caused a rapid drop in blood glucose via both a dramatic increase of β-cells and significantly improved muscle glucose uptake due to the induction of glucose transporter type 4 (GLUT4) expression and translocation of GLUT4 to the cell membrane. In contrast, OVX+5α-DHT-treated female ICER-Tg mice showed an elevation of blood glucose without any decrease of β-cells; instead, they showed decreased muscle glucose uptake due to decreased activation of serine/threonine-specific protein kinase AKT and GLUT4 expression. These findings suggest that androgen (5α-DHT) promotes insulin resistance in females, whereas E2 improves insulin sensitivity in severely diabetic male mice.

  6. The impact of increased loading rate on granular media, rapid depth filtration of wastewater.

    Science.gov (United States)

    Williams, Gordon J; Sheikh, Bahman; Holden, Robert B; Kouretas, Tom J; Nelson, Kara L

    2007-11-01

    The impact of loading rate on tertiary filtration of wastewater was studied using a pilot-scale, dual-media, rapid depth filtration system. Loading rates of 12.2, 15.3, 18.3, 21.4, and 24.4m/h were tested on parallel filter columns treating the same coagulated secondary wastewater to determine the impact on removal of turbidity, particles (2-15 microm), total coliform bacteria, Escherichia coli, and MS2 bacteriophage, as well as on the particle deposition profile in the filter bed. Increasing the loading rate from 12.2 to 24.4m/h decreased the removal efficiencies for all metrics. The observed impact of loading rate on particle removal was similar to that predicted by a clean-bed filtration model, although the model significantly underestimated the removal efficiencies of the smaller particles. For two loading rates, 12.2 and 18.3m/h, the effect of coagulant dose was also studied; the negative impact of loading rate on removal efficiency was eliminated by increasing the coagulant dose for the higher loading rate, which also resulted in removal of particles deeper in the filter bed. For all conditions studied, loading rate had no observable impact on the ability to disinfect filter effluents with chloramines. The results of this research indicate that loading rates higher than those typically used in tertiary filtration can produce acceptable effluent quality, and support a regulatory approach based on filter effluent turbidity.

  7. Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro

    Directory of Open Access Journals (Sweden)

    Weitao Song

    2014-12-01

    Full Text Available For more than 70 years, it has been believed that a severe reduction of serum androgen levels caused regression of prostate cancer (PCa and that increasing androgen levels enhanced growth of PCa. However, numerous recent studies have questioned this traditional belief. In our study, LNCaP and MDA PCa 2b PCa cells were treated with various levels of androgens for 10 or 20 days, and the cell growth was measured with crystal violet mitogenic assay. The results indicated that the effect of androgens on the proliferation of PCa cells occurs in a biphasic pattern, with the androgen levels promoting optimal cell growth at approximately 0.23 ng ml−1 for LNCaP cells and between 1 and 2 ng ml−1 for MDA PCa 2b cells. Both of the optimal androgen levels are within the adult men's physiological low range (<2.4 ng ml−1 . At lower concentrations than the optimal androgen level, increasing androgen concentration promoted the proliferation of PCa cells. However, at the higher concentrations, increasing androgen concentration resulted in a dose-dependent proliferative inhibition. We conclude that physiologically normal levels of androgen inhibit the proliferation of PCa cells in vitro. However, at very low levels androgens are essential for initial growth of PCa cells.

  8. Dermatologists and anabolic-androgenic drug abuse.

    Science.gov (United States)

    Scott, M J; Scott, M J

    1989-07-01

    The use of huge self-administered dosages of anabolic-androgenic steroids by athletes and body builders is widespread in the United States, increasing at a rapid rate among athletes of both sexes and involving an ever-expanding age group. Athletes are very wary of revealing steroid use to their physicians, so a high index of suspicion is a prerequisite in diagnosing the use of these agents. Since many of the side effects of steroids are manifested in the skin, dermatologists are in a unique and favorable position to detect their use, if they are aware of such clinical signs. Once alerted to this possibility during a dermatologic examination, the dermatologist has an excellent opportunity to make users aware of the potential hazards and dangers of taking such drugs. Counselling these athletes can do much to stem the tide against the rising problem of drug abuse. It is a worthwhile service to sports in general as well as to the patient's personal health. Many of our conclusions are based on our personal experience with elite and Olympic athletes in almost every sport, body builders, and junior high school, high school, and college students and athletes.

  9. Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gorin Frederic A

    2005-03-01

    Full Text Available Abstract Background Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. Methods We investigated the effects of androgen on glycogen phosphorylase (GP, glycogen synthase (GS and on glycogen accumulation in the androgen-receptor (AR reconstituted PC3 cell line containing either an empty vector (PC3-AR-V or vector with HPV-E7 (PC3-AR-E7 and the LNCaP cell line. Results Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. Conclusion Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence.

  10. Rapid increase of near atomic resolution virus capsid structures determined by cryo-electron microscopy.

    Science.gov (United States)

    Ho, Phuong T; Reddy, Vijay S

    2017-10-27

    The recent technological advances in electron microscopes, detectors, as well as image processing and reconstruction software have brought single particle cryo-electron microscopy (cryo-EM) into prominence for determining structures of bio-molecules at near atomic resolution. This has been particularly true for virus capsids, ribosomes, and other large assemblies, which have been the ideal specimens for structural studies by cryo-EM approaches. An analysis of time series metadata of virus structures on the methods of structure determination, resolution of the structures, and size of the virus particles revealed a rapid increase in the virus structures determined by cryo-EM at near atomic resolution since 2010. In addition, the data highlight the median resolution (∼3.0 Å) and size (∼310.0 Å in diameter) of the virus particles determined by X-ray crystallography while no such limits exist for cryo-EM structures, which have a median diameter of 508 Å. Notably, cryo-EM virus structures in the last four years have a median resolution of 3.9 Å. Taken together with minimal sample requirements, not needing diffraction quality crystals, and being able to achieve similar resolutions of the crystal structures makes cryo-EM the method of choice for current and future virus capsid structure determinations. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Settling into an increasingly hostile world: the rapidly closing "recruitment window" for corals.

    Science.gov (United States)

    Arnold, Suzanne N; Steneck, Robert S

    2011-01-01

    Free space is necessary for larval recruitment in all marine benthic communities. Settling corals, with limited energy to invest in competitive interactions, are particularly vulnerable during settlement into well-developed coral reef communities. This situation may be exacerbated for corals settling into coral-depauperate reefs where succession in nursery microhabitats moves rapidly toward heterotrophic organisms inhospitable to settling corals. To study effects of benthic organisms (at millimeter to centimeter scales) on newly settled corals and their survivorship we deployed terra-cotta coral settlement plates at 10 m depth on the Mesoamerican Barrier Reef in Belize and monitored them for 38 mo. During the second and third years, annual recruitment rates declined by over 50% from the previous year. Invertebrate crusts (primarily sponges) were absent at the start of the experiment but increased in abundance annually from 39, 60, to 73% of the plate undersides by year three. Subsequently, substrates hospitable to coral recruitment, including crustose coralline algae, biofilmed terra-cotta and polychaete tubes, declined. With succession, substrates upon which spat settled shifted toward organisms inimical to survivorship. Over 50% of spat mortality was due to overgrowth by sponges alone. This result suggests that when a disturbance creates primary substrate a "recruitment window" for settling corals exists from approximately 9 to 14 mo following the disturbance. During the window, early-succession, facilitating species are most abundant. The window closes as organisms hostile to coral settlement and survivorship overgrow nursery microhabitats.

  12. Settling into an increasingly hostile world: the rapidly closing "recruitment window" for corals.

    Directory of Open Access Journals (Sweden)

    Suzanne N Arnold

    Full Text Available Free space is necessary for larval recruitment in all marine benthic communities. Settling corals, with limited energy to invest in competitive interactions, are particularly vulnerable during settlement into well-developed coral reef communities. This situation may be exacerbated for corals settling into coral-depauperate reefs where succession in nursery microhabitats moves rapidly toward heterotrophic organisms inhospitable to settling corals. To study effects of benthic organisms (at millimeter to centimeter scales on newly settled corals and their survivorship we deployed terra-cotta coral settlement plates at 10 m depth on the Mesoamerican Barrier Reef in Belize and monitored them for 38 mo. During the second and third years, annual recruitment rates declined by over 50% from the previous year. Invertebrate crusts (primarily sponges were absent at the start of the experiment but increased in abundance annually from 39, 60, to 73% of the plate undersides by year three. Subsequently, substrates hospitable to coral recruitment, including crustose coralline algae, biofilmed terra-cotta and polychaete tubes, declined. With succession, substrates upon which spat settled shifted toward organisms inimical to survivorship. Over 50% of spat mortality was due to overgrowth by sponges alone. This result suggests that when a disturbance creates primary substrate a "recruitment window" for settling corals exists from approximately 9 to 14 mo following the disturbance. During the window, early-succession, facilitating species are most abundant. The window closes as organisms hostile to coral settlement and survivorship overgrow nursery microhabitats.

  13. Tricalcium phosphate nanoparticles enable rapid purification, increase transduction kinetics, and modify the tropism of mammalian viruses.

    Science.gov (United States)

    Dreesen, Imke A J; Lüchinger, Norman A; Stark, Wendelin J; Fussenegger, Martin

    2009-03-01

    Adenoviral, adeno-associated viral, and retroviral particles are chosen as gene delivery shuttles in more than 50% of all gene therapy clinical trials. Bulk availability of clinical-grade viral particles and their efficiency to transduce the therapeutic cargo into specific target cells remain the most critical bottlenecks in gene therapy applications to date. Capitalizing on the flame-spray technology for the reproducible economic large-scale production of amorphous tricalcium phosphate nanoparticulate powders (ATCP), we designed a scalable ready-to-use gravity-flow column set-up for the straightforward concentration and purification of transgenic adenoviral, adeno-associated viral, and lentiviral particles. Specific elution buffers enabled rapid release of viral particles from the ATCP matrix of the column and provided high-titer virus preparations in an unsurpassed period of time. The interaction of ATCP with adenoviral, adeno-associated viral, and lentiviral particles in solution increased the transduction kinetics of several mammalian cell lines in culture. The nanoparticles were also able to modify the tropism of murine leukemia virus (MLV) towards transduction of human cells. Based on these findings, we believe that the use of flame-spray tricalcium phosphate nanoparticles will lead to important progress in the development of future gene therapy initiatives.

  14. Learning new color names produces rapid increase in gray matter in the intact adult human cortex.

    Science.gov (United States)

    Kwok, Veronica; Niu, Zhendong; Kay, Paul; Zhou, Ke; Mo, Lei; Jin, Zhen; So, Kwok-Fai; Tan, Li Hai

    2011-04-19

    The human brain has been shown to exhibit changes in the volume and density of gray matter as a result of training over periods of several weeks or longer. We show that these changes can be induced much faster by using a training method that is claimed to simulate the rapid learning of word meanings by children. Using whole-brain magnetic resonance imaging (MRI) we show that learning newly defined and named subcategories of the universal categories green and blue in a period of 2 h increases the volume of gray matter in V2/3 of the left visual cortex, a region known to mediate color vision. This pattern of findings demonstrates that the anatomical structure of the adult human brain can change very quickly, specifically during the acquisition of new, named categories. Also, prior behavioral and neuroimaging research has shown that differences between languages in the boundaries of named color categories influence the categorical perception of color, as assessed by judgments of relative similarity, by response time in alternative forced-choice tasks, and by visual search. Moreover, further behavioral studies (visual search) and brain imaging studies have suggested strongly that the categorical effect of language on color processing is left-lateralized, i.e., mediated by activity in the left cerebral hemisphere in adults (hence "lateralized Whorfian" effects). The present results appear to provide a structural basis in the brain for the behavioral and neurophysiologically observed indices of these Whorfian effects on color processing.

  15. Androgen receptor characteristics in skin fibroblasts from hirsute women.

    Science.gov (United States)

    Eil, C; Cutler, G B; Loriaux, D L

    1985-01-01

    Hormonal measurements in some women with hirsutism often reveal little or no elevation in androgen levels to explain the disorder. Thus, it has been postulated that increased sensitivity of the hair follicle to androgen may contribute to the development of hirsutism in such patients. We, therefore, sought androgen receptor abnormalities in skin fibroblasts cultured from 10 hirsute women (ages 17-43) and normal or mildly elevated plasma testosterone levels (28-82 ng/dl). Androgen receptor content (Ro) and binding affinity (Kd) in cultured pubic skin fibroblasts were measured using a dispersed, whole cell assay. Ten such cell lines from these women were compared with 19 pubic skin cell lines from 9 normal volunteers (6 males and 3 females) and from 10 other subjects (males with gynecomastia or hypospadias). There was no statistically significant difference in the mean androgen receptor content (11,600 +/- 2700 (SE) sites/cell fibroblasts vs 7900 +/- 700 sites/cell or binding affinity (2.0 +/- 0.3 (SE) X 10(-9) M vs 1.5 +/- 0.2 X 10(-9) M, respectively) between the patients' fibroblasts and those of the controls. We conclude that hirsutism cannot be explained by abnormalities in fibroblast androgen receptor number or affinity. These observations do not exclude the possibility that other mechanisms might lead to increased peripheral androgen sensitivity in such patients.

  16. Increased Sensitivity of a New Coagglutination Test for Rapid Identification of Haemophilus influenzae Type b

    OpenAIRE

    Grasso, Robert J.; West, Loyd A.; Holbrook, Nikki J.; Halkias, Demetrios G.; Paradise, Lois J.; Friedman, Herman

    1981-01-01

    A newly developed rapid coagglutination test for identifying Haemophilus influenzae type b organisms isolated from clinical specimens correlated 100% with the slide agglutination test but was 100- to 200-fold more sensitive.

  17. Small Projects Rapid Integration and Test Environment (SPRITE): Application for Increasing Robustness

    Science.gov (United States)

    Rakoczy, John; Heater, Daniel; Lee, Ashley

    2013-01-01

    Marshall Space Flight Center's (MSFC) Small Projects Rapid Integration and Test Environment (SPRITE) is a Hardware-In-The-Loop (HWIL) facility that provides rapid development, integration, and testing capabilities for small projects (CubeSats, payloads, spacecraft, and launch vehicles). This facility environment focuses on efficient processes and modular design to support rapid prototyping, integration, testing and verification of small projects at an affordable cost, especially compared to larger type HWIL facilities. SPRITE (Figure 1) consists of a "core" capability or "plant" simulation platform utilizing a graphical programming environment capable of being rapidly re-configured for any potential test article's space environments, as well as a standard set of interfaces (i.e. Mil-Std 1553, Serial, Analog, Digital, etc.). SPRITE also allows this level of interface testing of components and subsystems very early in a program, thereby reducing program risk.

  18. Contributions by the CAG-repeat Polymorphism of the Androgen Receptor Gene and Circulating Androgens to Muscle Size. Odense Androgen Study - A Population-based Study of 20-29 Year-old Danish Men

    DEFF Research Database (Denmark)

    Nielsen, Torben Leo; Hagen, Claus; Wraae, Kristian

    2007-01-01

    Context: The number of CAG-repeats within the CAG-repeat polymorphism of the androgen receptor gene is inversely correlated with the transcriptional activity of the androgen receptor. Objective: To study the effect of the CAG-repeat number and circulating androgens on muscle size, to examine the ...... muscle size increased exponentially with decreasing androgen levels and was tripled at total testosterone levels...... the CAG-repeat number in relation to body fat mass and circulating androgens, and to identify the best hormonal marker of low muscle size amongst total testosterone, bioavailable testosterone, and dihydrotestosterone. Design, Setting, and Participants: Population-based study of 783 Danish men aged 20......, chronic disease, and age. The CAG-repeat number correlated positively with total body fat mass adjusted for weight, but not with the concentration of any of the circulating androgens. Total testosterone and dihydrotestosterone correlated positively with all outcomes of muscle size. The prevalence of low...

  19. Impact of male hormonal contraception on prostate androgens and androgen action in healthy men: a randomized, controlled trial.

    Science.gov (United States)

    Mostaghel, Elahe A; Lin, Daniel W; Amory, John K; Wright, Jonathan L; Marck, Brett T; Nelson, Peter S; Matsumoto, Alvin M; Bremner, William J; Page, Stephanie T

    2012-08-01

    Male hormonal contraception (MHC) combines hypothalamic-pituitary-gonadal axis blockade with exogenous androgen delivery to maintain extragonadal androgen end-organ effects. Concern exists that MHC may adversely impact prostate health. The objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action. This was a single-blind, randomized, placebo-controlled study. The study was conducted at an academic medical center. 32 healthy men aged 25-55 yr participated in the study. Interventions included placebo, daily transdermal testosterone (T) (T-gel), T-gel + depomedroxyprogesterone acetate (T+DMPA), or T-gel + dutasteride daily (T+D) for 12 wk, and prostate biopsy during treatment wk 10. Serum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured. Thirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P < 0.05) but were decreased with the addition of DMPA. Intraprostatic androgens were no different from placebo with T-gel treatment. Addition of DMPA to T resulted in 40% lower intraprostatic dihydrotestosterone (DHT) concentration (P = 0.0273 vs. placebo), whereas combining dutasteride with T resulted in a 90% decrease in intraprostatic DHT (P = 0.0012), 11-fold increased intraprostatic T (P = 0.0011), and 7-fold increased intraprostatic androstenedione (P = 0.0011). Significant differences in global or androgen-regulated prostate epithelial-cell gene expression were not observed. Androgen-regulated gene expression correlated with epithelial-cell androgen receptor and prostatic DHT in placebo, T-gel, and T+DMPA arms and with T and androstenedione levels in the T+D arm. MHC regimens do not markedly alter gene expression in benign prostate epithelium, suggesting they may not alter risk of prostate disease. Longer-term studies examining the impact of MHC on prostate health are needed.

  20. Androgen receptor expression is a biological marker for androgen sensitivity in high grade serous epithelial ovarian cancer.

    Science.gov (United States)

    Elattar, Ahmed; Warburton, Katharine G; Mukhopadhyay, Asima; Freer, Rebecca M; Shaheen, Fadhel; Cross, Paul; Plummer, E Ruth; Robson, Craig N; Edmondson, Richard J

    2012-01-01

    In the present study we explore the effects of androgens and anti-androgens on primary cultures of EOC cells. We also investigate the effects of chemotherapy on AR expression. Epithelial ovarian cancer (EOC) arises from ovarian surface epithelial cells (OSE), which express the androgen receptor (AR). Androgen stimulation of OSE cells results in increased proliferation and protection from apoptosis. Nevertheless, in clinical trials anti-androgens have had a low objective response rate in relapsed ovarian cancer. 1. Androgen receptor (AR) expression and response to androgenic stimulation were correlated in primary ovarian cancer cells derived from ascitic fluid from patients with advanced ovarian cancer, 2. AR expression in primary epithelial ovarian cancer was investigated before and after chemotherapy using paired histological samples which had been incorporated into a tissue microarray. Eleven primary ovarian cancer cultures were established from ascitic fluid. There was wide variation of expression of androgen receptor mRNA between cultures. Cell division increased after dihydro-testosterone (DHT) stimulation in 6 out of 11 primary cultures. The fraction of cells in S-phase increased from 4.4% in cells grown in serum-free medium to 8.3% in cells stimulated with 100 nM of DHT (PIHC) decreased significantly after chemotherapy (Povarian cancer is more likely to be effective as these data suggest that androgen receptor expression decreases with exposure to chemotherapy and this may explain the low response rates seen in clinical trials of patients heavily pre-treated with multiple courses of chemotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. New insights into androgen treatment of erectile dysfunction

    Directory of Open Access Journals (Sweden)

    Louis Gooren

    2006-01-01

    Full Text Available Erectile response in mammals is centrally and peripherally regulated by androgens. Severe hypogonadism in men usually results in loss of libido and potency which can be restored by androgen administration. The original insights into the mechanisms of action of androgens on sexual function indicated that androgens particularly exert effects on libido and that sleep-related erections were androgen-sensitive but erections in response to erotic stimuli were relatively androgen-independent. There are a number of recent developments which shed new light on testosterone treatment of erectile dysfunction in aging men. There is growing insight that testosterone has profound effects on tissues of the penis involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiological/biochemical substrate of erectile capacity, reversible upon androgen treatment. Several studies have indicated that the administration of PDE-5-inhibitors is not always sufficient to restore erectile potency in men and that administration of testosterone improves the therapeutical response to PDE-5-inhibitors considerably. There is increasing insight not to view erectile dysfunction (ED as a single entity but as part of the aging process. Circulating levels of testosterone are closely related to manifestations of other etiological factors in ED, such as atherosclerotic disease and diabetes mellitus. The latter are correlated with lower-than-normal testosterone levels.

  2. Androgen-Independent Prostate Cancer: Potential Role of Androgen and ErbB Receptor Signal Transduction Crosstalk

    Directory of Open Access Journals (Sweden)

    Soha Salama El Sheikh

    2003-03-01

    Full Text Available In prostate cancer (PC, increasing evidence suggests that androgen receptor (AR signalling is functional under conditions of maximal androgen blockade. PC cells survive and proliferate in the altered hormonal environment possibly by interactions between growth factor-activated pathways and AR signalling. The present review article summarizes the current evidence of this crosstalk and focuses on the interactions among the ErbB receptor network, its downstream pathways, the AR. The potential role of this crosstalk in the development of androgen independence and in relation to antiandrogen therapy is discussed. Such interactions provide insight into possible complementary or additional strategies in the management of PC.

  3. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin.

    Science.gov (United States)

    Sharma, Vikas; Kumar, Lokesh; Mohanty, Sujit K; Maikhuri, Jagdamba P; Rajender, Singh; Gupta, Gopal

    2016-08-15

    Epigenetic repression of Androgen Receptor (AR) gene by hypermethylation of its promoter causes resistance in prostate cancer (CaP) to androgen deprivation therapy with anti-androgens. Some dietary phytocompounds like quercetin (Q) and curcumin (C) with reported DNMT-inhibitory activity were tested for their ability to re-express the AR in AR-negative CaP cell lines PC3 and DU145. Combined treatment with Q+C was much more effective than either Q or C in inhibiting DNMT, causing global hypomethylation, restoring AR mRNA and protein levels and causing apoptosis via mitochondrial depolarization of PC3 and DU145. The functional AR protein expressed in Q+C treated cells sensitized them to dihydrotestosterone (DHT)-induced proliferation, bicalutamide-induced apoptosis, bound to androgen response element to increase luciferase activity in gene reporter assay and was susceptible to downregulation by AR siRNA. Bisulfite sequencing revealed high methylation of AR promoter CpG sites in AR-negative DU145 and PC3 cell lines that was significantly demethylated by Q+C treatment, which restored AR expression. Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis, their known safety in clinical use, and epidemiological evidences relating their dietary consumption with lower cancer incidences indicate their potential for use in chemoprevention of androgen resistance in prostate cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

    Directory of Open Access Journals (Sweden)

    Abbas Yavari

    2009-09-01

    Full Text Available According to the International Olympic Committee, the abuse of anabolic androgenic steroids (AASS is found in over 50% of positive doping tests. AASS abuse is not restricted to the organized sports andwidespread use. It remains as an unsolved public-health problem.Lower black market price, easier access to AASS, bodybuilding clubs and internet advertising are factors of this increasingly misuse. There is not real data about the prevalence of AASS abuse in various populations or countries, because most of athletes or students, due to their prohibition or ethical aspects do not admit to AASS abuse. Often they are aware of the risks of their choice and yet, are eager to put themselves at risk without deeper consideration. The abusers use them to improve their physical fitness and appearance.Present article has been collected to elucidate the risks and adverse effects of AASS and explanation of mechanisms of these events.

  5. Collateral damage: rapid exposure-induced evolution of pesticide resistance leads to increased susceptibility to parasites.

    Science.gov (United States)

    Jansen, Mieke; Stoks, Robby; Coors, Anja; van Doorslaer, Wendy; de Meester, Luc

    2011-09-01

    Although natural populations may evolve resistance to anthropogenic stressors such as pollutants, this evolved resistance may carry costs. Using an experimental evolution approach, we exposed different Daphnia magna populations in outdoor containers to the carbamate pesticide carbaryl and control conditions, and assessed the resulting populations for both their resistance to carbaryl as well as their susceptibility to infection by the widespread bacterial microparasite Pasteuria ramosa. Our results show that carbaryl selection led to rapid evolution of carbaryl resistance with seemingly no cost when assessed in a benign environment. However, carbaryl-resistant populations were more susceptible to parasite infection than control populations. Exposure to both stressors reveals a synergistic effect on sterilization rate by P. ramosa, but this synergism did not evolve under pesticide selection. Assessing costs of rapid adaptive evolution to anthropogenic stress in a semi-natural context may be crucial to avoid too optimistic predictions for the fitness of the evolving populations. © 2011 The Author(s).

  6. Probing the functional link between androgen receptor coactivator and ligand-binding sites in prostate cancer and androgen insensitivity.

    Science.gov (United States)

    He, Bin; Gampe, Robert T; Hnat, Andrew T; Faggart, Jonathan L; Minges, John T; French, Frank S; Wilson, Elizabeth M

    2006-03-10

    The androgen receptor (AR) is a ligand-activated transcription factor required for male sex development and virilization and contributes to prostate cancer initiation and progression. High affinity androgen binding triggers conformational changes required for AR transactivation. Here we characterized naturally occurring AR gene mutations in the region of activation function 2 (AF2) that decrease or increase AR transcriptional activity by altering the region bounded by AF2 and the ligand binding pocket without affecting equilibrium androgen binding affinity. In the androgen insensitivity syndrome, germ line AR mutations increase the androgen dissociation rate and reduce AR FXXLF motif binding and the recruitment of steroid receptor coactivator (SRC)/p160 coactivator LXXLL motifs. In prostate cancer, somatic AR mutations in AF2 or near the bound ligand slow androgen dissociation and increase AR stabilization and coactivator recruitment. Crystal structures of the AR ligand binding domain bound to R1881 and FXXLF or LXXLL motif peptide indicate the mutations are proximal to the AF2 bound peptide, adjacent to the ligand pocket, or in a putative ligand gateway. The results suggest a bidirectional structural relay between bound ligand and coactivator that establishes AR functional potency in vivo.

  7. Androgen receptor and histone lysine demethylases in ovine placenta.

    Directory of Open Access Journals (Sweden)

    Ellane R Cleys

    Full Text Available Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR. Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders.

  8. High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance.

    Science.gov (United States)

    Cai, J; Wu, C H; Zhang, Y; Wang, Y Y; Xu, W D; Lin, T C; Li, S X; Wang, L H; Zheng, J; Sun, Y; Liu, W; Tao, T

    2017-09-01

    Central obesity and insulin resistance (IR) are common conditions in women with polycystic ovary syndrome (PCOS) and in subjects with non-alcoholic fatty liver disease (NAFLD). However, few studies have addressed the association between hyperandrogenism (HA) and NAFLD. We aimed to determine whether variations in the free androgen index (FAI) might be associated with NAFLD prevalence. A cross-sectional study was performed including 400 Chinese women with PCOS and 100 age, and body mass index (BMI)-matched women. The anthropometric and serum biochemical parameters related to sex steroids, glucose and lipid profiles were examined. Liver fat content (LFC) was measured by quantitative ultrasound. The prevalence of NAFLD was 56.23% in PCOS patients and 38% in controls (P=0.001), and this prevalence increased with FAI quartile independently of obesity and homeostasis model assessment of insulin resistance (HOMA-IR). The FAI level increased from non-NAFLD group to NAFLD group. The FAI was positively associated with the metabolic parameters LFC, BMI, waist circumference, alanine aminotransferases, aspartate, triglyceride, total cholesterol and low-density lipoprotein cholesterol, and was negatively associated with high-density lipoprotein. Moreover, in multivariate logistic regression analysis BMI, high-sensitivity C-reactive protein (hsCRP), FAI, LFC and HOMA-IR were significantly associated with NAFLD. The cut-off values of FAI, LFC, BMI and hsCRP to predict NAFLD were 9.86%, 17.19%, 24.38% and 0.72%, respectively. The area under the curve for predicting NAFLD in PCOS patients showed comparable sensitivity and specificity between BMI and a new index combining FAI with hsCRP. A higher FAI level is associated with increased LFC and NAFLD prevalence independent of obesity and IR.

  9. Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

    Energy Technology Data Exchange (ETDEWEB)

    Whang, Kee Suk [Kyungpook National University School of Medicine, Deagu (Korea, Republic of)

    1967-03-15

    Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma-{sup 59}Fe-disappearance rate, RBC {sup 59}Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

  10. Increased insight in microbial processes in rapid sandfilters in drinking water treatment (DW BIOFILTERS)

    DEFF Research Database (Denmark)

    Albrechtsen, Hans-Jørgen; Gülay, Arda; Lee, Carson

    2012-01-01

    The aim of this research project is to improve our knowledge on biological rapid sand filters as they are present in thousands groundwater based water works. This includes molecular investigations of the microorganisms responsible for the individual processes (e.g. nitrification); and detailed...... monitoring and experiments in the filters and laboratory to provide insight in the process mechanisms, kinetics and effect of environmental factors. Management of the filters (e.g. backwashing, flow rate, carrier type) will be investigated at pilot and full scale, supported by mathematical models...... investigated by deep sequencing. This will also contribute to a verification of whether the selected qPCR probes include all important groups. Filters from three water works have been sampled and are currently being processed to investigate depth profiles and horizontal variation in filters. Assays...

  11. Rapid intervention and treatment zone: redesigning nursing services to meet increasing emergency department demand.

    Science.gov (United States)

    Considine, Julie; Lucas, Elspeth; Martin, Roslyn; Stergiou, Helen E; Kropman, Matthew; Chiu, Herman

    2012-02-01

    The impact of emergency nursing roles in demand management systems is poorly understood. The aim of this study was to evaluate emergency nurses' role in a specific emergency department (ED) demand management system: rapid intervention and treatment zone (RITZ). A descriptive exploratory approach was used. Data were collected from audit of 193 randomly selected patient records and 12 h of clinical practice observation. The median age of participants was 31 years, 51.8% were males and 99.5% were discharged home. Nurse qualifications or seniority had no significant effect on waiting time or length of stay (LOS). There were disparities between documented and observed nursing practice. The designation and qualifications of RITZ nurses made little difference to waiting times and ED LOS. Specific documentation and communication systems for areas of the ED that manage large numbers of low complexity patients warrant further research. © 2012 Blackwell Publishing Asia Pty Ltd.

  12. Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women.

    Science.gov (United States)

    Merritt, Paul; Stangl, Bethany; Hirshman, Elliot; Verbalis, Joseph

    2012-11-05

    The current study examines the effect of administering dehydroepiandrosterone (DHEA) on short-term memory. This experiment used a double-blind placebo-controlled cross-over design to explore the effects of a four week regimen of 50 mg oral DHEA on performance on the digit span, verbal span, and modified Sternberg (Oberauer) tasks. The results demonstrate that the current regimen of drug administration significantly increases serum levels of DHEA, DHEAS, testosterone and estrone and substantially alters the patterns of correlations among the serum levels of these hormones. Despite this substantial change in the hormonal milieu, DHEA administration produced no beneficial effects on cognitive performance in the digit span, verbal span, or modified Sternberg paradigm tasks. Ancillary analyses of the relation between hormone levels and cognitive performance demonstrated a strong positive correlation between DHEA levels and performance on digit span forward/backward and verbal span forward in the placebo drug condition, but not in the DHEA condition. We interpret the juxtaposition of the null results of DHEA administration and the correlation of DHEA levels and performance in the placebo condition to indicate that the referenced correlations arise because a third variable (i.e., age) is associated with both performance and DHEA levels. Additional analyses supported this hypothesis. Copyright © 2012 Elsevier B.V. All rights reserved.

  13. The use of digit ratios as markers for perinatal androgen action

    Directory of Open Access Journals (Sweden)

    McIntyre Matthew H

    2006-02-01

    Full Text Available Abstract Since the ratio of the second-to-fourth finger length was first proposed as a marker for prenatal androgen action in 1998, over 100 studies have been published that have either further tested the association between the digit ratio and prenatal androgens, or employed digit ratios as a marker to investigate the association between prenatal androgens and a variety of outcomes, including behavior, fertility, and disease risks. Despite the clear demand for an adult marker of prenatal androgen action and increased use of digit ratios as such a marker, its validity remains controversial. This review (1 evaluates current evidence for the relationship between digit ratios and prenatal androgens (using experimentation with animal models, amniotic testosterone, and congenital adrenal hyperplasia case-control studies, (2 describes opportunities for future validation tests, and (3 compares the potential advantages and disadvantages of digit ratio measures with more established methods for studying the effects of prenatal androgens.

  14. Altered corepressor SMRT expression and recruitment to target genes as a mechanism that change the response to androgens in prostate cancer progression.

    Science.gov (United States)

    Godoy, Alejandro S; Sotomayor, Paula C; Villagran, Marcelo; Yacoub, Rami; Montecinos, Viviana P; McNerney, Eileen M; Moser, Michael; Foster, Barbara A; Onate, Sergio A

    2012-07-06

    Androgen receptor (AR) is required for the development and progression of prostate cancer (CaP) from androgen-dependence to androgen-resistance. Both corepressors and coactivators regulate AR-mediated transcriptional activity, and aberrant expression or activity due to mutation(s) contributes to changes in AR function in the progression to androgen resistance acquired during hormonal ablation therapies. Primary culture of epithelial cells from androgen-dependent CWR22 and androgen-resistant CWR22R xenograft tumors were used to evaluate the effect of androgens on AR function, and the association with coactivators (SRC-1 and TIF-2) and corepressors (SMRT and NCoR). Both androgen-dependent CWR22 and androgen-resistant CWR22R cells expressed functional AR as the receptor bind ligand with high affinity and increased trafficking to the nuclei in the presence of androgens. However, in the presence of androgens, AR-mediated transcriptional activity in androgen-sensitive CWR22 cells was limited to a 2-fold increase, as compared to a 6-fold increase in androgen-resistance CWR22R cells. In androgen-sensitive CWR22 cells, immunoblot, confocal microscopy, and chromatin immunoprecipitation assays indicated that the androgen bound AR transcriptional initiation complex in the PSA promoter contained corepressor SMRT, resulting in limited receptor transcriptional activity. In contrast, increased AR-mediated transcriptional activity in the CWR22R cells was consistent with decreased expression and recruitment of the corepressors SMRT/NCoR, as well as increased recruitment of the coactivator TIF-2 to the receptor complex. Similar changes in the response to androgens were observed in the LNCaP/C4-2 model of androgen resistance prostate cancer. Thus, altered recruitment and loss of corepressors SMRT/NCoR may provide a mechanism that changes the response of AR function to ligands and contributes to the progression of the advanced stages of human prostate cancer. Copyright © 2012 Elsevier

  15. Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer.

    Science.gov (United States)

    Isaacs, John T; D'Antonio, Jason M; Chen, Shuangling; Antony, Lizamma; Dalrymple, Susan P; Ndikuyeze, Georges H; Luo, Jun; Denmeade, Samuel R

    2012-10-01

    Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in >25-fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts, however, when supraphysiologic androgen is acutely replaced. Cell synchronization/anti-androgen response is due to AR binding to replication complexes (RC) at origin of replication sites (ORS) in early G1 associated with licensing/restricting DNA for single round of duplication during S-phase. When CRPC cells are acutely exposed to supraphysiologic androgen, adaptively increased nuclear AR is over-stabilized, preventing sufficient degradation in mitosis, inhibiting DNA re-licensing, and thus death in the subsequent cell cycle. These mechanistic results and the fact that AR/RC binding occurs in metastatic CRPCs directly from patients provides a paradigm shifting rationale for bipolar androgen therapy (BAT) in patient progressing on chronic androgen ablation. BAT involves giving sequential cycles alternating between periods of acute supraphysiologic androgen followed by acute ablation to take advantage of vulnerability produced by adaptive auto-regulation and binding of AR to RC in CRPC cells. BAT therapy is effective in xenografts and based upon positive results has entered clinical testing. Copyright © 2012 Wiley Periodicals, Inc.

  16. Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells.

    Science.gov (United States)

    Levina, Elina; Ji, Hao; Chen, Mengqiang; Baig, Mirza; Oliver, David; Ohouo, Patrice; Lim, Chang-uk; Schools, Garry; Carmack, Steven; Ding, Ye; Broude, Eugenia V; Roninson, Igor B; Buttyan, Ralph; Shtutman, Michael

    2015-05-30

    Prostate cancer progression to castration refractory disease is associated with anomalous transcriptional activity of the androgen receptor (AR) in an androgen-depleted milieu. To identify novel gene products whose downregulation transactivates AR in prostate cancer cells, we performed a screen of enzymatically-generated shRNA lenti-libraries selecting for transduced LNCaP cells with elevated expression of a fluorescent reporter gene under the control of an AR-responsive promoter. The shRNAs present in selected populations were analyzed using high-throughput sequencing to identify target genes. Highly enriched gene targets were then validated with siRNAs against selected genes, testing first for increased expression of luciferase from an AR-responsive promoter and then for altered expression of endogenous androgen-regulated genes in LNCaP cells. We identified 20 human genes whose silencing affected the expression of exogenous and endogenous androgen-responsive genes in prostate cancer cells grown in androgen-depleted medium. Knockdown of four of these genes upregulated the expression of endogenous AR targets and siRNAs targeting two of these genes (IGSF8 and RTN1) enabled androgen-independent proliferation of androgen-dependent cells. The effects of IGSF8 appear to be mediated through its interaction with a tetraspanin protein, CD9, previously implicated in prostate cancer progression. Remarkably, homozygous deletions of IGSF8 are found almost exclusively in prostate cancers but not in other cancer types. Our study shows that androgen independence can be achieved through the inhibition of specific genes and reveals a novel set of genes that regulate AR signaling in prostate cancers.

  17. Mechanical stimulation evokes rapid increases in extracellular adenosine concentration in the prefrontal cortex

    Science.gov (United States)

    Ross, Ashley E.; Nguyen, Michael D.; Privman, Eve; Venton, B. Jill

    2014-01-01

    Mechanical perturbations can release ATP, which is broken down to adenosine. In this work, we used carbon-fiber microelectrodes and fast-scan cyclic voltammetry to measure mechanically-stimulated adenosine in the brain by lowering the electrode 50 μm. Mechanical stimulation evoked adenosine in vivo (average: 3.3 ± 0.6 μM) and in brain slices (average: 0.8 ± 0.1 μM) in the prefrontal cortex. The release was transient, lasting 18 ± 2 s. Lowering a 15 μm diameter glass pipette near the carbon-fiber microelectrode produced similar results as lowering the actual microelectrode. However, applying a small puff of artificial cerebral spinal fluid was not sufficient to evoke adenosine. Multiple stimulations within a 50 μm region of a slice did not significantly change over time or damage cells. Chelating calcium with EDTA or blocking sodium channels with tetrodotoxin (TTX) significantly decreased mechanically evoked adenosine, signifying that the release is activity-dependent. An alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), did not affect mechanically-stimulated adenosine; however, the nucleoside triphosphate diphosphohydrolase 1,2 and 3 (NTDPase) inhibitor POM-1 significantly reduced adenosine so a portion of adenosine is dependent on extracellular ATP metabolism. Thus, mechanical perturbations from inserting a probe in the brain cause rapid, transient adenosine signaling which might be neuroprotective. PMID:24606335

  18. False positive rate of rapid oral fluid HIV tests increases as kits near expiration date.

    Science.gov (United States)

    Facente, Shelley N; Dowling, Teri; Vittinghoff, Eric; Sykes, Deanna L; Colfax, Grant N

    2009-12-14

    Because a recent cluster of false positive results on the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test occurred in San Francisco on test kits close to their expiration date, we decided to assess the relationship between time to expiration and rate of false positive results from tests used with oral fluid. We analyzed results of 20,904 tests with either an initial HIV-negative result (n = 20,828) or a preliminary positive result that was then negative on confirmatory tests (n = 76). We computed specificity for kits with time to expiration from or = 6 months, with exact binomial confidence intervals, then used logistic regression to estimate the independent association of time to expiration with false positive results, adjusting for site and technician effects. For 1,108 kits used in the last month before expiration, specificity was 98.83% (95% exact binomial confidence interval (CI) 98.00%-99.37%); the upper bound is below the claimed specificity of 99.60%. After adjustment using regression standardization for the effects of site, test lot, and technician factors, adjusted specificity in the last month before expiration was 99.18% (95% bootstrap confidence interval 98.60-99.57%). We found that specificity of the OraQuick ADVANCE with oral fluid declined significantly with < or = 1 month remaining to expiration, leaving little margin for error from other sources.

  19. ANDROGEN REPLACEMENT THERAPY IN POSTMENOPAUSE

    Directory of Open Access Journals (Sweden)

    Helena Meden Vrtovec

    2008-12-01

    Scientific studies and clinical experiences have not provided until now the answers to thequestion: »Whom to treat, when, why and for how long should androgens be used for HRTin postmenopausal women?«

  20. Rapidly increasing prescribing of proton pump inhibitors in primary care despite interventions

    DEFF Research Database (Denmark)

    Haastrup, Peter; Paulsen, Maja Skov; Zwisler, Jon Eik

    2014-01-01

    2001-2011 and to assess the impacts of interventions on prescribing of antisecretory medication. Methods: Register-based cohort study covering the entire Danish population of currently 5.5 million inhabitants. Developments in the prescribing of antisecretory medication over time in Denmark between 2001...... increased substantially during the past decade. Both number of users and the average individual use have increased. The prescribing of ulcerogenic drugs to the elderly has stagnated in the same time range. Reimbursement modifications and scientific guidelines do not seem to have had a substantial influence...... on the steadily increasing prescribing of PPIs. Conclusion: Use of PPIs has increased substantially during the past decade, without a change in indications for use of PPIs in the same time range. Interventions to enhance adherence to guidelines and promote rational use of PPIs do not seem to have had...

  1. Rapid Growth and Apparent Total Nitrogen Increases in Rice and Corn Plants following Applications of Triacontanol.

    Science.gov (United States)

    Knowles, N R; Ries, S K

    1981-12-01

    Triacontanol (TRIA) increased fresh and dry weight and total reducible nitrogen (total N) of rice (Oryza sativa L.) seedlings within 40 minutes. Increases in total N in the supernatants from homogenates of corn (Zea mays L.) and rice leaves treated with TRIA for one minute before grinding occurred within 30 and 80 minutes, respectively. The source for the increase was investigated utilizing atmospheric substitution and enrichment and depletion studies with (15)N. The increase in total N in seedlings was shown to be independent of method of N analysis and the presence of nitrate in the plants. Automated Kjeldahl determinations showing apparent increases in N composition due to TRIA were shown to be correlated with hand Kjeldahl, elemental analysis, and chemiluminescent analysis in three independent laboratories. TRIA did not alter the nitrate uptake or endogenous levels of nitrate in corn and rice seedlings. Enrichment experiments revealed that the total N increases in rice seedlings, in vivo, and in supernatants of corn leaf homogenates, in vitro, are not due to atmospheric N(2). TRIA increased the soluble N pools of the plants, specifically the free amino acid and soluble protein fractions. No differences in depletion or enrichment of (15)N incorporated into soluble and insoluble N fractions of rice seedlings could be detected on an atom per cent (15)N basis. The apparent short-term total N increases cannot be explained by current knowledge of major N assimilation pathways. TRIA may stimulate a change in the chemical composition of the seedlings, resulting in interference with standard methods of N analysis.

  2. Rapid product analysis and increased sensitivity for quantitative determinations of botulinum neurotoxin proteolytic activity.

    Science.gov (United States)

    Rowe, Benjamin; Schmidt, James J; Smith, Leonard A; Ahmed, S Ashraf

    2010-01-15

    The ultimate molecular action of botulinum neurotoxin (BoNT) is a Zn-dependent endoproteolytic activity on one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. There are seven serotypes (A-G) of BoNT having distinct cleavage sites on the SNARE substrates. The proteolytic activity is located on the N-terminal light chain (Lc) domain and is used extensively as the primary target toward therapeutic development against botulism. Here we describe an improved method using ultra-performance liquid chromatography (UPLC) whereby quantitative data were obtained in 1/10th the time using 1/20th the sample and solvent volumes compared with a widely used high-performance liquid chromatography (HPLC) method. We also synthesized a VAMP (vesicle-associated membrane protein)-based peptide containing an intact V1 motif that was efficiently used as a substrate by BoNT/D Lc. Although serotype C1 cleaves the serotype A substrate at a bond separated by only one residue, we were able to distinguish the two reactions by UPLC. The new method can accurately quantify as low as 7 pmol of the peptide substrates for BoNT serotypes A, B, C1, and D. We also report here that the catalytic efficiency of serotype A can be stimulated 35-fold by the addition of Triton X-100 to the reaction mixture. Combining the use of Triton X-100 with the newly introduced UPLC method, we were able to accurately detect very low levels of proteolytic activity in a very short time. Sensitivity of the assay and accuracy and rapidity of product analysis should greatly augment efforts in therapeutic development.

  3. RAPID KNEE-EXTENSIONS TO INCREASE QUADRICEPS MUSCLE ACTIVITY IN PATIENTS WITH TOTAL KNEE ARTHROPLASTY

    DEFF Research Database (Denmark)

    Husted, Rasmus Skov; Wilquin, Lousia; Jakobsen, Thomas Linding

    2017-01-01

    BACKGROUND: Inhibition of the quadriceps muscle and reduced knee-extension strength is common shortly following total knee arthroplasty (weeks to months), due to reduced voluntary activation of the quadriceps muscle. In healthy subjects, strength training with heavy loads is known to increase ago...

  4. Rapid knee-extensions to increase quadriceps muscle activity in patients with total knee arthroplasty

    DEFF Research Database (Denmark)

    Husted, Rasmus Skov; Wilquin, Lousia; Jakobsen, Thomas Linding

    2017-01-01

    BACKGROUND: Inhibition of the quadriceps muscle and reduced knee-extension strength is common shortly following total knee arthroplasty (weeks to months), due to reduced voluntary activation of the quadriceps muscle. In healthy subjects, strength training with heavy loads is known to increase ago...

  5. Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast.

    Science.gov (United States)

    Yoda, Tomomi; McNamara, Keely May; Miki, Yasuhiro; Takagi, Mayu; Rai, Yoshiaki; Ohi, Yasuyo; Sagara, Yasuaki; Tamaki, Kentaro; Hirakawa, Hisashi; Ishida, Takanori; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2014-11-01

    Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen-responsive environment, the combined importance of AR and androgen metabolism in non-neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen-producing enzymes 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase type 1 (5αRed1) in 178 cases of ILC and surrounding histologically non-neoplastic lobular tissue using immunohistochemistry. Androgen receptor prevalence was higher but androgenic enzymes lower in ILC than non-neoplastic lobules. In ILC cases the status of 5αRed1 and 17βHSD5 was inversely correlated with tumor size (P = 0.0053) and nuclear grade (P = 0.0290), and significantly associated with better overall survival of the patients (P = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17βHSD2 (P < 0.0001) and intratumoral 17βHSD2 was inversely correlated with tumor size in ILC (P = 0.0075). These correlations suggest one protective mode of androgen action could be through modulation of estrogen metabolism. Results of our present study indicated that androgen-producing enzymes could play pivotal protective roles in AR-enriched ILC cases. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  6. Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

    Science.gov (United States)

    Speers, Corey; Zhao, Shuang G; Chandler, Ben; Liu, Meilan; Wilder-Romans, Kari; Olsen, Eric; Nyati, Shyam; Ritter, Cassandra; Alluri, Prasanna G; Kothari, Vishal; Hayes, Daniel F; Lawrence, Theodore S; Spratt, Daniel E; Wahl, Daniel R; Pierce, Lori J; Feng, Felix Y

    2017-01-01

    Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R(2) = 0.72, p triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen

  7. Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production

    Science.gov (United States)

    Bailey, Andy M.; Alberti, Fabrizio; Kilaru, Sreedhar; Collins, Catherine M.; de Mattos-Shipley, Kate; Hartley, Amanda J.; Hayes, Patrick; Griffin, Alison; Lazarus, Colin M.; Cox, Russell J.; Willis, Christine L.; O'Dwyer, Karen; Spence, David W.; Foster, Gary D.

    2016-05-01

    Semi-synthetic derivatives of the tricyclic diterpene antibiotic pleuromutilin from the basidiomycete Clitopilus passeckerianus are important in combatting bacterial infections in human and veterinary medicine. These compounds belong to the only new class of antibiotics for human applications, with novel mode of action and lack of cross-resistance, representing a class with great potential. Basidiomycete fungi, being dikaryotic, are not generally amenable to strain improvement. We report identification of the seven-gene pleuromutilin gene cluster and verify that using various targeted approaches aimed at increasing antibiotic production in C. passeckerianus, no improvement in yield was achieved. The seven-gene pleuromutilin cluster was reconstructed within Aspergillus oryzae giving production of pleuromutilin in an ascomycete, with a significant increase (2106%) in production. This is the first gene cluster from a basidiomycete to be successfully expressed in an ascomycete, and paves the way for the exploitation of a metabolically rich but traditionally overlooked group of fungi.

  8. Rapidly increasing use of proton pump inhibitors prescribed in primary care: a nationwide observational study

    DEFF Research Database (Denmark)

    Haastrup, Peter; Jarbøl, Dorte Ejg; Hansen, Jane Møller

    a change in indications for use of PPIs in the same time range. Use of ulcerogenic drugs among the elderly has stagnated. Reimbursement modifications do not seem to have had a substantial influence on the steadily increasing use of PPIs. Conclusions: Use of PPIs has increased substantially the past decade......Background: Antisecretory drugs (ADs) are often prescribed in primary care for upper gastrointestinal symptoms. Reimbursement modifications have been made in Denmark to minimize costs related to use of ADs. However knowledge about development in use of ADs over the past decade and the impacts...... of the reimbursement modifications is sparse. Research questions: How has use of ADs developed in Denmark 2001-2011? Which impacts have the reimbursement modifications had on the use of ADs? Methods: The Register of Medicinal Product Statistics includes all sales and redeemed prescriptions nationwide covering...

  9. Increases in myocardial workload induced by rapid atrial pacing trigger alterations in global metabolism.

    Directory of Open Access Journals (Sweden)

    Aslan T Turer

    Full Text Available To determine whether increases in cardiac work lead to alterations in the plasma metabolome and whether such changes arise from the heart or peripheral organs.There is growing evidence that the heart influences systemic metabolism through endocrine effects and affecting pathways involved in energy homeostasis.Nineteen patients referred for cardiac catheterization were enrolled. Peripheral and selective coronary sinus (CS blood sampling was performed at serial timepoints following the initiation of pacing, and metabolite profiling was performed by liquid chromatography-mass spectrometry (LC-MS.Pacing-stress resulted in a 225% increase in the median rate·pressure product from baseline. Increased myocardial work induced significant changes in the peripheral concentration of 43 of 125 metabolites assayed, including large changes in purine [adenosine (+99%, p = 0.006, ADP (+42%, p = 0.01, AMP (+79%, p = 0.004, GDP (+69%, p = 0.003, GMP (+58%, p = 0.01, IMP (+50%, p = 0.03, xanthine (+61%, p = 0.0006], and several bile acid metabolites. The CS changes in metabolites qualitatively mirrored those in the peripheral blood in both timing and magnitude, suggesting the heart was not the major source of the metabolite release.Isolated increases in myocardial work can induce changes in the plasma metabolome, but these changes do not appear to be directly cardiac in origin. A number of these dynamic metabolites have known signaling functions. Our study provides additional evidence to a growing body of literature on metabolic 'cross-talk' between the heart and other organs.

  10. Improved androgen specificity of AR-EcoScreen by CRISPR based glucocorticoid receptor knockout.

    Science.gov (United States)

    Zwart, Nick; Andringa, Dave; de Leeuw, Willem-Jan; Kojima, Hiroyuki; Iida, Mitsuru; Houtman, Corine J; de Boer, Jacob; Kool, Jeroen; Lamoree, Marja H; Hamers, Timo

    2017-12-01

    The AR-EcoScreen is a widely used reporter assay for the detection of androgens and anti-androgens. Endogenous expression of glucocorticoid receptors and their affinity for the androgen responsive element that drives reporter expression, however, makes the reporter cells sensitive to interference by glucocorticoids and less specific for (anti-)androgens. To create a glucocorticoid insensitive derivative of the AR-EcoScreen, CRISPR/Cas9 genome editing was used to develop glucocorticoid receptor knockout mutants by targeting various sites in the glucocorticoid gene. Two mutant cell lines were further characterized and validated against the unmodified AR-EcoScreen with a set of 19 environmentally relevant chemicals and a series of environmental passive sampler extracts with (anti-)androgenic activity. Sequencing of the targeted sites revealed premature stop codons following frame-shift mutations, leading to an absence of functional glucocorticoid receptor expression. The introduced mutations rendered cell lines insensitive to glucocorticoid activation and caused no significant difference in the responsiveness towards (anti-)androgens, compared to the unmodified AR-EcoScreen cells, allowing the selective, GR-independent, determination of (anti-)androgenicity in environmental passive sampler extracts. The increase in selectivity for (anti-)androgens improves reliability of the AR-EcoScreen and will provide higher accuracy in determining (anti-)androgenic potential when applied in toxicity screening and environmental monitoring of both single compounds and mixtures. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Rapidly increasing macroalgal cover not related to herbivorous fishes on Mesoamerican reefs

    Directory of Open Access Journals (Sweden)

    Adam Suchley

    2016-05-01

    Full Text Available Long-term phase shifts from coral to macroalgal dominated reef systems are well documented in the Caribbean. Although the impact of coral diseases, climate change and other factors is acknowledged, major herbivore loss through disease and overfishing is often assigned a primary role. However, direct evidence for the link between herbivore abundance, macroalgal and coral cover is sparse, particularly over broad spatial scales. In this study we use a database of coral reef surveys performed at 85 sites along the Mesoamerican Reef of Mexico, Belize, Guatemala and Honduras, to examine potential ecological links by tracking site trajectories over the period 2005–2014. Despite the long-term reduction of herbivory capacity reported across the Caribbean, the Mesoamerican Reef region displayed relatively low macroalgal cover at the onset of the study. Subsequently, increasing fleshy macroalgal cover was pervasive. Herbivorous fish populations were not responsible for this trend as fleshy macroalgal cover change was not correlated with initial herbivorous fish biomass or change, and the majority of sites experienced increases in macroalgae browser biomass. This contrasts the coral reef top-down herbivore control paradigm and suggests the role of external factors in making environmental conditions more favourable for algae. Increasing macroalgal cover typically suppresses ecosystem services and leads to degraded reef systems. Consequently, policy makers and local coral reef managers should reassess the focus on herbivorous fish protection and consider complementary measures such as watershed management in order to arrest this trend.

  12. Proton Pump Inhibition Increases Rapid Eye Movement Sleep in the Rat

    Directory of Open Access Journals (Sweden)

    Munazah Fazal Qureshi

    2014-01-01

    Full Text Available Increased bodily CO2 concentration alters cellular pH as well as sleep. The proton pump, which plays an important role in the homeostatic regulation of cellular pH, therefore, may modulate sleep. We investigated the effects of the proton pump inhibitor “lansoprazole” on sleep-wakefulness. Male Wistar rats were surgically prepared for chronic polysomnographic recordings. Two different doses of lansoprazole (low: 1 mg/kg; high: 10 mg/kg were injected intraperitoneally in the same animal (n=7 and sleep-wakefulness was recorded for 6 hrs. The changes in sleep-wakefulness were compared statistically. Percent REM sleep amount in the vehicle and lansoprazole low dose groups was 9.26±1.03 and 9.09±0.54, respectively, which increased significantly in the lansoprazole high dose group by 31.75% (from vehicle and 34.21% (from low dose. Also, REM sleep episode numbers significantly increased in lansoprazole high dose group. Further, the sodium-hydrogen exchanger blocker “amiloride” (10 mg/kg; i.p. (n=5 did not alter sleep-wake architecture. Our results suggest that the proton pump plays an important role in REM sleep modulation and supports our view that REM sleep might act as a sentinel to help maintain normal CO2 level for unperturbed sleep.

  13. Rapid increases and time-lagged declines in amphibian occupancy after wildfire.

    Science.gov (United States)

    Hossack, Blake R; Lowe, Winsor H; Corn, Paul Stephen

    2013-02-01

    Climate change is expected to increase the frequency and severity of drought and wildfire. Aquatic and moisture-sensitive species, such as amphibians, may be particularly vulnerable to these modified disturbance regimes because large wildfires often occur during extended droughts and thus may compound environmental threats. However, understanding of the effects of wildfires on amphibians in forests with long fire-return intervals is limited. Numerous stand-replacing wildfires have occurred since 1988 in Glacier National Park (Montana, U.S.A.), where we have conducted long-term monitoring of amphibians. We measured responses of 3 amphibian species to fires of different sizes, severity, and age in a small geographic area with uniform management. We used data from wetlands associated with 6 wildfires that burned between 1988 and 2003 to evaluate whether burn extent and severity and interactions between wildfire and wetland isolation affected the distribution of breeding populations. We measured responses with models that accounted for imperfect detection to estimate occupancy during prefire (0-4 years) and different postfire recovery periods. For the long-toed salamander (Ambystoma macrodactylum) and Columbia spotted frog (Rana luteiventris), occupancy was not affected for 6 years after wildfire. But 7-21 years after wildfire, occupancy for both species decreased ≥ 25% in areas where >50% of the forest within 500 m of wetlands burned. In contrast, occupancy of the boreal toad (Anaxyrus boreas) tripled in the 3 years after low-elevation forests burned. This increase in occupancy was followed by a gradual decline. Our results show that accounting for magnitude of change and time lags is critical to understanding population dynamics of amphibians after large disturbances. Our results also inform understanding of the potential threat of increases in wildfire frequency or severity to amphibians in the region. ©2012 Society for Conservation Biology.

  14. Rapid increases and time-lagged declines in amphibian occupancy after wildfire

    Science.gov (United States)

    Hossack, Blake R.; Lowe, Winsor H.; Corn, Paul Stephen

    2013-01-01

    Climate change is expected to increase the frequency and severity of drought and wildfire. Aquatic and moisture-sensitive species, such as amphibians, may be particularly vulnerable to these modified disturbance regimes because large wildfires often occur during extended droughts and thus may compound environmental threats. However, understanding of the effects of wildfires on amphibians in forests with long fire-return intervals is limited. Numerous stand-replacing wildfires have occurred since 1988 in Glacier National Park (Montana, U.S.A.), where we have conducted long-term monitoring of amphibians. We measured responses of 3 amphibian species to fires of different sizes, severity, and age in a small geographic area with uniform management. We used data from wetlands associated with 6 wildfires that burned between 1988 and 2003 to evaluate whether burn extent and severity and interactions between wildfire and wetland isolation affected the distribution of breeding populations. We measured responses with models that accounted for imperfect detection to estimate occupancy during prefire (0-4 years) and different postfire recovery periods. For the long-toed salamander (Ambystoma macrodactylum) and Columbia spotted frog (Rana luteiventris), occupancy was not affected for 6 years after wildfire. But 7-21 years after wildfire, occupancy for both species decreased ≥ 25% in areas where >50% of the forest within 500 m of wetlands burned. In contrast, occupancy of the boreal toad (Anaxyrus boreas) tripled in the 3 years after low-elevation forests burned. This increase in occupancy was followed by a gradual decline. Our results show that accounting for magnitude of change and time lags is critical to understanding population dynamics of amphibians after large disturbances. Our results also inform understanding of the potential threat of increases in wildfire frequency or severity to amphibians in the region.

  15. Androgen receptor drives cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yelena Mirochnik

    Full Text Available The accepted androgen receptor (AR role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

  16. Molecular basis of androgen insensitivity.

    Science.gov (United States)

    Brinkmann, A O

    2001-06-20

    Androgens are important steroid hormones for expression of the male phenotype. They have characteristic roles during male sexual differentiation, during development and maintenance of secondary male characteristics, and during the initiation and maintenance of spermatogenesis. The two most important androgens in this respect are testosterone and 5 alpha-dihydrotestosterone. Each androgen has its own specific role during male sexual differentiation, testosterone is involved in the development and differentiation of Wolffian duct derived structures, whereas 5 alpha-dihydrotestosterone, a metabolite of testosterone, is the active ligand in the urogenital sinus and tubercle and their derived structures. The actions of androgens are mediated by the androgen receptor. This ligand dependent transcription factor belongs to the superfamily of nuclear receptors, including those for the other steroid hormones. The androgen receptor gene is located on the X-chromosome at Xq11--12 and codes for a protein with a molecular mass of approximately 110 kDa. Only one androgen receptor cDNA has been identified sofar, despite two different ligands. It is generally accepted that defects in the androgen receptor gene prevent the normal development of both internal and external male structures in 46, XY individuals. The end-organ resistance to androgens has been designated as androgen insensitivity syndrome (AIS) and is distinct from other forms of male pseudohermaphroditism like 17 beta-hydroxy-steroid dehydrogenase type 3 deficiency, leydig cell hypoplasia due to inactivating LH receptor mutations or 5 alpha-reductase type 2 deficiency. Furthermore, two additional pathological situations are associated with abnormal androgen receptor structure and function -- spinal and bulbar muscular atrophy (SBMA, or Kennedy's disease) and prostate cancer. In the AR gene, four different types of mutations have been detected in DNA from individuals with AIS -- (i) single point mutations resulting in

  17. A rapid increase in lipoprotein (a) levels after ethanol withdrawal in alcoholic men

    Energy Technology Data Exchange (ETDEWEB)

    Kervinen, K.; Savolainen, J.J.; Kesaeniemi, Y.A. (Univ. of Oulu (Finland))

    1991-01-01

    Plasma concentrations of lipoprotein (a) (Lp(a)) were studied in 11 male alcoholics at the end of a drinking period and monitored during subsequent abstinence. Lp(a) levels showed a daily increase for four consecutive days after the beginning of abstinence, the values for the third and the fourth day being significantly higher than those of the first day. The changes in Lp(a) showed no association with the changes in low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels. In one alcoholic subject with a heterozygous form of familial hypercholesterolemia who was monitored for 11 days, the Lp(a) levels rose up to the fourth day and remained at a high level thereafter. These results suggest that ethanol ingestion may be associated with a lower of Lp(a) levels, which may contribute to the delayed progression of atherosclerosis observed in alcohol drinkers.

  18. Increased heterozygosity at the Mdh-B locus in fish inhabiting a rapidly fluctuating thermal environment

    Energy Technology Data Exchange (ETDEWEB)

    Zimmerman, E.G.; Richmond, M.C.

    1981-05-01

    Populations of a common forage fish, red shiner Notropis lutrensis, were sampled from four localities on the Brazos River, Texas, affected by cold-water discharge from a hydroelectric dam and from unaltered sites in the same region. Polymorphism at the Mdh-B locus, encoding supernatant malate dehydrogenase, indicates that populations within 57 km of the dam are distinctive from other regional populations and possess a unique Mdh-B allele, have significantly higher levels of heterozygosity at the Mdh-B locus, represent a homogeneous set that have significantly different Mdh-B zygotic frequencies from other regional populations, and have significantly different Mdh-B zygotic proportions than would be expected under a Hardy-Weinberg equilibrium. Increased levels of heterozygosity in fish within 57 km of the dam were correlated with discharge-associated fluctuations in water temperature at sampling stations.

  19. Rapidly increasing body mass index among children, adolescents and young adults in a transitioning population, South Africa, 2008-15.

    Science.gov (United States)

    Sartorius, B; Sartorius, K; Taylor, M; Aagaard-Hansen, J; Dukhi, N; Day, C; Ndlovu, N; Slotow, R; Hofman, K

    2017-12-14

    There is a global epidemic of overweight and obesity; however, this rate of increase is even greater in some low- and middle-income countries (LMIC). South Africa (SA) is undergoing rapid socioeconomic and demographic changes that have triggered a rapid nutrition transition. The paper focuses on the recent rate of change of body mass index (BMI) among children, adolescents and young adults, further stratified by key sociodemographic factors. We analysed mean BMI of 28 247 individuals (including children) from 7301 households by age and year, from anthropometric data from four national cross-sectional (repeated panel) surveys using non-linear fitted curves and associated 95% confidence intervals. From 2008 to 2015, there was rapid rise in mean BMI in the 6-25 age band, with the highest risk (3-4+ BMI unit increase) among children aged 8-10 years. The increase was largely among females in urban areas and of middle-high socioeconomic standing. Prominent gains were also observed in certain rural areas, with extensive geographical heterogeneity across the country. We have demonstrated a major deviation from the current understanding of patterns of BMI increase, with a rate of increase substantially greater in the developing world context compared with the global pattern. This population-wide effect will have major consequences for national development as the epidemic of related non-communicable disease unfolds, and will overtax the national health care budget. Our refined understanding highlights that risks are further compounded for certain groups/places, and emphasizes that urgent geographical and population-targeted interventions are necessary. These interventions could include a sugar tax, clearer food labelling, revised school feeding programmes and mandatory bans on unhealthy food marketing to children.The scenario unfolding in South Africa will likely be followed in other LMICs.

  20. Synthetic polymers in the marine environment: a rapidly increasing, long-term threat.

    Science.gov (United States)

    Moore, Charles James

    2008-10-01

    Synthetic polymers, commonly known as plastics, have been entering the marine environment in quantities paralleling their level of production over the last half century. However, in the last two decades of the 20th Century, the deposition rate accelerated past the rate of production, and plastics are now one of the most common and persistent pollutants in ocean waters and beaches worldwide. Thirty years ago the prevailing attitude of the plastic industry was that "plastic litter is a very small proportion of all litter and causes no harm to the environment except as an eyesore" [Derraik, J.G.B., 2002. The pollution of the marine environment by plastic debris: a review. Mar. Pollut. Bull. 44(9), 842-852]. Between 1960 and 2000, the world production of plastic resins increased 25-fold, while recovery of the material remained below 5%. Between 1970 and 2003, plastics became the fastest growing segment of the US municipal waste stream, increasing nine-fold, and marine litter is now 60-80% plastic, reaching 90-95% in some areas. While undoubtedly still an eyesore, plastic debris today is having significant harmful effects on marine biota. Albatross, fulmars, shearwaters and petrels mistake floating plastics for food, and many individuals of these species are affected; in fact, 44% of all seabird species are known to ingest plastic. Sea turtles ingest plastic bags, fishing line and other plastics, as do 26 species of cetaceans. In all, 267 species of marine organisms worldwide are known to have been affected by plastic debris, a number that will increase as smaller organisms are assessed. The number of fish, birds, and mammals that succumb each year to derelict fishing nets and lines in which they become entangled cannot be reliably known; but estimates are in the millions. We divide marine plastic debris into two categories: macro, >5 mm and micro, plastic micro-debris by filter feeders at the base of the food web is known to occur, but has not been quantified

  1. Androgen receptor function links human sexual dimorphism to DNA methylation.

    Science.gov (United States)

    Ammerpohl, Ole; Bens, Susanne; Appari, Mahesh; Werner, Ralf; Korn, Bernhard; Drop, Stenvert L S; Verheijen, Frans; van der Zwan, Yvonne; Bunch, Trevor; Hughes, Ieuan; Cools, Martine; Riepe, Felix G; Hiort, Olaf; Siebert, Reiner; Holterhus, Paul-Martin

    2013-01-01

    Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.

  2. Androgen receptor function links human sexual dimorphism to DNA methylation.

    Directory of Open Access Journals (Sweden)

    Ole Ammerpohl

    Full Text Available Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.

  3. Supported Liquid Membrane Extraction of Anabolic Androgenic ...

    African Journals Online (AJOL)

    NJD

    Anabolic androgenic compounds, supported liquid membrane, liquid chromatography, electrospray ionization, mass spectrometry. 1. Introduction ... monitoring of some of the anabolic hormones in muscles via pentafluoropropionyl derivatization and ... androgenic steroid hormones involve the use of solid phase extraction ...

  4. Genetics Home Reference: androgen insensitivity syndrome

    Science.gov (United States)

    ... 12(4):373-87. Review. Citation on PubMed Gottlieb B, Pinsky L, Beitel LK, Trifiro M. Androgen ... 89(4):210-7. Review. Citation on PubMed Gottlieb B, Trifiro MA. Androgen Insensitivity Syndrome. 1999 Mar ...

  5. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

    Directory of Open Access Journals (Sweden)

    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  6. Internet search query analysis can be used to demonstrate the rapidly increasing public awareness of palliative care in the USA.

    Science.gov (United States)

    McLean, Sarah; Lennon, Paul; Glare, Paul

    2017-01-27

    A lack of public awareness of palliative care (PC) has been identified as one of the main barriers to appropriate PC access. Internet search query analysis is a novel methodology, which has been effectively used in surveillance of infectious diseases, and can be used to monitor public awareness of health-related topics. We aimed to demonstrate the utility of internet search query analysis to evaluate changes in public awareness of PC in the USA between 2005 and 2015. Google Trends provides a referenced score for the popularity of a search term, for defined regions over defined time periods. The popularity of the search term 'palliative care' was measured monthly between 1/1/2005 and 31/12/2015 in the USA and in the UK. Results were analysed using independent t-tests and joinpoint analysis. The mean monthly popularity of the search term increased between 2008-2009 (pquery surveillance is a novel methodology, it is freely accessible and has significant potential to monitor health-seeking behaviour among the public. PC is rapidly growing in the USA, and the rapidly increasing public awareness of PC as demonstrated in this study, in comparison with the UK, where PC is relatively well established is encouraging in increasingly ensuring appropriate PC access for all. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  7. Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Madsen, Majbritt Busk; Lyauk, Yassine Kamal

    2017-01-01

    The carboxylesterase 1 gene (CES1) encodes a hydrolase implicated in the metabolism of commonly used drugs. CES1A2, a hybrid of CES1 and a CES1-like pseudogene, has a promoter that is weak in most individuals. However, some individuals harbor a promoter haplotype of this gene with two overlapping...... Sp1 sites that confer significantly increased transcription potentially leading to rapid drug metabolism. This CES1A2 haplotype has previously been reported to be common among Asians. Using polymerase chain reaction followed by sequencing, the present study examined variation in the promoter and 5...

  8. Platelet-Rich Plasma in Androgenic Alopecia: Indications, Technique, and Potential Benefits.

    Science.gov (United States)

    Ferneini, Elie M; Beauvais, Daniel; Castiglione, Concetta; Ferneini, Moniek V

    2017-04-01

    The purpose of this study was to provide an overview of platelet-rich plasma (PRP) injected into the scalp for the management of androgenic alopecia. A literature review was performed to evaluate the benefits of PRP in androgenic alopecia. Hair restoration has been increasing. PRP's main components of platelet-derived growth factor, transforming growth factor, and vascular endothelial growth factor have the potential to stimulate hard and soft tissue wound healing. In general, PRP showed a benefit on patients with androgenic alopecia, including increased hair density and quality. Currently, different PRP preparations are being used with no standard technique. This review found beneficial effects of PRP on androgenic alopecia. However, more rigorous study designs, including larger samples, quantitative measurements of effect, and longer follow-up periods, are needed to solidify the utility of PRP for treating patients with androgenic alopecia. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  9. A clinical data validated mathematical model of prostate cancer growth under intermittent androgen suppression therapy

    Science.gov (United States)

    Portz, Travis; Kuang, Yang; Nagy, John D.

    2012-03-01

    Prostate cancer is commonly treated by a form of hormone therapy called androgen suppression. This form of treatment, while successful at reducing the cancer cell population, adversely affects quality of life and typically leads to a recurrence of the cancer in an androgen-independent form. Intermittent androgen suppression aims to alleviate some of these adverse affects by cycling the patient on and off treatment. Clinical studies have suggested that intermittent therapy is capable of maintaining androgen dependence over multiple treatment cycles while increasing quality of life during off-treatment periods. This paper presents a mathematical model of prostate cancer to study the dynamics of androgen suppression therapy and the production of prostate-specific antigen (PSA), a clinical marker for prostate cancer. Preliminary models were based on the assumption of an androgen-independent (AI) cell population with constant net growth rate. These models gave poor accuracy when fitting clinical data during simulation. The final model presented hypothesizes an AI population with increased sensitivity to low levels of androgen. It also hypothesizes that PSA production is heavily dependent on androgen. The high level of accuracy in fitting clinical data with this model appears to confirm these hypotheses, which are also consistent with biological evidence.

  10. An Update on Plant Derived Anti-Androgens

    Science.gov (United States)

    Grant, Paul; Ramasamy, Shamin

    2012-01-01

    Anti-androgens are an assorted group of drugs and compounds that reduce the levels or activity of androgen hormones within the human body. Disease states in which this is relevant include polycystic ovarian syndrome, hirsutism, acne, benign prostatic hyperplasia, and endocrine related cancers such as carcinoma of the prostate. We provide an overview and discussion of the use of anti-androgen medications in clinical practice and explore the increasing recognition of the benefits of plant-derived anti-androgens, for example, spearmint tea in the management of PCOS, for which some evidence about efficacy is beginning to emerge. Other agents covered include red reishi, which has been shown to reduce levels 5-alpha reductase, the enzyme that facilitates conversion of testosterone to dihydrotestosterone (DHT); licorice, which has phytoestrogen effects and reduces testosterone levels; Chinese peony, which promotes the aromatization of testosterone into estrogen; green tea, which contains epigallocatechins and also inhibits 5-alpha reductase, thereby reducing the conversion of normal testosterone into the more potent DHT; black cohosh, which has been shown to kill both androgenresponsive and non-responsive human prostate cancer cells; chaste tree, which has a reduces prolactin from the anterior pituitary; and saw palmetto extract, which is used as an anti-androgen although it shown no difference in comparison to placebo in clinical trials. PMID:23843810

  11. Androgen effects on skeletal muscle: implications for the development and management of frailty

    Directory of Open Access Journals (Sweden)

    Matthew DL O'Connell

    2014-04-01

    Full Text Available Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults. The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention. This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty. Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear. Androgen treatment has been generally well-tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk. The first trials of selective androgen receptor modulators (SARMs suggest similar effects on muscle mass and function to traditional androgen therapies in older adults. Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies.

  12. Total testosterone levels are often more than three times elevated in patients with androgen-secreting tumours

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Lambaa Altinok, Magda; Petersen, Kresten Rubeck

    2015-01-01

    surgery. Terminal hair growth on lip and chin gradually increases after menopause, which complicates distinction from normal physiological variation. Precise testosterone assays have just recently become available in the daily clinic. We present three women diagnosed with testosterone-producing tumours....... Gold standard techniques were used to measure testosterone levels. All tumours originated from the ovaries. Based on the present cases and the existing literature, we suggest that androgen-producing tumours should be suspected in patients with rapid progression of hyperandrogen symptoms, particularly...... when total testosterone levels are above three times the upper reference limit....

  13. Ligand Activation of the Androgen Receptor Downregulates E-Cadherin-Mediated Cell Adhesion and Promotes Apoptosis of Prostatic Cancer Cells

    Directory of Open Access Journals (Sweden)

    Joanna Nightingale

    2003-07-01

    Full Text Available Androgen independence is the major cause of endocrine therapy failure in advanced prostate cancer (PC. To examine the effects of human androgen receptor (AR expression on growth of human PC cells, transfection of full-length AR cDNA in an androgen-insensitive human prostatic adenocarcinoma cell line (DU145 was performed. Transcriptional activity of AR was confirmed by the MMTV luciferase assay and AR expression was assessed by reverse transcriptase polymerase chain reaction, Western blotting, and immunocytochemistry. Two stable transfectant cell lines expressing functional AR were established and passaged over 60 times. Under standard culture conditions, AR expression in transfected cells was predominantly cytoplasmic. Exposure to dihydrotestosterone (DHT; 60 pM-10 nM resulted in a rapid (maximal at 30 minutes translocation of AR to the nucleus. Treatment with DHT (5 nM caused a significant reduction in cell-cell adhesion and aggregation accompanied by a decrease in E-cadherin expression. This was associated with up to 40% inhibition of proliferation and approximately two-fold increase in apoptosis. These results suggest that gene transfer-mediated AR expression in DU145 cells confers sensitivity to DHT, modulates cell-cell adhesion through E-cadherin, and suppresses cell growth by inhibiting proliferation and promoting apoptosis. This provides a model for studies of AR-regulated cell signalling and identification of novel androgenregulated genes in PC.

  14. Estrogen and androgen receptor activities of hydraulic fracturing chemicals and surface and ground water in a drilling-dense region

    Science.gov (United States)

    Kassotis, Christopher D.; Tillitt, Donald E.; Davis, J. Wade; Hormann, Anette M.; Nagel, Susan C.

    2014-01-01

    The rapid rise in natural gas extraction using hydraulic fracturing increases the potential for contamination of surface and ground water from chemicals used throughout the process. Hundreds of products containing more than 750 chemicals and components are potentially used throughout the extraction process, including more than 100 known or suspected endocrine-disrupting chemicals. We hypothesized thataselected subset of chemicalsusedin natural gas drilling operationsandalso surface and ground water samples collected in a drilling-dense region of Garfield County, Colorado, would exhibit estrogen and androgen receptor activities. Water samples were collected, solid-phase extracted, and measured for estrogen and androgen receptor activities using reporter gene assays in human cell lines. Of the 39 unique water samples, 89%, 41%, 12%, and 46% exhibited estrogenic, antiestrogenic, androgenic, and antiandrogenic activities, respectively. Testing of a subset of natural gas drilling chemicals revealed novel antiestrogenic, novel antiandrogenic, and limited estrogenic activities. The Colorado River, the drainage basin for this region, exhibited moderate levels of estrogenic, antiestrogenic, and antiandrogenic activities, suggesting that higher localized activity at sites with known natural gas–related spills surrounding the river might be contributing to the multiple receptor activities observed in this water source. The majority of water samples collected from sites in a drilling-dense region of Colorado exhibited more estrogenic, antiestrogenic, or antiandrogenic activities than reference sites with limited nearby drilling operations. Our data suggest that natural gas drilling operationsmayresult in elevated endocrine-disrupting chemical activity in surface and ground water.

  15. Androgen Receptor-Mediated Escape Mechanism from Androgen Ablation Therapy

    Science.gov (United States)

    2008-10-31

    except that no salmon sperm DNA was used as blocking reagent. The immunoprecipitated DNA and un- enriched input DNA were treated with RNase A and purified...A, Wang Y, Suzuki K, Mirosevich J, et al. (2005) Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes

  16. Repeated Administration of Korea Red Ginseng Extract Increases Non-Rapid Eye Movement Sleep via GABAAergic Systems.

    Science.gov (United States)

    Lee, Chung-Il; Kim, Chung-Soo; Han, Jin-Yi; Oh, Eun-Hye; Oh, Ki-Wan; Eun, Jae Soon

    2012-10-01

    The current inquiry was conducted to assess the change in sleep architecture after long periods of administration to determine whether ginseng can be used in the therapy of sleeplessness. Following post-surgical recovery, red ginseng extract (RGE, 200 mg/ kg) was orally administrated to rats for 9 d. Data were gathered on the 1st, 5th, and 9th day, and an electroencephalogram was recorded 24 h after RGE administration. Polygraphic signs of unobstructed sleep-wake activities were simultaneously recorded with sleep-wake recording electrodes from 11:00 a.m. to 5:00 p.m. for 6 h. Rodents were generally tamed to freely moving polygraphic recording conditions. Although the 1st and 5th day of RGE treatment showed no effect on power densities in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, the 9th day of RGE administration showed augmented α-wave (8.0 to 13.0 Hz) power densities in NREM and REM sleep. RGE increased total sleep and NREM sleep. The total percentage of wakefulness was only decreased on the 9th day, and the number of sleep-wake cycles was reduced after the repeated administration of RGE. Thus, the repeated administration of RGE increased NREM sleep in rats. The α-wave activities in the cortical electroencephalograms were increased in sleep architecture by RGE. Moreover, the levels of both α- and β-subunits of the γ-aminobutyric acid (GABA)A receptor were reduced in the hypothalamus of the RGE-treated groups. The level of glutamic acid decarboxylase was over-expressed in the hypothalamus. These results demonstrate that RGE increases NREM sleep via GABAAergic systems.

  17. Androgens and obesity in male adolescents.

    Science.gov (United States)

    Vandewalle, Sara; De Schepper, Jean; Kaufman, Jean-Marc

    2015-06-01

    Data on sex steroid levels and pubertal development in obese adolescent boys are scarce and contrasting. The present review summarizes the most recent results obtained with improved methodology to measure low sex steroid levels in children. Obese pubertal boys have lower serum sex hormone-binding globulin and consequently lower total testosterone levels compared to normal-weight peers. However, during pubertal development, free testosterone levels in obese adolescents are not different from controls, indicating preserved androgen exposure as is additionally suggested by similar clinical genital staging (Tanner), serum gonadotropins levels, and serum prostate-specific antigen concentrations compared to nonobese adolescents. In pre and early puberty, total testosterone levels is not decreased, notwithstanding low sex hormone-binding globulin, and free testosterone is slightly increased in obese boys. This may result from increased adrenal activity as revealed by elevated serum androstenedione and dehydroepiandrosterone sulfate. In obese adolescent boys, increased aromatization of testosterone to estradiol tends to accelerate skeletal maturation. In obese adolescent boys, free testosterone is a better index than total testosterone levels of androgen status, which is not different from nonobese controls. Increased aromatization of testosterone to estradiol underlies the dissociation between normal clinical sexual maturation and advanced skeletal maturation in the obese adolescent.

  18. The Central Effects of Androgenic-anabolic Steroid Use.

    Science.gov (United States)

    Mędraś, Marek; Brona, Anna; Jóźków, Paweł

    2018-02-21

    : Millions of men use androgenic-anabolic steroids (AAS) to stimulate muscle growth and improve physical appearance. Although 1 out of 3 people who uses androgenic-anabolic steroids develops a steroid use disorder, the effects of the drugs on the central nervous system and the psyche are still not well understood. Although most addictive substances improve mood immediately after administration, AAS exert less pronounced euphoric effects. Instead, they are primarily taken for the delayed gratification of increased muscle mass. Withdrawal from AAS may lead to a range of somatic and psychiatric symptoms, and, in many cases, comprehensive treatment supervised by an endocrinologist and a psychiatrist is required.

  19. Expression of Androgen Receptor Is Negatively Regulated By p53

    OpenAIRE

    Fatouma Alimirah; Ravichandran Panchanathan; Jianming Chen; Xiang Zhang; Shuk-Mei Ho; Divaker Choubey

    2007-01-01

    Increased expression of androgen receptor (AR) in prostate cancer (PC) is associated with transition to androgen independence. Because the progression of PC to advanced stages is often associated with the loss of p53 function, we tested whether the p53 could regulate the expression of AR gene. Here we report that p53 negatively regulates the expression of AR in prostate epithelial cells (PrECs). We found that in LNCaP human prostate cancer cells that express the wild-type p53 and AR and in hu...

  20. Penguin chicks benefit from elevated yolk androgen levels under sibling competition.

    Directory of Open Access Journals (Sweden)

    Maud Poisbleau

    Full Text Available Crested penguins (genus Eudyptes have a peculiar hatching pattern, with the first-laid egg (A-egg hatching after the second-laid egg (B-egg and chicks from A-eggs typically having a much lower survival probability. Maternal yolk androgens have been suggested to contribute to the competitive superiority of the B-chick in southern rockhopper penguins Eudyptes chrysocome, given their important role in mediating sibling competition in other species. We therefore increased the yolk androgen levels in freshly-laid eggs and examined the consequences for sibling competition--via effects on embryonic developmental times, chick growth and early survival. We placed one androgen-treated egg and one control egg into each foster nest, matching them for mass, laying date and laying order. The androgen treatment did not significantly affect embryonic developmental times or chick measurements at hatching. However, elevated yolk androgen levels benefitted chick growth in interaction with the number of siblings in a brood. Chicks from androgen-treated eggs had faster growth in the presence of a sibling than chicks from control eggs. Under these circumstances they also had a higher survival probability. Thus maternal androgens appear to reinforce the observed hatching pattern, facilitating brood reduction. This contrasts to most previous studies in other species where yolk androgens have been shown to compensate for the negative consequences of delayed hatching within the brood hierarchy.

  1. Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation

    National Research Council Canada - National Science Library

    Padalecki, Susan

    2002-01-01

    .... Treatment with androgen deprivation therapy leads to an increase in bone turnover as indicated by the loss of bone mineral density and the increase in markers of bone turnover in patients on treatment...

  2. Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans With Bone-Metastatic Prostate Cancer

    Science.gov (United States)

    2014-09-01

    Hereditary prostate cancer : epidemiologic and clinical features. J Urol., 150(3):797-802, 1993. 12. Boring, C. C. Cancer StatistiAC. (1991) CA...Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer . Cancer Res 2006;66(5):2815–2825. [PubMed: 16510604]. 12 ...Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans With Bone-Metastatic Prostate Cancer PRINCIPAL

  3. Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Pinilla, Mabel G. [Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C. [Department of Physiopathology, School of Biological Sciences, University of Concepcion, Concepcion (Chile); McNerney, Eileen M. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

    2015-11-27

    Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

  4. Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors.

    Directory of Open Access Journals (Sweden)

    Elahe A Mostaghel

    Full Text Available Prostate cancer (PCa is the second most common cancer in men. Androgen deprivation therapy (ADT leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC. Theories underlying the development of CRPC include androgen receptor (AR mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049 and intratumoral levels of testosterone (R = 0.41, p = 0.0023 in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025 Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the

  5. Blocking blue light during mania - markedly increased regularity of sleep and rapid improvement of symptoms: a case report.

    Science.gov (United States)

    Henriksen, Tone E G; Skrede, Silje; Fasmer, Ole Bernt; Hamre, Børge; Grønli, Janne; Lund, Anders

    2014-12-01

    Available pharmacological treatment of mania is insufficient. Virtual darkness therapy (blue light-blocking treatment by means of orange-tinted glasses) is a promising new treatment option for mania. The basis for this might be the recently identified blue light-sensitive retinal photoreceptor, which is solely responsible for light stimulus to the circadian master clock. This is the first case report describing the clinical course of a closely monitored, hospitalized patient in a manic episode first receiving clear-lensed, and then blue light-blocking glasses. A 58-year-old Caucasian man, with bipolar I disorder and three previous manic episodes, was hospitalized during a manic episode. In addition to pharmacological treatment, he was treated with clear-lensed glasses for seven days, then one day without glasses, followed by six days of blue light-blocking glasses. During the entire observational period, he wore an actigraph with internal light sensors. Manic symptoms were unaltered during the first seven days. The transition to the blue-blocking regime was followed by a rapid and sustained decline in manic symptoms accompanied by a reduction in total sleep, a reduction in motor activity during sleep intervals, and markedly increased regularity of sleep intervals. The patient's total length of hospital stay was 20 days shorter than the average time during his previous manic episodes. The unusually rapid decline in symptoms, accompanied by uniform sleep parameter changes toward markedly increased regularity, suggest that blue-blockers might be targeting a central mechanism in the pathophysiology of mania that needs to be explored both in clinical research and in basic science. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Rapid Increase in Serum Low-Density Lipoprotein Cholesterol Concentration during Hepatitis C Interferon-Free Treatment.

    Directory of Open Access Journals (Sweden)

    Satoru Hashimoto

    Full Text Available We performed lipid analyses at the early period of therapy in patients with chronic hepatitis C who underwent interferon (IFN-free direct-acting antiviral (DAA treatment, and we attempted to identify the factors that contributed to a rapid increase in the patients' serum low-density lipoprotein cholesterol (LDL-C concentration.We retrospectively analyzed the cases of 100 consecutive patients with HCV infection treated at the National Hospital Organization Nagasaki Medical Center: 24 patients underwent daclatasvir (DCV and asunaprevir (ASV combination therapy (DCV/ASV for 24 weeks, and the other 76 patients underwent ledipasvir and sofosbuvir combination therapy (LDV/SOF for 12 weeks. ΔLDL-C was defined as the changed in LDL-C level at 28 days from the start of therapy. To determine whether ΔLDL-C was associated with several kinds of factors including viral kinetics, we performed a stepwise multiple linear regression analysis.The LDL-C levels in patients treated with LDV/SOF were markedly and significantly elevated (87.45 to 122.5 mg/dl; p<10-10 compared to those in the DCV/ASV-treated patients (80.15 to 87.8 mg/dl; p = 0.0056. The median levels of ΔLDL-C in the LDV/SOF and DCV/ASV groups were 33.2 and 13.1, respectively. LDV/SOF combination therapy as an IFN-free regimen (p<0.001 and ΔHCV core antigen (0-1 day drop (p<0.044 were identified as independent factors that were closely related to the ΔLDL-C.A rapid increase in the serum LDL-C concentration during the IFN-free treatment of hepatitis C was associated with the type of HCV therapy and a decline of HCV core protein.

  7. Yolk androgens do not appear to mediate sexual conflict over parental investment in the collared flycatcher Ficedula albicollis.

    Science.gov (United States)

    Ruuskanen, Suvi; Doligez, Blandine; Tschirren, Barbara; Pitala, Natalia; Gustafsson, Lars; Groothuis, Ton G G; Laaksonen, Toni

    2009-04-01

    Males and females are in conflict over parental care, as it would be favourable for one parent to shift labour to the other. Yolk hormones may offer a mechanism through which female birds could influence offspring traits in ways that increase the relative investment by the male. We studied the role of yolk androgens in mediating sexual conflict over parental care in the collared flycatcher (Ficedula albicollis). In a cross-fostering experiment, the male's proportion of total feeding visits increased with increasing androgen levels in the foster eggs. This could suggest that sexual conflict over parental care may be influenced by the female's differential allocation of yolk androgens or a maternal effect associated with yolk androgens. However, when we experimentally elevated yolk androgen levels, male feeding rates did not differ between control and androgen-manipulated nests. This suggests that other egg components correlated with yolk androgen levels, rather than yolk androgen levels per se, may influence male parental effort. In conclusion, yolk androgens per se do not appear to mediate sexual conflict over parental investment in the collared flycatcher.

  8. Hypercholesterolemia in Male Power Lifters Using Anabolic-Androgenic Steroids.

    Science.gov (United States)

    Cohen, Jonathan C.; And Others

    1988-01-01

    Measurement of serum cholesterol concentrations in male power lifters who used anabolic-androgenic steroids for eight weeks, three years, or eight years indicated that mean serum cholesterol levels increased with drug use, but decreased promptly to near pre-steroid levels after steroid use ended. (Author/CB)

  9. Prevalence and awareness of anabolic androgenic steroid use ...

    African Journals Online (AJOL)

    Purpose: To examine the prevalence and awareness of anabolic-androgenic steroid (AAS) use among male bodybuilders visiting gyms in Jazan ... Health educational programs are required to increase the awareness about the side effects of anabolic steroids ..... Brand (generic name). Testosterone (Enanthate). 54. 37.5.

  10. Androgen interacts with exercise through the mTOR pathway to induce skeletal muscle hypertrophy

    Directory of Open Access Journals (Sweden)

    Fanxing Zeng

    2017-12-01

    Full Text Available This study was designed to investigate the effects of exogenous androgen and resistance exercise on skeletal muscle hypertrophy and the role of the mammalian target of rapamycin (mTOR signalling during the process. A total of 24 male Sprague-Dawley rats were randomly assigned to sham operation and dihydrotestosterone (DHT implantation groups with subgroups subjected to sedentary conditions or resistance exercise (SHAM+SED, SHAM+EX, DHT+SED, and DHT+EX. The experimental procedure lasted for 10 days. The mRNA expression of androgen receptor (AR and insulin-like growth factor I (IGF-I, the expression of myosin heavy chain (MHC, as well as the phosphorylation statuses of AR, mTOR, p70 ribosomal S6 kinase (p70S6K, and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1 were determined in the white gastrocnemius muscle. The cross sectional area and wet mass of the muscle were also measured. The cross sectional area and MHC expression were significantly higher in SHAM+EX, DHT+SED, and DHT+EX than in SHAM+SED. There was no significant difference among groups in muscle mass. The mRNA expression of AR and IGF-I and the phosphorylation of mTOR, p70S6K, and 4EBP1 were significantly increased in DHT+SED and SHAM+EX and were significantly enhanced in DHT+EX compared with either DHT or exercise alone. These data show that DHT causes hypertrophy in skeletal muscle and that exercise has a synergistic effect on DHT-induced hypertrophy. Exercise enhances androgen-induced rapid anabolic action, which involves activation of the mTOR pathway.

  11. Children treated for severe acute malnutrition experience a rapid increase in physical activity a few days after admission.

    Science.gov (United States)

    Faurholt-Jepsen, Daniel; Hansen, Kristina Beck; van Hees, Vincent T; Christensen, Line Brinch; Girma, Tsinuel; Friis, Henrik; Brage, Søren

    2014-06-01

    To assess physical activity at admission and during recovery from severe acute malnutrition. Ethiopian children who were admitted with severe acute malnutrition received a clinical examination each week to monitor their recovery during rehabilitation. Using accelerometry (24 h/d for 5 consecutive days) at admission and again after 10 days of rehabilitation, we assessed the level and changes of physical activity. Among 13 children included, the mean (SD) age was 31.1 months (15.5). At baseline, the day-night activity difference was relatively small, whereas the level of activity had substantially increased at follow-up. The diurnal mean acceleration level was significantly greater at follow-up for wrist (1158.8 vs 541.4 counts per minute, P = .003) but not hip movements (204.1 vs 141.5, P = .261). During daytime (6 a.m. to 10 p.m.), hip activity increased by 38% from baseline to follow-up (e(B) 1.38, 95% CI 1.17-1.62), and wrist activity more than doubled (e(B) 2.50, 95% CI 2.17-2.87). The level of physical activity among children with severe acute malnutrition is very low but increases rapidly during recovery. Accelerometry may be a useful approach in the recovery phase as an indicator of early improvement. Copyright © 2014 The Authors. Published by Mosby, Inc. All rights reserved.

  12. Molecular cloning and characterization of a nuclear androgen receptor activated by 11-ketotestosterone

    Directory of Open Access Journals (Sweden)

    Karlsson Johnny

    2005-08-01

    Full Text Available Abstract Although 11-ketotestosterone is a potent androgen and induces male secondary sex characteristics in many teleosts, androgen receptors with high binding affinity for 11-ketotestosterone or preferential activation by 11-ketotestosterone have not been identified. So, the mechanism by which 11-ketotestosterone exhibits such high potency remains unclear. Recently we cloned the cDNA of an 11-ketotestosterone regulated protein, spiggin, from three-spined stickleback renal tissue. As spiggin is the only identified gene product regulated by 11-ketotestosterone, the stickleback kidney is ideal for determination of the mechanism of 11-ketotestosterone gene regulation. A single androgen receptor gene with two splicing variants, belonging to the androgen receptor-β subfamily was cloned from stickleback kidney. A high affinity, saturable, single class of androgen specific binding sites, with the characteristics of an androgen receptor, was identified in renal cytosolic and nuclear fractions. Measurement of ligand binding moieties in the cytosolic and nuclear fractions as well as to the recombinant receptor revealed lower affinity for 11-ketotestosterone than for dihydrotestosterone. Treatment with different androgens did not up-regulate androgen receptor mRNA level or increase receptor abundance, suggesting that auto-regulation is not involved in differential ligand activation. However, comparison of the trans-activation potential of the stickleback androgen receptor with the human androgen receptor, in both human HepG2 cells and zebrafish ZFL cells, revealed preferential activation by 11-ketotestosterone of the stickleback receptor, but not of the human receptor. These findings demonstrate the presence of a receptor preferentially activated by 11-ketotestosterone in the three-spined stickleback, so far the only one known in any animal.

  13. Increased baseline proinflammatory cytokine production in chronic hepatitis C patients with rapid virological response to peginterferon plus ribavirin.

    Science.gov (United States)

    Par, Gabriella; Szereday, Laszlo; Berki, Timea; Palinkas, Laszlo; Halasz, Melinda; Miseta, Attila; Hegedus, Geza; Szekeres-Bartho, Julia; Vincze, Aron; Hunyady, Bela; Par, Alajos

    2013-01-01

    Chronic hepatitis C (CHC) patients achieving rapid virological response (RVR) on PEG-IFN/ribavirin (P/R) therapy have high chance of sustained virological response (SVR). To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) were studied prior to and during P/R therapy. TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll-like receptor 4 (TLR-4) or phorbol myristate acetate/Ionomycin stimulation in 20 healthy controls and in 50 CHC patients before receiving and during P/R therapy. RVR was achieved by 14, complete early virological response (cEVR) by 19 patients and 17 patients were null-responders (NR). Patients with RVR showed an increased baseline TNF-α and IL-6 production by TLR-4 activated monocytes and increased IFN-γ, decreased IL-4 and IL-10 production by lymphocytes compared to non-RVR patients. SVR was also associated with increased baseline TNF-α production and decreased IL-10 levels compared to patients who did not achieve SVR. Baseline IL-2 production was higher in cEVR compared to NR patients. Antiviral treatment increased TNF-α, IL-6 production by monocytes and IFN-γ secretion by lymphocytes and decreased IL-4 and IL-10 production by lymphocytes in cEVR compared to NR patients. RVR was associated with increased baseline proinflammatory cytokine production by TLR-4 stimulated monocytes and by activated lymphocytes. In null-responders and in patients who did not achieve SVR both TLR-4 sensing function and proinflammatory cytokine production were impaired, suggesting that modulation of TLR activity and controlled induction of inflammatory cytokine production may provide further therapeutic strategy for CHC patients non-responding to P/R treatment.

  14. Increased baseline proinflammatory cytokine production in chronic hepatitis C patients with rapid virological response to peginterferon plus ribavirin.

    Directory of Open Access Journals (Sweden)

    Gabriella Par

    Full Text Available BACKGROUND: Chronic hepatitis C (CHC patients achieving rapid virological response (RVR on PEG-IFN/ribavirin (P/R therapy have high chance of sustained virological response (SVR. To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC were studied prior to and during P/R therapy. METHODS: TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll-like receptor 4 (TLR-4 or phorbol myristate acetate/Ionomycin stimulation in 20 healthy controls and in 50 CHC patients before receiving and during P/R therapy. RVR was achieved by 14, complete early virological response (cEVR by 19 patients and 17 patients were null-responders (NR. RESULTS: Patients with RVR showed an increased baseline TNF-α and IL-6 production by TLR-4 activated monocytes and increased IFN-γ, decreased IL-4 and IL-10 production by lymphocytes compared to non-RVR patients. SVR was also associated with increased baseline TNF-α production and decreased IL-10 levels compared to patients who did not achieve SVR. Baseline IL-2 production was higher in cEVR compared to NR patients. Antiviral treatment increased TNF-α, IL-6 production by monocytes and IFN-γ secretion by lymphocytes and decreased IL-4 and IL-10 production by lymphocytes in cEVR compared to NR patients. CONCLUSION: RVR was associated with increased baseline proinflammatory cytokine production by TLR-4 stimulated monocytes and by activated lymphocytes. In null-responders and in patients who did not achieve SVR both TLR-4 sensing function and proinflammatory cytokine production were impaired, suggesting that modulation of TLR activity and controlled induction of inflammatory cytokine production may provide further therapeutic strategy for CHC patients non-responding to P/R treatment.

  15. Expression of androgen receptor target genes in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Kesha Rana

    2014-10-01

    Full Text Available We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (ARΔZF2 versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR∆ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7 , p57 Kip2, Igf2 and calcineurin Aa, was increased in AR∆ZF2 muscle, and the expression of all but p57 Kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

  16. Yersinia pestis endowed with increased cytotoxicity is avirulent in a bubonic plague model and induces rapid protection against pneumonic plague.

    Science.gov (United States)

    Zauberman, Ayelet; Tidhar, Avital; Levy, Yinon; Bar-Haim, Erez; Halperin, Gideon; Flashner, Yehuda; Cohen, Sara; Shafferman, Avigdor; Mamroud, Emanuelle

    2009-06-16

    An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica Oratio8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7)-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD(50) of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed new light on the

  17. Yersinia pestis endowed with increased cytotoxicity is avirulent in a bubonic plague model and induces rapid protection against pneumonic plague.

    Directory of Open Access Journals (Sweden)

    Ayelet Zauberman

    Full Text Available An important virulence strategy evolved by bacterial pathogens to overcome host defenses is the modulation of host cell death. Previous observations have indicated that Yersinia pestis, the causative agent of plague disease, exhibits restricted capacity to induce cell death in macrophages due to ineffective translocation of the type III secretion effector YopJ, as opposed to the readily translocated YopP, the YopJ homologue of the enteropathogen Yersinia enterocolitica Oratio8. This led us to suggest that reduced cytotoxic potency may allow pathogen propagation within a shielded niche, leading to increased virulence. To test the relationship between cytotoxic potential and virulence, we replaced Y. pestis YopJ with YopP. The YopP-expressing Y. pestis strain exhibited high cytotoxic activity against macrophages in vitro. Following subcutaneous infection, this strain had reduced ability to colonize internal organs, was unable to induce septicemia and exhibited at least a 10(7-fold reduction in virulence. Yet, upon intravenous or intranasal infection, it was still as virulent as the wild-type strain. The subcutaneous administration of the cytotoxic Y. pestis strain appears to activate a rapid and potent systemic, CTL-independent, immunoprotective response, allowing the organism to overcome simultaneous coinfection with 10,000 LD(50 of virulent Y. pestis. Moreover, three days after subcutaneous administration of this strain, animals were also protected against septicemic or primary pneumonic plague. Our findings indicate that an inverse relationship exists between the cytotoxic potential of Y. pestis and its virulence following subcutaneous infection. This appears to be associated with the ability of the engineered cytotoxic Y. pestis strain to induce very rapid, effective and long-lasting protection against bubonic and pneumonic plague. These observations have novel implications for the development of vaccines/therapies against Y. pestis and shed

  18. Androgenic effect of honeybee drone milk in castrated rats: roles of methyl palmitate and methyl oleate.

    Science.gov (United States)

    Seres, A B; Ducza, E; Báthori, M; Hunyadi, A; Béni, Z; Dékány, M; Hajagos-Tóth, J; Verli, J; Gáspár, Róbert

    2014-04-28

    Numerous honeybee (Apis mellifera) products have been used in traditional medicine to treat infertility and to increase vitality in both men and women. Drone milk (DM) is a relatively little-known honeybee product with a putative sexual hormone effect. The oestrogenic effect of a fraction of DM has recently been reported in rats. However, no information is available on the androgenic effects of DM. The purpose of the present study was to determine the androgen-like effect of DM in male rats and to identify effective compounds. A modified Hershberger assay was used to investigate the androgenic effect of crude DM, and the plasma level of testosterone was measured. The prostatic mRNA and protein expression of Spot14-like androgen-inducible protein (SLAP) were also examined with real-time PCR and Western blot techniques. GC-MS and NMR spectroscopic investigations were performed to identify the active components gained by bioactivity-guided fractionation. The crude DM increased the relative weights of the androgen-dependent organs and the plasma testosterone level in castrated rats and these actions were flutamide-sensitive. DM increased the tissue mRNA and protein level of SLAP, providing further evidence of its androgen-like character. After bioactivity-guided fractionation, two fatty acid esters, methyl palmitate (MP) and methyl oleate (MO), were identified as active compounds. MP alone showed an androgenic effect, whereas MO increased the weight of androgen-sensitive tissues and the plasma testosterone level only in combination. The experimental data of DM and its active compounds (MO and MP) show androgenic activity confirming the traditional usage of DM. DM or MP or/and MO treatments may project a natural mode for the therapy of male infertility. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Marked increase in the prevalence of obesity in children of the Seychelles, a rapidly developing country, between 1998 and 2004.

    Science.gov (United States)

    Bovet, Pascal; Chiolero, Arnaud; Madeleine, George; Gabriel, Anne; Stettler, Nicolas

    2006-01-01

    There are few data on overweight in children in developing countries. Such data are important to guide public health policy. We assessed trends in the prevalence of overweight and obesity in children from the Seychelles, a middle-income island state in the Indian Ocean. Multiple cross-sectional surveys were conducted each year between 1998 and 2004 on all students of all schools in four selected school grades (creche, 4th, 7th and 10th years of mandatory school). Weight and height were measured and children were asked about walking time and frequency of physical exercise at leisure time. Excess weight categories were defined according to the criteria of the International Obesity Task Force (IOTF) and the U.S. Centers for Disease Control and Prevention (CDC). Data were available for 33 340 observations in 1998-2004, corresponding to 23,459 individual children measured once or several times. Based on IOTF criteria, the prevalence of 'overweight' or 'obesity' increased from 8.7% to 13.5% in boys, and from 11.8% to 18.6% in girls from 1998 to 2004 (P risk of overweight' and 'overweight' increased by similar proportions. The shift towards higher values over time was larger in the upper than the lower tail of the BMI distribution. Physical activity decreased over calendar years and was inversely associated with excess weight. The prevalence of excess weight increased markedly over a seven-year period in children in the Seychelles. This is likely to reflect a rapid nutrition transition with increasingly positive energy balance. These findings stress the need for programs and policies aimed at promoting physical activity and healthy nutrition in countries in epidemiological transition.

  20. Androgens and estrogens in skeletal sexual dimorphism

    Directory of Open Access Journals (Sweden)

    Michaël Laurent

    2014-04-01

    Full Text Available Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T to estradiol (E2 by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis.

  1. Androgen deprivation modulates the inflammatory response induced by irradiation

    Directory of Open Access Journals (Sweden)

    Lin Paul-Yang

    2009-03-01

    Full Text Available Abstract Background The aim of this study was to determine whether radiation (RT-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. Methods The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2, TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT -induced fibrosis. Results We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. Conclusion When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

  2. Androgens and the ageing male

    DEFF Research Database (Denmark)

    Juul, Anders; Skakkebaek, Niels E

    2002-01-01

    with severe primary or secondary hypogonadism. Thus, androgen substitution therapy is warranted in men with true hypogonadism at all ages. Symptoms experienced by otherwise healthy ageing males are non-specific and vague, although some may be similar to symptoms of hypogonadism. Therefore, the term...... not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial...... in some elderly males with low-normal testosterone levels. However, at this point in time, widespread use of testosterone in an elderly male population outside controlled clinical trials seems inappropriate....

  3. Rapid, Transient Fluconazole Resistance in Candida albicans Is Associated with Increased mRNA Levels of CDR

    Science.gov (United States)

    Marr, Kieren A.; Lyons, Christopher N.; Rustad, Tiger; Bowden, Raleigh A.; White, Theodore C.

    1998-01-01

    Fluconazole-resistant Candida albicans, a cause of recurrent oropharyngeal candidiasis in patients with human immunodeficiency virus infection, has recently emerged as a cause of candidiasis in patients receiving cancer chemotherapy and marrow transplantation (MT). In this study, we performed detailed molecular analyses of a series of C. albicans isolates from an MT patient who developed disseminated candidiasis caused by an azole-resistant strain 2 weeks after initiation of fluconazole prophylaxis (K. A. Marr, T. C. White, J. A. H. vanBurik, and R. A. Bowden, Clin. Infect. Dis. 25:908–910, 1997). DNA sequence analysis of the gene (ERG11) for the azole target enzyme, lanosterol demethylase, revealed no difference between sensitive and resistant isolates. A sterol biosynthesis assay revealed no difference in sterol intermediates between the sensitive and resistant isolates. Northern blotting, performed to quantify mRNA levels of genes encoding enzymes in the ergosterol biosynthesis pathway (ERG7, ERG9, and ERG11) and genes encoding efflux pumps (MDR1, ABC1, YCF, and CDR), revealed that azole resistance in this series is associated with increased mRNA levels for members of the ATP binding cassette (ABC) transporter superfamily, CDR genes. Serial growth of resistant isolates in azole-free media resulted in an increased susceptibility to azole drugs and corresponding decreased mRNA levels for the CDR genes. These results suggest that C. albicans can become transiently resistant to azole drugs rapidly after exposure to fluconazole, in association with increased expression of ABC transporter efflux pumps. PMID:9756759

  4. Reptides and Proteins Interacting with the Androgen Receptor

    NARCIS (Netherlands)

    D.J. van de Wijngaart (Dennis)

    2009-01-01

    textabstractAndrogens are important sex steroid hormones. The androgens testosterone and dihydrotestosterone (DHT) are essential for normal male sexual differentiation and for the development and maintenance of male reproductive tissues, including the prostate. Androgens mediate their effects by

  5. Differential Mechanisms of Androgen Resistance

    Science.gov (United States)

    2007-12-01

    two infertile Finnish men. Fertility and Sterility , 79, Supple3, 2003. Miyake H, Hara I, Eto H.2005 Clinical outcome of maximum androgen blockade...identified in two infertile men (Lund et al 2003). It can be postulated that Q58L could change the conformation of the polyglutamide tract thereby...and PC3- LNCAP AR (C) tumour xenografts. 3 million cells in sterile PBS (1:1 ratio with Matrigel) were implanted s.c. into the flank of SCID mice

  6. Caffeine Ingestion after Rapid Weight Loss in Judo Athletes Reduces Perceived Effort and Increases Plasma Lactate Concentration without Improving Performance

    Science.gov (United States)

    Lopes-Silva, Joao P.; Felippe, Leandro J. C.; Silva-Cavalcante, Marcos D.; Bertuzzi, Romulo; Lima-Silva, Adriano E.

    2014-01-01

    The objective of this study was to examine the effect of caffeine on judo performance, perceived exertion, and plasma lactate response when ingested during recovery from a 5-day weight loss period. Six judokas performed two cycles of a 5-day rapid weight loss procedure to reduce their body weight by ~5%. After weigh-in, subjects re-fed and rehydrated over a 4-h recovery period. In the third hour of this “loading period”, subjects ingested a capsule containing either caffeine (6 mg·kg−1) or placebo. One hour later, participants performed three bouts of a judo fitness test with 5-min recovery periods. Perceived exertion and plasma lactate were measured before and immediately after each test bout. Body weight was reduced in both caffeine and placebo conditions after the weight loss period (−3.9% ± 1.6% and −4.0% ± 2.3% from control, respectively, p judo fitness test after a 5-day weight loss period, but reduced perceived exertion and increased plasma lactate. PMID:25054553

  7. Androgenic regulation of ventral epithelial bud number and pattern in mouse urogenital sinus.

    Science.gov (United States)

    Allgeier, Sarah H; Lin, Tien-Min; Moore, Robert W; Vezina, Chad M; Abler, Lisa L; Peterson, Richard E

    2010-02-01

    The ventral urogenital sinus (UGS) of control male mice has two rows of 3-4 prostatic buds at birth, but how androgens regulate ventral bud (VB) number and patterning is unclear. VBs in both sexes appeared to be a mixture of prostatic and urethral buds. UGSs from Tfm male and antiandrogen (flutamide)-exposed mice had small VBs, suggesting that initiation of some VBs is androgen independent. Tfm male mice are widely considered completely androgen insensitive yet their UGSs were 5alpha-dihydrotestosterone (DHT)- responsive. VBs (6-8) were generally distributed bimodally on the left-right axis at both minimal and normal male androgen signaling. Yet control females and DHT-exposed Tfm males had 13-14 VBs, whose left-right distribution was fairly uniform. These results suggest that VB number and distribution respond biphasically as androgen signaling increases from minimal, and that androgens regulate bud specification. Complete VB agenesis by the selective budding inhibitor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) required high androgen signaling.

  8. Anabolic androgenic steroids abuse and liver toxicity.

    Science.gov (United States)

    Neri, M; Bello, S; Bonsignore, A; Cantatore, S; Riezzo, I; Turillazzi, E; Fineschi, V

    2011-05-01

    In the athletes the wide use of Anabolic Androgenic Steroids (AAS) cause series damage in various organs, in particular, analyzing the liver, elevation on the levels of liver enzymes, cholestatic jaundice, liver tumors, both benign and malignant, and peliosis hepatis are described. A prolonged AAS administration provokes an increase in the activities of liver lysosomal hydrolases and a decrease in some components of the microsomal drug-metabolizing system and in the activity of the mitochondrial respiratory chain complexes without modifying classical serum indicators of hepatic function. Liver is a key organ actively involved in numerous metabolic and detoxifying functions. As a consequence, it is continuously exposed to high levels of endogenous and exogenous oxidants that are by-products of many biochemical pathways and, in fact, it has been demonstrated that intracellular oxidant production is more active in liver than in tissues, like the increase of inflammatory cytokines, apoptosis and the inhibitors of apoptosis NF- κB and Heat Shock Proteins.

  9. Lesser double-collared sunbirds Nectarinia chalybea do not compensate for hatching asynchrony by adjusting egg mass or yolk androgens

    NARCIS (Netherlands)

    Eising, Corine M.; Robles, Raquel; Lasthuizen, Maarten; Groothuis, Ton G. G.

    2009-01-01

    Substantial amounts of maternal androgens are found in birds' eggs and have been shown to benefit offspring development. Within-clutch patterns of increasing androgen concentrations over the laying sequence are often hypothesized to compensate for the negative effects of hatching asynchrony.

  10. Influence of endogenous androgens on carotid wall in postmenopausal women.

    Science.gov (United States)

    Bernini, G P; Moretti, A; Sgró, M; Argenio, G F; Barlascini, C O; Cristofani, R; Salvetti, A

    2001-01-01

    There is increasing evidence of a direct association between normal androgen levels and reduced cardiovascular morbidity and mortality in women. After menopause the influence of estrogens declines, whereas that of androgens increases. Therefore, we investigated the effects of androgens on atherosclerosis in postmenopausal women, by using carotid artery intimal-medial thickness as a marker of vascular damage. Blood pressure, body mass index, waist-to-hip ratio, serum dehydroepiandrosterone sulfate, androstenedione, total and free testosterone, estrone, insulin, lipid profile, and glucose were evaluated in 44 women in stable physiological menopause. All subjects underwent carotid ultrasound (Biosound 2000 II s.a. high-resolution unit). Spearman correlation coefficients indicated that serum androstenedione and free testosterone were negatively associated with several carotid intimal-medial thickness measures with correlation coefficients (r) ranging from 0.477 to 0.397 (p < 0.01-0.04). Moreover, age-adjusted androstenedione and free testosterone highest tertiles showed intimal-medial thickness values significantly (p < 0.03-0.05) lower than the other tertiles. There was a favorable association between hormones and the most important cardiovascular risk factors. This association, however, did not reach statistical significance. Stepwise multiple regression analysis showed that the inverse relationships between the hormones (androstenedione and free testosterone) and several intimal-medial thickness measures were maintained (F: 4.15-6.07, p < 0.05-0.02) after adjustment for major cardiovascular risk factors. Our data demonstrate that in postmenopausal women endogenous steroid precursors and androgens are inversely related to carotid intimal-medial thickness, an established marker of atherosclerosis. In addition, these hormones show favorable associations with cardiovascular risk factors. Therefore, our study suggests that, after menopause, normal androgen levels may

  11. Early androgen exposure and human gender development.

    Science.gov (United States)

    Hines, Melissa; Constantinescu, Mihaela; Spencer, Debra

    2015-01-01

    During early development, testosterone plays an important role in sexual differentiation of the mammalian brain and has enduring influences on behavior. Testosterone exerts these influences at times when the testes are active, as evidenced by higher concentrations of testosterone in developing male than in developing female animals. This article critically reviews the available evidence regarding influences of testosterone on human gender-related development. In humans, testosterone is elevated in males from about weeks 8 to 24 of gestation and then again during early postnatal development. Individuals exposed to atypical concentrations of testosterone or other androgenic hormones prenatally, for example, because of genetic conditions or because their mothers were prescribed hormones during pregnancy, have been consistently found to show increased male-typical juvenile play behavior, alterations in sexual orientation and gender identity (the sense of self as male or female), and increased tendencies to engage in physically aggressive behavior. Studies of other behavioral outcomes following dramatic androgen abnormality prenatally are either too small in their numbers or too inconsistent in their results, to provide similarly conclusive evidence. Studies relating normal variability in testosterone prenatally to subsequent gender-related behavior have produced largely inconsistent results or have yet to be independently replicated. For studies of prenatal exposures in typically developing individuals, testosterone has been measured in single samples of maternal blood or amniotic fluid. These techniques may not be sufficiently powerful to consistently detect influences of testosterone on behavior, particularly in the relatively small samples that have generally been studied. The postnatal surge in testosterone in male infants, sometimes called mini-puberty, may provide a more accessible opportunity for measuring early androgen exposure during typical development. This

  12. Androgen receptor roles in insulin resistance and obesity in males: the linkage of androgen-deprivation therapy to metabolic syndrome.

    Science.gov (United States)

    Yu, I-Chen; Lin, Hung-Yun; Sparks, Janet D; Yeh, Shuyuan; Chang, Chawnshang

    2014-10-01

    Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  13. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    DEFF Research Database (Denmark)

    Løssl, Kristine; Andersen, A N; Loft, A

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically.......Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  14. Impact of Androgen and Dietary Advanced Glycation End Products on Female Rat Liver

    Directory of Open Access Journals (Sweden)

    Eleni Palioura

    2015-09-01

    Full Text Available Background/Aims: Advanced glycation end products (AGEs have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS. The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. Methods: The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30 and adult rats (Group B, n=20 that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30. All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. Results: Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (γGT (p≤0.0002 and indices of AGE immunostaining in liver tissue (pper se constitutes an aggravating factor as demonstrated by the elevated γGT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002 and by the elevated AST and alanine aminotransferase (ALT levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002 followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007. Conclusion: The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions.

  15. Ovarian overproduction of androgens

    Science.gov (United States)

    ... body shape Decrease in breast size Increase in body hair in a male pattern, such as on the ... to decrease hair production in women with excess body hair, or to regulate menstrual cycles. In some cases, ...

  16. Androgen Receptor-Mediated Escape Mechanisms from Androgen Ablation Therapy

    Science.gov (United States)

    2005-10-01

    p. 132-138. 7. Han , G., et al., Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci U S A, 2005. 102...the confor- (1997) 306-360. mational state of the AR may recruit specific TPR- [9] K. Richter, J. Buchner , Hsp90: chaperoning signal transduc-tion...Biol. 42 connection, Trends Biochem. Sci. 22 (1997) 87-92. (1992) 803-812.[19] 2) D.F. 812. S[34] U. Jakob, J. Buchner , Assisting spontaneity: the role

  17. Serum luteinizing hormone follicle-stimulating hormone and prolactin in neonatal-androgenized rats.

    Science.gov (United States)

    Moguilevsky, J A; Scacchi, P; Dosoretz, D; Rubinstein, L

    1976-01-01

    Serum levels of LH, FSH, Prolactin and Testosterone of 90 days old male rats androgenized soon after birth were determined by specific radioimmunoassay and were compared to untreated rats. LH and FSH levels were also determined in 90 days old female rats neo-natally treated with testosterone and compared with normal diestrus rats. Androgenization of male rats significantly increased serum FSH and Prolactin levels without producing changes in plasma LH and testosterone concentrations. Similar increase in the FSH levels were found in androgenized female rats although plasma FSH concentrations were lower than in the male groups. These results obtained in male rats give an additional evidence that androgens acting in the first days of life are responsible of the higher levels of FSH and Prolactin that characterize the male or tonic pattern of gonadotrophin secretion.

  18. A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

    Science.gov (United States)

    Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

    2016-10-01

    The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT

  19. Anogenital distance as a marker of androgen exposure in humans.

    Science.gov (United States)

    Thankamony, A; Pasterski, V; Ong, K K; Acerini, C L; Hughes, I A

    2016-07-01

    Abnormal foetal testis development has been proposed to underlie common disorders of the male reproductive system such as cryptorchidism, hypospadias, reduced semen quality and testicular germ cell tumour, which are regarded as components of a 'testicular dysgenesis syndrome'. The increasing trends and geographical variation in their incidence have been suggested to result from in utero exposure to environmental chemicals acting as endocrine disruptors. In rodents, the anogenital distance (AGD), measured from the anus to the base of genital tubercle, is a sensitive biomarker of androgen exposure during a critical embryonic window of testis development. In humans, several epidemiological studies have shown alterations in AGD associated with prenatal exposure to several chemicals with potential endocrine disrupting activity. However, the link between AGD and androgen exposure in humans is not well-defined. This review focuses on the current evidence for such a relationship. As in rodents, a clear gender difference is detected during foetal development of the AGD in humans which is maintained thereafter. Reduced AGD in association with clinically relevant outcomes of potential environmental exposures, such as cryptorchidism or hypospadias, is in keeping with AGD as a marker of foetal testicular function. Furthermore, AGD may reflect variations in prenatal androgen exposure in healthy children as shorter AGD at birth is associated with reduced masculine play behaviour in preschool boys. Several studies provide evidence linking shorter AGD with lower fertility, semen quality and testosterone levels in selected groups of adults attending andrology clinics. Overall, the observational data in humans are consistent with experimental studies in animals and support the use of AGD as a biomarker of foetal androgen exposure. Future studies evaluating AGD in relation to reproductive hormones in both infants and adults, and to gene polymorphisms, will help to further delineate

  20. Meat Feeding Restricts Rapid Cold Hardening Response and Increases Thermal Activity Thresholds of Adult Blow Flies, Calliphora vicina (Diptera: Calliphoridae.

    Directory of Open Access Journals (Sweden)

    Paul C Coleman

    Full Text Available Virtually all temperate insects survive the winter by entering a physiological state of reduced metabolic activity termed diapause. However, there is increasing evidence that climate change is disrupting the diapause response resulting in non-diapause life stages encountering periods of winter cold. This is a significant problem for adult life stages in particular, as they must remain mobile, periodically feed, and potentially initiate reproductive development at a time when resources should be diverted to enhance stress tolerance. Here we present the first evidence of protein/meat feeding restricting rapid cold hardening (RCH ability and increasing low temperature activity thresholds. No RCH response was noted in adult female blow flies (Calliphora vicina Robineau-Desvoidy fed a sugar, water and liver (SWL diet, while a strong RCH response was seen in females fed a diet of sugar and water (SW only. The RCH response in SW flies was induced at temperatures as high as 10°C, but was strongest following 3h at 0°C. The CTmin (loss of coordinated movement and chill coma (final appendage twitch temperature of SWL females (-0.3 ± 0.5°C and -4.9 ± 0.5°C, respectively was significantly higher than for SW females (-3.2 ± 0.8°C and -8.5 ± 0.6°C. We confirmed this was not directly the result of altered extracellular K+, as activity thresholds of alanine-fed adults were not significantly different from SW flies. Instead we suggest the loss of cold tolerance is more likely the result of diverting resource allocation to egg development. Between 2009 and 2013 winter air temperatures in Birmingham, UK, fell below the CTmin of SW and SWL flies on 63 and 195 days, respectively, suggesting differential exposure to chill injury depending on whether adults had access to meat or not. We conclude that disruption of diapause could significantly impact on winter survival through loss of synchrony in the timing of active feeding and reproductive development with

  1. MicroRNAs related to androgen metabolism and polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Sørensen, Anja Elaine; Udesen, Pernille Bækgaard; Wissing, Marie Louise

    2016-01-01

    : Testosterone, androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), where the quantitatively highest amount of androgen is found as DHEAS. The sulfation of DHEA to DHEAS depends on a number of enzymes, and altered sulfate metabolism may be associated with and contribute......Polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women. PCOS is associated with altered features of androgen metabolism, increased insulin resistance and impaired fertility. Furthermore, PCOS, being a syndrome diagnosis, is heterogeneous and characterized by polycystic ovaries...

  2. Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial.

    Science.gov (United States)

    Price, Douglas K; Chau, Cindy H; Till, Cathee; Goodman, Phyllis J; Leach, Robin J; Johnson-Pais, Teresa L; Hsing, Ann W; Hoque, Ashraful; Parnes, Howard L; Schenk, Jeannette M; Tangen, Catherine M; Thompson, Ian M; Reichardt, Juergen K V; Figg, William D

    2016-08-01

    Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment. A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend associated with both circulating hormone levels and prostate cancer risk. Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016;122:2332-2340. © 2016 American Cancer Society. © 2016 American Cancer Society.

  3. Androgens and the ageing male

    DEFF Research Database (Denmark)

    Juul, Anders; Skakkebaek, Niels E

    2002-01-01

    'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do...... with severe primary or secondary hypogonadism. Thus, androgen substitution therapy is warranted in men with true hypogonadism at all ages. Symptoms experienced by otherwise healthy ageing males are non-specific and vague, although some may be similar to symptoms of hypogonadism. Therefore, the term...

  4. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1.

    Science.gov (United States)

    Goodman, Neil F; Cobin, Rhoda H; Futterweit, Walter; Glueck, Jennifer S; Legro, Richard S; Carmina, Enrico

    2015-11-01

    , alopecia, and acne. Cycle length >35 days suggests chronic anovulation, but cycle length slightly longer than normal (32 to 35 days) or slightly irregular (32 to 35-36 days) needs assessment for ovulatory dysfunction. Ovulatory dysfunction is associated with increased prevalence of endometrial hyperplasia and endometrial cancer, in addition to infertility. In PCOS, hirsutism develops gradually and intensifies with weight gain. In the neoplastic virilizing states, hirsutism is of rapid onset, usually associated with clitoromegaly and oligomenorrhea. Girls with severe acne or acne resistant to oral and topical agents, including isotretinoin (Accutane), may have a 40% likelihood of developing PCOS. Hair loss patterns are variable in women with hyperandrogenemia, typically the vertex, crown or diffuse pattern, whereas women with more severe hyperandrogenemia may see bitemporal hair loss and loss of the frontal hairline. Oral contraceptives (OCPs) can effectively lower androgens and block the effect of androgens via suppression of ovarian androgen production and by increasing sex hormone-binding globulin. Physiologic doses of dexamethasone or prednisone can directly lower adrenal androgen output. Anti-androgens can be used to block the effects of androgen in the pilosebaceous unit or in the hair follicle. Anti-androgen therapy works through competitive antagonism of the androgen receptor (spironolactone, cyproterone acetate, flutamide) or inhibition of 5α-reductase (finasteride) to prevent the conversion of T to its more potent form, 5α-dihydrotestosterone. The choice of antiandrogen therapy is guided by symptoms. The diagnosis of PCOS in adolescents is particularly challenging given significant age and developmental issues in this group. Management of infertility in women with PCOS requires an understanding of the pathophysiology of anovulation as well as currently available treatments. Many features of PCOS, including acne, menstrual irregularities, and hyperinsulinemia

  5. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study.

    Science.gov (United States)

    Schweizer, Michael T; Wang, Hao; Luber, Brandon; Nadal, Rosa; Spitz, Avery; Rosen, D Marc; Cao, Haiyi; Antonarakis, Emmanuel S; Eisenberger, Mario A; Carducci, Michael A; Paller, Channing; Denmeade, Samuel R

    2016-09-01

    We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Ovarian follicular dynamics after aromatizable or non aromatizable neonatal androgenization.

    Science.gov (United States)

    Anesetti, Gabriel; Chávez-Genaro, Rebeca

    2016-10-01

    The effects of neonatal testosterone or dihydrotestosterone exposure on ovarian follicular dynamics were analysed at prepubertal, pubertal or adult age in Wistar rats. Both androgens induced a transitory increase on follicular endowment that was partially corrected at puberty. At adult age testosterone prevented ovulation, without significant modifications on follicular dynamics. An increased number of cystic structures were observed from puberty to adult age. However, ovaries of rats treated with dihydrotestosterone showed follicles with evident morphological alterations in granulosa and thecal layers although several corpora lutea were observed. A significant increase in preantral follicles and few cystic structures were detected at advanced adulthood. The size of cyst increased with age. No immunohistochemical changes on growth factors or enzymes related to steroidogenesis in growing follicles were obvious in any group. In both androgenized groups, cysts shared immunohistochemical characteristics exhibited by preovulatory follicles but they were unable to ovulate spontaneously. Our results provide an insight into the role of different androgens in female reproductive system development, indicating a direct effect of dihydrotestosterone on ovarian tissues whereas a central effect would be the main feature of neonatal testosterone exposure. Heterogeneous clinical manifestations seen in pathologies such as polycystic ovary syndrome among women could be associated with subtle hormonal changes during follicular population development.

  7. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination.

    Science.gov (United States)

    Hussain, Rashad; Ghoumari, Abdel M; Bielecki, Bartosz; Steibel, Jérôme; Boehm, Nelly; Liere, Philippe; Macklin, Wendy B; Kumar, Narender; Habert, René; Mhaouty-Kodja, Sakina; Tronche, François; Sitruk-Ware, Regine; Schumacher, Michael; Ghandour, M Said

    2013-01-01

    Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic

  8. ANABOLIC-ANDROGENIC STEROID DEPENDENCE? INSIGHTS FROM ANIMALS AND HUMANS

    OpenAIRE

    Wood, Ruth I.

    2008-01-01

    Anabolic-androgenic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, with negative health consequences. As a result, in 1991 testosterone and related AAS were declared controlled substances. However, the relative abuse and dependence liability of AAS have not been fully characterized. In humans, it is difficult to separate the direct psychoactive effects of AAS from reinforcement due to their systemic anabolic effects. Howev...

  9. Increased extracellular collagen matrix in myocardial sleeves of pulmonary veins: an additional mechanism facilitating repetitive rapid activities in chronic pacing-induced sustained atrial fibrillation.

    Science.gov (United States)

    Chiu, Yung-Tsung; Wu, Tsu-Juey; Wei, Hao-Ji; Cheng, Ching-Chang; Lin, Nai-Nu; Chen, Ying-Tsung; Ting, Chih-Tai

    2005-07-01

    Increased ECM in canine PVs. Cell uncoupling due to fibrosis or increased extracellular collagen matrix (ECM) affects the formation of ectopic focal activity. Whether or not the increase of ECM also exists in the pulmonary veins (PVs) with rapid atrial pacing is unknown. We sought to test the hypothesis that in chronic atrial pacing dogs with sustained atrial fibrillation (AF), the amount of ECM was increased in both atria and the PVs. We induced sustained AF in dogs by rapid atrial pacing. Computerized mapping techniques were used to map both atria and the PVs. We also used histological assessment to quantify the amount of ECM. After 118+/-24 days of rapid atrial pacing, sustained AF was induced in 7 dogs. Repetitive rapid activities (RRAs) either continuously or intermittently arose from the PVs during sustained AF. Histological study shows that there was no fibrosis in both atrial free walls and the PVs. However, the amount of ECM was increased in these regions. The mean ECM surface area fraction at each region in the dogs with sustained AF was all significantly higher compared to the corresponding region in normal dogs. Similarly, the heterogeneity of the ECM surface area fraction at each region in the dogs with sustained AF was also all significantly higher compared to normal dogs. In chronic atrial pacing-induced sustained AF, structural remodeling (i.e., inhomogeneous increase of ECM) also involves the PVs. Reduced coupling of the myocytes in the PV due to histological changes may provide an additional mechanism facilitating RRAs.

  10. Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

    NARCIS (Netherlands)

    D. Chadha; T.D. Pache; F.J. Huikeshoven (Frans); A.O. Brinkmann (Albert); Th.H. van der Kwast (Theo)

    1994-01-01

    textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated

  11. Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure.

    Science.gov (United States)

    Fragkaki, A G; Angelis, Y S; Koupparis, M; Tsantili-Kakoulidou, A; Kokotos, G; Georgakopoulos, C

    2009-02-01

    Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone introduced for therapeutic purposes providing enhanced anabolic potency with reduced androgenic effects. Androgens mediate their action through their binding to the androgen receptor (AR) which is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver and central nervous system. This paper reviews some of the wide spectrum of testosterone and synthetic AAS structure modifications related to the intended enhancement in anabolic activity. The structural features of steroids necessary for effective binding to the AR and those which contribute to the stipulation of the androgenic and anabolic activities are also presented.

  12. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2003-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  13. Androgen effects on women's gendered behaviour.

    Science.gov (United States)

    Udry, J R; Morris, N M; Kovenock, J

    1995-07-01

    Test of the applicability of the hormonal theory of sex-dimorphic behaviour to adult women is achieved in this study by assembling measures of prenatal and adult androgen exposure, and a broad measure of gendered behaviour on a sample of white women aged 27-30. Androgen exposure in the second (and no other) trimester of fetal life, combined with and in interaction with adult androgens, masculineses women's behaviour and explains a substantial proportion of the within-sex variance in women's adult gendered behaviour.

  14. Increased Baseline Proinflammatory Cytokine Production in Chronic Hepatitis C Patients with Rapid Virological Response to Peginterferon Plus Ribavirin

    OpenAIRE

    Par, Gabriella; Szereday, Laszlo; Berki, Timea; et al.

    2013-01-01

    BACKGROUND: Chronic hepatitis C (CHC) patients achieving rapid virological response (RVR) on PEG-IFN/ribavirin (P/R) therapy have high chance of sustained virological response (SVR). To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) were studied prior to and during P/R therapy. METHODS: TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll...

  15. Cortical venous thrombosis following exogenous androgen use for bodybuilding.

    Science.gov (United States)

    Sveinsson, Olafur; Herrman, Lars

    2013-02-05

    There are only a few reports of patients developing cerebral venous sinus thrombosis (CVST) after androgen therapy. We present a young man who developed cortical venous thrombosis after using androgens to increase muscle mass. He was hospitalised for parasthesia and dyspraxia in the left hand followed by a generalised tonic-clonic seizure. At admission, he was drowsy, not fully orientated, had sensory inattention, pronation drift and a positive extensor response, all on the left side. The patient had been using anabolic steroids (dainabol 20 mg/day) for the last month for bodybuilding. CT angiography showed a right cortical venous thrombosis. Anticoagulation therapy was started with intravenous heparin for 11 days and oral anticoagulation (warfarin) thereafter. A control CT angiography 4 months later showed resolution of the thrombosis. He recovered fully.

  16. Fast mouse PK (Fast PK): a rapid screening method to increase pharmacokinetic throughput in pre-clinical drug discovery.

    Science.gov (United States)

    Reddy, Jitendar; Madishetti, Sreedhar; Vachaspati, Prakash R

    2012-09-29

    We describe a rapid screening methodology for performing pharmacokinetic (PK) studies in mice called Fast PK. In this Fast PK method, two mice were used per compound and four blood samples were collected from each mouse. The sampling times were staggered (sparse sampling) between the two mice, thus yielding complete PK profile in singlicate across eight time points. The plasma PK parameters from Fast PK were comparable to that obtained from conventional PK methods. This method has been used to rapidly screen compounds in the early stages of drug discovery and about 600 compounds have been profiled in the last 3 years, which has resulted in reduction in the usage of mice by 800 per year in compliance with the 3R principles of animal ethics. In addition, this Fast PK method can also help in evaluating the PK parameters from the same set of animals used in safety/toxicology/efficacy studies without the need for satellite groups. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Synthetic androgens as designer supplements.

    Science.gov (United States)

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed.

  18. ANABOLIC ANDROGENIC STEROIDS AND DEPENDENCE

    Directory of Open Access Journals (Sweden)

    IHSAN SARI

    2010-12-01

    Full Text Available Anabolic androgenic steroids are used for sportive, cosmetic, therapeutic and occupational reasons and there are many side effects reported (George, 2005; Nieminen et al., 1996; O'Sullivan et al., 2000. Prevalence of anabolic steroids’ use also indicates the importance of this topic. Moreover, it is now known that use of anabolic steroids could lead to dependence which could be psychological or/and physiological (Copeland et al., 2000. It isimportant to know about all aspects of anabolic steroids including dependence. Therefore, this study has attempted to give an insight into use of anabolic steroids and dependence. The discussion will focus on prevalence, reasons, and side effects of use and physiological and psychological dependence

  19. Synthetic Androgens as Designer Supplements

    Science.gov (United States)

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacological effects and metabolism of unapproved steroids due to the absence of clinical studies. The large number of designer steroid findings in dietary supplements and the detection of new compounds combined with legal loopholes for their distribution in many countries show that stricter regulations and better information policy are needed. PMID:26074745

  20. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    DEFF Research Database (Denmark)

    Løssl, Kristine; Andersen, A N; Loft, A

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  1. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial

    DEFF Research Database (Denmark)

    Lossl, K; Andersen, C Yding; Loft, A

    2008-01-01

    Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top...

  2. Brain masculinization requires androgen receptor function

    OpenAIRE

    Sato, Takashi; Matsumoto, Takahiro; Kawano, Hirotaka; Watanabe, Tomoyuki; Uematsu, Yoshikatsu; Sekine, Keisuke; Fukuda, Toru; Aihara, Ken-ichi; Krust, Andrée; Yamada, Takashi; NAKAMICHI, YUKO; Yamamoto, Yoko; Nakamura, Takashi; Yoshimura, Kimihiro; Yoshizawa, Tatsuya

    2004-01-01

    Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal...

  3. Rapid antidepressants stimulate the decoupling of GABAB receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η

    Science.gov (United States)

    Workman, E R; Haddick, P C G; Bush, K; Dilly, G A; Niere, F; Zemelman, B V; Raab-Graham, K F

    2015-01-01

    A single injection of N-methyl-D-aspartate receptor (NMDAR) antagonists produces a rapid antidepressant response. Lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. We recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (GABABR) signaling pathway, such that GABABR activation shifts from opening inwardly rectifiying potassium channels (Kir/GIRK) to increasing resting dendritic calcium signal and mammalian Target of Rapamycin activity. However, little is known about the molecular and biochemical mechanisms that initiate this shift. Herein, we show that GABABR signaling to Kir3 (GIRK) channels decreases with NMDAR blockade. Blocking NMDAR signaling stabilizes the adaptor protein 14-3-3η, which decouples GABABR signaling from Kir3 and is required for the rapid antidepressant efficacy. Consistent with these results, we find that key proteins involved in GABABR signaling bidirectionally change in a depression model and with rapid antidepressants. In socially defeated rodents, a model for depression, GABABR and 14-3-3η levels decrease in the hippocampus. The NMDAR antagonists AP5 and Ro-25-6981, acting as rapid antidepressants, increase GABABR and 14-3-3η expression and decrease Kir3.2. Taken together, these data suggest that the shift in GABABR function requires a loss of GABABR-Kir3 channel activity mediated by 14-3-3η. Our findings support a central role for 14-3-3η in the efficacy of rapid antidepressants and define a critical molecular mechanism for activity-dependent alterations in GABABR signaling. PMID:25560757

  4. Rapid antidepressants stimulate the decoupling of GABA(B) receptors from GIRK/Kir3 channels through increased protein stability of 14-3-3η.

    Science.gov (United States)

    Workman, E R; Haddick, P C G; Bush, K; Dilly, G A; Niere, F; Zemelman, B V; Raab-Graham, K F

    2015-03-01

    A single injection of N-methyl-D-aspartate receptor (NMDAR) antagonists produces a rapid antidepressant response. Lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. We recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (GABABR) signaling pathway, such that GABABR activation shifts from opening inwardly rectifiying potassium channels (Kir/GIRK) to increasing resting dendritic calcium signal and mammalian Target of Rapamycin activity. However, little is known about the molecular and biochemical mechanisms that initiate this shift. Herein, we show that GABABR signaling to Kir3 (GIRK) channels decreases with NMDAR blockade. Blocking NMDAR signaling stabilizes the adaptor protein 14-3-3η, which decouples GABABR signaling from Kir3 and is required for the rapid antidepressant efficacy. Consistent with these results, we find that key proteins involved in GABABR signaling bidirectionally change in a depression model and with rapid antidepressants. In socially defeated rodents, a model for depression, GABABR and 14-3-3η levels decrease in the hippocampus. The NMDAR antagonists AP5 and Ro-25-6981, acting as rapid antidepressants, increase GABABR and 14-3-3η expression and decrease Kir3.2. Taken together, these data suggest that the shift in GABABR function requires a loss of GABABR-Kir3 channel activity mediated by 14-3-3η. Our findings support a central role for 14-3-3η in the efficacy of rapid antidepressants and define a critical molecular mechanism for activity-dependent alterations in GABABR signaling.

  5. Expression of androgen receptor splice variants in clinical breast cancers.

    Science.gov (United States)

    Hickey, Theresa E; Irvine, Connie M; Dvinge, Heidi; Tarulli, Gerard A; Hanson, Adrienne R; Ryan, Natalie K; Pickering, Marie A; Birrell, Stephen N; Hu, Dong Gui; Mackenzie, Peter I; Russell, Roslin; Caldas, Carlos; Raj, Ganesh V; Dehm, Scott M; Plymate, Stephen R; Bradley, Robert K; Tilley, Wayne D; Selth, Luke A

    2015-12-29

    The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon. Herein, we show that in addition to the prototypical transcript, the AR gene produces a diverse range of AR-V transcripts in primary breast tumors. The most frequently and highly expressed variant was AR-V7 (exons 1/2/3/CE3), which was detectable at the mRNA level in > 50% of all breast cancers and at the protein level in a subset of ERα-negative tumors. Functionally, AR-V7 is a constitutively active and ADT-resistant transcription factor that promotes growth and regulates a transcriptional program distinct from AR in ERα-negative breast cancer cells. Importantly, we provide ex vivo evidence that AR-V7 is upregulated by the AR antagonist enzalutamide in primary breast tumors. These findings have implications for treatment response in the ongoing clinical trials of ADT in breast cancer.

  6. Prenatal androgen exposure and children's aggressive behavior and activity level.

    Science.gov (United States)

    Spencer, Debra; Pasterski, Vickie; Neufeld, Sharon; Glover, Vivette; O'Connor, Thomas G; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L; Hines, Melissa

    2017-11-01

    Some human behaviors, including aggression and activity level, differ on average for males and females. Here we report findings from two studies investigating possible relations between prenatal androgen and children's aggression and activity level. For study 1, aggression and activity level scores for 43 girls and 38 boys, aged 4 to 11years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) were compared to those of similarly-aged, unaffected relatives (41 girls, 31 boys). Girls with CAH scored higher on aggression than unaffected girls, d=0.69, and unaffected boys scored higher on activity level than unaffected girls, d=0.50. No other group differences were significant. For study 2, the relationship of amniotic fluid testosterone to aggression and activity level was investigated in typically-developing children (48 girls, 44 boys), aged 3 to 5years. Boys scored higher than girls on aggression, d=0.41, and activity level, d=0.50. However, amniotic fluid testosterone was not a significant predictor of aggression or activity level for either sex. The results of the two studies provide some support for an influence of prenatal androgen exposure on children's aggressive behavior, but not activity level. The within-sex variation in amniotic fluid testosterone may not be sufficient to allow reliable assessment of relations to aggression or activity level. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Analysis of complete mitochondrial genome sequences increases phylogenetic resolution of bears (Ursidae, a mammalian family that experienced rapid speciation

    Directory of Open Access Journals (Sweden)

    Ryder Oliver A

    2007-10-01

    Full Text Available Abstract Background Despite the small number of ursid species, bear phylogeny has long been a focus of study due to their conservation value, as all bear genera have been classified as endangered at either the species or subspecies level. The Ursidae family represents a typical example of rapid evolutionary radiation. Previous analyses with a single mitochondrial (mt gene or a small number of mt genes either provide weak support or a large unresolved polytomy for ursids. We revisit the contentious relationships within Ursidae by analyzing complete mt genome sequences and evaluating the performance of both entire mt genomes and constituent mtDNA genes in recovering a phylogeny of extremely recent speciation events. Results This mitochondrial genome-based phylogeny provides strong evidence that the spectacled bear diverged first, while within the genus Ursus, the sloth bear is the sister taxon of all the other five ursines. The latter group is divided into the brown bear/polar bear and the two black bears/sun bear assemblages. These findings resolve the previous conflicts between trees using partial mt genes. The ability of different categories of mt protein coding genes to recover the correct phylogeny is concordant with previous analyses for taxa with deep divergence times. This study provides a robust Ursidae phylogenetic framework for future validation by additional independent evidence, and also has significant implications for assisting in the resolution of other similarly difficult phylogenetic investigations. Conclusion Identification of base composition bias and utilization of the combined data of whole mitochondrial genome sequences has allowed recovery of a strongly supported phylogeny that is upheld when using multiple alternative outgroups for the Ursidae, a mammalian family that underwent a rapid radiation since the mid- to late Pliocene. It remains to be seen if the reliability of mt genome analysis will hold up in studies of other

  8. Adolescent anabolic/androgenic steroids: Aggression and anxiety during exposure predict behavioral responding during withdrawal in Syrian hamsters (Mesocricetus auratus).

    Science.gov (United States)

    Ricci, Lesley A; Morrison, Thomas R; Melloni, Richard H

    2013-11-01

    In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population. This is concerning given that anabolic/androgenic steroid use is associated with a higher incidence of aggressive behavior during exposure and anxiety during withdrawal. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that an inverse behavioral relationship exists between anabolic/androgenic steroid-induced aggression and anxiety across adolescent exposure and withdrawal. In the first experiment, we examined aggression and anxiety during adolescent anabolic/androgenic steroid exposure and withdrawal. Adolescent anabolic/androgenic steroid administration produced significant increases in aggression and decreases in anxiety during the exposure period followed by significant decreases in aggression and increases in anxiety during anabolic/androgenic steroid withdrawal. In a second experiment, anabolic/androgenic steroid exposed animals were separated into groups based on their aggressive response during the exposure period and then tested for anxiety during exposure and then for both aggression and anxiety during withdrawal. Data were analyzed using a within-subjects repeated measures predictive analysis. Linear regression analysis revealed that the difference in aggressive responding between the anabolic/androgenic steroid exposure and withdrawal periods was a significant predictor of differences in anxiety for both days of testing. Moreover, the combined data suggest that the decrease in aggressive behavior from exposure to withdrawal predicts an increase in anxiety-like responding within these same animals during this time span. Together these findings indicate that early anabolic/androgenic steroid exposure has potent aggression- and anxiety-eliciting effects and that these behavioral changes occur alongside a predictive relationship that exists between these two behaviors over time. © 2013.

  9. Adolescent Anabolic/Androgenic Steroids: Aggression and Anxiety During Exposure Predict Behavioral Responding During Withdrawal in Syrian Hamsters (Mesocricetus auratus)

    Science.gov (United States)

    Ricci, Lesley A.; Morrison, Thomas R.; Melloni, Richard H.

    2014-01-01

    In the U.S. and worldwide anabolic/androgenic steroid use remains high in the adolescent population. This is concerning given that anabolic/androgenic steroid use is associated with a higher incidence of aggressive behavior during exposure and anxiety during withdrawal. This study uses pubertal Syrian hamsters (Mesocricetus auratus) to investigate the hypothesis that an inverse behavioral relationship exists between anabolic/androgenic steroid-induced aggression and anxiety across adolescent exposure and withdrawal. In the first experiment, we examined aggression and anxiety during adolescent anabolic/androgenic steroid exposure and withdrawal. Adolescent anabolic/androgenic steroid administration produced significant increases in aggression and decreases in anxiety during the exposure period followed by significant decreases in aggression and increases in anxiety during anabolic/androgenic steroid withdrawal. In a second experiment, anabolic/androgenic steroid exposed animals were separated into groups based on their aggressive response during the exposure period and then tested for anxiety during exposure and then for both aggression and anxiety during withdrawal. Data were analyzed using a within subjects repeated measures predictive analysis. Linear regression analysis revealed that the difference in aggressive responding between the anabolic/androgenic steroid exposure and withdrawal periods was a significant predictor of differences in anxiety for both days of testing. Moreover, the combined data suggest that the decrease in aggressive behavior from exposure to withdrawal predicts an increase in anxiety-like responding within these same animals during this time span. Together these findings indicate that early anabolic/androgenic steroid exposure has potent aggression- and anxiety- eliciting effects and that these behavioral changes occur alongside a predictive relationship that exists between these two behaviors over time. PMID:24126136

  10. Androgen (dihydrotestosterone)-mediated regulation of food intake and obesity in female mice.

    Science.gov (United States)

    Kanaya, Noriko; Vonderfecht, Steven; Chen, Shiuan

    2013-11-01

    To better understand how elevated androgen levels regulate food intake and obesity in females, we treated ovariectomized female mice with dihydrotestosterone (DHT) (non-aromatazable androgen), measured food intake and body weight, and evaluated physiological changes in liver function, glucose tolerance, and leptin resistance. Ovariectomized mice were treated with DHT or placebo. Mice were then fed a high fat diet under free-feeding or pair-feeding conditions for 3 months. We found that when DHT-treated ovariectomized mice had free access to food (free-feeding), they had increased food intake and higher body weight compared with control animals. These mice also had a significantly greater accumulation of fat in the liver and exhibited increased fasting glucose, impaired glucose tolerance, and resistance to leptin. However, when these mice were placed on a restricted diet and fed the same caloric amounts as controls (pair-feeding), their body weight increased at the same rate as control animals. This suggests that androgen regulates food intake through altered leptin sensitivity, and this increase of food intake could significantly contribute to an obesity phenotype. In summary, we demonstrated a role for androgen in the regulation of food intake and weight gain in females using a mouse model. This model will be useful to further elucidate the role of elevated androgen in females. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Rapid Growth and Apparent Total Nitrogen Increases in Rice and Corn Plants following Applications of Triacontanol 1

    Science.gov (United States)

    Knowles, N. Richard; Ries, Stanley K.

    1981-01-01

    Triacontanol (TRIA) increased fresh and dry weight and total reducible nitrogen (total N) of rice (Oryza sativa L.) seedlings within 40 minutes. Increases in total N in the supernatants from homogenates of corn (Zea mays L.) and rice leaves treated with TRIA for one minute before grinding occurred within 30 and 80 minutes, respectively. The source for the increase was investigated utilizing atmospheric substitution and enrichment and depletion studies with 15N. The increase in total N in seedlings was shown to be independent of method of N analysis and the presence of nitrate in the plants. Automated Kjeldahl determinations showing apparent increases in N composition due to TRIA were shown to be correlated with hand Kjeldahl, elemental analysis, and chemiluminescent analysis in three independent laboratories. TRIA did not alter the nitrate uptake or endogenous levels of nitrate in corn and rice seedlings. Enrichment experiments revealed that the total N increases in rice seedlings, in vivo, and in supernatants of corn leaf homogenates, in vitro, are not due to atmospheric N2. TRIA increased the soluble N pools of the plants, specifically the free amino acid and soluble protein fractions. No differences in depletion or enrichment of 15N incorporated into soluble and insoluble N fractions of rice seedlings could be detected on an atom per cent 15N basis. The apparent short-term total N increases cannot be explained by current knowledge of major N assimilation pathways. TRIA may stimulate a change in the chemical composition of the seedlings, resulting in interference with standard methods of N analysis. PMID:16662092

  12. Current concepts in anabolic-androgenic steroids.

    Science.gov (United States)

    Evans, Nick A

    2004-03-01

    Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone. According to surveys and media reports, the legal and illegal use of these drugs is gaining popularity. Testosterone restores sex drive and boosts muscle mass, making it central to 2 of society's rising preoccupations: perfecting the male body and sustaining the male libido. The anabolic effects of AAS have been questioned for decades, but recent scientific investigation of supraphysiologic doses supports the efficacy of these regimens. Testosterone has potent anabolic effects on the musculoskeletal system, including an increase in lean body mass, a dose-related hypertrophy of muscle fibers, and an increase in muscle strength. For athletes requiring speed and strength and men desiring a cosmetic muscle makeover, illegal steroids are a powerful lure, despite the risk of subjective side effects. Recent clinical studies have discovered novel therapeutic uses for physiologic doses of AAS, without any significant adverse effects in the short term. In the wake of important scientific advances during the past decade, the positive and negative effects of AAS warrant reevaluation. Guidelines for the clinical evaluation of AAS users will be presented for sports medicine practitioners.

  13. Review of Androgenic Anabolic Steroid Use

    Energy Technology Data Exchange (ETDEWEB)

    T. Borges; G. Eisele; C. Byrd

    2001-07-31

    An area that has been overlooked within personnel security evaluations is employee use of androgenic-anabolic steroids (AAS). Current drug testing within the federal government does not include testing for anabolic steroids, and the difficulties to implement such testing protocols-not to mention the cost involved-make AAS testing highly improbable. The basis of this report is to bring to the forefront the damage that anabolic steroids can cause from both a physical and a psychological standpoint. Most individuals who use AASs do so to increase their muscle mass because they wish to gain some type of competitive edge during athletic competition or they wish to enhance their physical features for self-satisfaction and self-esteem (i.e., body building). Security officers are one group of men who often take high doses of anabolic steroids, according to the Second Report of the Senate Standing Committee (1990). The negative psychological characteristics for AAS use is extensive and includes prominent hostility, aggressiveness, irritability, euphoria, grandiose beliefs, hyperactivity, reckless behavior, increased sexual appetite, unpredictability, poor impulse control, mood fluctuations, and insomnia. The drug may invoke a sense of power and invincibility (Leckman and Scahill, 1990). Depressive symptoms, such as anhedonia, fatigue, impaired concentration, decreased libido, and even suicidality (Pope and Katz, 1992) have been noted with steroid withdrawal. It appears that long-term users of AAS experience similar characteristics as other substance abusers (i.e., craving, dependence, and withdrawal symptoms).

  14. Dissociable Effects on Birdsong of Androgen Signaling in Cortex-Like Brain Regions of Canaries.

    Science.gov (United States)

    Alward, Beau A; Balthazart, Jacques; Ball, Gregory F

    2017-09-06

    The neural basis of how learned vocalizations change during development and in adulthood represents a major challenge facing cognitive neuroscience. This plasticity in the degree to which learned vocalizations can change in both humans and songbirds is linked to the actions of sex steroid hormones during ontogeny but also in adulthood in the context of seasonal changes in birdsong. We investigated the role of steroid hormone signaling in the brain on distinct features of birdsong using adult male canaries (Serinus canaria), which show extensive seasonal vocal plasticity as adults. Specifically, we bilaterally implanted the potent androgen receptor antagonist flutamide in two key brain regions that control birdsong. We show that androgen signaling in the motor cortical-like brain region, the robust nucleus of the arcopallium (RA), controls syllable and trill bandwidth stereotypy, while not significantly affecting higher order features of song such syllable-type usage (i.e., how many times each syllable type is used) or syllable sequences. In contrast, androgen signaling in the premotor cortical-like brain region, HVC (proper name), controls song variability by increasing the variability of syllable-type usage and syllable sequences, while having no effect on syllable or trill bandwidth stereotypy. Other aspects of song, such as the duration of trills and the number of syllables per song, were also differentially affected by androgen signaling in HVC versus RA. These results implicate androgens in regulating distinct features of complex motor output in a precise and nonredundant manner.SIGNIFICANCE STATEMENT Vocal plasticity is linked to the actions of sex steroid hormones, but the precise mechanisms are unclear. We investigated this question in adult male canaries (Serinus canaria), which show extensive vocal plasticity throughout their life. We show that androgens in two cortex-like vocal control brain regions regulate distinct aspects of vocal plasticity. For

  15. Rapid Increases in forest understory diversity and productivity following a mountain pine beetle (Dendroctonus ponderosae outbreak in pine forests.

    Directory of Open Access Journals (Sweden)

    Gregory J Pec

    Full Text Available The current unprecedented outbreak of mountain pine beetle (Dendroctonus ponderosae in lodgepole pine (Pinus contorta forests of western Canada has resulted in a landscape consisting of a mosaic of forest stands at different stages of mortality. Within forest stands, understory communities are the reservoir of the majority of plant species diversity and influence the composition of future forests in response to disturbance. Although changes to stand composition following beetle outbreaks are well documented, information on immediate responses of forest understory plant communities is limited. The objective of this study was to examine the effects of D. ponderosae-induced tree mortality on initial changes in diversity and productivity of understory plant communities. We established a total of 110 1-m2 plots across eleven mature lodgepole pine forests to measure changes in understory diversity and productivity as a function of tree mortality and below ground resource availability across multiple years. Overall, understory community diversity and productivity increased across the gradient of increased tree mortality. Richness of herbaceous perennials increased with tree mortality as well as soil moisture and nutrient levels. In contrast, the diversity of woody perennials did not change across the gradient of tree mortality. Understory vegetation, namely herbaceous perennials, showed an immediate response to improved growing conditions caused by increases in tree mortality. How this increased pulse in understory richness and productivity affects future forest trajectories in a novel system is unknown.

  16. Rapid Increases in forest understory diversity and productivity following a mountain pine beetle (Dendroctonus ponderosae) outbreak in pine forests.

    Science.gov (United States)

    Pec, Gregory J; Karst, Justine; Sywenky, Alexandra N; Cigan, Paul W; Erbilgin, Nadir; Simard, Suzanne W; Cahill, James F

    2015-01-01

    The current unprecedented outbreak of mountain pine beetle (Dendroctonus ponderosae) in lodgepole pine (Pinus contorta) forests of western Canada has resulted in a landscape consisting of a mosaic of forest stands at different stages of mortality. Within forest stands, understory communities are the reservoir of the majority of plant species diversity and influence the composition of future forests in response to disturbance. Although changes to stand composition following beetle outbreaks are well documented, information on immediate responses of forest understory plant communities is limited. The objective of this study was to examine the effects of D. ponderosae-induced tree mortality on initial changes in diversity and productivity of understory plant communities. We established a total of 110 1-m2 plots across eleven mature lodgepole pine forests to measure changes in understory diversity and productivity as a function of tree mortality and below ground resource availability across multiple years. Overall, understory community diversity and productivity increased across the gradient of increased tree mortality. Richness of herbaceous perennials increased with tree mortality as well as soil moisture and nutrient levels. In contrast, the diversity of woody perennials did not change across the gradient of tree mortality. Understory vegetation, namely herbaceous perennials, showed an immediate response to improved growing conditions caused by increases in tree mortality. How this increased pulse in understory richness and productivity affects future forest trajectories in a novel system is unknown.

  17. Testosterone regulates keratin 33B expression in rat penis growth through androgen receptor signaling.

    Science.gov (United States)

    Ma, Yan-Min; Wu, Kai-Jie; Dang, Qiang; Shi, Qi; Gao, Yang; Guo, Peng; Xu, Shan; Wang, Xin-Yang; He, Da-Lin; Gong, Yong-Guang

    2014-01-01

    Androgen therapy is the mainstay of treatment for the hypogonadotropic hypogonadal micropenis because it obviously enhances penis growth in prepubescent microphallic patients. However, the molecular mechanisms of androgen treatment leading to penis growth are still largely unknown. To clarify this well-known phenomenon, we successfully generated a castrated male Sprague Dawley rat model at puberty followed by testosterone administration. Interestingly, compared with the control group, testosterone treatment stimulated a dose-dependent increase of penis weight, length, and width in castrated rats accompanied with a dramatic recovery of the pathological changes of the penis. Mechanistically, testosterone administration substantially increased the expression of androgen receptor (AR) protein. Increased AR protein in the penis could subsequently initiate transcription of its target genes, including keratin 33B (Krt33b). Importantly, we demonstrated that KRT33B is generally expressed in the rat penis and that most KRT33B expression is cytoplasmic. Furthermore, AR could directly modulate its expression by binding to a putative androgen response element sequence of the Krt33b promoter. Overall, this study reveals a novel mechanism facilitating penis growth after testosterone treatment in precastrated prepubescent animals, in which androgen enhances the expression of AR protein as well as its target genes, such as Krt33b.

  18. Trends in the incidence of nonmelanoma skin cancer in Denmark 1978-2007: Rapid incidence increase among young Danish women

    DEFF Research Database (Denmark)

    Birch-Johansen, Fatima; Jensen, Allan; Mortensen, Lone

    2010-01-01

    Nonmelanoma skin cancer (NMSC) is the most common cancer among Caucasian populations worldwide, and incidence rates are increasing. However, NMSC data are not routinely collected by cancer registries, but Denmark has extensive registration of NMSC in two nationwide population-based registries. We...

  19. Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism.

    Science.gov (United States)

    Ozaki, Yori; Saito, Kenji; Nakazawa, Kyoko; Konishi, Morichika; Itoh, Nobuyuki; Hakuno, Fumihiko; Takahashi, Shin-Ichiro; Kato, Hisanori; Takenaka, Asako

    2015-11-14

    Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production and retards growth. To identify new molecules involved in such changes, we conducted DNA microarray analysis on liver samples from rats fed an isoenergetic low-protein diet for 8 h. We identified the fibroblast growth factor 21 gene (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0·05, false-discovery rate<0·001). In addition, amino acid deprivation increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0·01). These results suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. FGF21 also promotes a growth hormone-resistance state and suppresses IGF-I in transgenic mice. Therefore, to determine further whether Fgf21 up-regulation causes hepatic steatosis and growth retardation after IGF-I decrease in protein malnutrition, we fed an isoenergetic low-protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration in these mice. Fgf21-KO mice showed greater epididymal white adipose tissue weight and increased hepatic TAG and cholesterol levels under protein malnutrition conditions (P<0·05). Overall, the results showed that protein deprivation directly increased Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression in protein malnutrition. Furthermore, FGF21 up-regulation rather appears to have a protective effect against obesity and hepatic steatosis in protein-malnourished animals.

  20. The updated Swedish family-cancer database used to assess familial risks of prostate cancer during rapidly increasing incidence

    Directory of Open Access Journals (Sweden)

    Hemminki Kari

    2006-12-01

    Full Text Available Abstract The Swedish Family-Cancer Database has been used for some 10 years in the study of familial risks at all common sites. In the present paper we describe some of the main features of version VII of this Database, assembled in year 2006. This update included all residents in Sweden born or immigrated in 1932 and later (offspring with their biological parents, a total of 11.5 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry from years 1958 to 2004, including over 1.2 million first and multiple primary cancers and in situ tumours. We show one application of the Database in the study of familial risks in prostate cancer, with special reference to the modification of familial risk at the time of about 50% increase in incidence due to prostate specific antigen (PSA screening. The familial risks for prostate cancer were 1.92 for sons of affected fathers, 3.03 for brothers and 5.44 for men with an affected father and an affected brother. Familial risk for prostate cancer according to the time since the first family member was diagnosed showed significant increases for two family members being diagnosed in the same year compared to 5+ years apart. Increased surveillance and the availability of PSA screening are the likely reasons for the overestimated familial relative risk shortly after the first diagnosis. This lead time bias should be considered in clinical counselling.

  1. Rapid insulin-mediated increase in microvascular glycocalyx accessibility in skeletal muscle may contribute to insulin-mediated glucose disposal in rats.

    Science.gov (United States)

    Eskens, Bart J M; Mooij, Hans L; Cleutjens, Jack P M; Roos, Jozef M A; Cobelens, Johanna E; Vink, Hans; Vanteeffelen, Jurgen W G E

    2013-01-01

    It has been demonstrated that insulin-mediated recruitment of microvascular blood volume is associated with insulin sensitivity. We hypothesize that insulin rapidly stimulates penetration of red blood cells (RBC) and plasma into the glycocalyx and thereby promotes insulin-mediated glucose uptake by increasing intracapillary blood volume. Experiments were performed in rats; the role of the glycocalyx was assessed by enzymatic degradation using a bolus of hyaluronidase. First, the effect of insulin on glycocalyx accessibility was assessed by measuring the depth of penetration of RBCs into the glycocalyx in microvessels of the gastrocnemius muscle with Sidestream Dark-field imaging. Secondly, peripheral insulin sensitivity was determined using intravenous insulin tolerance tests (IVITT). In addition, in a smaller set of experiments, intravital microscopy of capillary hemodynamics in cremaster muscle and histological analysis of the distribution of fluorescently labeled 40 kDa dextrans (D40) in hindlimb muscle was used to evaluate insulin-mediated increases in capillary blood volume. Insulin increased glycocalyx penetration of RBCs by 0.34±0.44 µm (Pglucose disposal compared to control rats. Insulin-mediated increases in capillary blood volume were reflected by a rapid increase in capillary tube hematocrit from 21.1±10.1% to 29.0±9.8% (Pblood in muscle, and this is associated with an increased blood volume in individual capillaries. Hyaluronidase treatment of the glycocalyx abolishes the effects of insulin on capillary blood volume and impairs insulin-mediated glucose disposal.

  2. Impaired gait function in adults with cerebral palsy is associated with reduced rapid force generation and increased passive stiffness

    DEFF Research Database (Denmark)

    Geertsen, Svend Sparre; Kirk, Henrik; Lorentzen, Jakob

    2015-01-01

    (mean age 34.3, range 18-57years) and fifteen healthy age-matched controls were biomechanically measured for passive and reflex-mediated stiffness of the ankle plantarflexors at rest, maximal voluntary plantarflexion and dorsiflexion effort (MVCpf,df) and rate of force development (RFDpf,df). Kinematic......, range of movement in the ankle joint and gait speed. Reflex-mediated stiffness was not correlated to any parameters of impaired gait. CONCLUSIONS: Impaired gait function in adults with CP is associated with reduced RFD and increased passive stiffness of ankle muscles. SIGNIFICANCE: These findings...

  3. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian

    2002-01-01

    The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease.......The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease....

  4. Performance of the Androgen Deficiency in Aging Male ...

    African Journals Online (AJOL)

    related decline in androgens that naturally accompanies the ageing process.3,4. Androgen deficiency is known to be associated with several adverse consequences including sexual disorders, mood changes (irritability and depression), ...

  5. Performance of the Androgen Deficiency in Aging Male ...

    African Journals Online (AJOL)

    Performance of the Androgen Deficiency in Aging Male questionnaire for the clinical detection of androgen deficiency in black sub-Saharan African men with Type-2 diabetes mellitus. Theophilus E. Ugwu, Rosemary T. Ikem ...

  6. Three novel and two known androgen receptor gene mutations ...

    Indian Academy of Sciences (India)

    BALACHANDRAN SARANYA

    Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. BALACHANDRAN SARANYA1, GUNASEKARAN BHAVANI1, BRINDHA ARUMUGAM1,. MEENA JAYASHANKAR2 and SATHIYAVEDU THYAGARAJAN SANTHIYA1∗.

  7. Alcohol consumption in Polish middle and high school pupils – has this rapidly increased during 2009–11?

    Directory of Open Access Journals (Sweden)

    Paulina Wojtyła-Buciora

    2014-09-01

    Full Text Available [b]Introduction.[/b] The dynamic rise of alcohol consumption in adolescents is a matter of serious concern, requiring frequently updated monitoring. By such means, it is possible to optimise preventative measures for dealing with this problem. [b]Objective[/b]. To estimate the magnitude/amount and frequency of alcohol consumed by middle and high school pupils in Poland, including the circumstances when alcohol was first drunk. [b]Materials and Methods[/b]. A randomised survey was performed throughout Poland on middle school (junior high school pupils, (n=9360 in 2009, followed by both middle and high school pupils in 2011 (n=7971. The questionnaire was devised by the Polish Chief Sanitary Inspectorate (GIS. [b]Results[/b]. A strikingly sharp increase in alcohol consumption (29% was observed in subjects between 2009 – 2011. In the latter year, 1 month prior to survey, respectively, 50% and 71% of middle school and high school pupils drank alcohol, and correspondingly, 36% and 63% of these pupils ever became intoxicated/drunk. [b]Conclusions[/b]. 1 Adolescent alcohol consumption increases with age and is highest in girls. Monitoring as well as in-depth analysis thus becomes necessary. 2 Systematic monitoring and analysis of changing healthy lifestyle behaviour should be used for taking the necessary corrective action. This should happen concurrently and consist of planned health education programmes, including health promotion.

  8. A Boom for Whom? Exploring the Impacts of a Rapid Increase in the Male Population Upon Women's Services in Darwin, Northern Territory.

    Science.gov (United States)

    Ennis, Gretchen; Tofa, Matalena; Finlayson, Mary; U'Ren, Julie

    2016-05-03

    A rapidly expanding natural-resource extraction industry and a growing military presence mean an increasingly male-skewed population for the city of Darwin, Australia. This has sparked concerns about the potential for increased violence against women. In this article, we present qualitative research detailing the views of 13 participants from 10 women's support services in the Darwin area. We argue that women's support services bear witness to and are tasked with responding to the impacts of population change on women, yet their work is undermined by uncertainties that stem from neoliberal funding rationales and limited demands on companies to address social issues. © The Author(s) 2016.

  9. Restriction of rapid eye movement sleep during adolescence increases energy gain and metabolic efficiency in young adult rats.

    Science.gov (United States)

    Ribeiro-Silva, Neila; Nejm, Mariana Bocca; da Silva, Sylvia Maria Affonso; Suchecki, Deborah; Luz, Jacqueline

    2016-02-01

    What is the central question of this study? Sleep curtailment in infancy and adolescence may lead to long-term risk for obesity, but the mechanisms involved have not yet been determined. This study examined the immediate and long-term metabolic effects produced by sleep restriction in young rats. What is the main finding and its importance? Prolonged sleep restriction reduced weight gain (body fat stores) in young animals. After prolonged recovery, sleep-restricted rats tended to save more energy and to store more fat, possibly owing to increased gross food efficiency. This could be the first step to understand this association. Sleep curtailment is associated with obesity and metabolic changes in adults and children. The aim of the present study was to evaluate the immediate and long-term metabolic alterations produced by sleep restriction in pubertal male rats. Male Wistar rats (28 days old) were allocated to a control (CTL) group or a sleep-restricted (SR) group. This was accomplished by the single platform technique for 18 h per day for 21 days. These groups were subdivided into the following four time points for assessment: sleep restriction and 1, 2 and 4 months of recovery. Body weight and food intake were monitored throughout the experiment. At the end of each time period, blood was collected for metabolic profiling, and the carcasses were processed for measurement of body composition and energy balance. During the period of sleep restriction, SR animals consumed less food in the home cages. This group also displayed lower body weight, body fat, triglycerides and glucose levels than CTL rats. At the end of the first month of recovery, despite eating as much as CTL rats, SR animals showed greater energy and body weight gain, increased gross food efficiency and decreased energy expenditure. At the end of the second and fourth months of recovery, the groups were no longer different, except for energy gain and gross food efficiency, which remained higher in SR

  10. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration.

    Science.gov (United States)

    Li, Yiqing; Andereggen, Lukas; Yuki, Kenya; Omura, Kumiko; Yin, Yuqin; Gilbert, Hui-Ya; Erdogan, Burcu; Asdourian, Maria S; Shrock, Christine; de Lima, Silmara; Apfel, Ulf-Peter; Zhuo, Yehong; Hershfinkel, Michal; Lippard, Stephen J; Rosenberg, Paul A; Benowitz, Larry

    2017-01-10

    Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn(2+)) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn(2+) increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn(2+) accumulation in amacrine cell processes involves the Zn(2+) transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn(2+) chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn(2+) chelation extends for several days after nerve injury. These results show that retinal Zn(2+) dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn(2+) chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

  11. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

    National Research Council Canada - National Science Library

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    .... Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods...

  12. Rapid and Slow Progressors Show Increased IL-6 and IL-10 Levels in the Pre-AIDS Stage of HIV Infection.

    Directory of Open Access Journals (Sweden)

    Rúbia M de Medeiros

    Full Text Available Cytokines are intrinsically related to disease progression in HIV infection. We evaluated the plasma levels of Th1/Th2/Th17 cytokines in extreme progressors, including slow (SPs and rapid (RPs progressors, who were thus classified based on clinical and laboratory follow-up covering a period of time before the initiation of HAART, ranging from 93-136.5 months for SPs and 7.5-16.5 months for RPs. Analyses were also performed based on the different stages of HIV infection (chronic, pre-HAART individuals-subjects sampled before initiating HAART but who initiated therapy from 12 to 24 months-and those receiving HAART. The plasma cytokine levels of 16 HIV-infected rapid progressors and 25 slow progressors were measured using a Human Th1/Th2/Th17 CBA kit. The IL-6 and IL-10 plasma levels differed significantly between the stages of HIV infection. The IL-6 levels were higher in slow progressors pre-HAART than in chronically infected SPs and HIV-seronegative individuals. The IL-10 levels were higher in slow progressors pre-HAART than in slow progressors receiving HAART and HIV-seronegative controls, and in rapid progressors, the IL-10 levels were higher in pre-HAART subjects than in HIV-seronegative controls. The results reflect the changes in the cytokine profile occurring during different clinical stages in HIV+ subjects. Our results suggest an association between increased IL-6 and IL-10 levels and pre-HAART stages independent of the slow or rapid progression status of the subjects. Thus, increased IL-6 and IL-10 levels could indicate a global inflammatory status and could be used as markers of the disease course in HIV-infected individuals.

  13. Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

    OpenAIRE

    Basile, John R.; Binmadi, Nada O.; Zhou, Hua; Yang, Ying-Hua; Paoli, Antonio; Proia, Patrizia

    2013-01-01

    Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few...

  14. Rapid increase in prevalence of male circumcision in rural Tanzania in the absence of a promotional campaign.

    Directory of Open Access Journals (Sweden)

    Harriet J Forbes

    Full Text Available To estimate the prevalence of circumcision among young men in rural Mwanza, North-Western Tanzania, and document trends in circumcision prevalence over time. To investigate associations of circumcision with socio-demographic characteristics, reported sexual behaviours and sexually transmitted infections (STIs.A cross-sectional survey in communities which had previously participated in a cluster-randomized trial of an adolescent sexual health intervention that did not include male circumcision in 20 rural communities.In 2007/08, 7300 young men (age 16-23 years were interviewed and examined by a clinician. The prevalence of circumcision by age was compared with data collected during the trial in 1998-2002. Odds ratios (OR and 95% confidence intervals (CI for the association of circumcision with socio-demographic characteristics, reported sexual behaviours and with HIV and other STIs were estimated using multivariable conditional logistic regression.The prevalence of male circumcision was 40.6%, and age-specific prevalence had more than doubled since 2001/2002. Circumcised men reported less risky sexual behaviours, being more likely to report having ever used a condom (adjusted OR = 2.62, 95%CI:2.32-2.95. Men circumcised before sexual debut were at reduced risk of being HIV seropositive compared with non-circumcised men (adjusted OR = 0.50, 95%CI:0.25-0.97, and also had reduced risks of HSV-2 infection and genital ulcer syndrome in the past 12 months compared with non-circumcised men.There was a steep increase in circumcision prevalence between 2001/02 and 2007/08 in the absence of a promotional campaign. Circumcised men reported safer sexual practices than non-circumcised men and had lower prevalence of HIV and HSV-2 infection.

  15. The Regulation of Spermatogenesis by Androgens

    Science.gov (United States)

    Smith, Lee B.

    2014-01-01

    Testosterone is essential for maintaining spermatogenesis and male fertility. However, the molecular mechanisms by which testosterone acts have not begun to be revealed until recently. With the advances obtained from the use of transgenic mice lacking or overexpressing the androgen receptor, the cell specific targets of testosterone action as well as the genes and signaling pathways that are regulated by testosterone are being identified. In this review, the critical steps of spermatogenesis that are regulated by testosterone are discussed as well as the intracellular signaling pathways by which testosterone acts. We also review the functional information that has been obtained from the knock out of the androgen receptor from specific cell types in the testis and the genes found to be regulated after altering testosterone levels or androgen receptor expression. PMID:24598768

  16. Dehydroepiandrosterone therapy as female androgen replacement.

    Science.gov (United States)

    Saltzman, Erin; Guay, André

    2006-04-01

    Dehydroepiandrosterone (DHEA) is an abundant circulating androgen precursor preferentially produced by the adrenal glands. DHEA has been shown to exert its effects via downstream conversion to sex steroid hormones, neuromodulation, improvement in endothelial cell function, and possibly by acting on a cell membrane-bound receptor. Low levels of circulating DHEA have been demonstrated in women with diminished libido and other symptoms of sexual dysfunction. DHEA deficiency has also been associated with various drugs, and endocrine, nonhormonal, and age-related disorders. DHEA supplementation has been shown to produce beneficial effects in women with adrenal insufficiency. However, DHEA supplementation in healthy euadrenal subjects (including premenopausal and postmenopausal women with androgen insufficiency) is controversial; studies have yielded conflicting results regarding its beneficial effects on sexual function, metabolism, and overall well-being. Further research is needed to better elucidate the efficacy and safety of DHEA supplementation for the treatment of androgen insufficiency in women.

  17. Delinquency, androgens, and the family: a test of evolutionary neuroandrogenic theory.

    Science.gov (United States)

    Ellis, Lee; Das, Shyamal

    2013-08-01

    There is little doubt that family factors can influence involvement in delinquency, although the full nature and extent of their influences remain unclear. In recent decades, testosterone has been increasingly implicated as a contributor to adolescent offending. The present study sought to determine whether two important types of familial factors--parental socioeconomic status and amicable parent-child relationships--are interacting with testosterone (and possibly other androgens) to affect delinquency. A large sample of North American college students self-reported their involvement in eight categories of delinquency along with self-ratings of various androgen-promoted traits (e.g., muscularity and low-deep voice), parental social status, and the quality of the relationships they had with parents. In both sexes, parent-child relationships and androgens were significantly associated with delinquency but parental social status was not. Factor analysis revealed that the authors' measures of all four categories of variables exhibited strong loadings onto their respective factors. Androgens and amicable parent-child relationships were associated with delinquency but parental social status was not. About one third of the influence of parent-child relationships on delinquency appeared to be attributable to androgens. Findings are discussed from the perspective of the evolutionary neuroandrogenic theory of delinquent and criminal behavior.

  18. Relationships between yolk androgens and nest density, laying date, and laying order in Western Burrowing Owls (Athene cunicularia hypugaea)

    Science.gov (United States)

    Welty, J.L.; Belthoff, J.R.; Egbert, J.; Schwabl, H.

    2012-01-01

    Increases in yolk androgens within and among avian clutches have been correlated with decreased incubation time, increased aggression within a nest, increased begging behaviour, decreased immune response, and decreased life span. Although the mechanisms that lead to variability in yolk androgens within and between clutches are not completely known, yolk androgens can be a function of both social and environmental conditions. We were interested in if and how nesting density, laying date, and laying order influenced yolk androgens in Western Burrowing Owls (Athene cunicularia hypugaea (Bonaparte, 1825)) in which nest density varies considerably. In 2006 and 2007, we used radioimmunoassay to quantify the concentrations of testosterone, 5a-dihydrotestosterone, and androstenedione in the egg yolks from one early and one latelaid egg in 47 nests of Burrowing Owls located in the Morley Nelson Snake River Birds of Prey National Conservation Area in southern Idaho. Nesting density had no detectable effect on yolk androgens. Yolk androgens varied temporally and peaked in the middle of the laying season while being low before and after this time period. Within nests, late-laid eggs had higher testosterone and dihydrotestosterone than early-laid eggs; adrostendione exhibited a similar pattern in one but not both years of our study. It is possible that the seasonal pattern in yolk androgens that we observed is related to aspects of mate quality for females or declining chances of fledging success for later nesting females, whereas rises in egg androgens between early and late eggs within clutches could reflect a mechanism to assist nestlings from late-laid eggs that hatch one to several days after their siblings to better compete for resources within the nest or promote survival in the presence of larger siblings.

  19. Differential effects of androgens on coronary blood flow regulation and arteriolar diameter in intact and castrated swine

    Directory of Open Access Journals (Sweden)

    O’Connor Erin K

    2012-05-01

    Full Text Available Abstract Background Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on in vivo coronary conductance and in vitro coronary microvascular diameter in intact and castrated male swine. Methods Pigs received intracoronary infusions of physiologic levels (1–100 nM of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels. Results In vivo, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. In vitro, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males. Conclusions Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.

  20. Sex differences in neuromuscular androgen receptor expression and sociosexual behavior in a sex changing fish.

    Directory of Open Access Journals (Sweden)

    Eric R Schuppe

    Full Text Available Androgen signaling, via receptor binding, is critical for regulating the physiological and morphological foundations of male-typical reproductive behavior in vertebrates. Muscles essential for male courtship behavior and copulation are highly sensitive to androgens. Differences in the distribution and density of the androgen receptor (AR are important for maintaining dimorphic musculature and thus may provide for anatomical identification of sexually selected traits. In Lythrypnus dalli, a bi-directional hermaphroditic teleost fish, both sexes produce agonistic approach displays, but reproductive behavior is sexually dimorphic. The male-specific courtship behavior is characterized by rapid jerky movements (involving dorsal fin erection towards a female or around their nest. Activation of the supracarinalis muscle is involved in dorsal fin contributions to both agonistic and sociosexual behavior in other fishes, suggesting that differences in goby sexual behavior may be reflected in sexual dimorphism in AR signaling in this muscle. We examined sex differences in the local distribution of AR in supracarinalis muscle and spinal cord. Our results demonstrate that males do express more AR in the supracarinalis muscle relative to females, but there was no sex difference in the number of spinal motoneurons expressing AR. Interestingly, AR expression in the supracarinalis muscle was also related to rates of sociosexual behavior in males, providing evidence that sexual selection may influence muscle androgenic sensitivity to enhance display vigor. Sex differences in the distribution and number of cells expressing AR in the supracarinalis muscle may underlie the expression of dimorphic behaviors in L. dalli.

  1. Sex differences in neuromuscular androgen receptor expression and sociosexual behavior in a sex changing fish.

    Science.gov (United States)

    Schuppe, Eric R; Pradhan, Devaleena S; Thonkulpitak, Kevin; Drilling, Cathleen; Black, Michael; Grober, Matthew S

    2017-01-01

    Androgen signaling, via receptor binding, is critical for regulating the physiological and morphological foundations of male-typical reproductive behavior in vertebrates. Muscles essential for male courtship behavior and copulation are highly sensitive to androgens. Differences in the distribution and density of the androgen receptor (AR) are important for maintaining dimorphic musculature and thus may provide for anatomical identification of sexually selected traits. In Lythrypnus dalli, a bi-directional hermaphroditic teleost fish, both sexes produce agonistic approach displays, but reproductive behavior is sexually dimorphic. The male-specific courtship behavior is characterized by rapid jerky movements (involving dorsal fin erection) towards a female or around their nest. Activation of the supracarinalis muscle is involved in dorsal fin contributions to both agonistic and sociosexual behavior in other fishes, suggesting that differences in goby sexual behavior may be reflected in sexual dimorphism in AR signaling in this muscle. We examined sex differences in the local distribution of AR in supracarinalis muscle and spinal cord. Our results demonstrate that males do express more AR in the supracarinalis muscle relative to females, but there was no sex difference in the number of spinal motoneurons expressing AR. Interestingly, AR expression in the supracarinalis muscle was also related to rates of sociosexual behavior in males, providing evidence that sexual selection may influence muscle androgenic sensitivity to enhance display vigor. Sex differences in the distribution and number of cells expressing AR in the supracarinalis muscle may underlie the expression of dimorphic behaviors in L. dalli.

  2. Abuse of anabolic androgenic steroids and related substances in sport and exercise.

    Science.gov (United States)

    Bahrke, Michael S; Yesalis, Charles E

    2004-12-01

    Anabolic androgenic steroids are synthetic derivatives of testosterone, which is the primary male sex hormone. Anabolic androgenic steroids are used to enhance athletic performance and appearance. Adverse effects include those on the liver, serum lipids, psyche/behavior and reproductive system. Androstenedione is an anabolic androgenic steroid used to increase blood testosterone levels for the purposes of increasing strength, lean body mass and sexual performance. However, there is no research indicating that androstenedione, or its related compounds, significantly increases strength and/or lean body mass in humans by increasing testosterone levels. The long-term health effects of prolonged androstenedione supplementation are unknown. Dehydroepiandrosterone (DHEA) is a weak androgen also used to elevate testosterone levels, and is advertised as an anti-obesity and anti-aging supplement capable of improving libido, vitality and immunity levels. However, research demonstrates that DHEA supplementation does not increase serum testosterone concentrations or increase strength in men, and may acutely increase testosterone levels in women, thus producing a virilizing effect.

  3. Cell Cycle Regulation of Estrogen and Androgen Receptor

    Science.gov (United States)

    2001-07-01

    hypersensitivity as- the transiently transfected MMTV promoter as shown say was performed as described previously [18]. In brief, cells were previously [3, 41...per 1 F 108 cells, in 10 mM his tris propane , pH 7, 10 mM MgC12, 1 mM DTT) significant increase of CAT activity was observed. Pre- and incubated for 15...within nucleosome B, which is remodeled and becomes hypersensitive to restriction enzyme (SstI) cleavage during androgen that at no time point during the

  4. Validation of a rapid type 1 diabetes autoantibody screening assay for community-based screening of organ donors to identify subjects at increased risk for the disease.

    Science.gov (United States)

    Wasserfall, C; Montgomery, E; Yu, L; Michels, A; Gianani, R; Pugliese, A; Nierras, C; Kaddis, J S; Schatz, D A; Bonifacio, E; Atkinson, M A

    2016-07-01

    The Network for Pancreatic Organ donors with Diabetes (nPOD) programme was developed in response to an unmet research need for human pancreatic tissue obtained from individuals with type 1 diabetes mellitus and people at increased risk [i.e. autoantibody (AAb)-positive] for the disease. This necessitated the establishment of a type 1 diabetes-specific AAb screening platform for organ procurement organizations (OPOs). Assay protocols for commercially available enzyme-linked immunosorbent assays (elisas) determining AAb against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA-2A) and zinc transporter-8 (ZnT8A) were modified to identify AAb-positive donors within strict time requirements associated with organ donation programmes. These rapid elisas were evaluated by the international islet AAb standardization programme (IASP) and used by OPO laboratories as an adjunct to routine serological tests evaluating donors for organ transplantation. The rapid elisas performed well in three IASPs (2011, 2013, 2015) with 98-100% specificity for all three assays, including sensitivities of 64-82% (GADA), 60-64% (IA-2A) and 62-68% (ZnT8A). Since 2009, nPOD has screened 4442 organ donors by rapid elisa; 250 (5·6%) were identified as positive for one AAb and 14 (0.3%) for multiple AAb with 20 of these cases received by nPOD for follow-up studies (14 GADA+, two IA-2A(+) , four multiple AAb-positive). Rapid screening for type 1 diabetes-associated AAb in organ donors is feasible, allowing for identification of non-diabetic, high-risk individuals and procurement of valuable tissues for natural history studies of this disease. © 2016 British Society for Immunology.

  5. Androgen receptor disorder in three brothers with bifid prepenile scrotum and hypospadias.

    Science.gov (United States)

    Bals-Pratsch, M; Schweikert, H U; Nieschlag, E

    1990-09-01

    Three brothers with congenital transposition of the penis, scrotal hypospadias, bifid scrotum, and bilateral undescended testes are described. Further signs of incomplete virilization, but no gynecomastia were seen. LH and FSH were elevated, whereas testosterone levels were reduced or in the normal range. Serum concentrations of 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 5 alpha-dihydrotestosterone and estradiol measured in two affected brothers were in the normal range. Fibroblasts from scrotal skin biopsies performed in two patients showed normal 5 alpha-reductase activity (419 and 214 pmol.(mg protein)-1.h-1; normal greater than 1), whereas androgen receptors had reduced maximal binding capacity (Bmax 4 and 14 fmol.(mg protein)-1; normal greater than 18) and an increased equilibrium dissociation constant (0.7 and 1.26 nmol/l: normal 0.2 +/- 0.08) indicating a quantitative and qualitative androgen receptor defect. These patients represent a further variant of androgen insensitivity.

  6. Mathematical Models of Androgen Resistance in Prostate Cancer Patients under Intermittent Androgen Suppression Therapy

    Directory of Open Access Journals (Sweden)

    Javier Baez

    2016-11-01

    Full Text Available Predicting the timing of a castrate resistant prostate cancer is critical to lowering medical costs and improving the quality of life of advanced prostate cancer patients. We formulate, compare and analyze two mathematical models that aim to forecast future levels of prostate-specific antigen (PSA. We accomplish these tasks by employing clinical data of locally advanced prostate cancer patients undergoing androgen deprivation therapy (ADT. While these models are simplifications of a previously published model, they fit data with similar accuracy and improve forecasting results. Both models describe the progression of androgen resistance. Although Model 1 is simpler than the more realistic Model 2, it can fit clinical data to a greater precision. However, we found that Model 2 can forecast future PSA levels more accurately. These findings suggest that including more realistic mechanisms of androgen dynamics in a two population model may help androgen resistance timing prediction.

  7. Androgen-Dependent Regulation of Human MUC1 Mucin Expression

    Directory of Open Access Journals (Sweden)

    Stephen Mitchell

    2002-01-01

    Full Text Available MUC1 mucin is transcriptionally regulated by estrogen, progesterone, and glucocorticoids. Our objective was to determine whether androgen receptor. (20AR activation regulates expression of MUC1. The following breast and prostatic cell lines were phenotyped and grouped according to AR and MUC1protein expression: 1 AR+MUCi + [DAR17+19. (20AR transfectants of DU-145, ZR-75-1, MDA-MB-453, and T47D]; 2 AR-MUCi+ [DZeoi. (20AR- vector control, DU-145, BT20, MDA-MB231, and MCF7]; 3 AIR +MUCi -. (20LNCaP and LNCaP-r. Cell proliferation was determined using the MTT assay in the presence of synthetic androgen R1881, 0.1 pM to 1 µM. Cell surface MUC1expression was determined by flow cytometry in the presence or absence of oestradiol, medroxy progesterone acetate or R1881, with and without 4 hydroxy-flutamide. (204-OH, a nonsteroidal AR antagonist. The functional significance of MUC1expression was investigated with a cell-cell aggregation assay. Only AR+ MUC1 + cell lines showed a significant increase in MUC1expression with AR activation. (20P. (20range =.01 to .0001, reversed in the presence of 4-OHF. Cell proliferation was unaffected. Increased expression of MUC1was associated with a significant. (20P. (20range =.002 to .001 reduction in cell-cell adhesion. To our knowledge, this is the first description of androgen-dependent regulation of MUC1mucin. This is also functionally associated with decreased cell-cell adhesion, a recognised feature of progressive malignancy. These findings have important implications for physiological and pathological processes.

  8. Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progress: a retrospective chart review.

    Science.gov (United States)

    Shams, Kim; Cameo, Tamara; Fennoy, Ilene; Hassoun, Abeer A; Lerner, Shulamit E; Aranoff, Gaya S; Sopher, Aviva B; Yang, Christine; McMahon, Donald J; Oberfield, Sharon E

    2014-07-01

    Aromatase inhibitors (AIs) have been used off-label to increase adult height in short adolescent males. Studies have shown that AIs increase the predicted adult height (PAH) while delaying bone age (BA) maturation. We sought to determine whether AI therapy increases PAH in boys with short stature or rapid pubertal progression, and to evaluate any untoward effects. The charts of 27 boys with BA ≥ 13 and short stature [height ≥ 2 standard deviation (SD) below the mean or ≥ 2 SD below mid-parental target height (MPTH)] or rapid pubertal progress, treated with anastrozole were reviewed. Outcome measures included anthropomorphic, hormonal, and metabolic data. The AI therapy averaged 21 months (range 14-30 months) for all, with Rx group 1 receiving height SDS, or BA/chronological age (CA). In Rx group 2, there was a small, nonsignificant increase in PAH, no change in height SDS, and a small decrease in BA/CA. Post-therapy PAH was different from MPTH in all and in both Rx groups 1 and 2, pheight, averaging 6.73 ± 1.40 cm less than MPTH and 1.91 ± 0.86 cm less than the pre-therapy PAH. Post-therapy, the initially decreased estradiol did not persist but mildly increased testosterone and decreased high-density lipoprotein were noted, as was an increase in hematocrit, and decrease in growth velocity. We suggest that although bone age progression may be slightly delayed with longer duration of therapy, an overall short-term AI therapy does not lead to a final height that is greater than the predicted pre-therapy height.

  9. Sarcopenia and androgens: A link between pathology and treatment

    Directory of Open Access Journals (Sweden)

    Carla eBasualto-Alarcón

    2014-12-01

    Full Text Available Sarcopenia, the age-related loss of skeletal muscle mass and function, is becoming more prevalent as the lifespan continues to increase in most populations. As sarcopenia is highly disabling, being associated with increased risk of dependence, falls, fractures, weakness, disability, and death, development of approaches to its prevention and treatment are required. Androgens are the main physiologic anabolic steroid hormones and normal testosterone levels are necessary for a range of developmental and biological processes, including maintenance of muscle mass. Testosterone concentrations decline as age increase, suggesting that low plasma testosterone levels can cause or accelerate muscle- and age-related diseases, as sarcopenia. Currently, there is increasing interest on the anabolic properties of testosterone for therapeutic use in muscle diseases including sarcopenia. However, the pathophysiological mechanisms underlying this muscle syndrome and its relationship with plasma level of androgens are not completely understood. This review discusses the recent findings regarding sarcopenia, the intrinsic and extrinsic mechanisms involved in the onset and progression of this disease and the treatment approaches that have been developed based on testosterone deficiency and their implications.

  10. [Transdisciplinary Approach for Sarcopenia. Appication of selective androgen receptor modulator to the therapy of sarcopenia].

    Science.gov (United States)

    Yanase, Toshihiko; Tanabe, Makito; Nomiyama, Takashi

    2014-10-01

    The research to develop a drug, so called selective androgen receptor modulator (SARM) , which shows beneficial androgenic action on bone and muscle, but hardly possesses the stimulatory action on prostate has been making a progress. However, no drug is available in the market at present. Most of such drugs are developed, aiming at the application to age-related muscle reduction (sarcopenia) and osteoporosis. Recently, in a clinical trial of SARM (enbosarm) administration to healthy elderly men, a promising data showing the increase of lean body mass and physical function has been reported. Future clinical applications of SARMs are expected.

  11. Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta.

    Science.gov (United States)

    Mishra, Jay S; Hankins, Gary D; Kumar, Sathish

    2016-10-01

    Blood pressure is lower in females than males. Angiotensin II type-2 receptor (AT2R) induces vasodilation. This study determined whether sex differences in vascular AT2R expression occur and if androgens exert control on AT2R expression in the vasculature. AT2Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. AT2R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT2R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT2R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT2R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT2R downregulation in isolated aorta was blocked by an androgen receptor antagonist. Furthermore, blockade of ERK1/2 but not p38 MAP kinase or TGFβ signaling with specific inhibitors abolished dihydrotestosterone-induced AT2R downregulation. Androgens downregulate AT2R expression levels in aorta, in vivo and ex vivo. The androgen receptor-mediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT2R expression, implicating androgens' contributing role to gender differences in vascular AT2R expression. © The Author(s) 2016.

  12. PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Zheng [Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034 (China); Jin, Bo [Department of Clinical Laboratory, Peking University First Hospital, Beijing 100034 (China); Jin, Yaqiong [Biobank for Clinical Data and Samples in Pediatric, Beijing Pediatric Research Institute, Beijing Children' s Hospital, Capital Medical University, Beijing 100045 (China); Huang, Shengquan; Niu, Xiaohua [Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034 (China); Mao, Zebin [The Department of Biochemistry and Molecular Biology, Health Science Center, Peking University, 38 Xueyuan Road, Beijing 100191 (China); Xin, Dianqi, E-mail: xin-dianqi@163.com [Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034 (China)

    2017-01-01

    Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.

  13. Transfection of Sertoli cells with androgen receptor alters gene expression without androgen stimulation.

    Science.gov (United States)

    Fietz, D; Markmann, M; Lang, D; Konrad, L; Geyer, J; Kliesch, S; Chakraborty, T; Hossain, H; Bergmann, M

    2015-12-29

    Androgens play an important role for the development of male fertility and gained interest as growth and survival factors for certain types of cancer. Androgens act via the androgen receptor (AR/Ar), which is involved in various cell biological processes such as sex differentiation. To study the functional mechanisms of androgen action, cell culture systems and AR-transfected cell lines are needed. Transfection of AR into cell lines and subsequent gene expression analysis after androgen treatment is well established to investigate the molecular biology of target cells. However, it remains unclear how the transfection with AR itself can modulate the gene expression even without androgen stimulation. Therefore, we transfected Ar-deficient rat Sertoli cells 93RS2 by electroporation using a full length human AR. Transfection success was confirmed by Western Blotting, immunofluorescence and RT-PCR. AR transfection-related gene expression alterations were detected with microarray-based genome-wide expression profiling of transfected and non-transfected 93RS2 cells without androgen stimulation. Microarray analysis revealed 672 differentially regulated genes with 200 up- and 472 down-regulated genes. These genes could be assigned to four major biological categories (development, hormone response, immune response and metabolism). Microarray results were confirmed by quantitative RT-PCR analysis for 22 candidate genes. We conclude from our data, that the transfection of Ar-deficient Sertoli cells with AR has a measurable effect on gene expression even without androgen stimulation and cause Sertoli cell damage. Studies using AR-transfected cells, subsequently stimulated, should consider alterations in AR-dependent gene expression as off-target effects of the AR transfection itself.

  14. Structural features discriminate androgen receptor N/C terminal and coactivator interactions.

    Science.gov (United States)

    Askew, Emily B; Minges, John T; Hnat, Andrew T; Wilson, Elizabeth M

    2012-01-30

    Human androgen receptor (AR) transcriptional activity involves interdomain and coactivator interactions with the agonist-bound AR ligand binding domain (LBD). Structural determinants of the AR NH(2)- and carboxyl-terminal interaction between the AR NH(2)-terminal FXXLF motif and activation function 2 (AF2) in the LBD were shown previously by crystallography. In this report, we provide evidence for a region in AR LBD helix 12 outside the AF2 binding cleft that facilitates interactions with the FXXLF and LXXLL motifs. Mutagenesis of glutamine 902 to alanine in AR LBD helix 12 (Q902A) disrupted AR FXXLF motif binding to AF2, but enhanced coactivator LXXLL motif binding. Functional compensation for defective FXXLF motif binding by AR-Q902A was suggested by the slower dissociation rate of bound androgen. Functional importance of glutamine 902 was indicated by the charged residue germline mutation Q902R that caused partial androgen insensitivity, and a similar somatic mutation Q902K reported in prostate cancer, both of which increased the androgen dissociation rate and decreased AR transcriptional activity. High affinity equilibrium androgen binding was retained by alanine substitution mutations at Tyr-739 in AR LBD helix 5 or Lys-905 in helix 12 structurally adjacent to AF2, whereas transcriptional activity decreased and the androgen dissociation increased. Deleterious effects of these loss of function mutations were rescued by the helix stabilizing AR prostate cancer somatic mutation H874Y. Sequence NH(2)-terminal to the AR FXXLF motif contributed to the AR NH(2)- and carboxyl-terminal interaction based on greater AR-2-30 FXXLF motif peptide binding to the agonist-bound AR LBD than a shorter AR-20-30 FXXLF motif peptide. We conclude that helix 12 residues outside the AF2 binding cleft modulate AR transcriptional activity by providing flexibility to accommodate FXXLF or LXXLL motif binding. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  15. The androgen receptor and estrogen receptor

    NARCIS (Netherlands)

    Oosterkamp, H.M.; Bernards, R.A.

    2002-01-01

    The androgen receptor (AR) and the estrogen receptors (ER) are members of the nuclear receptor (NR) family. These NRs are distinguished from the other transcription factors by their ability to control gene expression upon ligand binding (steroids, retinoids, thyroid hormone, vitamin D, fatty

  16. Leverpatologi associeret med anaboliske-androgene steroider

    DEFF Research Database (Denmark)

    Søe, Katrine; Søe, Martin Jensen; Gluud, C N

    1994-01-01

    This review regards the liver damaging side-effects of anabolic-androgenic steroids (AAS). It seems that AAS can cause development of peliosis hepatis, subcellular changes of hepatocytes, hepatocellular hyperplasia and hepatocellular adenomas. On the other hand, it has not been convincingly proved...

  17. The relationship between follicular fluid androgen concentrations ...

    African Journals Online (AJOL)

    Polycystic ovary syndrome (PCOS) is the most common cause of oligoanovulation, infertility, and hyperandrogenism in women and characterized by abnormal folliculogenesis. The androgen receptoe ( AR) is present in the ovary in almost all stages of folliculogenesis and has been suggested to play a proliferative role for ...

  18. Expression of Androgen Receptor Is Negatively Regulated By p53

    Directory of Open Access Journals (Sweden)

    Fatouma Alimirah

    2007-12-01

    Full Text Available Increased expression of androgen receptor (AR in prostate cancer (PC is associated with transition to androgen independence. Because the progression of PC to advanced stages is often associated with the loss of p53 function, we tested whether the p53 could regulate the expression of AR gene. Here we report that p53 negatively regulates the expression of AR in prostate epithelial cells (PrECs. We found that in LNCaP human prostate cancer cells that express the wild-type p53 and AR and in human normal PrECs, the activation of p53 by genotoxic stress or by inhibition of p53 nuclear export downregulated the expression of AR. Furthermore, forced expression of p53 in LNCaP cells decreased the expression of AR. Conversely, knockdown of p53 expression in LNCaP cells increased the AR expression. Consistent with the negative regulation of AR expression by p53, the p53-null HCT116 cells expressed higher levels of AR compared with the isogenic HCT116 cells that express the wildtype p53. Moreover, we noted that in etoposide treated LNCaP cells p53 bound to the promoter region of the AR gene, which contains a potential p53 DNA-binding consensus sequence, in chromatin immunoprecipitation assays. Together, our observations provide support for the idea that the loss of p53 function in prostate cancer cells contributes to increased expression of AR.

  19. The rapid climate change-caused dichotomy on subtropical evergreen broad-leaved forest in Yunnan: Reduction in habitat diversity and increase in species diversity

    Directory of Open Access Journals (Sweden)

    Zhe Ren

    2016-06-01

    Full Text Available Yunnan's biodiversity is under considerable pressure and subtropical evergreen broad-leaved forests in this area have become increasingly fragmented through agriculture, logging, planting of economic plants, mining activities and changing environment. The aims of the study are to investigate climate change-induced changes of subtropical evergreen broad-leaved forests in Yunnan and identify areas of current species richness centers for conservation preparation. Stacked species distribution models were created to generate ensemble forecasting of species distributions, alpha diversity and beta diversity for Yunnan's subtropical evergreen broad-leaved forests in both current and future climate scenarios. Under stacked species distribution models in rapid climate changes scenarios, changes of water-energy dynamics may possibly reduce beta diversity and increase alpha diversity. This point provides insight for future conservation of evergreen broad-leaved forest in Yunnan, highlighting the need to fully consider the problem of vegetation homogenization caused by transformation of water-energy dynamics.

  20. Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.

    Science.gov (United States)

    Holm, Jacob Bak; Chalmey, Clementine; Modick, Hendrik; Jensen, Lars Skovgaard; Dierkes, Georg; Weiss, Tobias; Jensen, Benjamin Anderschou Holbech; Nørregård, Mette Marie; Borkowski, Kamil; Styrishave, Bjarne; Martin Koch, Holger; Mazaud-Guittot, Severine; Jegou, Bernard; Kristiansen, Karsten; Kristensen, David Møbjerg

    2015-11-01

    Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet, and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolized to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here, we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into antiandrogenic paracetamol, impairs male reproductive development. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Androgen deprivation therapy in prostate cancer and risk of developing renal calculi: Results of a case-control study.

    Science.gov (United States)

    Díaz Convalía, Enrique Javier; Cano-García, María Del Carmen; Miján-Ortiz, José Luis; Arrabal-Martín, Miguel; Arrabal-Polo, Miguel Ángel; Cózar-Olmo, José Manuel

    2017-06-07

    Androgenic deprivation therapy in prostate cancer is associated with the onset of different adverse effects, including osteoporosis and metabolic syndrome. Both are related to the onset of nephrolithiasis. The objective of this article is to study the incidence of renal stones in patients undergoing androgen deprivation therapy with LHRH analogue. Case-control study including a total of 85 patients divided into 2 groups: group 1, with 41 patients on androgen deprivation therapy, and group 2, with 44 patients not receiving androgen deprivation therapy. New-onset lithiasis was observed in 12 cases (29.3%) in group 1 compared to 2 cases (4.5%) in group 2 (P=.0001), 4.4 years after starting the androgen deprivation therapy. The estimated odds ratio was 8.69 (95% CI 1.81-41.76). The incidence of renal stones could be increased in patients receiving treatment with analogue LHRH. However, long-term prospective studies with a metabolic control are required to be able to establish the causes explaining the development of this phenomenon in patients undergoing treatment with androgen deprivation therapy. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  2. Season- and Age-related Reproductive Changes Based on Fecal Androgen Concentrations in Male Koalas, Phascolarctos cinereus

    Science.gov (United States)

    KUSUDA, Satoshi; HASHIKAWA, Hisashi; TAKEDA, Masato; ITO, Hideki; GOTO, Atsushi; OGUCHI, Jun; DOI, Osamu

    2013-01-01

    Abstract The purposes of the present study were to clarify age- and season- related androgen patterns, and to compare the reproductive physiology between Japanese captive koala populations and Australian populations. To measure fecal androgens, feces were collected from male koalas (4.2 to 13.8 years of age) kept in Japanese zoos. Fecal androgens were extracted with methanol from the lyophilized samples and determined by enzyme immunoassay using 4-androstene-3,17-dione antibody. Fecal androgen concentration in male koalas increased after sexual maturation and remained relatively high until old age. In the survey with the Japanese zoo studbook of koalas, copulation (conception) month showed a pyramid shape with a peak in March to June (60.7%) in koalas born and reared in Japanese zoos and from July to April with the highest concentration in September to January (69.7%) in Australian institutes. Japanese zoo koala populations have a characteristic physiological cycle adapted to Japan's seasonal changes. The suitable month of year for copulation or conception in Japan is diametrically opposed to that in Australia. Mean fecal androgen concentrations by month in the males born and reared in Japan indicated annual changes with the highest concentration in May and the lowest value in November. Fecal androgen analysis may be a noninvasive alternative tool to monitor circulating testosterone and may be helpful in understanding reproductive activity and physiology in male koalas. PMID:23502854

  3. [Contribution of bioavailable testosterone assay for the diagnosis of androgen deficiency in elderly men].

    Science.gov (United States)

    Lejeune, H; Déchaud, H; Pugeat, M

    2003-04-01

    With age, some men develop symptoms resembling hypogonadism. Several cross-sectional and longitudinal studies have shown a decrease in testosterone levels with ageing in men. This finding has equally been observed in elderly men in good health. Testosterone levels decline progressively as of the thirties, at a rate which remains constant throughout life. While total testosterone levels decrease, sex hormone binding globulin (SHBG) levels on the contrary increase with age, with the result that the levels of free and non-SHBG-bound testosterone (corresponding to the fraction which is bioavailable to target cells) decrease more abruptly than that of total testosterone. Higher LH levels, decreased testosterone response to hCG and less Leydig cells all indicate that ageing induces partial testicular failure. However, the gonadotropic function is also affected in ageing. The hypothalamus-pituitary becomes more sensitive to gonad steroid feedback, LH pulse amplitude decreases, and the LH response to GnRH is blunted compared to the situation in young men. Thus LH level is not a valid index of androgen deficiency in elderly males. None of the androgen-dependent functions (libido, erection, sense of well-being, muscle mass and strength, fat mass, bone mass, erythropoiesis, etc.) are under exclusively androgen control, and there is no elderly male symptom which is completely specific to androgen deficiency. Thus, in elderly men, when clinical symptoms might indicate androgen deficiency, biological confirmation is needed. An assay which is independent of SHBG fluctuations is mandatory. Bioavailable testosterone assay by ammonium sulfate precipitation seems to us to be the optimum method for diagnosing androgen deficiency: it gives a reliable measurement for the testosterone fraction available to target cells, is adapted to clinical practice, and provides results that can be directly compared with current reference values for healthy young men.

  4. Therapeutic effects of anabolic androgenic steroids on chronic diseases associated with muscle wasting

    NARCIS (Netherlands)

    Woerdeman, J.T.; de Ronde, W.

    2011-01-01

    Introduction: A variety of clinical conditions are complicated by loss of weight and skeletal muscle which may contribute to morbidity and mortality. Anabolic androgenic steroids have been demonstrated to increase fat-free mass, muscle mass and strength in healthy men and women without major adverse

  5. Maternal androgens in black-headed gull (Larus ridibundus) eggs : Consequences for chick development

    NARCIS (Netherlands)

    Eising, C.M; Eikenaar, C.; Schwabl, H; Groothuis, A.G.G.

    2001-01-01

    We tested the hypothesis that mother birds counterbalance the negative effects of hatching asynchrony for later-hatched chicks by increasing the yolk androgen concentrations in consecutive eggs of their clutch. In doing so, they may adaptively tune each offspring’s competitive ability and, thus,

  6. Yolk androgens and begging behaviour in black-headed gull chicks : an experimental field study

    NARCIS (Netherlands)

    Eising, CM; Groothuis, TGG; Groothuis, Ton G.G.

    2003-01-01

    Black-headed gulls, Larus ridibundus, produce clutches of three eggs, which contain high levels of maternal androgens in the yolk. These levels increase with laying order and the eggs hatch asynchronously. Experiments have supported the hypothesis that this within-clutch variation in maternal

  7. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

    Science.gov (United States)

    Miranda, Benjamin H; Charlesworth, Matthew R; Tobin, Desmond J; Sharpe, David T; Randall, Valerie A

    2017-10-18

    Male sex hormones-androgens-regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs (e.g., beard). Follicle response is epigenetically varied: some remain unaffected (e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors-androgen-activated gene transcription regulators-are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.-Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life. © FASEB.

  8. Relative importance of prenatal and postnatal androgen action in determining growth of the penis and anogenital distance in the rat before, during and after puberty.

    Science.gov (United States)

    van den Driesche, S; Scott, H M; MacLeod, D J; Fisken, M; Walker, M; Sharpe, R M

    2011-12-01

    Experimental animal studies show that measurement of anogenital distance (AGD) and/or penis length may provide lifelong 'read-outs' of foetal androgen exposure during the masculinization programming window (MPW). However, variation in postnatal androgen exposure may complicate interpretation of such measurements. This is important to clarify if such measurements are to be applied to humans. The present aim was to evaluate effects of prenatal and/or postnatal manipulation of androgen production/action on growth of AGD and the penis in rats. Pregnant rats were treated daily before (e13.5-e21.5) and after birth (postnatal days 1-15) with either vehicle, 500 mg/kg di(n-butyl) phthalate (DBP) or 100 mg/kg flutamide (postnatal only) in prenatal + postnatal treatment combinations (N = 6 treatment combinations); DBP impairs androgen production whereas flutamide impairs androgen action. Male offspring were killed on postnatal day 8 (prepuberty), 25 (early puberty) or 90 (adulthood) when AGD was measured, the penis dissected out and its weight and length measured; plasma testosterone and ventral prostate weight were measured at day 90 to assess endogenous androgen exposure. In controls, penis length, girth and AGD increased 2.2-, 5.3-and 5.9-fold respectively from day 8 to day 90. Significant inhibition of penis growth and final length and girth was induced by treatments that inhibited postnatal androgen action. Conversely, growth and ultimate (adult) AGD was inhibited by prenatal inhibition of androgen production whereas postnatal androgen inhibition had negligible effect. Nevertheless, AGD and penis length were highly correlated at every age (R(2) > 0.33; p penis size reflects both prenatal + postnatal androgen exposure. At the group treatment level, prepubertal measurement of either AGD or penis size accurately predicts their size in adulthood. © 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

  9. Effects of anabolic-androgens on brain reward function

    Directory of Open Access Journals (Sweden)

    Emanuela eMhillaj

    2015-08-01

    Full Text Available Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming the so called androgen anabolic steroids (AAS. These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, the off-label utilization is very wide. Furthermore, combination of different steroids, and doses largely higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. Among the AAS abusers, the frequency of side effects is higher, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because the collection of data is very difficult due to reticent subjects and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in reward process, leading to an increased sensitivity toward opioid narcotics and central stimulants. The aim of this review is to discuss what is present in literature in regard to steroid abuse and alteration of reward system in preclinical and clinical studies.

  10. Effects of anabolic-androgens on brain reward function.

    Science.gov (United States)

    Mhillaj, Emanuela; Morgese, Maria G; Tucci, Paolo; Bove, Maria; Schiavone, Stefania; Trabace, Luigia

    2015-01-01

    Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies.

  11. Effects of anabolic-androgens on brain reward function

    Science.gov (United States)

    Mhillaj, Emanuela; Morgese, Maria G.; Tucci, Paolo; Bove, Maria; Schiavone, Stefania; Trabace, Luigia

    2015-01-01

    Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming androgen anabolic steroids (AAS). These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, their off-label utilization is very wide. Furthermore, combinations of different steroids and doses generally higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. The frequency of side effects is higher among AAS abusers, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because data collection is very difficult due to the subjects' reticence and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in the reward process, leading to increased sensitivity toward opioid narcotics and central stimulants. The goal of this article is to review the literature on steroid abuse and changes to the reward system in preclinical and clinical studies. PMID:26379484

  12. Microscale methods to rapidly evaluate bioprocess options for increasing bioconversion yields: application to the ω-transaminase synthesis of chiral amines.

    Science.gov (United States)

    Halim, Murni; Rios-Solis, Leonardo; Micheletti, Martina; Ward, John M; Lye, Gary J

    2014-05-01

    This work aims to establish microscale methods to rapidly explore bioprocess options that might be used to enhance bioconversion reaction yields: either by shifting unfavourable reaction equilibria or by overcoming substrate and/or product inhibition. As a typical and industrially relevant example of the problems faced we have examined the asymmetric synthesis of (2S,3R)-2-amino-1,3,4-butanetriol from l-erythrulose using the ω-transaminase from Chromobacterium violaceum DSM30191 (CV2025 ω-TAm) and methylbenzylamine as the amino donor. The first process option involves the use of alternative amino donors. The second couples the CV2025 ω-TAm with alcohol dehydrogenase and glucose dehydrogenase for removal of the acetophenone (AP) by-product by in situ conversion to (R)-1-phenylethanol. The final approaches involve physical in-situ product removal methods. Reduced pressure conditions, attained using a 96-well vacuum manifold were used to selectively increase evaporation of the volatile AP while polymeric resins were also utilised for selective adsorption of AP from the bioconversion medium. For the particular reaction studied here the most promising bioprocess options were use of an alternative amino donor, such as isopropylamine, which enabled a 2.8-fold increase in reaction yield, or use of a second enzyme system which achieved a 3.3-fold increase in yield.

  13. Luteinizing hormone (LH)-releasing hormone agonist reduces serum adrenal androgen levels in prostate cancer patients: implications for the effect of LH on the adrenal glands.

    Science.gov (United States)

    Nishii, Masahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Oyama, Tetsunari; Suzuki, Kazuhiro

    2012-01-01

    Recently, adrenal androgens have been targeted as key hormones for the development of castration-resistant prostate cancer therapeutics. Although circulating adrenal androgens originate mainly from the adrenal glands, the testes also supply about 10%. Although widely used in androgen deprivation medical castration therapy, the effect of luteinizing hormone-releasing hormone (LH-RH) agonist on adrenal androgens has not been fully studied. In this study, changes in testicular and adrenal androgen levels were measured and compared to adrenocorticotropic hormone levels. To assess the possible role of LH in the adrenal glands, immunohistochemical studies of the LH receptor in normal adrenal glands were performed. Forty-seven patients with localized or locally progressive prostate cancer were treated with LH-RH agonist with radiotherapy. Six months after initiation of treatment, testosterone, dihydrotestosterone, and estradiol levels were decreased by 90%-95%, and dehydroepiandrosterone-sulfate, dehydroepiandrosterone, and androstenedione levels were significantly decreased by 26%-40%. The suppressive effect of LH-RH agonist at 12 months was maintained. Adrenocorticotropic hormone levels showed an increasing trend at 6 months and a significant increase at 12 months. LH receptors were positively stained in the cortex cells of the reticular layer of the adrenal glands. The long-term LH-RH agonist treatment reduced adrenal-originated adrenal androgens. LH receptors in the adrenal cortex cells of the reticular layer might account for the underlying mechanism of reduced adrenal androgens.

  14. Ectoparasite-modulated deposition of maternal androgens in great tit eggs.

    Science.gov (United States)

    Tschirren, Barbara; Richner, Heinz; Schwabl, Hubert

    2004-07-07

    Maternal yolk androgens can promote growth and competitive abilities of nestling birds but are also suggested to increase susceptibility to parasites or suppress immune function. We tested the hypothesis that females exposed to ectoparasites during egg formation will adjust the content of androgens in the yolk. We predicted that when anticipating high levels of parasitism, females deposit (i) less androgens into all eggs of their clutch and (ii) smaller amounts of androgens in eggs late in the laying sequence to facilitate brood reduction. In a field experiment we exposed female great tits (Parus major) to hen fleas (Ceratophyllus gallinae), or kept them free of ectoparasites prior to egg laying. We collected the eggs and measured yolk concentrations of androstenedione (A4), testosterone (T) and 5alpha-dihydrotestosterone (DHT) by radioimmunoassay. Among clutches, eggs of ectoparasite-exposed females contained significantly less A4 and tended to contain less T, whereas DHT content was unaffected. Within clutches, content of A4 and T increased significantly with laying order whereas DHT content significantly decreased. These patterns were unaffected by ectoparasites. In summary, our results provide no evidence for hormone-based facilitation of brood reduction under ectoparasite exposure but support the hypothesis that females exposed to ectoparasites reduce levels of T and its precursor A4 in yolk and might thereby reduce the negative effects of parasites on offspring.

  15. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.

    Science.gov (United States)

    Fagman, Johan B; Wilhelmson, Anna S; Motta, Benedetta M; Pirazzi, Carlo; Alexanderson, Camilla; De Gendt, Karel; Verhoeven, Guido; Holmäng, Agneta; Anesten, Fredrik; Jansson, John-Olov; Levin, Malin; Borén, Jan; Ohlsson, Claes; Krettek, Alexandra; Romeo, Stefano; Tivesten, Åsa

    2015-04-01

    Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism. © FASEB.

  16. Functional and structural changes in internal pudendal arteries underlie erectile dysfunction induced by androgen deprivation

    Directory of Open Access Journals (Sweden)

    Rhéure Alves-Lopes

    2017-01-01

    Full Text Available Androgen deficiency is strongly associated with erectile dysfunction (ED. Inadequate penile arterial blood flow is one of the major causes of ED. The blood flow to the corpus cavernosum is mainly derived from the internal pudendal arteries (IPAs; however, no study has evaluated the effects of androgen deprivation on IPA′s function. We hypothesized that castration impairs IPAs reactivity and structure, contributing to ED. In our study, Wistar male rats, 8-week-old, were castrated and studied 30 days after orchiectomy. Functional and structural properties of rat IPAs were determined using wire and pressure myograph systems, respectively. Protein expression was determined by Western blot and immunohistochemistry. Plasma testosterone levels were determined using the IMMULITE 1000 Immunoassay System. Castrated rats exhibited impaired erectile function, represented by decreased intracavernosal pressure/mean arterial pressure ratio. IPAs from castrated rats exhibited decreased phenylephrine- and electrical field stimulation (EFS-induced contraction and decreased acetylcholine- and EFS-induced vasodilatation. IPAs from castrated rats exhibited decreased internal diameter, external diameter, thickness of the arterial wall, and cross-sectional area. Castration decreased nNOS and α-actin expression and increased collagen expression, p38 (Thr180/Tyr182 phosphorylation, as well as caspase 3 cleavage. In conclusion, androgen deficiency is associated with impairment of IPA reactivity and structure and increased apoptosis signaling markers. Our findings suggest that androgen deficiency-induced vascular dysfunction is an event involving hypotrophic vascular remodeling of IPAs.

  17. Androgen receptors and experimental bone loss - an in vivo and in vitro study.

    Science.gov (United States)

    Steffens, Joao Paulo; Coimbra, Leila Santana; Rossa, Carlos; Kantarci, Alpdogan; Van Dyke, Thomas E; Spolidorio, Luis Carlos

    2015-12-01

    Testosterone is a sex hormone that exhibits many functions beyond reproduction; one such function is the regulation of bone metabolism. The role played by androgen receptors during testosterone-mediated biological processes associated with bone metabolism is largely unknown. This study aims to use a periodontal disease model in vivo in order to assess the involvement of androgen receptors on microbial-induced inflammation and alveolar bone resorption in experimental bone loss. The impact of hormone deprivation was tested through both orchiectomy and chemical blockage of androgen receptor using flutamide (FLU). Additionally, the direct effect of exogenous testosterone, and the role of the androgen receptor, on osteoclastogenesis were investigated. Thirty male adult rats (n=10/group) were subjected to: 1-orchiectomy (OCX); 2-OCX sham surgery; or 3-OCX sham surgery plus FLU, four weeks before the induction of experimental bone loss. Ten OCX sham-operated rats were not subjected to experimental bone loss and served as healthy controls. The rats were euthanized two weeks later, so as to assess bone resorption and the production of inflammatory cytokines in the gingival tissue and serum. In order to study the in vitro impact of testosterone, osteoclasts were differentiated from RAW264.7 cells and testosterone was added at increasing concentrations. Both OCX and FLU increased bone resorption, but OCX alone was observed to increase osteoclast count. IL-1β production was increased only in the gingival tissue of OCX animals, whereas FLU-treated animals presented a decreased expression of IL-6. Testosterone reduced the osteoclast formation in a dose-dependent manner, and significantly impacted the production of TNF-α; FLU partially reversed these actions. When taken together, our results indicate that testosterone modulates experimental bone loss, and that this action is mediated, at least in part, via the androgen receptor. Copyright © 2015 Elsevier Inc. All rights

  18. A study of the prostate, androgens and sexual activity of male rats

    Directory of Open Access Journals (Sweden)

    Garcia Luis I

    2007-03-01

    Full Text Available Abstract Background The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. Methods The effect of four consecutive ejaculations was investigated by determining levels of (i testosterone in serum by solid phase RIA, (ii androgen receptors at the ventral prostate with Western Blots, and (iii androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. Results The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. Conclusion Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four

  19. A study of the prostate, androgens and sexual activity of male rats

    Science.gov (United States)

    Hernandez, Maria Elena; Soto-Cid, Abraham; Aranda-Abreu, Gonzalo E; Díaz, Rosaura; Rojas, Fausto; Garcia, Luis I; Toledo, Rebeca; Manzo, Jorge

    2007-01-01

    Background The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. Methods The effect of four consecutive ejaculations was investigated by determining levels of (i) testosterone in serum by solid phase RIA, (ii) androgen receptors at the ventral prostate with Western Blots, and (iii) androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. Results The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. Conclusion Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four ejaculations. All of these changes

  20. The Androgen Receptor Gene Mutations Database.

    Science.gov (United States)

    Gottlieb, B; Lehvaslaiho, H; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

    1998-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca).

  1. The Androgen Receptor Gene Mutations Database.

    Science.gov (United States)

    Gottlieb, B; Lehvaslaiho, H; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

    1998-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca). PMID:9399843

  2. Extremely rapid increase in fatty acid transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats.

    Science.gov (United States)

    Bonen, Arend; Jain, Swati S; Snook, Laelie A; Han, Xiao-Xia; Yoshida, Yuko; Buddo, Kathryn H; Lally, James S; Pask, Elizabeth D; Paglialunga, Sabina; Beaudoin, Marie-Soleil; Glatz, Jan F C; Luiken, Joost J F P; Harasim, Ewa; Wright, David C; Chabowski, Adrian; Holloway, Graham P

    2015-10-01

    The mechanisms for diet-induced intramyocellular lipid accumulation and its association with insulin resistance remain contentious. In a detailed time-course study in rats, we examined whether a high-fat diet increased intramyocellular lipid accumulation via alterations in fatty acid translocase (FAT/CD36)-mediated fatty acid transport, selected enzymes and/or fatty acid oxidation, and whether intramyocellular lipid accretion coincided with the onset of insulin resistance. We measured, daily (on days 1-7) and/or weekly (for 6 weeks), the diet-induced changes in circulating substrates, insulin, sarcolemmal substrate transporters and transport, selected enzymes, intramyocellular lipids, mitochondrial fatty acid oxidation and basal and insulin-stimulated sarcolemmal GLUT4 and glucose transport. We also examined whether upregulating fatty acid oxidation improved glucose transport in insulin-resistant muscles. Finally, in Cd36-knockout mice, we examined the role of FAT/CD36 in intramyocellular lipid accumulation, insulin sensitivity and diet-induced glucose intolerance. Within 2-3 days, diet-induced increases occurred in insulin, sarcolemmal FAT/CD36 (but not fatty acid binding protein [FABPpm] or fatty acid transporter [FATP]1 or 4), fatty acid transport and intramyocellular triacylglycerol, diacylglycerol and ceramide, independent of enzymatic changes or muscle fatty acid oxidation. Diet-induced increases in mitochondria and mitochondrial fatty acid oxidation and impairments in insulin-stimulated glucose transport and GLUT4 translocation occurred much later (≥21 days). FAT/CD36 ablation impaired insulin-stimulated fatty acid transport and lipid accumulation, improved insulin sensitivity and prevented diet-induced glucose intolerance. Increasing fatty acid oxidation in insulin-resistant muscles improved glucose transport. High-fat feeding rapidly increases intramyocellular lipids (in 2-3 days) via insulin-mediated upregulation of sarcolemmal FAT/CD36 and fatty acid

  3. Evaluation of capillary and myofiber density in the pectoralis major muscles of rapidly growing, high-yield broiler chickens during increased heat stress.

    Science.gov (United States)

    Joiner, K S; Hamlin, G A; Lien, A R J; Bilgili, S F

    2014-09-01

    Skeletal muscle development proceeds from early embryogenesis through marketing age in broiler chickens. While myofiber formation is essentially complete at hatching, myofiber hypertrophy can increase after hatch by assimilation of satellite cell nuclei into myofibers. As the diameter of the myofibers increases, capillary density peripheral to the myofiber is marginalized, limiting oxygen supply and subsequent diffusion into the myofiber, inducing microischemia. The superficial and deep pectoralis muscles constitute 25% of the total body weight in a market-age bird; thus compromise of those muscle groups can have profound economic impact on broiler production. We hypothesized that marginal capillary support relative to the hypertrophic myofibers increases the incidence of microischemia, especially in contemporary high-yield broilers under stressing conditions such as high environmental temperatures. We evaluated the following parameters in four different broiler strains at 39 and 53 days of age when reared under thermoneutral (20 to 25 C) versus hot (30 to 35 C) environmental conditions: capillary density, myofiber density and diameter, and degree of myodegeneration. Our data demonstrate that myofiber diameter significantly increased with age (P > or = 0.0001), while the absolute numbers of capillaries, blood vessels, and myofibers visible in five 400 x microscopic fields decreased (P > or = 0.0001). This is concomitant with marginalization of vascular support in rapidly growing myofibers. The myofiber diameter was significantly lower with hot environmental temperatures (P > or = 0.001); therefore, the absolute number of myofibers visible in five 400X microscopic fields was significantly higher. The incidence and subjective degree of myodegeneration characterized by loss of cross-striations, myocyte hyperrefractility, sarcoplasmic vacuolation, and nuclear pyknosis or loss also increased in hot conditions. Differences among strains were not observed.

  4. Osmotic Edema Rapidly Increases Neuronal Excitability Through Activation of NMDA Receptor-Dependent Slow Inward Currents in Juvenile and Adult Hippocampus

    Directory of Open Access Journals (Sweden)

    Kelli Lauderdale

    2015-09-01

    Full Text Available Cellular edema (cell swelling is a principal component of numerous brain disorders including ischemia, cortical spreading depression, hyponatremia, and epilepsy. Cellular edema increases seizure-like activity in vitro and in vivo, largely through nonsynaptic mechanisms attributable to reduction of the extracellular space. However, the types of excitability changes occurring in individual neurons during the acute phase of cell volume increase remain unclear. Using whole-cell patch clamp techniques, we report that one of the first effects of osmotic edema on excitability of CA1 pyramidal cells is the generation of slow inward currents (SICs, which initiate after approximately 1 min. Frequency of SICs increased as osmolarity decreased in a dose-dependent manner. Imaging of real-time volume changes in astrocytes revealed that neuronal SICs occurred while astrocytes were still in the process of swelling. SICs evoked by cell swelling were mainly nonsynaptic in origin and NMDA receptor-dependent. To better understand the relationship between SICs and changes in neuronal excitability, recordings were performed in increasingly physiological conditions. In the absence of any added pharmacological reagents or imposed voltage clamp, osmotic edema induced excitatory postsynaptic potentials and burst firing over the same timecourse as SICs. Like SICs, action potentials were blocked by NMDAR antagonists. Effects were more pronounced in adult (8–20 weeks old compared with juvenile (P15–P21 mice. Together, our results indicate that cell swelling triggered by reduced osmolarity rapidly increases neuronal excitability through activation of NMDA receptors. Our findings have important implications for understanding nonsynaptic mechanisms of epilepsy in relation to cell swelling and reduction of the extracellular space.

  5. Androgen deprivation therapy-associated vasomotor symptoms

    OpenAIRE

    Jones, Jason M; Kohli, Manish; Loprinzi, Charles L

    2012-01-01

    Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer. While efficacious, ADT is associated with multiple side effects, including decreased libido, erectile dysfunction, diabetes, loss of muscle tone and altered body composition, osteoporosis, lipid changes, memory loss, gynecomastia and hot flashes. The breadth of literature for the treatment of hot flashes is much smaller in men than that in women. While hor...

  6. ANABOLIC ANDROGENIC STEROIDS AND ADVERSE EVENTS OF THEIR APPLICATION

    OpenAIRE

    Nina Đukanović; Vesko Drašković; Svetlana Višnjić; Zoran Mašić

    2011-01-01

    Anabolic androgenic steroids are synthetic compounds originating from testosterone. Their main effects are the control of development and expression of male secondary sexual characteristics, which are known as androgenic effects, and encourage muscle growth or anabolic effects. Anabolic androgenic steroids are most commonly used illegal substances. Besides these physiological effects, which are achieved using therapeutic doses of these preparations, higher doses than recommended, especially o...

  7. Structure and function of the androgen receptor.

    Science.gov (United States)

    Brinkmann, A O; Klaasen, P; Kuiper, G G; van der Korput, J A; Bolt, J; de Boer, W; Smit, A; Faber, P W; van Rooij, H C; Geurts van Kessel, A

    1989-01-01

    The androgen receptor in several species (human, rat, calf) is a monomeric protein with a molecular mass of 100-110 kDa. The steroid binding domain is confined to a region of 30 kDa, while the DNA-binding domain has the size of approx. 10 kDa. A 40 kDa fragment containing both the DNA and steroid binding domain displayed a higher DNA binding activity than did the intact 100 kDa molecule. cDNA encoding the major part of the human androgen receptor was isolated. The cDNA contains an open reading frame of 2,277 bp but still lacks part of the 5'-coding sequence. Homology with the progesterone and glucocorticoid receptor was about 80% in the DNA binding domain and 50% in the steroid binding domain. The present data provide evidence that the androgen receptor belongs to the superfamily of ligand responsive transcriptional regulators and consists of three distinct domains each with a specialized function.

  8. Selective androgen receptor modulator RAD140 is neuroprotective in cultured neurons and kainate-lesioned male rats.

    Science.gov (United States)

    Jayaraman, Anusha; Christensen, Amy; Moser, V Alexandra; Vest, Rebekah S; Miller, Chris P; Hattersley, Gary; Pike, Christian J

    2014-04-01

    The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.

  9. Improved real-life adherence of 6-monthly denosumab injections due to positive feedback based on rapid 6-month BMD increase and good safety profile.

    Science.gov (United States)

    Ringe, J D; Farahmand, P

    2014-05-01

    Almost 50 % of osteoporosis (OP) patients discontinue bisphosphonate (BP) therapy within 1-2 years after the start of their treatment. Denosumab's longer dosing interval with its administration every 6 months (Q6M) as a subcutaneous (sc) injection might result in a better real-life treatment adherence and persistence than weekly or monthly oral BP treatment regimen. The objectives of this open, investigator-initiated, prospective, observational, single-center study were to evaluate adherence with denosumab 60 mg sc every 6 months (Q6M) (Prolia(®)) injections in osteoporotic patients in a routine clinical care setting and to describe whether positive feedback to OP patients based on measured bone mineral density (BMD) increases and good safety profile have an impact on patients' real-life adherence. Results indicate that the rarity of adverse events and reduced dosage frequency together with the consistency of rapid and highly significant increases in BMD already after 6 months of denosumab therapy used as a positive reinforcement during doctor-patient interactions had a significant, positive impact on osteoporotic patient's adherence to continue with the 6-monthly sc denosumab injections.

  10. Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

    Science.gov (United States)

    Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

    2016-01-01

    Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

  11. Androgen and PARP-1 regulation of TRPM2 channels after ischemic injury.

    Science.gov (United States)

    Shimizu, Takeru; Macey, Tara A; Quillinan, Nidia; Klawitter, Jelena; Perraud, Anne-Laure L; Traystman, Richard J; Herson, Paco S

    2013-10-01

    The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.

  12. Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2

    Directory of Open Access Journals (Sweden)

    Zuzana Pernicová

    2011-06-01

    Full Text Available Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT, a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.

  13. Insulin resistance in patients with advanced prostate cancer undergoing intermittent or continuous androgen blockade.

    Science.gov (United States)

    Chen, Wei; Yu, Zhi-Xian; Xie, Hui; Deng, Zhe-Xian; Zhang, Fang-Yi; Chen, Sheng-Ye; Weng, Zhi-Liang

    2009-02-01

    Androgen blockade is the principle strategy in the treatment of advanced prostate cancer. Impaired glucose tolerance often occurs in those patients after androgen blockade. This study was to investigate the correlation of insulin resistance to intermittent androgen blockade (IAB) or continuous androgen blockade, which is also named surgical castration, in patients with advanced prostate cancer. A total of 139 patients with advanced prostate cancer were classified into four groups according to the body mass index (BMI) and the treatment method. Group A consisted of 30 patients receiving surgical castration with BMI >or= 24 kg/m(2), group B consisted of 32 patients treated with IAB with BMI >or= kg/m(2), group C consisted of 37 patients undergoing surgical castration with BMI Fasting plasma glucose (FPG) and fasting serum level of insulin (FINS) were assessed before treatment, six months and 12 months after treatment, respectively. Insulin resistance index (IRI) was also calculated. Six months after treatment, FINS and IRI were all increased in the four groups compared with those before treatment; FINS and IRI were significantly higher in groups B and D than in A and C (FINS: t(A:B)=7.7516, p intermittent period of the IAB method, FINS returned to the pretreatment level in group D (q=2.5255, p > 0.05), and dramatically decreased in group B compared to the value six months after treatment (q = 9.0942, p cancer. Insulin resistance gradually disappears during the intermittent period of IAB.

  14. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    Directory of Open Access Journals (Sweden)

    Abeer M Mahmoud

    Full Text Available Blocking the androgen receptor (AR activity is the main goal of therapies for advanced prostate cancer (PCa. However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  15. Longitudinal Magnetic Resonance Imaging-Based Assessment of Vascular Changes and Radiation Response in Androgen-Sensitive Prostate Carcinoma Xenografts under Androgen-Exposed and Androgen-Deprived Conditions

    Directory of Open Access Journals (Sweden)

    Kathrine Røe

    2010-10-01

    Full Text Available Prostate cancer (PCa patients receive androgen-deprivation therapy (ADT to reduce tumor burden. However, complete eradication of PCa is unusual, and recurrent disease is evident within approximately 2 years in high-risk patients. Clinical evidence suggests that combining ADT with radiotherapy improves local control and disease-free survival in these patients compared with radiotherapy alone. We investigated whether vascularization of androgen-sensitive PCa xenografts changed after ADT and whether such therapy affected radiation response. CWR22 xenografts received combinations of ADT by castration (CWR22-cas and 15 Gy of single-dose irradiation. At a shortest tumor diameter of 8 mm, vascularization was visualized by dynamic contrast-enhanced magnetic resonance imaging before radiation and 1 and 9 days after radiation. Voxel-wise quantitative modeling of contrast enhancement curves extracted the hemodynamic parameter Ktrans, reflecting a combination of permeability, density, and blood flow. Tumor volumes and prostate-specific antigen (PSA were monitored during the experiment. The results showed that Ktrans of CWR22-cas tumors 36±4 days after ADT was 47.1% higher than Ktrans of CWR22 tumors (P = .01. CWR22-cas tumors showed no significant changes in Ktrans after radiation, whereas Ktrans of CWR22 tumors at day 1 decreased compared with pretreatment values (P = .04 before a continuous increase from day 1 to day 9 followed (P = .01. Total PSA in blood correlated positively to tumor volume (r = 0.59, P < .01. In conclusion, androgen-exposed xenografts demonstrated radiation-induced reductions in vascularization and tumor volumes, whereas androgen-deprived xenografts showed increased vascularization and growth inhibition, but no significant additive effect of radiation.

  16. Selection shaped the evolution of mouse androgen-binding protein (ABP) function and promoted the duplication of Abp genes.

    Science.gov (United States)

    Karn, Robert C; Laukaitis, Christina M

    2014-08-01

    In the present article, we summarize two aspects of our work on mouse ABP (androgen-binding protein): (i) the sexual selection function producing incipient reinforcement on the European house mouse hybrid zone, and (ii) the mechanism behind the dramatic expansion of the Abp gene region in the mouse genome. Selection unifies these two components, although the ways in which selection has acted differ. At the functional level, strong positive selection has acted on key sites on the surface of one face of the ABP dimer, possibly to influence binding to a receptor. A different kind of selection has apparently driven the recent and rapid expansion of the gene region, probably by increasing the amount of Abp transcript, in one or both of two ways. We have shown previously that groups of Abp genes behave as LCRs (low-copy repeats), duplicating as relatively large blocks of genes by NAHR (non-allelic homologous recombination). The second type of selection involves the close link between the accumulation of L1 elements and the expansion of the Abp gene family by NAHR. It is probably predicated on an initial selection for increased transcription of existing Abp genes and/or an increase in Abp gene number providing more transcriptional sites. Either or both could increase initial transcript production, a quantitative change similar to increasing the volume of a radio transmission. In closing, we also provide a note on Abp gene nomenclature.

  17. Targeting androgen receptor/Src complex impairs the aggressive phenotype of human fibrosarcoma cells.

    Science.gov (United States)

    Castoria, Gabriella; Giovannelli, Pia; Di Donato, Marzia; Hayashi, Ryo; Arra, Claudio; Appella, Ettore; Auricchio, Ferdinando; Migliaccio, Antimo

    2013-01-01

    Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the conservation of this process across divergent cancer

  18. Eating ‘Junk-Food' Produces Rapid and Long-Lasting Increases in NAc CP-AMPA Receptors: Implications for Enhanced Cue-Induced Motivation and Food Addiction

    Science.gov (United States)

    Oginsky, Max F; Goforth, Paulette B; Nobile, Cameron W; Lopez-Santiago, Luis F; Ferrario, Carrie R

    2016-01-01

    Urges to eat are influenced by stimuli in the environment that are associated with food (food cues). Obese people are more sensitive to food cues, reporting stronger craving and consuming larger portions after food cue exposure. The nucleus accumbens (NAc) mediates cue-triggered motivational responses, and activations in the NAc triggered by food cues are stronger in people who are susceptible to obesity. This has led to the idea that alterations in NAc function similar to those underlying drug addiction may contribute to obesity, particularly in obesity-susceptible individuals. Motivational responses are mediated in part by NAc AMPA receptor (AMPAR) transmission, and recent work shows that cue-triggered motivation is enhanced in obesity-susceptible rats after ‘junk-food' diet consumption. Therefore, here we determined whether NAc AMPAR expression and function is increased by ‘junk-food' diet consumption in obesity-susceptible vs -resistant populations using both outbred and selectively bred models of susceptibility. In addition, cocaine-induced locomotor activity was used as a general ‘read out' of mesolimbic function after ‘junk-food' consumption. We found a sensitized locomotor response to cocaine in rats that gained weight on a ‘junk-food' diet, consistent with greater responsivity of mesolimbic circuits in obesity-susceptible groups. In addition, eating ‘junk-food' increased NAc calcium-permeable-AMPAR (CP-AMPAR) function only in obesity-susceptible rats. This increase occurred rapidly, persisted for weeks after ‘junk-food' consumption ceased, and preceded the development of obesity. These data are considered in light of enhanced cue-triggered motivation and striatal function in obesity-susceptible rats and the role of NAc CP-AMPARs in enhanced motivation and addiction. PMID:27383008

  19. Eating 'Junk-Food' Produces Rapid and Long-Lasting Increases in NAc CP-AMPA Receptors: Implications for Enhanced Cue-Induced Motivation and Food Addiction.

    Science.gov (United States)

    Oginsky, Max F; Goforth, Paulette B; Nobile, Cameron W; Lopez-Santiago, Luis F; Ferrario, Carrie R

    2016-12-01

    Urges to eat are influenced by stimuli in the environment that are associated with food (food cues). Obese people are more sensitive to food cues, reporting stronger craving and consuming larger portions after food cue exposure. The nucleus accumbens (NAc) mediates cue-triggered motivational responses, and activations in the NAc triggered by food cues are stronger in people who are susceptible to obesity. This has led to the idea that alterations in NAc function similar to those underlying drug addiction may contribute to obesity, particularly in obesity-susceptible individuals. Motivational responses are mediated in part by NAc AMPA receptor (AMPAR) transmission, and recent work shows that cue-triggered motivation is enhanced in obesity-susceptible rats after 'junk-food' diet consumption. Therefore, here we determined whether NAc AMPAR expression and function is increased by 'junk-food' diet consumption in obesity-susceptible vs -resistant populations using both outbred and selectively bred models of susceptibility. In addition, cocaine-induced locomotor activity was used as a general 'read out' of mesolimbic function after 'junk-food' consumption. We found a sensitized locomotor response to cocaine in rats that gained weight on a 'junk-food' diet, consistent with greater responsivity of mesolimbic circuits in obesity-susceptible groups. In addition, eating 'junk-food' increased NAc calcium-permeable-AMPAR (CP-AMPAR) function only in obesity-susceptible rats. This increase occurred rapidly, persisted for weeks after 'junk-food' consumption ceased, and preceded the development of obesity. These data are considered in light of enhanced cue-triggered motivation and striatal function in obesity-susceptible rats and the role of NAc CP-AMPARs in enhanced motivation and addiction.

  20. Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP-Glucuronosyltransferases 2B15 and 2B17.

    Science.gov (United States)

    Hu, Dong G; Selth, Luke A; Tarulli, Gerard A; Meech, Robyn; Wijayakumara, Dhilushi; Chanawong, Apichaya; Russell, Roslin; Caldas, Carlos; Robinson, Jessica L L; Carroll, Jason S; Tilley, Wayne D; Mackenzie, Peter I; Hickey, Theresa E

    2016-10-01

    Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3' to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα(+) tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα(+) breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881-93. ©2016 AACR. ©2016 American Association for Cancer Research.

  1. Dynamic Nucleosome-Depleted Regions at Androgen Receptor Enhancers in the Absence of Ligand in Prostate Cancer Cells ▿

    Science.gov (United States)

    Andreu-Vieyra, Claudia; Lai, John; Berman, Benjamin P.; Frenkel, Baruch; Jia, Li; Jones, Peter A.; Coetzee, Gerhard A.

    2011-01-01

    Nucleosome positioning at transcription start sites is known to regulate gene expression by altering DNA accessibility to transcription factors; however, its role at enhancers is poorly understood. We investigated nucleosome positioning at the androgen receptor (AR) enhancers of TMPRSS2, KLK2, and KLK3/PSA in prostate cancer cells. Surprisingly, a population of enhancer modules in androgen-deprived cultures showed nucleosome-depleted regions (NDRs) in all three loci. Under androgen-deprived conditions, NDRs at the TMPRSS2 enhancer were maintained by the pioneer AR transcriptional collaborator GATA-2. Androgen treatment resulted in AR occupancy, an increased number of enhancer modules with NDRs without changes in footprint width, increased levels of histone H3 acetylation (AcH3), and dimethylation (H3K4me2) at nucleosomes flanking the NDRs. Our data suggest that, in the absence of ligand, AR enhancers exist in an equilibrium in which a percentage of modules are occupied by nucleosomes while others display NDRs. We propose that androgen treatment leads to the disruption of the equilibrium toward a nucleosome-depleted state, rather than to enhancer de novo “remodeling.” This allows the recruitment of histone modifiers, chromatin remodelers, and ultimately gene activation. The “receptive” state described here could help explain AR signaling activation under very low ligand concentrations. PMID:21969603

  2. Differential Effects of Leptin on the Invasive Potential of Androgen-Dependent and -Independent Prostate Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Dayanand D. Deo

    2008-01-01

    Full Text Available Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP cells as well as androgen-insensitive (PC-3 and DU-145 cells. At a concentration of 200_nm, LNCaP cells showed a significant increase (20% above control; P<.0001 in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P<.01 to P<.0001 dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity.

  3. Essential roles of GABA transporter-1 in controlling rapid eye movement sleep and in increased slow wave activity after sleep deprivation.

    Directory of Open Access Journals (Sweden)

    Xin-Hong Xu

    Full Text Available GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1 constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep-wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep.

  4. Photoperiod modulation of aggressive behavior is independent of androgens in a tropical cichlid fish.

    Science.gov (United States)

    Gonçalves-de-Freitas, Eliane; Carvalho, Thaís Billalba; Oliveira, Rui F

    2014-10-01

    Photoperiod is a major environmental cue that signals breeding conditions in animals living in temperate climates. Therefore, the activity of the reproductive (i.e. hypothalamic-pituitary-gonadal, HPG) axis and of the expression of reproductive behaviors, including territoriality, is responsive to changes in day length. However, at low latitudes the seasonal variation in day length decreases dramatically and photoperiod becomes less reliable as a breeding entraining cue in tropical species. In spite of this, some tropical mammals and birds have been found to still respond to small amplitude changes in photoperiod (e.g. 17min). Here we tested the effect of 2 photoperiod regimes, referred to as long-day (LD: 16L:08D) and short-day (SD: 08L:16D), on the activity of the HPG axis, on aggressive behavior and in the androgen response to social challenges in males of the tropical cichlid fish Tilapia rendalli. For each treatment, fish were transferred from a pre-treatment photoperiod of 12L:12D to their treatment photoperiod (either LD or SD) in which they were kept for 20days on stock tanks. Afterwards, males were isolated for 4days in glass aquaria in order to establish territories and initial androgen levels (testosterone, T; 11-ketotestosterone, KT) were assessed. On the 4th day, territorial intrusions were promoted such that 1/3 of the isolated males acted as residents and another 1/3 as intruders. Territorial intrusions lasted for 1h to test the effects of a social challenge under different photoperiod regimes. Photoperiod treatment (either SD or LD) failed to induce significant changes in the HPG activity, as measured by androgen levels and gonadosomatic index. However, SD increased the intensity of aggressive behaviors and shortened the time to settle a dominance hierarchy in an androgen-independent manner. The androgen responsiveness to the simulated territorial intrusion was only present in KT but not for T. The percent change in KT levels in response to the

  5. Androgen deprivation therapy as backbone therapy in the management of prostate cancer

    Directory of Open Access Journals (Sweden)

    Merseburger AS

    2016-11-01

    Full Text Available Axel S Merseburger,1 Antonio Alcaraz,2 Christoph A von Klot3 1Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Germany; 2Department of Urology, Hospital Clínic, Barcelona, Spain; 3Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany Abstract: Androgen deprivation therapy (ADT is well established as a backbone therapy for metastatic prostate cancer (mPCa, and both European and American guidelines emphasize the importance of maintaining ADT after progression to metastatic castration-resistant prostate cancer (CRPC. However, the use of ADT varies widely in clinical practice despite these recommendations. Both research and development of increasingly precise assay technologies have improved our understanding of androgen production and signaling, and the recent data have suggested that a new serum testosterone cutoff value of <0.7 nmol/L should be employed. Most clinical trials to date have used the historical 1.7 nmol/L cutoff, but the <0.7 nmol/L cutoff has been associated with improved patient outcomes. Combining agents with different mechanisms of action to achieve intense androgen blockade may improve survival both before and after progression to CRPC. Data suggest that this intensive approach to androgen deprivation could delay the transition to CPRC and hence improve survival dramatically. Various combinations of backbone ADT with chemotherapy or radiotherapy are under investigation. Administration of ADT is established in patients with intermediate or high-risk localized prostate cancer (PCa receiving radiotherapy with curative intent. This article reviews the current and potential role of ADT as backbone therapy in both hormone-sensitive PCa and CRPC with a focus on mPCa. Keywords: prostate cancer, androgen deprivation therapy, ADT, chemotherapy, radiotherapy, treatment guidelines

  6. Localization and androgen regulation of metastasis-associated protein 1 in mouse epididymis.

    Directory of Open Access Journals (Sweden)

    Li Ma

    Full Text Available BACKGROUND: Metastasis-associated protein 1 (MTA1, the founding member of the MTA family of genes, can modulate transcription by influencing the status of chromatin remodeling. Despite its strong correlation with the metastatic potential of cancer cells, MTA1 can also regulate crucial cellular pathways by modifying the acetylation status. We have previously reported the presence of MTA1/MTA1 in human and mouse testes, providing the evidence for its involvement in the regulation of testicular function during murine spermatogenesis. The objective of present study was to further assess the localization of MTA1 in mouse epididymis on both transcriptional and translational level, and then to explore whether MTA1 expression is regulated by androgens and postnatal epididymal development. METHODOLOGY/PRINCIPAL FINDINGS: Mice were deprived of circulating androgen by bilaterally castration and were then supplemented with exogenous testosterone propionate for one week. MTA1 was immunolocalized in the epithelium of the entire epididymis with the maximal expression in the nuclei of principal cells and of clear cells in proximal region. Its expression decreased gradually after castration, whereas testosterone treatment could restore the expression, indicating that the expression of this gene is dependent on androgen. During postnatal development, the protein expression in the epididymis began to appear from day 7 to day 14, increased dramatically from postnatal day 28, and peaked at adulthood onwards, coinciding with both the well differentiated status of epididymis and the mature levels of circulating androgens. This region- and cell-specific pattern was also conservative in normal human epididymis. CONCLUSIONS: Our data suggest that the expression of MTA1 protein could be regulated by androgen pathway and its expression level is closely associated with the postnatal development of the epididymis, giving rise to the possibility that this gene plays a

  7. Androgenic potential of human fetal adrenals at the end of the first trimester

    Directory of Open Access Journals (Sweden)

    I Savchuk

    2017-07-01

    Full Text Available The onset of steroidogenesis in human fetal adrenal glands (HFA during the first trimester is poorly investigated. An unresolved question is the capacity of the HFA to produce potent androgen DHT via conventional and/or the backdoor pathway(s at the end of first trimester, when androgen-responsive organs are developed. Our aim was to explore steroidogenesis and the expression of steroidogenic enzymes and transcription factors in HFA at gestational weeks (GW 9–12 with focus on their androgenic potential. Steroids in the HFA were analyzed by gas chromatography/mass spectrometry. The expression of steroidogenic enzymes and transcription factors in the HFA at GW9–12 was investigated by qPCR, automated Western blotting and immunohistochemistry. We demonstrated that during GW9–12 HFA produced steroids of the Δ5, Δ4 and the backdoor pathways of the biosynthesis of DHT, though the latter was limited to production of 17α-OH-dihydroprogesterone, androsterone and androstanedione without further conversion to DHT. The only androgens identified in the HFA were testosterone and androsterone, a precursor in the biosynthesis of DHT. We also observed higher levels of CYP17A1 but low expression of 3βHSD2 at GW11–12 in the HFA. Elevated levels of CYP17A1 were associated with an increased expression of SF-1 and GATA-6. Altogether, our data demonstrate that of those steroids analyzed, the only potent androgen directly produced by the HFA at GW9–12 was testosterone. The onset of steroidogenesis in the HFA is a complex process that is regulated by the coordinated action of related transcription factors.

  8. Effect of small molecules modulating androgen receptor (SARMs in human prostate cancer models.

    Directory of Open Access Journals (Sweden)

    Anna Tesei

    Full Text Available The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S-11 and (R-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC. In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R-9 and (S-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R-bicalutamide, also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R-9 was higher than that of (S-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S-11 and (R-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R-9 did not reveal the presence of adverse events. Furthermore, (R-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R-9 and (S-11, making them a potentially attractive option for the treatment of CRPC.

  9. A Competitive Inhibitor That Reduces Recruitment of Androgen Receptor to Androgen-responsive Genes*

    Science.gov (United States)

    Cherian, Milu T.; Wilson, Elizabeth M.; Shapiro, David J.

    2012-01-01

    The androgen receptor (AR) has a critical role in the growth and progression of androgen-dependent and castration-resistant prostate cancers. To identify novel inhibitors of AR transactivation that block growth of prostate cancer cells, a luciferase-based high-throughput screen of ∼160,000 small molecules was performed in cells stably expressing AR and a prostate-specific antigen (PSA)-luciferase reporter. CPIC (1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile) was identified as a small molecule that blocks AR transactivation to a greater extent than other steroid receptors. CPIC inhibited AR-mediated proliferation of androgen-sensitive prostate cancer cell lines, with minimal toxicity in AR-negative cell lines. CPIC treatment also reduced the anchorage-independent growth of LAPC-4 prostate cancer cells. CPIC functioned as a pure antagonist by inhibiting the expression of AR-regulated genes in LAPC-4 cells that express wild-type AR and exhibited weak agonist activity in LNCaP cells that express the mutant AR-T877A. CPIC treatment did not reduce AR levels or alter its nuclear localization. We used chromatin immunoprecipitation to identify the site of action of CPIC. CPIC inhibited recruitment of androgen-bound AR to the PSA promoter and enhancer sites to a greater extent than bicalutamide. CPIC is a new therapeutic inhibitor that targets AR-mediated gene activation with potential to arrest the growth of prostate cancer. PMID:22589544

  10. Androgen Receptor in Laryngeal Carcinoma: Could There Be an Androgen-Refractory Tumor?

    Science.gov (United States)

    Goulioumis, Anastasios K.; Varakis, John; Goumas, Panos; Papadaki, Helen

    2011-01-01

    Androgen receptors (ARs) which are implicated in the pathogenesis of several malignancies can also be a possible downstream effector in laryngeal cancer. In the present study, 97 invasive squamous laryngeal carcinomas were studied by immunohistochemistry for protein expression of AR. Androgen receptors were expressed in 52.6% of tumor specimens, suggesting their implication in the pathogenesis of this tumor. Our study's aim was to investigate the hypothetical scenario of an androgen refractory laryngeal carcinoma where androgen receptors can be activated by nodal molecules in the course of an Epithelial-to-mesenchymal transition (EMT) phenomenon. In line with this we correlated AR expression with the expression of ILK, p-Akt, E-cadherin, β-catenin in our sample as well as with tumor grade and TNM stage. A reverse correlation between nuclear AR and cytoplasmic ILK expression was evidenced, indicating an interaction of those molecules in laryngeal carcinoma. Finally in our material, in those carcinomas that were expressing ARs, stronger nuclear expression of the receptor was characterized by poorer cell differentiation and correlated with the acquisition of EMT features like E-cadherin loss and β-catenin translocation raising a question whether activated ARs can drive an EMT procedure. PMID:22191056

  11. ORIGINAL ARTICLE A Study of the androgen receptor gene ...

    African Journals Online (AJOL)

    salah

    The aim of the work is to study the genotype of the androgen receptor gene. (StuI polymorphism) and its relationship to AGA in a case control study and to determine the level of androgen receptor expression (AR) in the balding scalp relative to the non-balding scalp area. Subjects and Methods: This study was conducted on ...

  12. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2006-01-01

    Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

  13. Three novel and two known androgen receptor gene mutations ...

    Indian Academy of Sciences (India)

    male breast cancer (Wooster et al. 1992) and prostate cancer. (Tilley et al. 1996). The two most important androgens are testosterone and. 5α-dihydrotestosterone, whose actions are mediated by func- tional androgen receptor, which upon receipt of signal acti- vate transcription of specific genes in target tissues (Melo et al.

  14. ENVIRONMENTAL ANDROGENS AND ANTIANDROGENS: AN EXPANDING CHEMICAL UNIVERSE

    Science.gov (United States)

    Within the last ten years, awareness has grown about environmental chemicals that display antiandrogenic or androgenic activity. While studies in the early 1990s focused on pesticides that acted as androgen receptor (AR) antagonists, it soon became evident that this was not the ...

  15. ASSESSMENT OF IN VITRO ANDROGENIC ACTIVITY IN KRAFT MILL EFFLUENT

    Science.gov (United States)

    Detection of In Vitro Androgenic Activity in Feedlot Effluent. Lambright, CS 1 , Guillette, LJ, Jr.2, Gray, LE, Jr.1 , 1USEPA, NHEERL, RTP, NC, 2 University of Florida, Dept. of Zoology, Gainesville FLRecent studies have shown the presence of androgenic activity in water...

  16. Lxrα regulates the androgen response in prostate epithelium.

    Science.gov (United States)

    Viennois, Emilie; Esposito, Teresa; Dufour, Julie; Pommier, Aurélien; Fabre, Stephane; Kemeny, Jean-Louis; Guy, Laurent; Morel, Laurent; Lobaccaro, Jean-Marc; Baron, Silvère

    2012-07-01

    Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

  17. ANABOLIC-ANDROGENIC STEROID DEPENDENCE? INSIGHTS FROM ANIMALS AND HUMANS

    Science.gov (United States)

    Wood, Ruth I.

    2008-01-01

    Anabolic-androgenic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, with negative health consequences. As a result, in 1991 testosterone and related AAS were declared controlled substances. However, the relative abuse and dependence liability of AAS have not been fully characterized. In humans, it is difficult to separate the direct psychoactive effects of AAS from reinforcement due to their systemic anabolic effects. However, using conditioned place preference and self-administration, studies in animals have demonstrated that AAS are reinforcing in a context where athletic performance is irrelevant. Furthermore, AAS share brain sites of action and neurotransmitter systems in common with other drugs of abuse. In particular, recent evidence links AAS with opioids. In humans, AAS abuse is associated with prescription opioid use. In animals, AAS overdose produces symptoms resembling opioid overdose, and AAS modify the activity of the endogenous opioid system. PMID:18275992

  18. [Metabolic syndrome and insulin resistance in patients with prostate cancer treated with androgen deprivation hormone].

    Science.gov (United States)

    Terrier, J-E; Mottet, N

    2013-02-01

    Androgen suppression in prostate cancer is responsible for many side effects. Many studies, mostly retrospective, have found an association between androgen deprivation and increased cardiovascular morbidity. If the cardiovascular impact was chosen, an etiological explanation would be the occurrence of metabolic disorders, particularly insulin resistance. The objective of our work was to conduct a review of the literature assessing the impact of androgen deprivation on the onset of insulin resistance, the metabolic syndrome and changes in key markers of insulin resistance. A systematic review of literature from the Pubmed database search was performed using the following keywords: androgen deprivation therapy, metabolic syndrome, insulin resistance, hyperglycemia, cardiovascular diseases, cardiovascular risk, abdominal obesity. Twelve studies were included, bringing into focus a 55% prevalence of metabolic syndrome in patients treated for more than 12 months, an increase in fat mass and decreased lean body mass, an increase in abdominal subcutaneous fat and in visceral adiposity. The insulin was increased in four studies (25 to 60% three months dice). The increased insulin resistance was assessed by the Homeostasis Model Assessment (HOMA) was postponed three times (12% in two prospective cohort studies of type). The increase in triglycerides (20 to 40% at 12 months) and total cholesterol (7 to 11%) was observed in five studies, and increased LDL cholesterol and HDL in three studies (9 to 22%). All studies of this analysis appeared to converge towards the development of insulin resistance and metabolic disorders, however, no prospective cohort study of good methodological quality were identified. It would be necessary to conduct a prospective multicenter study in order to have a causal quality. Copyright © 2012. Published by Elsevier Masson SAS.

  19. Metabolic Syndrome, Androgens, and Hypertension

    OpenAIRE

    Moulana, Mohadetheh; Lima, Roberta; Reckelhoff, Jane F.

    2011-01-01

    Obesity is one of the constellation of factors that make up the definition of the metabolic syndrome. Metabolic syndrome is also associated with insulin resistance, dyslipidemia, hypertriglyceridemia, and type 2 diabetes mellitus. The presence of obesity and metabolic syndrome in men and women is also associated with increased risk of cardiovascular disease and hypertension. In men, obesity and metabolic syndrome are associated with reductions in testosterone levels. In women, obesity and met...

  20. Proteomic interrogation of androgen action in prostate cancer cells reveals roles of aminoacyl tRNA synthetases.

    Directory of Open Access Journals (Sweden)

    Adaikkalam Vellaichamy

    2009-09-01

    Full Text Available Prostate cancer remains the most common malignancy among men in United States, and there is no remedy currently available for the advanced stage hormone-refractory cancer. This is partly due to the incomplete understanding of androgen-regulated proteins and their encoded functions. Whole-cell proteomes of androgen-starved and androgen-treated LNCaP cells were analyzed by semi-quantitative MudPIT ESI- ion trap MS/MS and quantitative iTRAQ MALDI- TOF MS/MS platforms, with identification of more than 1300 high-confidence proteins. An enrichment-based pathway mapping of the androgen-regulated proteomic data sets revealed a significant dysregulation of aminoacyl tRNA synthetases, indicating an increase in protein biosynthesis- a hallmark during prostate cancer progression. This observation is supported by immunoblot and transcript data from LNCaP cells, and prostate cancer tissue. Thus, data derived from multiple proteomics platforms and transcript data coupled with informatics analysis provides a deeper insight into the functional consequences of androgen action in prostate cancer.

  1. CBCT of skeletal changes following rapid maxillary expansion to increase arch-length with a development-dependent bonded or banded appliance.

    Science.gov (United States)

    Kanomi, Ryuzo; Deguchi, Toru; Kakuno, Eriko; Takano-Yamamoto, Teruko; Roberts, W Eugene

    2013-09-01

    To assess the three-dimensional (3D) skeletal response to a standardized 5 mm of rapid maxillary expansion (RME) in growing children (6-15 years) with maxillary width deficiency and crowding. A bonded appliance was used prior to the eruption of the maxillary first premolars (Mx4s), and a banded appliance was used thereafter. A consecutive sample of 89 patients (29 boys and 60 girls) from a large pediatric dentistry and orthodontics practice was divided into four groups: 1) 6-8 years old (n = 26), 2) 9-11 years old with unerupted Mx4s (n = 21), 3) 9-11 years with erupted Mx4s (n = 23), and 4) 12-15 years (n = 19). For all patients, the 3D evaluation of dental and skeletal effects was performed with cone-beam computed tomography (CBCT). For both appliances in all patients, CBCT confirmed a triangular pattern of expansion in both the frontal and sagittal planes. Overall, both appliances produced significant maxillary expansion (>80% of the 5-mm activation), but older children showed a progressively more dental (less skeletal) response. Comparison of the two types of expanders in the crossover sample, children aged 9-11 years, showed that the bonded RME produced the most efficient skeletal expansion in the preadolescent sample. Increased maxillary width at the level of the zygomaticomaxillary suture was the best indicator for development of maxillary arch circumference. Development-dependent appliances (bonded RPE before Mx4s erupt, and a banded device thereafter) provided optimal RME treatment for all children from age 6-15 years.

  2. Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity.

    Directory of Open Access Journals (Sweden)

    Andrei V Derbenev

    Full Text Available Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV. Whole-cell patch-clamp recordings revealed that DEX (1-10 µM rapidly (i.e. within three minutes increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 µM, and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane-impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP βS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5'-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other 'endovanilloid', suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids.

  3. Computer-assisted glucose regulation during rapid step-wise increases of parenteral nutrition in critically ill patients: a proof of concept study.

    Science.gov (United States)

    Hoekstra, Miriam; Schoorl, Michiel A; van der Horst, Iwan C C; Vogelzang, Mathijs; Wietasch, J K Götz; Zijlstra, Felix; Nijsten, Maarten W N

    2010-01-01

    Early delivery of calories is important in critically ill patients, and the administration of parenteral nutrition (PN) is sometimes required to achieve this goal. However, PN can induce acute hyperglycemia, which is associated with adverse outcome. We hypothesized that initiation of PN using a rapid "step-up" approach, coupled with a computerized insulin-dosing protocol, would result in a desirable caloric intake within 24 hours without causing hyperglycemia. In our surgical intensive care unit (ICU), glucose is regulated by a nurse-centered computerized glucose regulation program. When adequate enteral feeding was not possible, PN was initiated according to a simple step-up rule at an infusion rate of 10 mL/h (approximately 10 kcal/h) and subsequently increased by steps of 10 mL/h every 4 hours, provided glucose was up period and for 24 hours after achieving target feeding. In all 23 consecutive patients requiring PN, mean intake was 1 kcal/kg/h within 24 hours. Of the 280 glucose samples during the 48-hour study period, mean ± standard deviation glucose level was 7.4 ± 1.4 mmol/L. Only 4.5% of glucose measurements during the step-up period were transiently ≥10 mmol/L. After initiating PN, the insulin requirement rose from 1.1 ± 1.5 units/h to 2.9 ± 2.5 units/h (P initiation of PN using a step-up approach coupled with computerized glucose control resulted in adequate caloric intake within 24 hours while maintaining adequate glycemic control.

  4. Bone vs. fat: embryonic origin of progenitors determines response to androgen in adipocytes and osteoblasts.

    Science.gov (United States)

    Wiren, Kristine M; Hashimoto, Joel G; Semirale, Anthony A; Zhang, Xiao-Wei

    2011-10-01

    Although androgen is considered an anabolic hormone, the consequences of androgen receptor (AR) overexpression in skeletally-targeted AR-transgenic lines highlight the detrimental effect of enhanced androgen sensitivity on cortical bone quality. A compartment-specific anabolic response is observed only in male and not in female AR3.6-transgenic (tg) mice, with increased periosteal bone formation and calvarial thickening. To identify anabolic signaling cascades that have the potential to increase bone formation, qPCR array analysis was employed to define expression differences between AR3.6-tg and wild-type (WT) periosteal tissue. Notably, categories that were significantly different between the two genotypes included axonal guidance, CNS development and negative regulation of Wnt signaling with a node centered on stem cell pathways. Further, fine mapping of AR3.6-tg calvaria revealed that anabolic thickening in vivo is not uniform across the calvaria, occurring only in frontal and in not parietal bones. Multipotent fraction 1 progenitor populations from both genotypes were cultured separately as frontal bone neural crest stem-like cells (fNCSC) and parietal bone mesenchymal stem-like cells (pMSC). Both osteoblastic and adipogenic differentiation in these progenitor populations was influenced by embryonic lineage and by genotype. Adipogenesis was enhanced in WT fNCSC compared to pMSC, but transgenic cultures showed strong suppression of lipid accumulation only in fNCSC cells. Osteoblastogenesis was significantly increased in transgenic fNCSC cultures compared to WT, with elevated alkaline phosphatase (ALP) activity and induction of mineralization and nodule formation assessed by alizarin red and von Kossa staining. Osteocalcin (OC) and ALP mRNA levels were also increased in fNCSC cultures from AR3.6-tg vs. WT, but in pMSC cultures ALP mRNA levels, mineralization and nodule formation were decreased in AR3.6-tg cells. Expression differences identified by array in long

  5. Bringing androgens up a NOTCH in breast cancer.

    Science.gov (United States)

    Tarulli, Gerard A; Butler, Lisa M; Tilley, Wayne D; Hickey, Theresa E

    2014-08-01

    While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer

  6. Masking effect of anti-androgens on androgenic activity in European river sediment unveiled by effect-directed analysis

    NARCIS (Netherlands)

    Weiss, J.M.; Hamers, T.; Thomas, K.; van der Linden, S.C.; Leonards, P.E.G.; Lamoree, M.H.

    2009-01-01

    This study shows that the androgen receptor agonistic potency is clearly concealed by the effects of androgen receptor antagonists in a total sediment extract, demonstrating that toxicity screening of total extracts is not enough to evaluate the full in vitro endocrine disrupting potential of a

  7. Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet.

    Science.gov (United States)

    Van Wagoner, Ryan M; Eichner, Amy; Bhasin, Shalender; Deuster, Patricia A; Eichner, Daniel

    2017-11-28

    Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels. Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association-approved analytical procedures. Analytical findings were compared against the label information. Products marketed and sold as selective androgen receptor modulators. Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators. Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products

  8. Androgen Signaling Disruption during Fetal and Postnatal Development Affects Androgen Receptor and Connexin 43 Expression and Distribution in Adult Boar Prostate

    Directory of Open Access Journals (Sweden)

    Anna Hejmej

    2013-01-01

    Full Text Available To date, limited knowledge exists regarding the role of the androgen signaling during specific periods of development in the regulation of androgen receptor (AR and connexin 43 (Cx43 in adult prostate. Therefore, in this study we examined mRNA and protein expression, and tissue distribution of AR and Cx43 in adult boar prostates following fetal (GD20, neonatal (PD2, and prepubertal (PD90 exposure to an antiandrogen flutamide (50 mg/kg bw. In GD20 and PD2 males we found the reduction of the luminal compartment, inflammatory changes, decreased AR and increased Cx43 expression, and altered localization of both proteins. Moreover, enhanced apoptosis and reduced proliferation were detected in the prostates of these animals. In PD90 males the alterations were less evident, except that Cx43 expression was markedly upregulated. The results presented herein indicate that in boar androgen action during early fetal and neonatal periods plays a key role in the maintenance of normal phenotype and functions of prostatic cells at adulthood. Furthermore, we demonstrated that modulation of Cx43 expression in the prostate could serve as a sensitive marker of hormonal disruption during different developmental stages.

  9. Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

    Directory of Open Access Journals (Sweden)

    Wendy J. Huss

    2007-11-01

    Full Text Available Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR. Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

  10. Effects of fetal brain grafting on adult behavioral masculinization and defeminization in neonatally androgenized female rats.

    Science.gov (United States)

    Tsai, Y F; Chen, T J; Pi, W P; Tai, M Y; Huang, R L; Chiueh, C C; Peng, M T

    1995-05-05

    Treatment of neonatal female rats with androgen results not only in decreased female sexual behavior but also in enhanced male sexual behavior examined in adulthood. The effects of grafting fetal preoptic area (POA) neurons into the POA, and fetal hypothalamic (HPT) neurons into the ventromedial hypothalamus (VMH), were tested in neonatally androgen-sterilized rats (ASR). The rats were injected subcutaneously with 80 micrograms testosterone propionate within the 24 hours after birth to see if sexual behavior could be normalized by fetal brain grafts. In repeated tests on ASR grafted with fetal HPT into the VMH, the lordotic response was seen to increase to the level seen in non-ASR controls, while the increase in mounting behavior in ASR was suppressed following grafting of fetal POA or cerebral cortex into the POA. These results suggest that there are dysfunctions of POA and VMH in ASR, and that the dysfunctions revealed by sexual behavior can be overcome by fetal POA or HPT grafting.

  11. Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: Evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys.

    Science.gov (United States)

    Pasterski, Vickie; Acerini, Carlo L; Dunger, David B; Ong, Ken K; Hughes, Ieuan A; Thankamony, Ajay; Hines, Melissa

    2015-03-01

    The masculinizing effects of prenatal androgens on human neurobehavioral development are well established. Also, the early postnatal surge of androgens in male infants, or mini-puberty, has been well documented and is known to influence physiological development, including penile growth. However, neurobehavioral effects of androgen exposure during mini-puberty are largely unknown. The main aim of the current study was to evaluate possible neurobehavioral consequences of mini-puberty by relating penile growth in the early postnatal period to subsequent behavior. Using multiple linear regression, we demonstrated that penile growth between birth and three months postnatal, concurrent with mini-puberty, significantly predicted increased masculine/decreased feminine behavior assessed using the Pre-school Activities Inventory (PSAI) in 81 healthy boys at 3 to 4years of age. When we controlled for other potential influences on masculine/feminine behavior and/or penile growth, including variance in androgen exposure prenatally and body growth postnally, the predictive value of penile growth in the early postnatal period persisted. More specifically, prenatal androgen exposure, reflected in the measurement of anogenital distance (AGD), and early postnatal androgen exposure, reflected in penile growth from birth to 3months, were significant predictors of increased masculine/decreased feminine behavior, with each accounting for unique variance. Our findings suggest that independent associations of PSAI with AGD at birth and with penile growth during mini-puberty reflect prenatal and early postnatal androgen exposures respectively. Thus, we provide a novel and readily available approach for assessing effects of early androgen exposures, as well as novel evidence that early postnatal aes human neurobehavioral development. Copyright © 2015. Published by Elsevier Inc.

  12. Mutation of androgen receptor N-terminal phosphorylation site Tyr-267 leads to inhibition of nuclear translocation and DNA binding.

    Directory of Open Access Journals (Sweden)

    Mehmet Karaca

    Full Text Available Reactivation of androgen receptor (AR may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain. Y267F and Y363F mutants showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The Y363F mutant was less severely affected than the Y267F mutant. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. These results support the concept that phosphorylation of Tyr-267, and to a lesser extent Tyr-363, is required for AR nuclear translocation and recruitment and DNA binding and provide a rationale for development of novel approaches to inhibit AR activity.

  13. Mutation of androgen receptor N-terminal phosphorylation site Tyr-267 leads to inhibition of nuclear translocation and DNA binding.

    Science.gov (United States)

    Karaca, Mehmet; Liu, Yuanbo; Zhang, Zhentao; De Silva, Dinuka; Parker, Joel S; Earp, H Shelton; Whang, Young E

    2015-01-01

    Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain. Y267F and Y363F mutants showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The Y363F mutant was less severely affected than the Y267F mutant. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. These results support the concept that phosphorylation of Tyr-267, and to a lesser extent Tyr-363, is required for AR nuclear translocation and recruitment and DNA binding and provide a rationale for development of novel approaches to inhibit AR activity.

  14. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies.

    Science.gov (United States)

    Geier, David A; Geier, Mark R

    2007-10-01

    Impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction characterize autism spectrum disorders (ASDs). Seventy consecutive patients with an ASD diagnosis (DSM-IV criteria, >/= 6 years-old) who presented to the Genetic Centers of America for outpatient genetic/developmental evaluations from 2005-2007 were examined. Patients were evaluated using CLIA-approved Laboratory Cooperation of America (LabCorp) testing for: serum testosterone, serum free testosterone, % free testosterone, serum/plasma dehydroepiandrosterone (DHEA), androstendione, and follicle-stimulating hormone (FSH). Morning blood samples collected following an overnight fast, compared to the pertinent reference means, showed significantly increased relative mean levels for: serum testosterone (158%), serum free testosterone (214%), percent free testosterone (121%), DHEA (192%), and androstenedione (173%). By contrast, compared to the pertinent reference mean, the relative mean level of FSH (51%) was significantly decreased. Additionally, at least one of the androgen attributes examined exceeded its recognized laboratory age- and sex-specific reference range in 81.4% (57 of 70) of the patients examined. With respect to their age- and sex-specific reference ranges, females had significantly higher overall mean relative testosterone and relative free testosterone levels than males. Increased androgens in patients diagnosed with ASDs may involve cyclical interactions between the androgen and the transsulfuration pathways, particularly following mercury exposure. A review of therapies that have significantly improved clinical outcomes in ASD patients indicates they share commonality in helping lower androgens. Thus, androgens should be routinely clinically measured in patients with an ASD diagnosis and appropriate androgen-lowering therapies considered for those who have significantly elevated levels.

  15. The effect of oral contraception on cardiometabolic risk factors in women with elevated androgen levels.

    Science.gov (United States)

    Krysiak, Robert; Gilowska, Małgorzata; Okopień, Bogusław

    2017-02-01

    In unselected reproductive-aged women, use of combined estrogen-progestin oral contraceptive pills has been linked with an increased risk of vascular disease. The aim of this study was to investigate the effect of oral contraception on cardiometabolic risk factors in a population of women with hyperandrogenism. The study included 16 untreated women with elevated testosterone levels and 15 matched healthy women who were then treated with oral contraceptive pills containing ethinyl estradiol (30μg) and drospirenone (3mg). Plasma lipids, glucose homeostasis markers, circulating levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, as well as urinary albumin-to-creatinine ratio (UACR) were assessed at baseline and after 12 weeks of treatment. Compared to healthy women, women with elevated androgen levels showed increased plasma levels of hsCRP, fibrinogen and homocysteine, as well as a higher value of UACR. Oral contraception reduced androgen levels only in hyperandrogenic women. In healthy women, ethinyl estradiol plus drospirenone increased plasma levels of insulin, hsCRP, fibrinogen and homocysteine, while in women with elevated androgen levels their effect was limited only to a small increase in hsCRP. Our results suggest that a deteriorating effect of oral contraceptive pills containing ethinyl estradiol and drospirenone in hyperandrogenic women is weaker than in healthy young women and that ethinyl estradiol/drospirenone combination therapy may be safely used in the former group of patients. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  16. Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate

    DEFF Research Database (Denmark)

    Boberg, Julie; Johansson, Hanna Katarina Lilith; Hadrup, Niels

    2015-01-01

    BACKGROUND: Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. METHODS: We examine...... disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life. Prostate....

  17. Integrin Involvement in Freeze Resistance of Androgen-Insensitive Prostate Cancer

    Science.gov (United States)

    Baust, John G.; Klossner, Daniel P.; VanBuskirk, Robert G.; Gage, Andrew A.; Mouraviev, Vladimir; Polascik, Thomas J.; Baust, John M.

    2010-01-01

    Cryoablation has emerged as a primary therapy to treat prostate cancer. While effective, the assumption that freezing serves as a ubiquitous lethal stress is challenged by clinical experience and experimental evidence demonstrating time-temperature related cell death dependence. The age-related transformation from an androgen-sensitive (AS) to an androgen-insensitive (AI) phenotype is a major challenge in the management of prostate cancer. AI cells exhibit morphological changes and treatment resistance to many therapies. Since this resistance has been linked with α6β4 integrin overexpression as a result of androgen receptor (AR) loss, we investigated whether α6β4 integrin expression, as a result AR loss, contributes to the reported increased freeze tolerance of AI prostate cancer. A series of studies using AS (LNCaP LP and PC-3 AR) and AI (LNCaP HP and PC-3) cell lines were designed to investigate the cellular mechanisms contributing to variations in freezing response. Investigation into α6β4 integrin expression revealed that AI cell lines overexpressed this protein, thereby altering morphological characteristics and increasing adhesion characteristics. Molecular investigations revealed a significant decrease in caspase 8, 9, and 3 levels AI cells following freezing. Inhibition of α6β4 integrin resulted in increased caspase activity following freezing (similar to AS cells) and enhanced cell death. These data demonstrate that AI cells show an increase in post-freeze susceptibility following inhibition of α6β4 integrin function. Further understanding the role of androgen-receptor related α6β4 integrin expression in prostate cancer cells responses to freezing might lead to novel options for neo-adjunctive treatments targeting the AR signaling pathway. PMID:20066006

  18. Androgenic anabolic steroids also impair right ventricular function.

    Science.gov (United States)

    Kasikcioglu, Erdem; Oflaz, Huseyin; Umman, Berrin; Bugra, Zehra

    2009-05-01

    Chronic anabolic steroid use suppresses left ventricular functions. However, there is no information regarding the chronic effects of anabolic steroids on right ventricular function which also plays a key role in global cardiac function. The main objective of the present study was to investigate the effects of androgenic anabolic steroids usage among athletes on remodeling the right part of the heart. Androgenic-anabolic steroids-using bodybuilders had smaller diastolic velocities of both ventricles than drug-free bodybuilders and sedentary counterparts. This study shows that androgenic anabolic steroids-using bodybuilders exhibited depressed diastolic functions of both ventricles.

  19. [Anabolic androgenic steroids in amateur sports in the Netherlands].

    Science.gov (United States)

    Woerdeman, Jorn; de Hon, Olivier; Levi, Marcel; de Ronde, W Pim

    2010-01-01

    In the Netherlands an estimated 20,000 people use anabolic androgenic steroids (AAS). The use of AAS is particularly common in regular visitors to gyms and fitness centres. AAS are usually synthetic derivatives of testosterone with both an anabolic and an androgenic effect. AAS have many side effects like liver damage (oral use) or infections (intramuscular use), which can be explained partly by the androgenic effect and partly by the manner of use. Many of these side effects are only reported in case studies and have not been systematically investigated.

  20. ANABOLIC ANDROGENIC STEROIDS AND ADVERSE EVENTS OF THEIR APPLICATION

    Directory of Open Access Journals (Sweden)

    Nina Đukanović

    2011-08-01

    Full Text Available Anabolic androgenic steroids are synthetic compounds originating from testosterone. Their main effects are the control of development and expression of male secondary sexual characteristics, which are known as androgenic effects, and encourage muscle growth or anabolic effects. Anabolic androgenic steroids are most commonly used illegal substances. Besides these physiological effects, which are achieved using therapeutic doses of these preparations, higher doses than recommended, especially over the longer term, may be associated with the emergence of numerous adverse events. Adverse events may be registered in almost all organs and organ systems, but usually include changes in the reproductive system, skin, liver and cardiovascular system.

  1. Transcriptional regulation of myotrophic actions by testosterone and trenbolone on androgen-responsive muscle.

    Science.gov (United States)

    Ye, Fan; McCoy, Sean C; Ross, Heather H; Bernardo, Joseph A; Beharry, Adam W; Senf, Sarah M; Judge, Andrew R; Beck, Darren T; Conover, Christine F; Cannady, Darryl F; Smith, Barbara K; Yarrow, Joshua F; Borst, Stephen E

    2014-09-01

    Androgens regulate body composition and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. Recently, we demonstrated that trenbolone (a potent synthetic testosterone analogue that is not a substrate for 5-alpha reductase or for aromatase) induces myotrophic effects in skeletal muscle without causing prostate enlargement, which is in contrast to the known prostate enlarging effects of testosterone. These previous results suggest that the 5α-reduction of testosterone is not required for myotrophic action. We now report differential gene expression in response to testosterone versus trenbolone in the highly androgen-sensitive levator ani/bulbocavernosus (LABC) muscle complex of the adult rat after 6weeks of orchiectomy (ORX), using real time PCR. The ORX-induced expression of atrogenes (Muscle RING-finger protein-1 [MuRF1] and atrogin-1) was suppressed by both androgens, with trenbolone producing a greater suppression of atrogin-1 mRNA compared to testosterone. Both androgens elevated expression of anabolic genes (insulin-like growth factor-1 and mechano-growth factor) after ORX. ORX-induced increases in expression of glucocorticoid receptor (GR) mRNA were suppressed by trenbolone treatment, but not testosterone. In ORX animals, testosterone promoted WNT1-inducible-signaling pathway protein 2 (WISP-2) gene expression while trenbolone did not. Testosterone and trenbolone equally enhanced muscle regeneration as shown by increases in LABC mass and in protein expression of embryonic myosin by western blotting. In addition, testosterone increased WISP-2 protein levels. Together, these findings identify specific mechanisms by which testosterone and trenbolone may regulate skeletal muscle maintenance and growth. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Urinary profiles of progestin and androgen metabolites in female polar bears during parturient and non-parturient cycles.

    Science.gov (United States)

    Knott, Katrina K; Mastromonaco, Gabriela F; Owen, Megan A; Kouba, Andrew J

    2017-01-01

    Due to the environmental and anthropogenic impacts that continue to threaten the reproductive success of polar bears, a more detailed understanding of their reproductive cycle is needed. Captive populations of polar bears provide an excellent opportunity to learn more about the reproductive physiology of the species. Progestin (P4) and androgen (T) metabolites in urine, and their ratio (P4:T), were examined during 11 reproductive cycles of captive female polar bears (n = 4) to characterize the steroid hormone profile during pregnancy and determine possible variations related to reproductive failure. The concentration of hormone metabolites in urine were determined through enzyme immunoassay. Reproductive cycles were classified as pregnant (n = 3), anovulatory (n = 4) and ovulatory-non-parturient (n = 4) based on the changes in urinary hormone metabolite values and cub production. In the absence of a lactational suppression of estrus, elevated androgen concentrations suggested resumption of follicular development within 3 weeks of parturition. Breeding behaviours were most often observed when androgen values were at their highest or in decline. Ovulation was identified by a return to basal androgen concentration and elevation of progestins within 1-4 weeks after breeding. As a result, urinary concentrations of progestins were greater than androgens (P4:T ratio ≥ 1.0) during ovulatory cycles whereas the P4:T ratio was Non-invasive monitoring of hormone metabolites in urine provided a rapid determination of endocrine function for improved husbandry and reproductive management of polar bears in captivity. Further research is warranted to understand the reproductive endocrinology of polar bears and its impact on conservation and management of this species in captivity and the wild.

  3. Mouldy feed: A possible explanation for the excretion of anabolic-androgenic steroids in horses.

    Science.gov (United States)

    Decloedt, A I; Bailly-Chouriberry, L; Vanden Bussche, J; Garcia, P; Popot, M-A; Bonnaire, Y; Vanhaecke, L

    2016-05-01

    To ensure fair competition and to protect the horse's welfare, horses have to compete on their own merits, without any unfair advantage that might follow the use of drugs. Therefore, regulatory authorities list all substances that are not allowed in competition, including most anabolic-androgenic steroids. As zero-tolerance is retained, the question arose whether the consumption of mouldy feed could lead to the excretion of steroids, due to the biotransformation of plant phytosterols to steroids. A rapid ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analytical method, previously validated according to AORC (Association of Official Racing Chemists) and EC (European Commission) guidelines, was used to measure steroids in different sample types. Multiple mouldy feed samples were tested for the presence of steroids. The effect of digestion was tested by in vitro simulation of the horse's hindgut in batch incubations. In most feed samples no steroids were detected, even when the products were mouldy. Mouldy corn however showed to contain up to 3.0 ± 0.4 µg/kg AED (4-androstenedione), the main testosterone precursor. This concentration increased when mouldy corn (with added phytosterols) was digested in vitro. An herbal phytosupplement also showed to contain α-testosterone. These results demonstrate that it is important to caution against the consumption of any feed or (herbal) supplement of which the detailed ingredients and quantitative analysis are unknown. The consumption of mouldy corn should especially be avoided, not only from a horse health and welfare point of view, but also to avoid possible inadvertent positive doping results. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  4. Therapeutic effects of anabolic androgenic steroids on chronic diseases associated with muscle wasting.

    Science.gov (United States)

    Woerdeman, Jorn; de Ronde, Willem

    2011-01-01

    A variety of clinical conditions are complicated by loss of weight and skeletal muscle which may contribute to morbidity and mortality. Anabolic androgenic steroids have been demonstrated to increase fat-free mass, muscle mass and strength in healthy men and women without major adverse events and therefore could be beneficial in these conditions. This review provides an overview of clinical trials with anabolic androgenic steroids in the treatment of chronic diseases including HIV-wasting, chronic renal failure, chronic obstructive lung disease, muscular disease, alcoholic liver disease, burn injuries and post operative recovery. Relevant studies were identified in PubMed (years 1950 - 2010), bibliographies of the identified studies and the Cochrane database. Although the beneficial effects of AAS in chronic disorders are promising, clinically relevant endpoints such as quality of life, improved physical functioning and survival were mainly missing or not significant, except for burn injuries. Therefore, more studies are needed to confirm their long term safety and efficacy.

  5. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

    Directory of Open Access Journals (Sweden)

    Kathy Bailey

    Full Text Available Testosterone (T and related androgens are performance enhancing drugs (PEDs abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS to detect androgens, synthetic anabolic-androgenic steroids (AASs and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR, cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22. All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact.

  6. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

    Science.gov (United States)

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete’s urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as ‘T-equivalent’ concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

  7. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

    Science.gov (United States)

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact.

  8. Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Stefanie V Schütz

    Full Text Available In order to generate genomic signals, the androgen receptor (AR has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.

  9. Androgenic anabolic steroid abuse and the cardiovascular system.

    Science.gov (United States)

    Vanberg, Paul; Atar, Dan

    2010-01-01

    Abuse of anabolic androgenic steroids (AAS) has been linked to a variety of different cardiovascular side effects. In case reports, acute myocardial infarction is the most common event presented, but other adverse cardiovascular effects such as left ventricular hypertrophy, reduced left ventricular function, arterial thrombosis, pulmonary embolism and several cases of sudden cardiac death have also been reported. However, to date there are no prospective, randomized, interventional studies on the long-term cardiovascular effects of abuse of AAS. In this review we have studied the relevant literature regarding several risk factors for cardiovascular disease where the effects of AAS have been scrutinized:(1) Echocardiographic studies show that supraphysiologic doses of AAS lead to both morphologic and functional changes of the heart. These include a tendency to produce myocardial hypertrophy (Fig. 3), a possible increase of heart chamber diameters, unequivocal alterations of diastolic function and ventricular relaxation, and most likely a subclinically compromised left ventricular contractile function. (2) AAS induce a mild, but transient increase of blood pressure. However, the clinical significance of this effect remains modest. (3) Furthermore, AAS confer an enhanced pro-thrombotic state, most prominently through an activation of platelet aggregability. The concomitant effects on the humoral coagulation cascade are more complex and include activation of both pro-coagulatory and fibrinolytic pathways. (4) Users of AAS often demonstrate unfavorable measurements of vascular reactivity involving endothelial-dependent or endothelial-independent vasodilatation. A degree of reversibility seems to be consistent, though. (5) There is a comprehensive body of evidence documenting that AAS induce various alterations of lipid metabolism. The most prominent changes are concomitant elevations of LDL and decreases of HDL, effects that increase the risk of coronary artery disease

  10. Androgenic alopecia in women: an Indian perspective.

    Science.gov (United States)

    Sehgal, Virendra N; Srivastava, Govind; Aggarwal, Ashok K; Midha, Reshmi

    2013-01-01

    The authors sought to investigate androgenic alopecia (AA) utilizing clinical and investigative procedures to establish the pattern of AA in the Indian subcontinent. A total of 35 consecutive women presenting with AA were included. After obtaining informed consent, a detailed history/examination, hair pull test, trichogram, and a scalp biopsy were performed in patients. AA classification was attempted across Ludwig and Norwood guidelines. Of 35 women, 16 had grade I, 10 had grade II, and 1 had grade III Ludwig classification. In addition, 6 other women had Christmas tree baldness: 1 each of fronto-parietal and male pattern baldness. Several investigations including hormonal profile were inconclusive; however, hair pull test and trichogram may be helpful in understanding the sequence in AA in women. AA has infrequently been reported, particularly India and in Asia in general.

  11. [Control measures for anabolic androgenic steroid medicines].

    Science.gov (United States)

    Vázquez-Mourelle, Raquel; Carracedo-Martínez, Eduardo; Ces Gens, Eugenio; Cadórniga Valiño, Luis; Álvaro Esteban, Pilar; Pose Reino, José Manuel

    2015-01-01

    Anabolic androgenic steroids (AAS) can cause serious adverse effects when used without a therapeutic purpose. This article aims to show that the AAS are susceptible to being sold on the black market. We also aim to describe how certain limitations on the health inspection services of the Galician health service to pursue these illegal actions prompted a regulatory initiative demanding that additional actions be granted to community pharmacies when dispensing AAS. Four pharmacy inspections detected the diversion of a total of 3118 packages of AAS, which led to the opening of four disciplinary proceedings. In two of these, specialized police forces were called in as there was sufficient evidence of possible diversion to gymnasiums, resulting in a police operation called Operation Fitness. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

  12. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Anabolic Androgenic Steroids and Intracellular Calcium Signaling: A Mini Review on Mechanisms and Physiological Implications

    Science.gov (United States)

    Vicencio, J.M.; Estrada, M.; Galvis, D.; Bravo, R.; Contreras, A.E.; Rotter, D.; Szabadkai, G.; Hill, J.A.; Rothermel, B.A.; Jaimovich, E.; Lavandero, S.

    2015-01-01

    Increasing evidence suggests that nongenomic effects of testosterone and anabolic androgenic steroids (AAS) operate concertedly with genomic effects. Classically, these responses have been viewed as separate and independent processes, primarily because nongenomic responses are faster and appear to be mediated by membrane androgen receptors, whereas long-term genomic effects are mediated through cytosolic androgen receptors regulating transcriptional activity. Numerous studies have demonstrated increases in intracellular Ca2+ in response to AAS. These Ca2+ mediated responses have been seen in a diversity of cell types, including osteoblasts, platelets, skeletal muscle cells, cardiac myocytes and neurons. The versatility of Ca2+ as a second messenger provides these responses with a vast number of pathophysiological implications. In cardiac cells, testosterone elicits voltage-dependent Ca2+ oscillations and IP3R-mediated Ca2+ release from internal stores, leading to activation of MAPK and mTOR signaling that promotes cardiac hypertrophy. In neurons, depending upon concentration, testosterone can provoke either physiological Ca2+ oscillations, essential for synaptic plasticity, or sustained, pathological Ca2+ transients that lead to neuronal apoptosis. We propose therefore, that Ca2+ acts as an important point of crosstalk between nongenomic and genomic AAS signaling, representing a central regulator that bridges these previously thought to be divergent responses. PMID:21443511

  14. Maternal androgens in avian brood parasites and their hosts: responses to parasitism and competition?

    Science.gov (United States)

    Hahn, Caldwell; Wingfield, John C.; Fox, David M.; Walker, Brian G.; Thomley, Jill E

    2017-01-01

    In the coevolutionary dynamic of avian brood parasites and their hosts, maternal (or transgenerational) effects have rarely been investigated. We examined the potential role of elevated yolk testosterone in eggs of the principal brood parasite in North America, the brown-headed cowbird, and three of its frequent host species. Elevated maternal androgens in eggs are a common maternal effect observed in many avian species when breeding conditions are unfavorable. These steroids accelerate embryo development, shorten incubation period, increase nestling growth rate, and enhance begging vigor, all traits that can increase the survival of offspring. We hypothesized that elevated maternal androgens in host eggs are a defense against brood parasitism. Our second hypothesis was that elevated maternal androgens in cowbird eggs are a defense against intra-specific competition. For host species, we found that elevated yolk testosterone was correlated with parasitized nests of small species, those whose nest success is most reduced by cowbird parasitism. For cowbirds, we found that elevated yolk testosterone was correlated with eggs in multiply-parasitized nests, which indicate intra-specific competition for nests due to high cowbird density. We propose experimental work to further examine the use of maternal effects by cowbirds and their hosts.

  15. Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells.

    Science.gov (United States)

    Kilcoyne, Karen R; Smith, Lee B; Atanassova, Nina; Macpherson, Sheila; McKinnell, Chris; van den Driesche, Sander; Jobling, Matthew S; Chambers, Thomas J G; De Gendt, Karel; Verhoeven, Guido; O'Hara, Laura; Platts, Sophie; Renato de Franca, Luiz; Lara, Nathália L M; Anderson, Richard A; Sharpe, Richard M

    2014-05-06

    Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.

  16. Multiple arterial thromboses associated with anabolic androgenic steroids.

    Science.gov (United States)

    McCulloch, Neil Arthur; Abbas, Jonathan Raihan; Simms, Malcolm Harold

    2014-03-01

    The use of supraphysiological doses of anabolic androgenic steroids can have serious side effects. This article reports the case of a young man who suffered potentially life-threatening arterial thromboses following the use of these drugs.

  17. Effects of Androgen Ablation on Anti-Tumor Immunity

    National Research Council Canada - National Science Library

    Kast, W

    2003-01-01

    ... prostate. Castration of mice stimulates B and T lymphopoiesis, thymic and bone marrow hyperplasia. The induction of apoptotic cell death following androgen ablation is accompanied by an inflammatory infiltrate comprised predominantly of activated T cells...

  18. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, A; Iaquinto, G; Gluud, C

    2003-01-01

    Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

  19. Impact of early postnatal androgen exposure on voice development.

    Directory of Open Access Journals (Sweden)

    Leila Grisa

    Full Text Available BACKGROUND: The impact of early postnatal androgen exposure on female laryngeal tissue may depend on certain characteristics of this exposure. We assessed the impact of the dose, duration, and timing of early androgen exposure on the vocal development of female subjects who had been treated for adrenocortical tumor (ACT in childhood. METHODS: The long-term effects of androgen exposure on the fundamental vocal frequency (F0, vocal pitch, and final height and the presence of virilizing signs were examined in 9 adult (age, 18.4 to 33.5 years and 10 adolescent (13.6 to 17.8 years female ACT patients. We also compared the current values with values obtained 0.9 years to 7.4 years after these subjects had undergone ACT surgery, a period during which they had shown normal androgen levels. RESULTS: Of the 19 subjects, 17 (89% had been diagnosed with ACT before 4 years of age, 1 (5% at 8.16 years, and 1 (5% at 10.75 years. Androgen exposure (2 to 30 months was sufficiently strong to cause pubic hair growth in all subjects and clitoromegaly in 74% (14/19 of the subjects, but did not reduce their height from the target value. Although androgen exposure induced a remarkable reduction in F0 (132 Hz and moderate pitch virilization in 1 subject and partial F0 virilization, resulting in F0 of 165 and 169 Hz, in 2 subjects, the majority had normal F0 ranging from 189 to 245 Hz. CONCLUSIONS: Female laryngeal tissue is less sensitive to androgen exposure between birth and adrenarche than during other periods. Differential larynx sensitivity to androgen exposure in childhood and F0 irreversibility in adulthood are age-, concentration-, duration-, and timing-dependent events that may also be affected by exposure to inhibitory or stimulatory hormones. Further studies are required to better characterize each of these factors.

  20. Targeting Androgen Receptor by Lysosomal Degradation in Prostate Cancer

    Science.gov (United States)

    2015-11-01

    cellular proteins turn over by ubiquitin-proteasome-dependent mechanism, steroid hormone receptors including AR were recently shown to be substrates of...patients develop androgen- independent disease, which no longer responds to hormonal therapies. Importantly, even at this advanced stage of androgen...and Yuzuru Shiio*’t,:t: t Greehey Children’s Cancer Research Institute and *Department of Biochemistry , The University of Texas Health Science Center

  1. Selective androgen receptor modulators in preclinical and clinical development

    OpenAIRE

    Narayanan, Ramesh; Mohler, Michael L.; Bohl, Casey E.; Miller, Duane D.; Dalton, James T.

    2008-01-01

    Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic o...

  2. Androgen receptor: structure, role in prostate cancer and drug discovery

    Science.gov (United States)

    Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

    2015-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

  3. Biochemistry and physiology of anabolic androgenic steroids doping.

    Science.gov (United States)

    Lippi, G; Franchini, M; Banfi, G

    2011-05-01

    Anabolic Androgenic Steroids (AASs) are chemical and pharmacological derivatives of the male hormone testosterone which are widely used for increasing burst and sprinting activities in sports. Although AASs are thought to be transversal to the plurality of sports disciplines, they are principally misused by bodybuilders, weightlifters, shot, hammer, discus or javelin throwers, rugby and American football players as well as by swimmers and runners. AAS exert a kaleidoscope of effects on human biology, principally through the 5-α-reductase-mediated conversion into dihydrotestosterone, the aromatase-mediated conversion into female sex hormones, a competitive antagonism to the glucocorticoid receptors, the potential stimulation of erythropoietin secretion as well as psychoactive effects on the brain. The influence of AASs on physical performance is still undefined, since the large number of studies published so far have described discordant and often contradictory outcomes. Nevertheless, animal and human investigations support the hypothesis that the administration of AASs might increase lean body mass, muscle mass, and maximal voluntary strength especially in men, so that they would represent an appealing form of doping for increasing power capacity, sustaining intensive training periods and, last but not least, as a cosmetic muscle makeover. The aim of this article is to review the biochemistry, physiology and the ergogenic effects of AASs.

  4. PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

    Science.gov (United States)

    Oostdijk, Wilma; Idkowiak, Jan; Mueller, Jonathan W.; House, Philip J.; Taylor, Angela E.; O'Reilly, Michael W.; Hughes, Beverly A.; de Vries, Martine C.; Kant, Sarina G.; Santen, Gijs W. E.; Verkerk, Annemieke J. M. H.; Uitterlinden, André G.; Wit, Jan M.; Losekoot, Monique

    2015-01-01

    Context: PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome. Patients and Methods: We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro. Results: We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction. Conclusions: We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome. PMID:25594860

  5. Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives

    Energy Technology Data Exchange (ETDEWEB)

    Kloosterboer, H.J.; Vonk-Noordegraaf, C.A.; Turpijn, E.W.

    1988-09-01

    The relative binding affinities (RBAs) of four progestational compounds (norethisterone, levonorgestrel, 3-keto-desogestrel and gestodene) for the human progesterone and androgen receptors were measured in MCF-7 cytosol and intact MCF-7 cells. For the binding to the progesterone receptor, both Org 2058 and Org 3236 (or 3-keto-desogestrel) were used as labelled ligands. The following ranking (low to high) for the RBA of the nuclear (intact cells) progesterone receptor irrespective of the ligand used is found: norethisterone much less than levonorgestrel less than 3-keto-destogestrel less than gestodene. The difference between the various progestagens is significant with the exception of that between 3-keto-desogestrel and gestodene, when Org 2058 is used as ligand. For the cytosolic progesterone receptor, the same order is found with the exception that similar RBAs are found for gestodene and 3-keto-desogestrel. The four progestagens clearly differ with respect to binding to the androgen receptor using dihydrotestosterone as labelled ligand in intact cells; the ranking (low to high) is: norethisterone less than 3 keto-desogestrel less than levonorgestrel and gestodene. The difference between 3-keto-desogestrel and levonorgestrel or gestodene is significant. The selectivity indices (ratio of the mean RBA for the progesterone receptor to that of androgen receptor) in intact cells are significantly higher for 3-keto-desogestrel and gestodene than for levonorgestrel and norethisterone. From these results we conclude that the introduction of the 18-methyl in norethisterone (levonorgestel) increases both the binding to the progesterone and androgen receptors.

  6. Correlates of androgens in wild male Barbary macaques: Testing the challenge hypothesis.

    Science.gov (United States)

    Rincon, Alan V; Maréchal, Laëtitia; Semple, Stuart; Majolo, Bonaventura; MacLarnon, Ann

    2017-10-01

    Investigating causes and consequences of variation in hormonal expression is a key focus in behavioral ecology. Many studies have explored patterns of secretion of the androgen testosterone in male vertebrates, using the challenge hypothesis (Wingfield, Hegner, Dufty, & Ball, 1990; The American Naturalist, 136(6), 829-846) as a theoretical framework. Rather than the classic association of testosterone with male sexual behavior, this hypothesis predicts that high levels of testosterone are associated with male-male reproductive competition but also inhibit paternal care. The hypothesis was originally developed for birds, and subsequently tested in other vertebrate taxa, including primates. Such studies have explored the link between testosterone and reproductive aggression as well as other measures of mating competition, or between testosterone and aspects of male behavior related to the presence of infants. Very few studies have simultaneously investigated the links between testosterone and male aggression, other aspects of mating competition and infant-related behavior. We tested predictions derived from the challenge hypothesis in wild male Barbary macaques (Macaca sylvanus), a species with marked breeding seasonality and high levels of male-infant affiliation, providing a powerful test of this theoretical framework. Over 11 months, 251 hr of behavioral observations and 296 fecal samples were collected from seven adult males in the Middle Atlas Mountains, Morocco. Fecal androgen levels rose before the onset of the mating season, during a period of rank instability, and were positively related to group mating activity across the mating season. Androgen levels were unrelated to rates of male-male aggression in any period, but higher ranked males had higher levels in both the mating season and in the period of rank instability. Lower androgen levels were associated with increased rates of male-infant grooming during the mating and unstable periods. Our results

  7. Platelet-rich plasma in androgenic alopecia: Myth or an effective tool

    Directory of Open Access Journals (Sweden)

    Swapna S Khatu

    2014-01-01

    Full Text Available Platelet-rich plasma (PRP has become a newer method for the treatment of various types of alopecia. In this prospective study, safety, efficacy and feasibility of PRP injections in treating androgenic alopecia were assessed. Eleven patients suffering from hair loss due to androgenic alopecia and not responding to 6 months treatment with minoxidil and finasteride were included in this study. The hair pull test was performed before every treatment session. A total volume of 2-3 cc PRP was injected in the scalp by using an insulin syringe. The treatment was repeated every two weeks, for a total of four times. The outcome was assessed after 3 months by clinical examination, macroscopic photos, hair pull test and patient′s overall satisfaction. Results: A significant reduction in hair loss was observed between first and fourth injection. Hair count increased from average number of 71 hair follicular units to 93 hair follicular units. Therefore, average mean gain is 22.09 follicular units per cm 2. After the fourth session, the pull test was negative in 9 patients. Conclusion: PRP injection is a simple, cost effective and feasible treatment option for androgenic alopecia, with high overall patient satisfaction.

  8. Anabolic androgenic steroids reverse the beneficial effect of exercise on tendon biomechanics: an experimental study.

    Science.gov (United States)

    Tsitsilonis, Serafim; Chatzistergos, Panayiotis E; Panayiotis, Chatzistergos E; Mitousoudis, Athanasios S; Athanasios, Mitousoudis S; Kourkoulis, Stavros K; Stavros, Kourkoulis K; Vlachos, Ioannis S; Ioannis, Vlachos S; Agrogiannis, George; George, Agrogiannis; Fasseas, Konstantinos; Konstantinos, Fasseas; Perrea, Despina N; Despina, Perrea N; Zoubos, Aristides B; Aristides, Zoubos B

    2014-06-01

    The effect of anabolic androgenic steroids on tendons has not yet been fully elucidated. Aim of the present study was the evaluation of the impact of anabolic androgenic steroids on the biomechanical and histological characteristics of Achilles tendons. Twenty-four male Wistar rats were randomized into four groups with exercise and anabolic steroids (nandrolone decanoate) serving as variables. Protocol duration was 12 weeks. Following euthanasia, tendons' biomechanical properties were tested with the use of a modified clamping configuration. Histological examination with light and electron microscopy were also performed. In the group of anabolic steroids and exercise the lowest fracture stress values were observed, while in the exercise group the highest ones. Histological examination by light and electron microscopy revealed areas of collagen dysplasia and an increased epitendon in the groups receiving anabolic steroids and exercise. These findings suggest that anabolic androgenic steroids reverse the beneficial effect of exercise, thus resulting in inferior maximal stress values. Copyright © 2013 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

  9. Androgen receptor levels during progression of prostate cancer in the transgenic adenocarcinoma of mouse prostate model

    Directory of Open Access Journals (Sweden)

    Krisna Murti

    2010-02-01

    Full Text Available Aim To construct tissue microarrays (TMAs that consisted of prostate tumours from the transgenic adenocarcinoma of mouse prostate (TRAMP mice and non-transgenic murine prostates and to assess androgen receptor (AR levels during progression of prostate cancer in TRAMP mice by immunohistochemistry.Methods Haematoxylin and eosin (H&E sections from the ventral and dorso-lateral prostate lobes of non-transgenic, intact TRAMP and castrated TRAMP were used to demarcate regions of interest for TMAs construction. The samples on TMAs were used to evaluate AR expression using video image analysis (VIA.Results AR was expressed during cancer progression, but AR levels were reduced or absent in late stage disease. Furthermore, when AR levels were compared in tumours from intact and castrate animals, a significant increase in AR levels was observed following androgen ablation.Conclusion Similar to clinical prostate cancer, in the TRAMP model, prostate tumours evolve mechanisms to maintain AR expression and AR responsive gene pathways following castration to facilitate continued tumour growth. (Med J Indones 2010; 19:5-13Keywords : androgen ablation therapy, tissue microarrays, haematoxylin and eosin, video image analysis

  10. Olfactory attractants and parity affect prenatal androgens and territoriality of coyote breeding pairs.

    Science.gov (United States)

    Schell, Christopher J; Young, Julie K; Lonsdorf, Elizabeth V; Mateo, Jill M; Santymire, Rachel M

    2016-10-15

    Hormones are fundamental mediators of personality traits intimately linked with reproductive success. Hence, alterations to endocrine factors may dramatically affect individual behavior that has subsequent fitness consequences. Yet it is unclear how hormonal or behavioral traits change with environmental stressors or over multiple reproductive opportunities, particularly for biparental fauna. To simulate an environmental stressor, we exposed captive coyote (Canis latrans) pairs to novel coyote odor attractants (i.e. commercial scent lures) mid-gestation to influence territorial behaviors, fecal glucocorticoid (FGMs) and fecal androgen metabolites (FAMs). In addition, we observed coyote pairs as first-time and experienced breeders to assess the influence of parity on our measures. Treatment pairs received the odors four times over a 20-day period, while control pairs received water. Odor-treated pairs scent-marked (e.g. urinated, ground scratched) and investigated odors more frequently than control pairs, and had higher FAMs when odors were provided. Pairs had higher FAMs as first-time versus experienced breeders, indicating that parity also affected androgen production during gestation. Moreover, repeatability in scent-marking behaviors corresponded with FGMs and FAMs, implying that coyote territoriality during gestation is underpinned by individually-specific hormone profiles. Our results suggest coyote androgens during gestation are sensitive to conspecific olfactory stimuli and prior breeding experience. Consequently, fluctuations in social or other environmental stimuli as well as increasing parity may acutely affect coyote traits essential to reproductive success. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Age and socially related changes in fecal androgen metabolite concentrations in free-ranging male giraffes.

    Science.gov (United States)

    Wolf, T E; Schaebs, F S; Bennett, N C; Burroughs, R; Ganswindt, A

    2018-01-01

    In many mammal species, androgen levels in males are elevated during periods of mating activity, often to facilitate aggressive behavior between males over access to fertile females. However, this pattern might be less obvious in species with a rather low male-male aggression rate, or in those that are not strictly seasonal breeders. A complex social structure, as well as additional social and environmental factors, might add more to the complexity. Here, we applied a non-invasive method to monitor fecal androgen metabolite (fAM) levels in free-ranging giraffe bulls over a period of months to examine longitudinal patterns of androgen metabolite concentrations in relation to observed male sexual behavior in different age classes. Giraffes are non-seasonal breeders, living in a fission-fusion social system and males show a roaming strategy to search for fertile females. Our results show that season has an impact on fAM levels in free-ranging giraffes, with respective steroid concentrations being higher in summer. In the presence of females, fAM levels of bulls are significantly higher compared to when found in all-male groups, with old adult bulls showing the highest fAM levels. In contrast, young adult bulls have overall slightly higher fAM levels compared to old adult bulls when residing in all male groups. Sexual behavior increases fAM levels only in old adult bulls. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Piperine, a Bioactive Component of Pepper Spice Exerts Therapeutic Effects on Androgen Dependent and Androgen Independent Prostate Cancer Cells

    OpenAIRE

    Abhilash Samykutty; Aditya Vittal Shetty; Gajalakshmi Dakshinamoorthy; Mary Margaret Bartik; Gary Leon Johnson; Brian Webb; Guoxing Zheng; Aoshuang Chen; Ramaswamy Kalyanasundaram; Gnanasekar Munirathinam

    2013-01-01

    Prostate cancer is the most common solid malignancy in men, with 32,000 deaths annually. Piperine, a major alkaloid constituent of black pepper, has previously been reported to have anti-cancer activity in variety of cancer cell lines. The effect of piperine against prostate cancer is not currently known. Therefore, in this study, we investigated the anti-tumor mechanisms of piperine on androgen dependent and androgen independent prostate cancer cells. Here, we show that piperine inhibited th...

  13. Fluoroquinolone resistance mechanisms in urinary tract pathogenic Escherichia coli isolated during rapidly increasing fluoroquinolone consumption in a low-use country

    DEFF Research Database (Denmark)

    Christiansen, Nina; Nielsen, Lene; Jakobsen, Lotte

    2011-01-01

    Resistance to ciprofloxacin in Escherichia coli from urinary tract infections (UTI) in Denmark is increasing parallel to increased use of fluoroquinolones both in Denmark and in other European countries. The objective was to investigate the occurrence of ciprofloxacin resistance mechanisms...

  14. Androgen deprivation of the PC-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation

    NARCIS (Netherlands)

    J. Jongsma (Johan); M.H. Oomen; M.A. Noordzij (Marinus); W.M. van Weerden (Wytske); G.J. Martens; Th.H. van der Kwast (Theo); F.H. Schröder (Fritz); G.J. van Steenbrugge (Gert Jan)

    2000-01-01

    textabstractNeuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating neuropeptides via a regulated secretory pathway (RSP). We studied NE differentiation after androgen withdrawal in the androgen-dependent prostate cancer xenograft PC-310.

  15. Effect of Androgen Blockade on HER-2 and Matrix Metalloproteinase-2 Expression on Bone Marrow Micrometastasis and Stromal Cells in Men with Prostate Cancer

    Directory of Open Access Journals (Sweden)

    N. P. Murray

    2013-01-01

    Full Text Available Introduction. HER-2 has been associated with castrate resistant prostate cancer and matrix metalloproteinase-2 (MMP-2 in the dissemination and invasion of tumor cells as well as activating angiogenesis. We present an immunocytochemical study of the effect of androgen blockade on the expression of HER-2 and MMP-2 in bone marrow micrometastasis and the surrounding stromal cells in men with prostate cancer. Methods and Patients. A cross-sectional study of men with prostate cancer. Touch preps were obtained from bone marrow biopsies of men with prostate cancer, before and after radical prostatectomy and during androgen blockade. Micrometastasis detected with anti-PSA immunocytochemistry underwent processing with anti-HER-2 and anti-MMP-2 immunocytochemistry. Patients were defined as HER-2 positive or negative, MMP-2 negative or an MMP-2 pattern described as border or central and stromal MMP-2 defined as positive or negative. The expression of the biomarkers was compared before and after primary treatment and during androgen blockade in relation to the serum PSA at the time of sampling and duration of androgen blockade. Results. 191 men participated, 35 men before surgery and 43 after surgery; there were no significant differences in HER-2 expression between groups, there was no MMP-2 expression centrally or stromal expression of MMP-2. In men with androgen blockade, HER-2 expression was significantly higher; there was a trend for increasing HER-2 expression up to 5 years; central MMP-2 expression significantly increased after 3 years, while stromal MMP-2 significantly increased after 6 years. MMP-2 expression both in micrometastasis and stroma was significantly associated with HER-2 expression. Expression of MMP-2 at the border of the micrometastasis was not associated with HER-2 expression and occurred in the absence of androgen blockade. Conclusions. Androgen blockade decreases serum PSA by eliminating HER-2 negative prostate cancer cells. However

  16. Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development

    DEFF Research Database (Denmark)

    Metzler, Veronika M.; de Brot, Simone; Robinson, Robert S.

    2017-01-01

    . In this review we focus on the well-established role of androgen regulation of angiogenesis in cancer and relate these mechanisms to placental angiogenesis. The physiological actions of androgens are mediated by the androgen receptor (AR), a ligand dependent transcription factor. Androgens and the AR...... molecular mechanisms of androgen regulation of angiogenesis and infer the potential significance of these pathways to normal and pathogenic placental function. Finally, we offer potential research applications of androgen-targeting molecules developed to treat cancer as investigative tools to help further...

  17. Exposure to the androgenic brominated flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)-cyclohexane alters reproductive and aggressive behaviors in birds.

    Science.gov (United States)

    Marteinson, Sarah C; Letcher, Robert J; Fernie, Kimberly J

    2015-10-01

    Detected in environmental samples, 1,2-dibromo-4-(1,2-dibromoethyl) cyclohexane (DBE-DBCH) is a bioaccumulative isomer of a current-use brominated flame retardant. All 4 structural isomers are androgen agonists; however, little toxicological information exists for this compound. The objective of the present study was to determine if β-DBE-DBCH, the isomer found most prominently in animal tissue, affects androgen-dependent behavior of breeding American kestrels (Falco sparverius). The authors hypothesized that if β-DBE-DBCH acts as an androgen agonist in kestrels, androgen-dependent behaviors (i.e., copulation, courtship, aggression) would increase and behaviors inhibited by androgens (i.e., parental care behaviors) would decrease. Sixteen captive experimental kestrel pairs were exposed to 0.239 ng β-DBE-DBCH/g kestrel/d by diet from 4 wk prior to pairing until their nestlings hatched (mean 82 d) and compared with vehicle only-exposed control pairs (n = 15). Androgen-dependent behaviors were significantly increased in β-DBE-DBCH-exposed birds, consistent with the authors' hypothesis. These behavioral changes included copulation and other sexual behaviors in males and females and aggression in males, suggesting that β-DBE-DBCH may have acted like an androgen agonist in these birds. Parental behaviors were not reduced in exposed birds as predicted, although dietary exposure had ceased before chicks hatched. Further assessment of β-DBE-DBCH is recommended given these behavioral changes and the previously reported reproductive changes in the same birds. © 2015 SETAC.

  18. Targeting Androgen Receptor/Src Complex Impairs the Aggressive Phenotype of Human Fibrosarcoma Cells

    Science.gov (United States)

    Di Donato, Marzia; Hayashi, Ryo; Arra, Claudio; Appella, Ettore; Auricchio, Ferdinando; Migliaccio, Antimo

    2013-01-01

    Background Hormones and growth factors influence the proliferation and invasiveness of human mesenchymal tumors. The highly aggressive human fibrosarcoma HT1080 cell line harbors classical androgen receptor (AR) that responds to androgens triggering cell migration in the absence of significant mitogenesis. As occurs in many human cancer cells, HT1080 cells also express epidermal growth factor receptor (EGFR). Experimental Findings: We report that the pure anti-androgen Casodex inhibits the growth of HT1080 cell xenografts in immune-depressed mice, revealing a novel role of AR in fibrosarcoma progression. In HT1080 cultured cells EGF, but not androgens, robustly increases DNA synthesis. Casodex abolishes the EGF mitogenic effect, implying a crosstalk between EGFR and AR. The mechanism underlying this crosstalk has been analyzed using an AR-derived small peptide, S1, which prevents AR/Src tyrosine kinase association and androgen-dependent Src activation. Present findings show that in HT1080 cells EGF induces AR/Src Association, and the S1 peptide abolishes both the assembly of this complex and Src activation. The S1 peptide inhibits EGF-stimulated DNA synthesis, cell matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of HT1080 cells. Both Casodex and S1 peptide also prevent DNA synthesis and migration triggered by EGF in various human cancer-derived cells (prostate, breast, colon and pancreas) that express AR. Conclusion This study shows that targeting the AR domain involved in AR/Src association impairs EGF signaling in human fibrosarcoma HT1080 cells. The EGF-elicited processes inhibited by the peptide (DNA synthesis, MMP-9 secretion and invasiveness) cooperate in increasing the aggressive phenotype of HT1080 cells. Therefore, AR represents a new potential therapeutic target in human fibrosarcoma, as supported by Casodex inhibition of HT1080 cell xenografts. The extension of these findings in various human cancer-derived cell lines highlights the

  19. Possible Role of HER-2 in the Progression of Prostate Cancer from Primary Tumor to Androgen Independence.

    Science.gov (United States)

    Murray, Nigel P; Reyes, Eduardo; Fuentealba, Cynthia; Jacob, Omar; Orellana, Nelson

    2015-01-01

    The expression of HER-2 in prostate cancer has been linked to disease progression. We analysed the presence of HER-2 expression in primary tumors in men undergoing radical prostatectomy, its association with clinical and pathological findings, and its expression in secondary circulating prostate cells (CPCs) during follow up, as well as links with biochemical failure and the effects of androgen blockade. Consecutive men undergoing radical prostatectomy for histologically confirmed prostate cancer were analyzed. HER-2 expression in the primary tumor was assessed using the HercepTest®, CPCs were identified from blood samples using standard immunocytochemistry with anti-PSA and positive samples with the HercepTest® to determine HER-2 expression. The influence of HER-2 expression on the frequency of biochemical failure and effects of androgen blockade was determined. 144 men with a mean age of 64.8±10.3 years participated, with a median follow up of 8.2 years. HER-2 was expressed in 20.8% of primary tumors; it was associated with vascular infiltration and older age, but not with other clinical pathological findings. Some 40.3% of men had secondary CPCs detected, of which 38% expressed HER-2. Men CPC (+) had a higher frequency of biochemical failure, but there was no difference in HER-2 expression of CPCs with the frequency of biochemical failure. After androgen blockade, men with HER-2 (+) positive secondary CPCs had a higher frequency of disease progression to castrate resistant disease. HER-2 plays a dual role in the progression of prostate cancer; firstly it may increase the potential of tumor cells to disseminate from the primary tumor via the blood by increasing vascular infiltration. In the presence of androgens, there is no survival advantage of expressing HER-2, but once biochemical failure has occurred and androgen blockade started, HER-2 positive cells are resistant to treatment, survive and grow leading to castration resistant disease.

  20. Illicit Anabolic-Androgenic Steroid Use

    Science.gov (United States)

    Kanayama, Gen; Hudson, James I.; Pope, Harrison G.

    2009-01-01

    The anabolic-androgenic steroids (AAS) are a family of hormones that includes testosterone and its derivatives. These substances have been used by elite athletes since the 1950s, but they did not become widespread drugs of abuse in the general population until the 1980s. Thus, knowledge of the medical and behavioral effects of illicit AAS use is still evolving. Surveys suggest that many millions of boys and men, primarily in Western countries, have abused AAS to enhance athletic performance or personal appearance. AAS use among girls and women is much less common. Taken in supraphysiologic doses, AAS show various long-term adverse medical effects, especially cardiovascular toxicity. Behavioral effects of AAS include hypomanic or manic symptoms, sometimes accompanied by aggression or violence, which usually occur while taking AAS, and depressive symptoms occurring during AAS withdrawal. However, these symptoms are idiosyncratic and afflict only a minority of illicit users; the mechanism of these idiosyncratic responses remains unclear. AAS users may also ingest a range of other illicit drugs, including both “body-image” drugs to enhance physical appearance or performance, and classical drugs of abuse. In particular, AAS users appear particularly prone to opioid use. There may well be a biological basis for this association, since both human and animal data suggest that AAS and opioids may share similar brain mechanisms. Finally, AAS may cause a dependence syndrome in a substantial minority of users. AAS dependence may pose a growing public health problem in future years, but remains little studied. PMID:19769977

  1. Anesthetic pregnanes counteract androgen-induced defeminization.

    Science.gov (United States)

    Gonzalez-Mariscal, G; Fernandez-Guasti, A; Beyer, C

    1982-01-01

    The capacity of various pregnanes for counteracting androgen-induced defeminization was evaluated in an attempt to define some cellular mechanisms involved in the defeminization process. 5-day-old female rats received 60 microgram testosterone propionate (TP) along with one of various pregnanes: progesterone, 5 beta-pregnandione, 5 beta, 3 alpha-pregnanolone, 5 beta, 3 beta-pregnanolone, 5 alpha-pregnandione, 5 alpha, 3 beta-pregnanolone, 5 alpha, 3 alpha-pregnanolone or chlormadinone acetate. Protection against defeminization was defined as a significantly smaller proportion of anovulatory animals in a group compared to the control TP group. Data were analyzed at 60, 90 and 120 days of age. The anesthetic potency of the pregnanes was evaluated in 5-day-old male rats through the analysis of EEG and EMG records. Anesthetic pregnanes - progesterone, 5 beta-pregnandione and 5 beta, 3 alpha-pregnanolone - counteracted defeminization while nonanesthetic pregnanes - 5 alpha-pregnanes, chlormadinone acetate and 5 beta, 3 beta-pregnanolone - did not. The results show a clear relation between anesthetic capacity and protection against defeminization.

  2. Androgene und Androgentherapie bei der Frau

    Directory of Open Access Journals (Sweden)

    Fischl F

    2001-01-01

    Full Text Available Testosteron und Androstendion sind die beiden androgenen Hormone, die im Ovar im fertilen Lebensalter produziert werden. Aber auch das postmenopausale Ovar bleibt weiterhin endokrin kompetent, d. h. die Androgene werden noch bis in das 6. Lebensjahrzehnt produziert, wobei jedoch die Androstendionproduktion deutlich reduziert wird. Ebenso sinkt die Testosteronproduktion deutlich ab. Neben den führenden Symptomen des Klimakteriums wie Leistungsverlust und Libidoverlust, die auch durch eine alleinige Östrogensubstitution oft nicht ausreichend gebessert werden können, ergeben sich durch den auftretenden Androgenmangel weitere klinische Symptome. So treten während des Klimakteriums und in der Postmenopause bei vielen Frauen, die sonst keine Gewichtsprobleme hatten, Figurprobleme und Übergewicht auf. Es kommt zu typischen Veränderungen der Körperform und Art der Fettverteilung, denn durch den Androgenmangel kommt es zu einer verminderten Lipolyse und damit zu einer Vergrößerung des abdominalen Fettes. Aus diesem Grunde ist die prophylaktische Ovarektomie bei einer nötigen Hysterektomie im vierten bis fünften Lebensjahrzehnt genau zu überlegen und das Risiko einer malignen Entartung sowie möglichen Ausfallserscheinungen durch das vorzeitige Entfernen der Ovarien abzuwägen und individuell in jedem einzelnen Fall mit der betroffenen Frau zu besprechen.

  3. Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency.

    Science.gov (United States)

    Rodie, M E; Mudaliar, M A V; Herzyk, P; McMillan, M; Boroujerdi, M; Chudleigh, S; Tobias, E S; Ahmed, S F

    2017-10-01

    It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC). To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation. Median pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (hCG stimulation with a pre and post median serum testosterone of hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248 , non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5 . On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 ( P  = 0.01). The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency. © 2017 The authors.

  4. Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses.

    Science.gov (United States)

    Roselli, Charles E; Reddy, Radhika C; Estill, Charles T; Scheldrup, Melissa; Meaker, Mary; Stormshak, Fred; Montilla, Hernán J

    2014-12-01

    The ovine sexually dimorphic nucleus (oSDN) is 2 times larger in rams than in ewes. Sexual differentiation of the oSDN is produced by testosterone exposure during the critical period occurring between gestational day (GD)60 and GD90 (term, 147 d). We tested the hypothesis that testosterone acts through the androgen receptor to control development of the male-typical oSDN. In experiment 1, pregnant ewes received injections of vehicle, androgen receptor antagonist flutamide, or nonaromatizable androgen dihydrotestosterone (DHT) propionate during the critical period. Fetuses were delivered at GD135. Both antagonist and agonist treatments significantly reduced mean oSDN volume in males but had no effects in females. Experiment 2, we analyzed the effect of treatments on the fetal hypothalamic-pituitary-gonadal axis to determine whether compensatory changes in hormone secretion occurred that could explain the effect of DHT. Pregnant ewes were injected with vehicle, flutamide, or DHT propionate from GD60 to GD84, and fetuses were delivered on GD85. Flutamide significantly increased LH and testosterone in males, whereas DHT significantly decreased both hormones. In females, LH was unaffected by flutamide but significantly reduced by DHT exposure. DHT significantly decreased pituitary gonadotropin and hypothalamic kisspeptin mRNA expression in males and females. These results suggest that androgen receptor mediates the effect of testosterone on oSDN masculinization, because this process was blocked by the androgen receptor antagonist flutamide in eugonadal males. In contrast, the reduction of oSDN volume observed after DHT exposure appears to be mediated by a negative feedback mechanism exerted on the hypothalamus to reduce LH and testosterone secretion. The reduced androgen exposure most likely accounted for the decreased oSDN volume. We conclude that, during the critical period, the male reproductive axis in long gestation species, such as sheep, is sufficiently developed

  5. Testosterone downregulates angiotensin II type-2 receptor via androgen receptor-mediated ERK1/2 MAP kinase pathway in rat aorta

    Directory of Open Access Journals (Sweden)

    Jay S Mishra

    2016-10-01

    Full Text Available Introduction: Blood pressure is lower in females than males. Angiotensin II type-2 receptor (AT2R induces vasodilation. This study determined whether sex differences in vascular AT2R expression occur and if androgens exert control on AT2R expression in the vasculature. Methods: AT2Rs in the aorta of male and female Sprague-Dawley rats were examined following alteration in androgen levels by gonadectomy or hormone supplementation. Results: AT2R mRNA and protein expression levels were lower in the aortas of males than females. In males, testosterone withdrawal by castration significantly elevated AT2R mRNA and protein levels and testosterone replacement restored them. In females, increasing androgen levels decreased AT2R mRNA and protein expression and this was attenuated by androgen receptor blocker flutamide. Ex vivo, dihydrotestosterone downregulated AT2R in endothelium-intact but not endothelium-denuded aorta. Dihydrotestosterone-induced AT2R downregulation in isolated aorta was blocked by an androgen receptor antagonist. Furthermore, blockade of ERK1/2 but not p38 MAP kinase or TGFβ signaling with specific inhibitors abolished dihydrotestosterone-induced AT2R downregulation. Conclusion: Androgens downregulate AT2R expression levels in aorta, in vivo and ex vivo. The androgen receptor-mediated ERK1/2 MAP kinase-signaling pathway may be a key mechanism by which testosterone downregulates AT2R expression, implicating androgens’ contributing role to gender differences in vascular AT2R expression.

  6. GATA3 in the urinary bladder: suppression of neoplastic transformation and down-regulation by androgens.

    Science.gov (United States)

    Li, Yi; Ishiguro, Hitoshi; Kawahara, Takashi; Miyamoto, Yurina; Izumi, Koji; Miyamoto, Hiroshi

    2014-01-01

    Recent evidence suggests the involvement of sex hormone receptors in bladder cancer initiation, while precise functions of androgens and estrogens in the carcinogenesis step remain poorly understood. We recently found down-regulation of GATA3, a zinc-finger transcription factor and a new urothelial marker, in bladder cancer, which also correlated with expression status of androgen receptor (AR) and estrogen receptors (ERs). We here assessed whether GATA3 acted as a suppressor of bladder tumorigenesis and sex hormones exerted an influence on GATA3 in non-neoplastic urothelial cells. Androgen (R1881, dihydrotestosterone) treatment in SVHUC immortalized normal urothelial cells stably expressing AR (SVHUC-AR) decreased GATA3 expression at both mRNA and protein levels, which was abolished by anti-androgens. Conversely, 17β-estradiol treatment increased it in SVHUC-control endogenously expressing ERβ. GATA3 levels were also found to be higher in intact female mouse bladders compared with intact males, and orchiectomy/ovariectomy augmented/reduced GATA3 expression, respectively, which was at least partially restored by dihydrotestosterone/17β-estradiol supplement. Additionally, GATA3 silencing via short hairpin RNA (shRNA) promoted cell proliferation of SVHUC with exposure to a chemical carcinogen 3-methylcholanthrene. In vitro transformation assay with 3-methylcholanthrene then showed a significantly higher number of colonies in SVHUC-AR/GATA3-shRNA, compared with control SVHUC, and R1881 further induced colony formation. GATA3 knockdown also resulted in down-regulation of the molecules that play a protective role in bladder tumorigenesis (i.e. UGT1A, PTEN, p53, p21) and up-regulation of oncogenic genes (i.e. c-myc, cyclin D1, cyclin D3, cyclin E, FGFR3). Thus, GATA3 likely prevented neoplastic transformation of urothelial cells. Furthermore, sex hormone signals contrary regulated GATA3 in the bladder. These findings may offer not only a molecular basis for the gender

  7. 17beta-hydroxy-5alpha-androst-1-en-3-one (1-testosterone) is a potent androgen with anabolic properties.

    Science.gov (United States)

    Friedel, A; Geyer, H; Kamber, M; Laudenbach-Leschowsky, U; Schänzer, W; Thevis, M; Vollmer, G; Zierau, O; Diel, P

    2006-08-20

    Since the begining of the year 2005, the use of steroid precursors (prohormones) is illegal in the United States; nevertheless, there is still an enormous abuse of such substances. One of the most frequently misused steroids, often declared to be a prohormone, is 1-testosterone (17beta-hydroxy-5alpha-androst-1-en-3-one, 1-Testo). In this study, we have characterised molecular mechanisms of its action, determined its tissue specific androgenic and anabolic potency and investigated potential adverse effects. 1-Testo binds highly selective to the androgen receptor (AR) and has a high potency to stimulate AR dependent transactivation. In vivo an equimolar dose of 1-Testo has the same potency to stimulate the growth of the prostate, the seminal vesicles and the androgen sensitive levator ani muscle as the reference compound testosterone propionate (TP). Administration of 1-Testo, in contrast to TP, results in a significant increase of liver weight. Our results demonstrate that 1-Testo, even without being metabolised, is a very potent androgen. It binds selectively to the AR and transactivates AR dependent reporter genes. In vivo it has a high androgenic and anabolic potency and increases liver weight. In summary 1-Testo can be characterised as a typical anabolic steroid. It has to be assumed that consumption of this substance is associated with adverse side effects typical for this class of compounds. Therefore, a strict control of its ban is essential.

  8. Adverse health effects of anabolic-androgenic steroids.

    Science.gov (United States)

    van Amsterdam, Jan; Opperhuizen, Antoon; Hartgens, Fred

    2010-06-01

    Anabolic-androgenic steroids (AAS) are synthetic drugs derived from testosterone. Illegally, these drugs are regularly self-administered by body builders and power lifters to enhance their sportive performance. Adverse side effects of AAS include sexual dysfunction, alterations of the cardiovascular system, psyche and behavior, and liver toxicity. However, severe side effects appear only following prolonged use of AAS at high dose and their occurrence is limited. Occasionally, AAS abuse may be linked to certain social and psychological traits of the user, like low self-esteem, low self-confidence, suffered hostility, childhood conduct disorder, and tendency to high-risk behavior. The overwhelming stereotype about AAS is that these compounds cause aggressive behavior in males. However, the underlying personality traits of a specific subgroup of the AAS abusers, who show aggression and hostility, may be relevant, as well. Use of AAS in combination with alcohol largely increases the risk of violence and aggression. The dependence liability of AAS is very low, and withdrawal effects are relatively mild. Based on the scores for acute and chronic adverse health effects, the prevalence of use, social harm and criminality, AAS were ranked among 19 illicit drugs as a group of drugs with a relatively low harm. (c) 2010 Elsevier Inc. All rights reserved.

  9. The effects of anabolic androgenic steroid abuse on gingival tissues.

    Science.gov (United States)

    Ozcelik, Onur; Haytac, M Cenk; Seydaoglu, Gulsah

    2006-07-01

    Anabolic androgenic steroid (AAS) is the familiar name for synthetic derivatives of the male sex hormone, testosterone. A large number of young adults abuse AAS to enhance performance and physical appearance. The aim of this study was to evaluate the effects of AAS abuse on the gingival tissues in a group of bodybuilders and weight lifters. The test group was composed of 24 athletes aged between 17 and 29 years who had been using AAS for >1 year. All subjects were clinically examined for plaque levels (plaque index), gingival inflammation (gingival index), and gingival enlargement. The results were compared to a control group of 20 bodybuilders who had never used AAS drugs and who matched for age, educational level, and oral habits according to the data obtained from the test group. Although there were no statistical differences between the plaque index (P>0.05) and gingival index (P>0.05) scores of the study group and the control group, the AAS abusers had statistically higher scores of gingival thickness, extent of gingival encroachment, and total gingival enlargement scores (Psports seem to increase despite legislation, dentists and periodontists should be familiar with the adverse effects of these synthetic derivatives of testosterone on the gingival tissues.

  10. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V

    2016-09-14

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors.

  11. The use of exercise interventions to overcome adverse effects of androgen deprivation therapy

    DEFF Research Database (Denmark)

    Østergren, Peter Busch; Kistorp, Caroline; Bennedbæk, Finn Noe

    2016-01-01

    Androgen deprivation therapy (ADT) induces severe hypogonadism and is associated with several adverse effects that negatively affect health and quality of life in patients with prostate cancer. ADT changes body composition characterized by an increase in fat mass and a reduction in muscle mass...... existing cardiovascular disease. In this initial phase of ADT, metabolic changes are also most prominent. In addition, ADT increases the rate of bone loss and fracture risk. Currently available evidence supports the use of exercise interventions to improve physical function and mitigate ADT-induced fatigue...

  12. Changes in Underlying Determinants Explain Rapid Increases in Child Linear Growth in Alive & Thrive Study Areas between 2010 and 2014 in Bangladesh and Vietnam.

    Science.gov (United States)

    Nguyen, Phuong Hong; Headey, Derek; Frongillo, Edward A; Tran, Lan Mai; Rawat, Rahul; Ruel, Marie T; Menon, Purnima

    2017-03-01

    nutritional change in intervention and comparison areas. Improvements in underlying determinants explained rapid improvements in HAZs between 2010 and 2014 in Bangladesh and Vietnam.

  13. Rapid burst of H2O2 by plant growth regulators increases intracellular Ca2+ amounts and modulates CD4+ T cell activation.

    Science.gov (United States)

    Ahmed, Asma; Mukherjee, Sambuddho; Deobagkar, Mukta; Naik, Tanushree; Nandi, Dipankar

    2010-11-01

    The identification of small molecules that affect T cell activation is an important area of research. Three molecules that regulate plant growth and differentiation, but not their structurally similar analogs, were identified to enhance primary mouse CD4(+) T cell activation in conjunction with soluble anti-CD3 stimulation: Indoleacetic acid (natural plant auxin), 1-Napthaleneacetic acid (synthetic plant auxin) and 2,4-Dichlorophenoxyacetic acid (synthetic plant auxin and herbicide). These effects are distinct in comparison to Curcumin, the well known phenolic immunomodulator, which lowers T cell activation. An investigation into the mechanisms of action of the three plant growth regulators revealed a rapid induction of reactive oxygen species (ROS), mainly comprising H(2)O(2). In addition, these three molecules synergize with soluble anti-CD3 signaling to enhance intracellular Ca(2+) concentrations [Ca(2+)](i), leading to greater T cell activation, e.g. induction of CD25 and IL-2. Enhanced production of TNFα and IFNγ by CD4(+) T cells is also observed upon plant growth regulator treatment with soluble anti-CD3. Interestingly, maximal IL-2 production and CD4(+) T cell cycle progression are observed upon activation with soluble anti-CD3 and phorbol 12-myristate 13-acetate (PMA), a phorbol ester. Additionally, stimulation with PMA and Ionomcyin (a Ca(2+) ionophore), which activates T cells by circumventing the TCR, and plant growth regulators also demonstrated the role of the strength of signal (SOS): T cell cycle progression is enhanced with gentle activation conditions but decreased with strong activation conditions. This study demonstrates the direct effects of three plant growth regulators on CD4(+) T cell activation and cycling. Copyright © 2010 Elsevier B.V. All rights reserved.

  14. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    .... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

  15. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigsby, James

    2004-01-01

    .... Our major hypothesis is the patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

  16. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigaby, James

    2003-01-01

    .... Our major hypothesis is that patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

  17. Endogenous androgens and carotid intimal-medial thickness in women.

    Science.gov (United States)

    Bernini, G P; Sgro', M; Moretti, A; Argenio, G F; Barlascini, C O; Cristofani, R; Salvetti, A

    1999-06-01

    The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and post-menopausal 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 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.

  18. Innate immunity and testosterone rapidly respond to acute stress, but is corticosterone at the helm?

    Science.gov (United States)

    Davies, S; Noor, S; Carpentier, E; Deviche, P

    2016-10-01

    When faced with a stressor, vertebrates can rapidly increase the secretion of glucocorticoids, which is thought to improve the chances of survival. Concurrent changes in other physiological systems, such as the reproductive endocrine or innate immune systems, have received less attention, particularly in wild vertebrates. It is often thought that glucocorticoids directly modulate immune performance during a stress response, but, in many species, androgens also rapidly respond to stress. However, to our knowledge, no study has simultaneously examined the interactions between the glucocorticoid, androgen, and innate immune responses to stress in a wild vertebrate. To address this issue, we tested the hypothesis that the change in plasma corticosterone (CORT) in response to the acute stress of capture and restraint is correlated with the concurrent changes in plasma testosterone (T) and innate immune performance (estimated by the capacity of plasma to agglutinate and lyse foreign cells) in the Abert's Towhee (Melozone aberti). Furthermore, to broaden the generality of the findings, we compared male and female towhees, as well as males from urban and non-urban populations. Acute stress increased plasma CORT, decreased plasma T in males, and decreased innate immune performance, but the increase in CORT during stress was not correlated with the corresponding decreases in either plasma T or innate immunity. By contrast, the plasma T stress response was positively correlated with the innate immune stress response. Collectively, our results challenge the proposition that the glucocorticoid stress response is correlated with the concurrent changes in plasma T, a key reproductive hormone, and innate immunity, as estimated by agglutination and lysis.

  19. Rapid Increase in Ownership and Use of Long-Lasting Insecticidal Nets and Decrease in Prevalence of Malaria in Three Regional States of Ethiopia (2006-2007

    Directory of Open Access Journals (Sweden)

    Estifanos Biru Shargie

    2010-01-01

    Full Text Available Following recent large scale-up of malaria control interventions in Ethiopia, this study aimed to compare ownership and use of long-lasting insecticidal nets (LLIN, and the change in malaria prevalence using two population-based household surveys in three regions of the country. Each survey used multistage cluster random sampling with 25 households per cluster. Household net ownership tripled from 19.6% in 2006 to 68.4% in 2007, with mean LLIN per household increasing from 0.3 to 1.2. Net use overall more than doubled from 15.3% to 34.5%, but in households owning LLIN, use declined from 71.7% to 48.3%. Parasitemia declined from 4.1% to 0.4%. Large scale-up of net ownership over a short period of time was possible. However, a large increase in net ownership was not necessarily mirrored directly by increased net use. Better targeting of nets to malaria-risk areas and sustained behavioural change communication are needed to increase and maintain net use.

  20. Impact of anabolic androgenic steroids on adolescent males.

    Science.gov (United States)

    Lumia, Augustus R; McGinnis, Marilyn Y

    2010-06-01

    Anabolic androgenic steroid (AAS) use increased dramatically among adolescent males. This review focuses on studies using animal models of AAS exposure during adolescence which is a hormonally sensitive developmental period. AAS exposure during this critical period has wide-ranging consequences, including increased dendritic spine density, altered brain serotonin levels and escalated aggression in response to physical provocation. Human data suggest that AAS induces indiscriminate and unprovoked aggression often described as "'roid rage". However, animal studies indicate that the behavioral impact of AAS is modulated by experiential and social contingencies, a perceived provocation, and the chemical composition of the AAS. The AAS, testosterone increases aggression in juvenile and adult male rats when physically provoked. In contrast, stanzolol, inhibits aggression in both juvenile and adult male rats, even when physically provoked. Nandrolone has minimal effects on aggression, unless preceded by attack training. Exposure to AAS during adolescence may have a host of unintended bio-behavioral consequences. Yet, the perception of harmlessness surrounds AAS use. The perception of harmlessness is promoted by the availability of AAS especially through internet pharmacies. The perception of acceptability is reflected in current cultural ethics that no longer condemn cheating to obtain personal achievement or success. A prevailing conviction is that although AAS are illegal they are not really bad. Reduction of the availability of AAS to adolescents requires ardent legislative and legal intervention. The problem of acceptability can be addressed by educating adolescents about the short-term and long-term effects of AAS on brain and behavior, to increase awareness of the potential consequences of AAS use that apply directly to them. Published by Elsevier Inc.

  1. Androgen receptor is overexpressed in boys with severe hypospadias, and ZEB1 regulates androgen receptor expression in human foreskin cells

    Science.gov (United States)

    Qiao, Liang; Tasian, Gregory E.; Zhang, Haiyang; Cao, Mei; Ferretti, Max; Cunha, Gerald R.; Baskin, Laurence S.

    2012-01-01

    INTRODUCTION ZEB1 is overexpressed in patients with severe hypospadias. We examined the interaction between ZeB1 and the androgen receptor (AR) in vitro and the expression of AR in boys with hypospadias. RESULTS ZEB1 and AR colocalize to the nucleus. Estrogen upregulated ZEB1 and AR expression. Chromatin immunoprecipitation (ChIP) demonstrated that ZEB1 binds to an E-box sequence in the AR gene promoter. AR expression is higher in subjects with severe hypospadias than those with mild hypospadias and control subjects (P hypospadias. Environmental estrogenic compounds may increase the risk of hypospadias by facilitating the interaction between ZEB1 and AR. METHODS Hs68 cells, a fibroblast cell line derived from neonatal human foreskin, were exposed to 0, 10, and 100 nmol/l of estrogen, after which the cellular localization of ZEB1 and AR was assessed using immunocytochemistry. To determine if ZEB1 interacted with the AR gene, ChIP was performed using ZEB1 antibody and polymerase chain reaction (PCR) for AR. Second, AR expression was quantified using real-time PcR and western blot in normal subjects (n = 32), and subjects with mild (n = 16) and severe hypospadia (n = 16). PMID:22391641

  2. Androgen Deprivation Therapy and Risk of Rheumatoid Arthritis in Patients with Localized Prostate Cancer.

    Science.gov (United States)

    Yang, D D; Krasnova, A; Nead, K T; Choueiri, T K; Hu, J C; Hoffman, K E; Yu, J B; Spratt, D E; Feng, F Y; Trinh, Q-D; Nguyen, P L

    2017-12-18

    Androgens are generally immunosuppressive, and men with untreated hypogonadism are at increased risk for autoimmune conditions. To date, there has been no evidence linking androgen deprivation therapy (ADT) to autoimmune diseases, including rheumatoid arthritis (RA). We investigated the association between ADT and RA in patients with prostate cancer. We identified 105,303 men age 66 years or older who were diagnosed with stage I-III prostate cancer from 1992 through 2006 using the Surveillance, Epidemiology, and End Results-Medicare linked database, excluding patients with a history of RA. χ2 test was used to compare 5-year Kaplan-Meier rates of RA diagnoses. Competing risk Cox regression using inverse probability of treatment weighting was utilized to examine the association between pharmacologic ADT and diagnosis of RA. The 43% of patients (N=44,785) who received ADT experienced a higher 5-year rate of RA diagnoses compared to men who did not (5.4% versus 4.4%, P<0.001). Receipt of any ADT was associated with a 23% increased risk of being diagnosed with RA (hazard ratio 1.23, 95% confidence interval 1.09-1.40, P=0.001). The risk of being diagnosed with RA increased with a longer duration of ADT, from 19% with 1-6 months and 29% with 7-12 months to 33% with ≥13 months (Ptrend<0.001). Consistent with the immunosuppressive properties of androgens, we demonstrated for the first time that ADT was associated with an elevated risk of being diagnosed with RA in this large cohort of elderly men with prostate cancer. The risk was higher with a longer duration of ADT. Linking ADT to an increased risk of being diagnosed with an autoimmune condition adds to mounting evidence of the adverse effects of ADT that should prompt physicians to thoughtfully weigh its risks and benefits.

  3. A surge of p-values between 0.041 and 0.049 in recent decades (but negative results are increasing rapidly too)

    Science.gov (United States)

    Dodou, Dimitra

    2015-01-01

    It is known that statistically significant (positive) results are more likely to be published than non-significant (negative) results. However, it has been unclear whether any increasing prevalence of positive results is stronger in the “softer” disciplines (social sciences) than in the “harder” disciplines (physical sciences), and whether the prevalence of negative results is decreasing over time. Using Scopus, we searched the abstracts of papers published between 1990 and 2013, and measured longitudinal trends of multiple expressions of positive versus negative results, including p-values between 0.041 and 0.049 versus p-values between 0.051 and 0.059, textual reporting of “significant difference” versus “no significant difference,” and the reporting of p 0.05. We found no support for a “hierarchy of sciences” with physical sciences at the top and social sciences at the bottom. However, we found large differences in reporting practices between disciplines, with p-values between 0.041 and 0.049 over 1990–2013 being 65.7 times more prevalent in the biological sciences than in the physical sciences. The p-values near the significance threshold of 0.05 on either side have both increased but with those p-values between 0.041 and 0.049 having increased to a greater extent (2013-to-1990 ratio of the percentage of papers = 10.3) than those between 0.051 and 0.059 (ratio = 3.6). Contradictorily, p 0.05 (ratios = 1.4 and 4.8, respectively), while the use of “significant difference” has shown only a modest increase compared to “no significant difference” (ratios = 1.5 and 1.1, respectively). We also compared reporting of significance in the United States, Asia, and Europe and found that the results are too inconsistent to draw conclusions on cross-cultural differences in significance reporting. We argue that the observed longitudinal trends are caused by negative factors, such as an increase of questionable research practices, but also by

  4. Anabolic Androgenic Steroid (AAS) related deaths: autoptic, histopathological and toxicological findings.

    Science.gov (United States)

    Frati, Paola; Busardò, Francesco P; Cipolloni, Luigi; Dominicis, Enrico De; Fineschi, Vittorio

    2015-01-01

    Anabolic androgenic steroids (AASs) represent a large group of synthetic derivatives of testosterone, produced to maximize anabolic effects and minimize the androgenic ones. AAS can be administered orally, parenterally by intramuscular injection and transdermally. Androgens act by binding to the nuclear androgen receptor (AR) in the cytoplasm and then translocate into the nucleus. This binding results in sequential conformational changes of the receptor affecting the interaction between receptor and protein, and receptor and DNA. Skeletal muscle can be considered as the main target tissue for the anabolic effects of AAS, which are mediated by ARs which after exposure to AASs are up-regulated and their number increases with body building. Therefore, AASs determine an increase in muscle size as a consequence of a dose-dependent hypertrophy resulting in an increase of the cross-sectional areas of both type I and type II muscle fibers and myonuclear domains. Moreover, it has been reported that AASs can increase tolerance to exercise by making the muscles more capable to overload therefore shielding them from muscle fiber damage and improving the level of protein synthesis during recovery. Despite some therapeutic use of AASs, there is also wide abuse among athletes especially bodybuilders in order to improve their performances and to increase muscle growth and lean body mass, taking into account the significant anabolic effects of these drugs. The prolonged misuse and abuse of AASs can determine several adverse effects, some of which may be even fatal especially on the cardiovascular system because they may increase the risk of sudden cardiac death (SCD), myocardial infarction, altered serum lipoproteins, and cardiac hypertrophy. The aim of this review is to focus on deaths related to AAS abuse, trying to evaluate the autoptic, histopathological and toxicological findings in order to investigate the pathophysiological mechanism that underlines this type of death, which

  5. Identification of an AR mutation-negative class of androgen insensitivity by determining endogenous AR activity

    NARCIS (Netherlands)

    Hornig, N.C.; Ukat, M.; H.U. Schweikert (H.); O. Hiort (Olaf); Werner, R.; S.L.S. Drop (Stenvert); M.L. Cools (Martine); I.A. Hughes (Ieuan A.); L. Audí (Laura); S.F. Ahmed (Faisal); Demiri, J.; Rodens, P.; Worch, L.; Wehner, G.; Kulle, A.E.; Dunstheimer, D.; Müller-Roßberg, E.; T. Reinehr (Thomas); Hadidi, A.T.; Eckstein, A.K.; Van Der Horst, C.; Seif, C.; R. Siebert (Reiner); O. Ammerpohl (Ole); P-M. Holterhus (Paul-Martin)

    2016-01-01

    textabstractContext: Only approximately 85%of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30%with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene. Objective: The objective of the study

  6. Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails.

    Science.gov (United States)

    Niu, Y; Chang, T-M; Yeh, S; Ma, W-L; Wang, Y Z; Chang, C

    2010-06-24

    Prostate cancer is one of the major causes of cancer-related death in the western world. Androgen-deprivation therapy (ADT) for the suppression of androgens binding to the androgen receptor (AR) has been the norm of prostate cancer treatment. Despite early success to suppress prostate tumor growth, ADT eventually fails leading to recurrent tumor growth in a hormone-refractory manner, even though AR remains to function in hormone-refractory prostate cancer. Interestingly, some prostate cancer survivors who received androgen replacement therapy had improved quality of life without adverse effect on their cancer progression. These contrasting clinical data suggest that differential androgen/AR signals in individual cells of prostate tumors can exist in the same or different patients, and may be used to explain why ADT of prostate cancer fails. Such a hypothesis is supported by the results obtained from transgenic mice with selective knockout of AR in prostatic stromal vs epithelial cells and orthotopic transplants of various human prostate cancer cell lines with AR over-expression or knockout. These studies concluded that AR functions as a stimulator for prostate cancer proliferation and metastasis in stromal cells, as a survival factor of prostatic cancer epithelial luminal cells, and as a suppressor for prostate cancer basal intermediate cell growth and metastasis. These dual yet opposite functions of the stromal and epithelial AR may challenge the current ADT to battle prostate cancer and should be taken into consideration when developing new AR-targeting therapies in selective prostate cancer cells.

  7. Rapid and Sensitive Reporter Gene Assays for Detection of Antiandrogenic and Estrogenic Effects of Environmental Chemicals

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Bonefeld-Jørgensen, Eva Cecilie; Larsen, John Christian

    1999-01-01

    Reports on increasing incidences in developmental abnormalities of the human male reproductive tract and the recent identifications of environmental chemicals with antiandrogenic activity necessitate the screening of a larger number of compounds in order to get an overview of potential...... antiandrogenic chemicals present in our environment. Thus, there is a great need for an effectivein vitroscreening method for (anti)androgenic chemicals. We have developed a rapid, sensitive, and reproducible reporter gene assay for detection of antiandrogenic chemicals. Chinese Hamster Ovary cells were......-on laboratory time. This assay is a powerful tool for the efficient and accurate determination and quantification of the effects of antiandrogens on reporter gene transcription. To extend the application of FuGene, the reagent was shown to be superior compared to Lipofectin for transfecting MCF7 human breast...

  8. [Incomplete androgen insensitivity syndrome. Difficulties of diagnosis and management].

    Science.gov (United States)

    Forest, M G; Mollard, P; David, M; Morel, Y; Bertrand, J

    1990-02-01

    A familial form of incomplete androgen insensitivity syndrome (AIS) is reported. The index case was first seen at 9 months of age for ambiguous genitalia. Diagnosis of AIS, suspected but first discarded on the basis of an androgen sensitivity test, was finally made at puberty on the discordance between poor virilization and elevated levels of both testosterone and LH, a florid gynecomastia, and the exclusion of any enzymatic defect in testosterone biosynthesis of 5 alpha-reductase deficiency. Androgen receptors in public skin were within the limits of normal for total number, with normal affinity. Familial occurrence included 2 first cousins born 7 and 10 years later, a maternal grand-uncle with similar ambiguous genitalia, and a maternal uncle with the gynecomastia-preserved fertility syndrome. This case report illustrates the heterogeneity of AIS in a given family and the difficulty of and early positive diagnosis in a newborn presenting with sexual ambiguity.

  9. Gonadotropin regulation of in vitro androgen production by reptilian testes.

    Science.gov (United States)

    Wo Tsui, H; Licht, P

    1977-04-01

    The hormonal regulation of in vitro androgen production by minced testes from 7 species of reptiles representing the 3 major orders was studied using purified follicle stimulating hormone (FSH) and luteinizing hormone (LH) from tetrapod species. Androgen content was measured by radioimmunoassay. All 7 species showed a dose-dependent response to all preparations of FSH and LH tested. However, variations were found depending on the species tested and the source of the hormone. All snake hormones were particularly inactive in turtles. Some of the variation in relative potencies of hormone reflect phylogenetic specificity in the testes. Synergism between FSH and LH was tested in the sea turtle. While subliminal doses of FSH and LH produced a small stimulation of androgen production, each alone was ineffective. Both gonadotropins have intrinsic activity with regard to the stimulation of steroidogenesis.

  10. High androgen levels protect against hypothyroidism.

    Science.gov (United States)

    Schmidt, Johanna; Dahlgren, Eva; Bryman, Inger; Berntorp, Kerstin; Trimpou, Penelope; Wilhelmsen, Lars; Landin-Wilhelmsen, Kerstin

    2017-01-01

    Hypothyroidism is a common disorder, appearing mainly in women although less frequently found in women with polycystic ovary syndrome (PCOS). The objective was to test the hypothesis that hyperandrogenism might protect against hypothyroidism. The data from three prospective follow-up studies (up to 21 years) and one register study were compared: women with PCOS (Rotterdam criteria), n = 25, women with Turner syndrome, n = 217, a random population sample of women, n = 315, and men, n = 95 (the WHO MONICA study). Findings were to be verified or rejected in all females, n = 553 716, from the same region. The proportion of hypothyroidism was calculated and thyroid peroxidase antibodies (TPO) in serum were measured. Hypothyroidism at >50 years of age was found in 8% of women with PCOS, 4% in men (PCOS vs. men; ns), 43% of women with Turner syndrome, irrespective of karyotype (p 25 years (5.5%) than in women without PCOS (6.8%) from the same region (p < 0.01). Hypothyroidism was less frequently seen in women with PCOS and in men compared with women in the general population and among women with Turner syndrome. This was not explained by altered autoimmunity or the Y-chromosome. Androgens seem to protect against hypothyroidism. © 2016 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology.

  11. Illicit anabolic-androgenic steroid use.

    Science.gov (United States)

    Kanayama, Gen; Hudson, James I; Pope, Harrison G

    2010-06-01

    The anabolic-androgenic steroids (AAS) are a family of hormones that includes testosterone and its derivatives. These substances have been used by elite athletes since the 1950s, but they did not become widespread drugs of abuse in the general population until the 1980s. Thus, knowledge of the medical and behavioral effects of illicit AAS use is still evolving. Surveys suggest that many millions of boys and men, primarily in Western countries, have abused AAS to enhance athletic performance or personal appearance. AAS use among girls and women is much less common. Taken in supraphysiologic doses, AAS show various long-term adverse medical effects, especially cardiovascular toxicity. Behavioral effects of AAS include hypomanic or manic symptoms, sometimes accompanied by aggression or violence, which usually occur while taking AAS, and depressive symptoms occurring during AAS withdrawal. However, these symptoms are idiosyncratic and afflict only a minority of illicit users; the mechanism of these idiosyncratic responses remains unclear. AAS users may also ingest a range of other illicit drugs, including both "body image" drugs to enhance physical appearance or performance, and classical drugs of abuse. In particular, AAS users appear particularly prone to opioid use. There may well be a biological basis for this association, since both human and animal data suggest that AAS and opioids may share similar brain mechanisms. Finally, AAS may cause a dependence syndrome in a substantial minority of users. AAS dependence may pose a growing public health problem in future years but remains little studied. Copyright 2009 Elsevier Inc. All rights reserved.

  12. The Relationship between Androgenic Alopecia and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ghasem Rahmatpour Rokni

    2016-07-01

    Full Text Available Prostate cancer (PC and Androgenic Alopecia (AGA i are both common diseases in elder men. It seems that androgen plays a crucial role in the growth and development of prostate cancer. Therefore, the current study intended to investigate the relationship between androgenic alopecia and prostate cancer. The present study is a case-control study conducted on 75 patients with prostate cancer (case group referring to Imam Khomeini Hospital in Sari, Iran. The case group was compared with the control group (75 healthy individuals. The intended questionnaire of the study included information such as the age, sex, duration of disease, stage of disease, level of PSA, time diagnosis and time of interview for all the participants. The results of interview and clinical examination along with the patient’s information all were filled in the questionnaire and were statistically analyzed by SPSS after data collection. The mean age of PC group and healthy group was respectively 69.08 ± 8.97 and 68 .45 ± 10.16 years. The average level of PSA was 10.86 ± 11.7 and 2.66 ± 2.7 ng/ml in PC and healthy group in turn. The average duration of cancer was 12.63 ± 9.19 months in PC group. Furthermore, about 6.7% of cancer patients were in stage I, 48% were stage II, 29.3% were in stage III and 16% were in stage IV of prostate cancer. Besides, the number of cancer patients who had both frontal and vertex alopecia (baldness altogether exceeded healthy individuals (P=0.002. According to the results of the present study, there was a significant relationship between prostate cancer and androgenic alopecia which might have been caused by the effect of androgens on both diseases. Consequently, androgenic alopecia can be considered as one of the risk factors associated with prostate cancer.

  13. Evaluation of the Implementation of a Rapid Response Treatment Protocol for Patients with Acute Onset Stroke: Can We Increase the Number of Patients Treated and Shorten the Time Needed

    Directory of Open Access Journals (Sweden)

    Rajiv Advani

    2014-06-01

    Full Text Available Aims: This study aims to evaluate the implementation of a rapid response treatment protocol for patients presenting with acute onset ischemic stroke. Improvements of routines surrounding the admission and treatment of patients with intravenous thrombolysis (IVT, such as door-to-needle (DTN times, and increasing the numbers of patients treated are discussed. Methods: We conducted a retrospective analysis of all patients (n = 320 treated with IVT for acute onset ischemic stroke at the Stavanger University Hospital, Norway, between 2003 and 2012. In 2009, a succession of changes to pre- and intra-hospital routines were made as well as an improvement in the education of primary health care physicians, nurses and paramedics involved in the treatment of acute onset stroke patients (rapid response treatment protocol. Analyses of DTN times, onset-to-needle times and the number of patients treated per year were carried out to ascertain the effect of the changes made. The primary aim was to analyze DTN times to look for any changes, and the secondary aim was to analyze changes in the number of patients treated per year. Results: In the years after the implementation of the rapid treatment protocol, we saw an improvement in the median DTN time with a decrease from 73 to 50 min in the first year (p = 0.03, a decrease of 45 min in the second year (p = 0.01 and a decrease of 31 min in the third year (p Conclusions: The implementation of the rapid treatment protocol for acute onset ischemic stroke patients led to a significant decrease in the DTN time at our center. These improvements also produced an increase in the number of patients treated per year. The extension of the therapeutic window from 3 to 4.5 h for the use of intravenous recombinant tissue plasminogen activator also played a role in the increased treatment numbers.

  14. Nrdp1-Mediated ErbB3 Increase During Androgen Ablation and Its Contribution to Androgen-Independence

    Science.gov (United States)

    2012-09-01

    electrophoresis cells (Mini-PROTEAN 3 Electrophoresis Cell, Bio-Rad, Hercules, CA). The gels were electroblotted for 2 h at 200 mA using a Mini Trans-Blot...added for 1.5 hr at 4 degrees Celsius and pulled down with 20 µl of Protein G Agarose/Salmon Sperm DNA beads (Millipore Billerica, MA) at room...separate aliquots. Following cleanup, the samples were run on a 1% agarose gel and the region between 200 to 500 bp was cut out and purified using the

  15. Localized infusions of the partial alpha 7 nicotinic receptor agonist SSR180711 evoke rapid and transient increases in prefrontal glutamate release

    DEFF Research Database (Denmark)

    Bortz, D M; Mikkelsen, J D; Bruno, J P

    2013-01-01

    that inhibited (threo-beta-benzyl-oxy-aspartate (TβOA), 100.0μM) or facilitated (ceftriaxalone, 200mg/kg, i.p.) excitatory amino acid transporters. TβOA slowed both the clearance (s) and rate of clearance (μM/s) by 10-fold, particularly at the mid-late stages of the return to baseline. Ceftriaxone reduced......The ability of local infusions of the alpha 7 nicotinic acetycholine receptor (α7 nAChR) partial agonist SSR180711 to evoke glutamate release in prefrontal cortex was determined in awake rats using a microelectrode array. Infusions of SSR180711 produced dose-dependent increases in glutamate levels...

  16. Antagonism of miR-328 increases the antimicrobial function of macrophages and neutrophils and rapid clearance of non-typeable Haemophilus influenzae (NTHi from infected lung.

    Directory of Open Access Journals (Sweden)

    Hock L Tay

    2015-04-01

    Full Text Available Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

  17. Antagonism of miR-328 increases the antimicrobial function of macrophages and neutrophils and rapid clearance of non-typeable Haemophilus influenzae (NTHi) from infected lung.

    Science.gov (United States)

    Tay, Hock L; Kaiko, Gerard E; Plank, Maximilian; Li, JingJing; Maltby, Steven; Essilfie, Ama-Tawiah; Jarnicki, Andrew; Yang, Ming; Mattes, Joerg; Hansbro, Philip M; Foster, Paul S

    2015-04-01

    Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.

  18. Analysis of a rapid increase of stratospheric ozone during late austral summer 2008 over Kerguelen (49.4° S, 70.3° E

    Directory of Open Access Journals (Sweden)

    H. Bencherif

    2011-01-01

    Full Text Available This paper reports on an increase of ozone event observed over Kerguelen (49.4° S, 70.3° E in relationship with large-scale isentropic transport. This is evidenced by ground-based observations (co-localised radiosonde and SAOZ experiments together with satellite global observations (Aura/MLS assimilated into MOCAGE, a Méteo-France model.

    The study is based on the analyses of the first ozonesonde experiment never recorded at the Kerguelen site within the framework of a French campaign called ROCK that took place from April to August 2008.

    Comparisons and interpretations of the observed event are supported by co-localised SAOZ observations, by global mapping of tracers (O3, N2O and columns of O3 from Aura/MLS and Aura/OMI experiments, and by model simulations of Ertel Potential Vorticity initialised by the ECMWF (European Centre for Medium-Range Weather Forecasts data reanalyses.

    Satellite and ground-based observational data revealed a consistent increase of ozone in the local stratosphere by mid-April 2008. Additionally, Ozone (O3 and nitrous oxide (N2O profiles obtained during January–May 2008 using the Microwave Limb Sounder (MLS aboard the Aura satellite are assimilated into MOCAGE (MOdèle de Chimie Atmosphérique à Grande Echelle, a global three-dimensional chemistry transport model of Météo-France. The assimilated total O3 values are consistent with SAOZ ground observations (within ±5%, and isentropic distributions of O3 match well with maps of advected potential vorticity (APV derived from the MIMOSA model, a high-resolution advection transport model, and from the ECMWF reanalysis.

    The event studied seems to be related to the isentropic transport of air masses that took place simultaneously in the lower- and middle-stratosphere, respectively from the polar region and from the tropics to the mid-latitudes.

    In

  19. Vitamin D3 and androgen receptors in testis and epididymal region of roosters (Gallus domesticus) as affected by epididymal lithiasis.

    Science.gov (United States)

    Oliveira, André G; Dornas, Rubem A P; Kalapothakis, Evanguedes; Hess, Rex A; Mahecha, Germán A B; Oliveira, Cleida A

    2008-12-01

    Epididymal lithiasis is a dysfunction characterized by formation of calcium-rich stones in the epididymal region of roosters, associated with decreased serum testosterone and loss of fertility. The segment most affected by the lithiasis is the efferent ductules, which, in birds, are responsible for reabsorption of calcium and luminal fluid. Therefore, we postulated that epididymal lithiasis could result from local impairment of calcium or fluid homeostasis, culminating in initiation of stone formation. Transepithelial calcium transport depends on vitamin D3 and vitamin D3 receptor (VDR). Based on the fact that VDR are present in efferent ductules, possible changes in the pattern of VDR in roosters affected by the epididymal lithiasis was investigated, to start to gain an understanding of the molecular mechanisms involved in the development of calcium stones. To evaluate the potential impact of androgen reduction, changes in androgen receptor (AR) were also investigated. Both VDR and AR were increased in specific segments of the epididymal region, whereas no alterations were found in the testes of affected animals. The increase in VDR was most likely due to an increase in the number of VDR-positive mononuclear leukocyte infiltrates found in the connective tissue followed by an increase in epithelial receptors. The AR were increased, however, mainly in the epididymal duct epithelium. These results suggest that the vitamin D3 and androgen responsive system may be directly/indirectly involved in the development of the disease.

  20. Rapid increase of Plasmodium falciparum dhfr/dhps resistant haplotypes, after the adoption of sulphadoxine-pyrimethamine as first line treatment in 2002, in southern Mozambique.

    Science.gov (United States)

    Enosse, Sonia; Magnussen, Pascal; Abacassamo, Fatima; Gómez-Olivé, Xavier; Rønn, Anita M; Thompson, Ricardo; Alifrangis, Michael

    2008-07-01

    In late 2002, the health authorities of Mozambique implemented sulphadoxine-pyrimethamine (SP)/amodiaquine (AQ) as first-line treatment against uncomplicated falciparum malaria. In 2004, this has been altered to SP/artesunate in line with WHO recommendations of using Artemisinin Combination Therapies (ACTs), despite the fact that all the neighbouring countries have abandoned SP-drug combinations due to high levels of SP drug resistance. In the study area, one year prior to the change to SP/AQ, SP alone was used to treat uncomplicated malaria cases. The study described here investigated the immediate impact of the change to SP on the frequency of SP and CQ resistance-related haplotypes in the Plasmodium falciparum genes Pfdhfr, Pfdhps and Pfcrt before and a year after the introduction of SP. Samples were collected during two cross sectional surveys in early 2002 and 2003 involving 796 and 692 children one year or older and adults randomly selected living in Maciana, an area located in Manhiça district, Southern Mozambique. Out of these, 171 and 173 P. falciparum positive samples were randomly selected to measure the frequency of resistance- related haplotypes in Pfdhfr, Pfdhps and Pfcrt based on results obtained by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)-ELISA. The frequency of the SP-resistance associated Pfdhps double mutant (SGEAA) haplotype increased significantly from 14% to 35% (P drug, Coartem.

  1. Are Koreans Prepared for the Rapid Increase of the Single-Household Elderly? Life Satisfaction and Depression of the Single-Household Elderly in Korea

    Directory of Open Access Journals (Sweden)

    Mi-Ra Won

    2013-01-01

    Full Text Available Purpose. In Korea, it has been estimated that the number of the single-household elderly increased 45% from 2005 to 2010. This research was conducted to provide empirical resources for development of a community mental health program by an explorative investigation on depression, coping mechanism, and life satisfaction of a single-household elderly population. Design and Methods. This research applied a descriptive survey research design. Participants were 225 single-household elderlies residing in Seoul, Korea. The geriatric depression scale and the satisfaction with life scale were used to check the level of depression and life satisfaction of the participants. Results. Results showed that 46.3 percent of the participants were categorized as having light-to-severe level of depression, and 80.5 percent of the participants responded that they were dissatisfied with their lives. This research demonstrated that the level of depression and life satisfaction of the Korean single-household elderly is statistically significantly related to age and gender as well as coping resources and human resources. Implications. Current public health services in Korea for the single-household elderly are still lacking and require active support, intervention, and research to provide effective programs and services. Case management, counseling, and various programs based on Korean culture including support from family members and community-based assistance are recommended to help the vulnerable population.

  2. Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1

    Directory of Open Access Journals (Sweden)

    Yao Jorge L

    2008-04-01

    Full Text Available Abstract Background Steroid hormones influence mitogenic signaling pathways, apoptosis, and cell cycle checkpoints, and it has long been known that incidence of bladder cancer (BC in men is several times greater than in women, a difference that cannot be attributed to environmental or lifestyle factors alone. Castration reduces incidence of chemically-induced BC in rodents. It is unclear if this effect is due to hormonal influences on activation/deactivation of carcinogens or a direct effect on urothelial cell proliferation or other malignant processes. We examined the effect of castration on BC growth in UPII-SV40T transgenic mice, which express SV40 T antigen specifically in urothelium and reliably develop BC. Furthermore, because BC growth in UPII-SV40T mice is exophytic, we speculated BC growth was dependent on angiogenesis and angiogenesis was, in turn, androgen responsive. Methods Flat panel detector-based cone beam computed tomography (FPDCT was used to longitudinally measure exophytic BC growth in UPII-SV40T male mice sham-operated, castrated, or castrated and supplemented with dihydrotestosterone (DHT. Human normal bladder and BC biopsies and mouse bladder were examined quantitatively for thrombospondin-1 (TSP1 protein expression. Results Mice castrated at 24 weeks of age had decreased BC volumes at 32 weeks compared to intact mice (p = 0.0071 and castrated mice administered DHT (p = 0.0233; one-way ANOVA, JMP 6.0.3, SAS Institute, Inc.. Bladder cancer cell lines responded to DHT treatment with increased proliferation, regardless of androgen receptor expression levels. TSP1, an anti-angiogenic factor whose expression is inhibited by androgens, had decreased expression in bladders of UPII-SV40T mice compared to wild-type. Castration increased TSP1 levels in UPII-SV40T mice compared to intact mice. TSP1 protein expression was higher in 8 of 10 human bladder biopsies of normal versus malignant tissue from the same patients. Conclusion

  3. Identification and characterisation of an androgen receptor from zebrafish Danio rerio

    DEFF Research Database (Denmark)

    Jørgensen, Anne; Andersen, Ole; Bjerregaard, Poul

    2007-01-01

    ) and goldfish (Carassius auratus). Binding assays with zfAR demonstrated high affinity, saturable, single class binding site, with the characteristics of an androgen receptor. Saturation experiments along with subsequent Scatchard analysis determined that the Kd of the zfAR for 3H-testosterone was 2 n......Androgens play key roles in vertebrate sex differentiation, gonadal differentiation and sexual behaviour. The action of androgens is primarily mediated through androgen receptors (ARs). The present study describes the isolation, sequencing and initial characterisation of an androgen receptor from...

  4. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States.

    Science.gov (United States)

    Gilbert, Scott M; Kuo, Yong-Fang; Shahinian, Vahakn B

    2011-01-01

    Androgen deprivation therapy (ADT) for prostate cancer increased substantially through the 1990s, but more recent national trends regarding incident and prevalent use have been incompletely characterized. Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data were used to study patterns of ADT utilization. Prevalence of ADT in the male Medicare population was estimated by examining a cohort of prostate cancer patients and a 5% noncancer control population, from 1991 to 2005. ADT use across different indications was examined for men with incident cancers from 2000 to 2002. Nested logit models were used to examine determinants of ADT use in men with lower risk prostate cancer not treated definitively by surgery or radiation. Prevalent ADT use increased through the 1990s, peaked in 2000 at 3.17% of all male Medicare beneficiaries, subsequently stabilized, then dropped in 2005 to 2.92%. Between 2000 and 2002, use in incident prostate cancer was stable, with 44.8% use in all cases, 15% of cases as an adjuvant with radiation, and 14% as a primary therapy. In the nested logit model, predictors of ADT use in a lower risk setting were older age, higher stage and grade, and elevated prostate-specific antigen levels. Following a period of rapid expansion during the 1990s, incident and prevalent use of ADT has leveled, and may be starting to decline. Further research is needed to monitor how reductions in reimbursement for GnRH agonists will affect appropriate use of ADT as well as use in settings where its benefits may be marginal. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Predictors of diabetic foot and leg ulcers in a developing country with a rapid increase in the prevalence of diabetes mellitus.

    Science.gov (United States)

    Sriyani, Kumarasinghe A; Wasalathanthri, Sudharshani; Hettiarachchi, Priyadharshika; Prathapan, Shamini

    2013-01-01

    To identify the socio demographic, life style and foot examination related predictors of diabetic foot and leg ulcers with a view to develop a screening tool appropriate for the use in an outpatient setting. This cross sectional study included type 2 diabetes mellitus (DM) patients; 88 subjects with leg and foot ulcers and 80 non ulcer controls. Socio demographic data and life style factors were documented. Foot was examined for skin changes and structural abnormalities. Distal peripheral neuropathy was assessed by pressure sense, vibration sense and joint position sense. Multivariate analysis by logistic regression was used to determine the significant predictors in screening for foot ulcers. Education of grade 6 and below (OR--1.41, 95% CI; 1.03-4.68), low income (OR--23.3, 95% CI; 1.5-34.0), impaired vibration sense (OR--24.79, 95% CI; 9.3-66.2), abnormal monofilament test on first (OR--1.69, 95% CI; 1.36-16.6), third (OR--3.4, 95% CI; 1.1-10.6) and fifth (OR--1.8, 95% CI; 1.61-12.6) toes are found to be predictors of increased risk whereas incidental diagnosis of DM (OR--0.03, 95% CI; 0.003-0.28), wearing covered shoes (OR--0.003, 95% CI; 0.00-0.28), presence of normal skin color (OR--0.01, 95% CI; 0.001-0.14) and normal monofilament test on first metatarsal head (OR--0.10, 95% CI; 0.00-0.67) are protective factors for ulcers. Ten independent risk and protective factors identified in this study are proposed as a simple screening tool to predict the risk of developing leg and foot ulcers in patients with DM.

  6. Predictors of diabetic foot and leg ulcers in a developing country with a rapid increase in the prevalence of diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Kumarasinghe A Sriyani

    Full Text Available OBJECTIVE: To identify the socio demographic, life style and foot examination related predictors of diabetic foot and leg ulcers with a view to develop a screening tool appropriate for the use in an outpatient setting. RESEARCH DESIGN AND METHODS: This cross sectional study included type 2 diabetes mellitus (DM patients; 88 subjects with leg and foot ulcers and 80 non ulcer controls. Socio demographic data and life style factors were documented. Foot was examined for skin changes and structural abnormalities. Distal peripheral neuropathy was assessed by pressure sense, vibration sense and joint position sense. Multivariate analysis by logistic regression was used to determine the significant predictors in screening for foot ulcers. RESULTS: Education of grade 6 and below (OR--1.41, 95% CI; 1.03-4.68, low income (OR--23.3, 95% CI; 1.5-34.0, impaired vibration sense (OR--24.79, 95% CI; 9.3-66.2, abnormal monofilament test on first (OR--1.69, 95% CI; 1.36-16.6, third (OR--3.4, 95% CI; 1.1-10.6 and fifth (OR--1.8, 95% CI; 1.61-12.6 toes are found to be predictors of increased risk whereas incidental diagnosis of DM (OR--0.03, 95% CI; 0.003-0.28, wearing covered shoes (OR--0.003, 95% CI; 0.00-0.28, presence of normal skin color (OR--0.01, 95% CI; 0.001-0.14 and normal monofilament test on first metatarsal head (OR--0.10, 95% CI; 0.00-0.67 are protective factors for ulcers. CONCLUSIONS: Ten independent risk and protective factors identified in this study are proposed as a simple screening tool to predict the risk of developing leg and foot ulcers in patients with DM.

  7. Effect of androgen deprivation therapy on cardiovascular risk factors in prostate cancer

    Directory of Open Access Journals (Sweden)

    Mahnaz Roayaei

    2013-01-01

    Full Text Available Background: Androgen deprivation is the basis of treatment for advanced stages of prostate cancer. Cardiovascular disease may be a risk factor for mortality in prostate cancer. Therefore, we decided to evaluate the effect of androgen deprivation therapy (ADT on the cardiovascular risk factors in patients with prostate cancer. Materials and Methods: In a cross-sectional study on 2011, 35 patients suffering from metastatic prostate cancer as candidates for ADT were enrolled. Serum levels of fasting blood sugar (FBS, triglyceride (TG and total cholesterol (TC were measured at the beginning and after the 5 th month of ADT. Results: The mean level of TG increased significantly from 130.82 ± 41.57 mg/dl to 150.05 ± 48.29 mg/dl (P < 0.012. Furthermore, serum level of TC increased from 197.62 ± 40.71 mg/dl to 212.54 ± 38.25 mg/dl, which is statistically significant (P < 0.001. A non-significant increase in the serum level of FBS from 96.74 ± 14.04 mg/dl to 99.17 ± 15.23 mg/dl was also seen (P = 0.27. Conclusion: ADT in prostate cancer may lead to an increase in TG and TC levels. In patients with a high risk of cardiovascular disease patient′s lipid profile should be considered during ADT.

  8. Evidence that cytochrome b{sub 5} acts as a redox donor in CYP17A1 mediated androgen synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Duggal, Ruchia [Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL (United States); Liu, Yilin [Department of Chemistry, Marquette University, Milwaukee, WI (United States); Gregory, Michael C.; Denisov, Ilia G. [Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL (United States); Kincaid, James R. [Department of Chemistry, Marquette University, Milwaukee, WI (United States); Sligar, Stephen G., E-mail: s-sligar@illinois.edu [Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, IL (United States); Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL (United States)

    2016-08-19

    Cytochrome P450 17A1 (CYP17A1) is an important drug target for castration resistant prostate cancer. It is a bi-functional enzyme, catalyzing production of glucocorticoid precursors by hydroxylation of pregnene-nucleus, and androgen biosynthesis by a second C−C lyase step, at the expense of glucocorticoid production. Cytochrome b{sub 5} (cyt b{sub 5}) is known to be a key regulator of the androgen synthesis reaction in vivo, by a mechanism that is not well understood. Two hypotheses have been proposed for the mechanism by which cyt b{sub 5} increases androgen biosynthesis. Cyt b{sub 5} could act as an allosteric effector, binding to CYP17A1 and either changing its selective substrate affinity or altering the conformation of the P450 to increase the catalytic rate or decrease unproductive uncoupling channels. Alternatively, cyt b{sub 5} could act as a redox donor for supply of the second electron in the P450 cycle, reducing the oxyferrous complex to form the reactive peroxo-intermediate. To understand the mechanism of lyase enhancement by cyt b{sub 5}, we generated a redox-inactive form of cyt b{sub 5}, in which the heme is replaced with a Manganese-protoporphyrin IX (Mn-b{sub 5}), and investigated enhancement of androgen producing lyase reaction by CYP17A1. Given the critical significance of a stable membrane anchor for all of the proteins involved and the need for controlled stoichiometric ratios, we employed the Nanodisc system for this study. The redox inactive form was observed to have no effect on the lyase reaction, while reactions with the normal heme-iron containing cyt b{sub 5} were enhanced ∼5 fold as compared to reactions in the absence of cyt b{sub 5}. We also performed resonance Raman measurements on ferric CYP17A1 bound to Mn-b{sub 5}. Upon addition of Mn-b{sub 5} to Nanodisc reconstituted CYP17A1, we observed clear evidence for the formation of a b{sub 5}-CYP17A1 complex, as noted by changes in the porphyrin modes and alteration in the proximal

  9. Influence of androgens on circulating adiponectin in male and female rodents.

    Directory of Open Access Journals (Sweden)

    Joshua F Yarrow

    Full Text Available Several endocrine factors, including sex-steroid hormones are known to influence adiponectin secretion. Our purpose was to evaluate the influence of testosterone and of the synthetic non-aromatizable/non-5α reducible androgen 17β-hydroxyestra-4,9,11-trien-3-one (trenbolone on circulating adiponectin and adiponectin protein expression within visceral fat. Young male and female F344 rats underwent sham surgery (SHAM, gonadectomy (GX, or GX plus supraphysiologic testosterone-enanthate (TE administration. Total circulating adiponectin was 39% higher in intact SHAM females than SHAM males (p<0.05. GX increased total adiponectin by 29-34% in both sexes (p<0.05, while TE reduced adiponectin to concentrations that were 46-53% below respective SHAMs (p≤0.001 and ablated the difference in adiponectin between sexes. No differences in high molecular weight (HMW adiponectin were observed between sexes or treatments. Adiponectin concentrations were highly and negatively associated with serum testosterone (males: r = -0.746 and females: r = -0.742, p≤0.001; however, no association was present between adiponectin and estradiol. In separate experiments, trenbolone-enanthate (TREN prevented the GX-induced increase in serum adiponectin (p≤0.001 in young animals, with Low-dose TREN restoring adiponectin to the level of SHAMs and higher doses of TREN reducing adiponectin to below SHAM concentrations (p≤0.001. Similarly, TREN reduced adiponectin protein expression within visceral fat (p<0.05. In adult GX males, Low-dose TREN also reduced total adiponectin and visceral fat mass to a similar magnitude as TE, while increasing serum HMW adiponectin above SHAM and GX animals (p<0.05. Serum adiponectin was positively associated with visceral fat mass in young (r = 0.596, p≤0.001 and adult animals (r = 0.657, p≤0.001. Our results indicate that androgens reduce circulating total adiponectin concentrations in a dose-dependent manner, while maintaining HMW

  10. A Novel Mutation in Human Androgen Receptor Gene Causing Partial Androgen Insensitivity Syndrome in a Patient Presenting with Gynecomastia at Puberty

    National Research Council Canada - National Science Library

    Koçyiğit, Cemil; Sarıtaş, Serdar; Çatlı, Gönül; Onay, Hüseyin; Dündar, Bumin Nuri

    2016-01-01

    Partial androgen insensitivity syndrome (PAIS) typically presents with micropenis, perineoscrotal hypospadias, and a bifid scrotum with descending or undescending testes and gynecomastia at puberty...

  11. A Novel Mutation in Human Androgen Receptor Gene Causing Partial Androgen Insensitivity Syndrome in a Patient Presenting with Gynecomastia at Puberty

    National Research Council Canada - National Science Library

    Cemil Koçyigit; Serdar Saritas; Gönül Çatli; Hüseyin Onay; Bumin Nuri Dündar

    2016-01-01

      Partial androgen insensitivity syndrome (PAIS) typically presents with micropenis, perineoscrotal hypospadias, and a bifid scrotum with descending or undescending testes and gynecomastia at puberty...

  12. A case of androgen-secreting adrenal carcinoma with non-classical congenital adrenal hyperplasia

    Directory of Open Access Journals (Sweden)

    Tarun Varma

    2013-01-01

    Full Text Available Androgen excess is one of the most common and disturbing endocrine disorder of reproductive-aged women, affecting approximately 7% of this population Androgen excess results in the development of androgenic features in the women affected, with the development of hirsutism, androgenic alopecia, ovulatory dysfunction, and, if extreme, even virilization and masculinization. Adrenocortical carcinoma (ACC is a rare malignancy accounting for 0.02% of all annual cancers reported. About 60% are functional tumors secreting hormones, with its consequent clinical manifestations, the Cushing′s syndrome due to cortisone, virilization due to androgens, feminization due to estrogens, or hypertension due to aldosterone. Adrenal tumors that secrete androgens exclusively are extremely rare. Here, we present a rare case of androgen-secreting adrenocortical carcinoma with non-classical congenital adrenal hyperplasia.

  13. Effects of environmentally relevant concentrations of the xeno-androgen, methyldihydrotestosterone, on male and female mating behavior in Xenopus laevis.

    Science.gov (United States)

    Hoffmann, Frauke; Kloas, Werner

    2012-06-01

    Endocrine disrupting compounds (EDCs) are well known to interfere with the hormone system of aquatic vertebrates and to affect their reproductive biology. 17α-Methyldihydrotestosterone (MDHT) is a widely used model compound for the assessment of androgenic EDCs, because it binds with high affinity to nuclear androgen receptors. It was previously shown to affect various aspects of reproductive biology in aquatic vertebrates, however, evidence for MDHT affecting mating behavior of aquatic vertebrate species is lacking. In order to test the assumption that MDHT affects reproductive behavior of aquatic vertebrates, we exposed male and female Xenopuslaevis to three environmentally relevant concentrations of MDHT (30.45 ng L(-1), 3.05 μg L(-1) and 30.45 μg L(-1)). In males, MDHT at all concentrations led to enhanced levels of advertisement calling and decreased the relative proportions of rasping, a call type characterizing a sexually unaroused state of the male, indicating an increase in sexual arousal of MDHT exposed males. Temporal and spectral parameters of the advertisement call itself, however, were not affected by MDHT exposure. In females, MDHT (30.45 ng L(-1)) did not have any effects, while MDHT at 3.05 μg L(-1) increased female receptivity, increased the duration of time females spent close to the speaker playing male advertisement calls and reduced their latency to respond. MDHT at 30.45 μg L(-1), on the other hand, decreased female receptivity and increased their latency to respond. In summary, this study illustrates that exposure to environmentally relevant concentrations of the androgenic EDC MDHT affects male and female mating behavior of X. laevis. Hence, we suggest that nonaromatizable androgens might play a direct and predominant role in the physiology and regulation of reproduction not only in male but also in female frogs. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

    Science.gov (United States)

    2013-10-01

    and ProduXion Manager® from Aries Systems Corporation 2 Bifunctional Ligand Control of Nuclear Receptors 1 Bifunctional Ligands Allow...androgen receptor. Genes Dev 21:2005-2017 23. Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Núñez G 2000 An Induced Proximity

  15. REPRODUCTIVE TOXICITY OF ANDROGENIC GROWTH PROMOTORS IN THE FATHEAD MINNOW

    Science.gov (United States)

    Reproductive Toxicity of Androgenic Growth Promoters in the Fathead Minnow. Jensen, KM*, Kahl, MD, Makynen, EA, Hornung, MW, Ankley, GT. U.S. Environmental Protection Agency, Duluth, MN. Trenbolone acetate is a synthetic steroid which is extensively used in the US as a growth pro...

  16. Prevalence and awareness of anabolic androgenic steroid use ...

    African Journals Online (AJOL)

    Purpose: To examine the prevalence and awareness of anabolic-androgenic steroid (AAS) use among male bodybuilders visiting gyms in Jazan region, Saudi Arabia. Methods: A cross-sectional survey was conducted among 500 male bodybuilders visiting gyms in the Jazan region of Saudi Arabia. Information on ...

  17. Psychological and Behavioral Effects of Anabolic-Androgenic Steroids.

    Science.gov (United States)

    Bahrke, Michael S.

    This review of the literature on the psychological and behavioral effects of anabolic-androgenic steroids (AS) first looks at aspects of the history and prevalence of AS use in competitive sports. Research suggests that one-quarter to one-half million adolescents in the United States have used, or are currently using AS. Some effects of androgens…

  18. Genetic variations in androgen metabolism genes and associations ...

    African Journals Online (AJOL)

    We investigated the role of genetic variants in the androgen metabolism genes and the probability of developing PCa in South African coloured and white men. Methods. Genotype and allele counts and frequencies of single nucleotide polymorphisms (SNPs) in CYP3A5, CYP3A4 and CYP3A43 were assessed in coloured ...

  19. Baldness, benign prostate hyperplasia, prostate cancer and androgen levels.

    Science.gov (United States)

    Faydaci, Gökhan; Bilal, Eryildirim; Necmettin, Penpegül; Fatih, Tarhan; Asuman, Orçun; Uğur, Kuyumcuoğlu

    2008-12-01

    We evaluated the pattern of baldness and serum androgen levels in patients with benign prostate hyperplasia (BPH) and prostate cancer. BPH, prostate cancer and androgenic alopecia (AA) were somehow androgen dependent and affect large population of elderly men. A total of 152 patients, 108 patients with BPH and 44 patients with prostate cancer were included in the study. We measured serum total, free and bioavailable testosterone, FSH, LH, prolactin, estradiol, albumin and SHBG levels. Baldness classification was based on Norwood's classification and we categorised baldness as vertex and frontal baldness. The frequency of AA in BPH and prostate cancer groups were not different. We looked for some correlation between the two groups with respect to AA and hormone levels. We did not find any correlation between AA and total testosterone, free testosterone, bioavailable testosterone or SHBG levels in both groups. This prospective study with selected small group of patients showed that there is no difference of male pattern baldness in BPH and prostate cancer patients and also there is no correlation between pattern of baldness and serum androgen levels.

  20. Additive effects of dietary glycotoxins and androgen excess on the ...

    African Journals Online (AJOL)

    Sotiria Palimeri

    2015-08-08

    Aug 8, 2015 ... PCOS. Abstract Background: Dietary glycotoxins and androgen excess have been independently associ- ated with a negative influence on the kidney. There are no data concerning the additive effects of these two factors on the kidney function and structure, in females. The present study aims to inves-.

  1. Reduced fetal androgen exposure compromises Leydig cell function in adulthood

    NARCIS (Netherlands)

    Teerds, K.J.; Keijer, J.

    2015-01-01

    Disruption of normal fetal development can influence functioning of organs and cells in adulthood. Circumstantial evidence suggests that subtle reductions in fetal androgen production may be the cause of adult male reproductive disorders due to reduced testosterone production. The mechanisms through

  2. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

    Science.gov (United States)

    Thevis, Mario; Schänzer, Wilhelm

    2010-01-01

    The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

  3. ORIGINAL ARTICLE A Study of the androgen receptor gene ...

    African Journals Online (AJOL)

    salah

    Background: Androgenetic alopecia (AGA) occurs in men and women. The nature of the genetic predisposition to androgenetic alopecia is still unresolved. The aim of the work is to study the genotype of the androgen receptor gene. (StuI polymorphism) and its relationship to AGA in a case control study and to determine the ...

  4. Male pubertal development and the role of androgen therapy.

    Science.gov (United States)

    Richmond, Erick J; Rogol, Alan D

    2007-04-01

    In boys, the hormonal changes that accompany normal puberty are well defined, as are the physical signs of pubertal development and the kinetics of the growth spurt. Most androgens are derived from the testes, although adrenal androgens may also contribute; testosterone can also be aromatized to estrogen to exert important effects during puberty. Androgens, but especially their conversion to estrogens by aromatase, have a major role in the dramatic changes in linear growth, secondary sexual characteristics, and changes to bone, muscle and fat distribution that occur during puberty. Androgen therapy for delayed puberty should permit full normal pubertal development and thereby also address some of the associated psychosocial problems. Adolescent boys with conditions of permanent hypogonadism (hypogonadotropic or hypergonadotropic) or transient hypogonadotropic hypogonadism (constitutional delay of growth and puberty) can benefit from testosterone therapy. Long-term testosterone therapy should be given for hypothalamic or pituitary gonadotropin deficiency, or for primary hypogonadism such as for adolescents with Klinefelter syndrome, if endogenous testosterone levels drop or levels of luteinizing hormone rise. Intramuscular administration every few weeks is effective, but newer cutaneous forms, for example, gels or patches, also show promise in permitting adolescent males to reach adult body composition.

  5. Androgenic potential and anther in vitro culture of Lagenaria ...

    African Journals Online (AJOL)

    Androgenic potential and anther in vitro culture of Lagenaria siceraria (Molina) Standl an edible-seed cucurbit. Kouakou Laurent Kouakou, Tra Serge Doubi, Tra Serge Koffi, Kouadio Ignace Kouassi, Tanoh Hilaire Kouakou, Jean-Pierre Baudoin, Irié Arsène Zoro Bi ...

  6. Environmental polycyclic aromatic hydrocarbons affect androgen receptor activation in vitro

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Hnida, Christina; Larsen, John Christian

    2000-01-01

    Nine structurally different polycyclic aromatic hydrocarbons (PAHs) were tested for their ability to either agonize or antagonize the human androgen receptor (hAR) in a sensitive reporter gene assay based on CHO cells transiently cotransfected with a hAR vector and an MMTV-LUC vector. Benz...

  7. Androgen correlates of male reproductive effort in wild male long-tailed macaques (Macaca fascicularis): A multi-level test of the challenge hypothesis.

    Science.gov (United States)

    Girard-Buttoz, Cédric; Heistermann, Michael; Rahmi, Erdiansyah; Agil, Muhammad; Ahmad Fauzan, Panji; Engelhardt, Antje

    2015-03-15

    The challenge hypothesis (Wingfield et al., 1990) has been broadly utilised as a conceptual framework to study male androgen correlates of reproductive challenges in mammals. These studies mainly assessed male androgen responsiveness to a general degree of challenge over extended periods of time. Short term co-variation between the socio-sexual challenging context and androgen levels remains, however, largely understudied. We thus aim at providing a multi-level test of the challenge hypothesis by investigating the inter- and intra-individual variations in faecal androgen excretion associated to 1) breeding seasonality, 2) dominance rank, 3) mate-guarding activity and 4) value of the guarded female. We studied long-tailed macaques, a species in which males engage in highly challenging monopolisation of females over discreet periods of time. This particularity allows testing specifically the predicted increase from level B to level C in the challenge hypothesis. The study was carried out during two reproductive seasons on three groups of wild long-tailed macaques. We combined behavioural observations and non-invasive measurements of faecal androgen metabolite (fAM) levels. We found that, as predicted by the challenge hypothesis, male long-tailed macaques respond not only to seasonal but also to short term reproductive challenges by adapting their androgen levels. First, males exhibited a seasonal rise in fAM levels during the mating period which may be triggered by fruit availability as shown by our phenological data. Second, males had increased androgen levels when mate-guarding females and, across mate-guarding periods, males had higher fAM levels when monopolising high-ranking parous females than when monopolising low-ranking ones. Finally, high-ranking males had higher fAM levels than low-ranking males year round. Our study confirms that, in species with a high degree of female monopolisability, androgen may be an important physiological fitness enhancing tool

  8. The agonistic adrenal: melatonin elicits female aggression via regulation of adrenal androgens

    Science.gov (United States)

    Rudolph, Lauren M.; Sengelaub, Dale R.; Demas, Gregory E.

    2015-01-01

    Classic findings have demonstrated an important role for sex steroids as regulators of aggression, but this relationship is lacking within some environmental contexts. In mammals and birds, the adrenal androgen dehydroepiandrosterone (DHEA), a non-gonadal precursor of biologically active steroids, has been linked to aggression. Although females, like males, use aggression when competing for limited resources, the mechanisms underlying female aggression remain understudied. Here, we propose a previously undescribed endocrine mechanism regulating female aggression via direct action of the pineal hormone melatonin on adrenal androgens. We examined this in a solitary hamster species, Phodopus sungorus, in which both sexes are highly territorial across the seasons, and display increased aggression concomitant with decreased serum levels of sex steroids in short ‘winter-like' days. Short- but not long-day females had increased adrenal DHEA responsiveness co-occurring with morphological changes in the adrenal gland. Further, serum DHEA and total adrenal DHEA content were elevated in short days. Lastly, melatonin increased DHEA and aggression and stimulated DHEA release from cultured adrenals. Collectively, these findings demonstrate that DHEA is a key peripheral regulator of aggression and that melatonin coordinates a ‘seasonal switch’ from gonadal to adrenal regulation of aggression by direct action on the adrenal glands. PMID:26582025

  9. The androgen receptor and prostate cancer: a role for sexual selection and sexual conflict?

    Science.gov (United States)

    Summers, Kyle; Crespi, Bernard

    2008-01-01

    We propose and evaluate the hypothesis that the CAG repeat region of the androgen receptor represents a locus of antagonistic pleiotropy in the context of sexual selection and sexual conflict. Short repeats are associated with increased transactivation of the androgen receptor at the molecular level, and increased fertility at the phenotypic level. However, short repeats are also associated with increased risk of prostate cancer, and with more aggressive forms of the disease. The somatic evolution of cancer cell lineages also shows a repeated pattern of shortening of the CAG repeat in association with cancer progression, apparently as a result of positive selection among cell lineages. We further postulate that other genes associated with prostate cancer are likely to mediate antagonistic pleiotropy in the context of sexual selection and sexual conflict. A key prediction of this hypothesis is that the genes mediating antagonistic pleiotropy will show historical evidence of positive selection, particularly in the context of sexual conflict. Previous research on the molecular evolution of specific genes associated with prostate cancer supports this prediction, and we suggest further critical tests of the role for genomic conflicts and tradeoffs in the evolution of cancer risk.

  10. Prenatal androgen receptor activation determines adult alcohol and water drinking in a sex-specific way.

    Science.gov (United States)

    Huber, Sabine E; Zoicas, Iulia; Reichel, Martin; Mühle, Christiane; Büttner, Christian; Ekici, Arif B; Eulenburg, Volker; Lenz, Bernd; Kornhuber, Johannes; Müller, Christian P

    2017-08-04

    Alcohol use disorders are major psychiatric disorders. Correlational studies in humans suggested organizational hormonal effects during embryonic development as a risk factor for adult alcohol dependence. Permanent changes can be induced by the activity of sex hormones, like testosterone. Here, we demonstrate a relationship between prenatal androgen receptor (AR)-activation and adult alcohol as well as water drinking in mice in a sex-dependent fashion. Prenatal AR inhibition using the antagonist flutamide decreased adult male alcohol consumption. In contrast, prenatal AR activation by dihydrotestosterone (DHT) led to an increase in adult alcohol consumption in females. These effects were different in adult water drinking, flutamide increased water consumption in females and DHT increased water consumption in males. Prenatal flutamide reduced locomotion and anxiety in adult males but was ineffective in females. We found that prenatal AR activation controls adult levels of monoaminergic modulatory transmitters in the brain and blood hormone levels in a sex-specific way. RNA-Seq analysis confirmed a prenatal AR mediated control of adult expression of alcohol drinking-related genes like Bdnf and Per2. These findings demonstrate that prenatal androgen activity is a risk factor for the establishment of alcohol consumption in adults by its organizational effects. © 2017 Society for the Study of Addiction.

  11. Association Between Androgen Deprivation Therapy and Risk of Dementia.

    Science.gov (United States)

    Nead, Kevin T; Gaskin, Greg; Chester, Cariad; Swisher-McClure, Samuel; Leeper, Nicholas J; Shah, Nigam H

    2017-01-01

    A growing body of evidence supports a link between androgen deprivation therapy (ADT) and cognitive dysfunction, including Alzheimer disease. However, it is currently unknown whether ADT may contribute to the risk of dementia more broadly. To use an informatics approach to examine the association of ADT as a treatment for prostate cancer with the subsequent development of dementia (eg, senile dementia, vascular dementia, frontotemporal dementia, and Alzheimer dementia). In this cohort study, a text-processing method was used to analyze electronic medical record data from an academic medical center from 1994 to 2013, with a median follow-up of 3.4 years (interquartile range, 1.0-7.2 years). We identified 9455 individuals with prostate cancer who were 18 years or older at diagnosis with data recorded in the electronic health record and follow-up after diagnosis. We excluded 183 patients with a previous diagnosis of dementia. Our final cohort comprised 9272 individuals with prostate cancer, including 1826 men (19.7%) who received ADT. We tested the effect of ADT on the risk of dementia using propensity score-matched Cox proportional hazards regression models and Kaplan-Meier survival analysis. Among 9272 men with prostate cancer (mean [SD] age, 66.9 [10.9] years; 5450 [58.8%] white), there was a statistically significant association between use of ADT and risk of dementia (hazard ratio, 2.17; 95% CI, 1.58-2.99; P dementia among those who received ADT was 4.4% at 5 years (7.9% among those who received ADT vs 3.5% in those who did not receive ADT). Analyses stratified by duration of ADT found that individuals with at least 12 months of ADT use had the greatest absolute increased risk of dementia (hazard ratio, 2.36; 95% CI, 1.64-3.38; P dementia free (log-rank P dementia. This finding should be further evaluate