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Sample records for non-peptide gnrh agents

  1. Probing the GnRH receptor agonist binding site identifies methylated triptorelin as a new anti-proliferative agent

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    Robert P Millar

    2012-06-01

    Full Text Available D-amino acid substitutions at Glycine postion-6 in GnRH-I decapeptide can possess super-agonist activity and enhanced in vivo pharmacokinetics. Agonists elicit growth-inhibition in tumorigenic cells expressing the GnRH receptor above threshold levels. However, new agonists with modified properties are required to improve the anti-proliferative range. Effects of residue substitutions and methylations on tumourigenic HEK293[SCL60] and WPE-1-NB26-3 prostate cells expressing the rat GnRH receptor were compared. Peptides were ranked according to receptor binding affinity, induction of inositol phosphate production and cell growth-inhibition. Analogues possessing D-Trp6 (including Triptorelin, D-Leu6 (including Leuprolide, D-Ala6, D-Lys6, or D-Arg6 exhibited agonist and anti-proliferative activity. Residues His5 or His5,Trp7,Tyr8, corresponding to residues found in GnRH-II , were tolerated, with retention of sub-nanomolar/low nanomolar binding affinities and EC50s for receptor activation and IC50s for cell growth-inhibition. His5D-Arg6-GnRH-I exhibited reduced binding affinity and potency, effective in the mid-nanomolar range. However, all GnRH-II-like analogues were less potent than Triptorelin. By comparison, three methylated-Trp6 Triptorelin variants showed differential binding, receptor activation and anti-proliferation potency. Significantly, 5-Methyl-DL-Trp6-Triptorelin was equipotent to triptorelin. Subsequent studies should determine whether pharmacologically enhanced derivatives of Triptorelin can be developed by further alkylations, without substitutions or cleavable cytotoxic adducts, to improve the extent of growth-inhibition of tumour cells expressing the GnRH receptor.

  2. Backbone metal cyclization: Novel {sup 99m}Tc labeled GnRH analog as potential SPECT molecular imaging agent in cancer

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    Barda, Yaniv; Cohen, Nasi; Lev, Vered; Ben-Aroya, Nurit; Koch, Yitzhak; Mishani, Eyal; Fridkin, Mati; Gilon, Chaim E-mail: gilon@vms.huji.ac.il

    2004-10-01

    Gonadotropin-releasing hormone (GnRH) is a decapeptide secreted to the pituitary where it binds to specific receptors on the gonadotropes to regulate gonadotropic hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) synthesis and secretion. Specific GnRH receptors are overexpressed in breast, prostatic, ovarian, and other tumors. The aim of this study was to synthesize a cyclic GnRH analog with high affinity to GnRH receptors that can be radiolabeled with {sup 99m}Tc. A precyclic GnRH analog, [Cys-Gly]{sup 1}[D-Ala]{sup 6}[N{sup {alpha}}({eta}-Cys-amino hexyl)]{sup 10}GnRH (Gn-2), containing two hemi-chelator groups was synthesized. It was cyclized applying the recently reported backbone metal cyclization (BMC) approach, to obtain cyclo(Re(O)1-10)[Cys-Gly]{sup 1}[D-Ala]{sup 6}[N{sup {alpha}}({eta}-Cys-amino hexyl)]{sup 10}GnRH (cyclo[Re(O)-Gn-2]). For comparative evaluations, Gn-2 was oxidized on-resin to yield cyclo(S-S,1-10)[Cys-Gly]{sup 1}[D-Ala]{sup 6}[N{sup {alpha}}({eta}-Cys-amino hexyl)]{sup 10}GnRH, (cyclo[S-S-Gn-2]). The binding affinity of cyclo[Re(O)-Gn-2] to rat pituitary membranes showed IC{sub 50} of 50nM, compared to IC{sub 50} = 10 nM in the native GnRH. Cyclo({sup 99m}Tc(O)1-10)[Cys-Gly]{sup 1}[D-Ala]{sup 6}[N{sup {alpha}}({eta}-Cys-amino hexyl)]{sup 10}GnRH (cyclo[{sup 99m}Tc(O)-Gn-2]) was synthesized from Gn-2 and showed similar chromatographic behavior to its rhenium surrogate.

  3. EFFECT OF INVIVO PRETREATMENT WITH ESTRADIOL AND EITHER GNRH, GNRH AGONISTIC ANALOG OR GNRH ANTAGONISTIC ANALOG ON GNRH-STIMULATED SECRETION OF LH INVITRO

    NARCIS (Netherlands)

    SCHUILING, GA; KOITER, TR; MOES, H

    1991-01-01

    In vivo treatment with GnRH or with GnRH agonistic analog (AG), but not with GnRH antagonistic analog (ANT), depleted the LH stores of the rat pituitary gland. This depletion was potentiated by oestradiol. Oestradiol augmented the in vitro LH response of the pituitary gland to GnRH. This augmenting

  4. Non-peptide metabolites from the genus Bacillus.

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    Hamdache, Ahlem; Lamarti, Ahmed; Aleu, Josefina; Collado, Isidro G

    2011-04-25

    Bacillus species produce a number of non-peptide metabolites that display a broad spectrum of activity and structurally diverse bioactive chemical structures. Biosynthetic, biological, and structural studies of these metabolites isolated from Bacillus species are reviewed. This contribution also includes a detailed study of the activity of the metabolites described, especially their role in biological control mechanisms.

  5. [Non-peptide furin inhibitors based on amidinohydrazones of diarylaldehydes].

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    Kibirev, V K; Osadchuk, T V; Kozachenko, A P; Vadziuk, O B; Brovarets, V S

    2013-01-01

    A series of novel non-peptidic furin inhibitors containing amidinohydrazone moieties has been synthesized under interaction of dialdehydes, the derivatives of ethylene diethylvanillin ethers, with aminoguanidine bicarbonate. Two aryl cycles were bridged by 1,2-ethylene-, 1,4-buthylene- or 1,4-dimethylenebenzene-group. The compounds have been found to inhibit furin. The antifurin activity was shown to grow with the increase of the length and/or hydrophobicity of the bridge. The most potent compound, containing in the bridge the lypophylic benzene cycle was found to inhibit the activity of furin with Ki = 0.51 microM.

  6. Kisspeptin Excitation of GnRH Neurons

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    Rønnekleiv, Oline K.; Kelly, Martin J.

    2014-01-01

    Kisspeptin binding to its cognate G protein-coupled receptor (GPR54, aka Kiss1R) in gonadotropin-releasing hormone (GnRH) neurons stimulates peptide release and activation of the reproductive axis in mammals. Kisspeptin has pronounced pre- and postsynaptic effects, with the latter dominating the excitability of GnRH neurons. Presynaptically, kisspeptin increases the excitatory drive (both GABA-A and glutamate) to GnRH neurons and postsynaptically, kisspeptin inhibits an A-type and inwardly rectifying K + (Kir 6.2 and GIRK) currents and activates nonselective cation (TRPC) currents to cause long-lasting depolarization and increased action potential firing. The signaling cascades and the multiple intracellular targets of kisspeptin actions in native GnRH neurons are continuing to be elucidated. This review summarizes our current state of knowledge about kisspeptin signaling in GnRH neurons. PMID:23550004

  7. In vivo biodistribution of an androgen receptor avid PET imaging agent 7-{alpha}-fluoro-17 {alpha}-methyl-5-{alpha}-dihydrotestosterone ([{sup 18}F]FMDHT) in rats pretreated with cetrorelix, a GnRH antagonist

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    Garg, Sudha; Doke, Aniruddha; Black, Kimberly W.; Garg, Pradeep K. [Wake Forest University Health Sciences, PET Center, Department of Radiological Sciences, Winston Salem, NC (United States)

    2008-02-15

    For this study, we have assessed the in vivo distribution and androgen receptor (AR) seeking properties of an F-18-labeled androgen [{sup 18}F]FMDHT in rats castrated with a GnRH antagonist. The radiochemical synthesis of [{sup 18}F]FMDHT was performed using a previously published method. The radiochemical synthesis provided the desired product in good radiochemical yields and radiochemical purity. In vivo biodistribution studies were performed in chemically castrated rats. The animals were castrated using cetrorelix, a GnRH antagonist. To assess the specificity of [{sup 18}F]FMDHT towards ARs, a separate group of animals was pretreated with a large dose of androgen before the [{sup 18}F]FMDHT injection. The in vivo biodistribution results show selective uptake of [{sup 18}F]FMDHT in the prostate that ranged from 0.46 + 0.10 %ID/g at 1 h to 0.59 + 0.16 %ID/g at 3 h with prostate to muscle ratio ranging from 8.06 + 2.46 at 1 h to 18.81 + 4.90 at 3 h. These in vivo distribution studies document a high selectivity and specificity of [{sup 18}F]FMDHT towards AR rich tissues and suggests that [{sup 18}F]FMDHT may be a useful in vivo PET imaging ligand. (orig.)

  8. GnRH agonist triggering

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    Kol, Shahar; Humaidan, Peter; Al Humaidan, Peter Samir Heskjær

    2013-01-01

    The concept that a bolus of gonadotrophin-releasing hormone agonist (GnRHa) can replace human chorionic gonadotrophin (HCG) as a trigger of final oocyte maturation was introduced several years ago. Recent developments in the area strengthen this premise. GnRHa trigger offers important advantages...... triggering concept should be challenged and that the GnRHa trigger is the way to move forward with thoughtful consideration of the needs, safety and comfort of our patients. Routinely, human chorionic gonadotrophin (HCG) is used to induce ovulation in fertility treatments. This approach deviates...... significantly from physiology and often results in insufficient hormonal support in early pregnancy and in ovarian hyperstimulation syndrome (OHSS). An alternative approach is to use a gonadotrophin-releasing hormone (GnRH) agonist which allows a more physiological trigger of ovulation and, most importantly...

  9. Melatonin Inhibits GnRH-1, GnRH-3 and GnRH Receptor Expression in the Brain of the European Sea Bass, Dicentrarchus labrax

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    José Antonio Muñoz-Cueto

    2013-04-01

    Full Text Available Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 µg/g body mass in male specimens. The brain mRNA transcript levels of the three GnRH forms and the five GnRH receptors present in this species were determined by real time quantitative PCR. Our findings revealed day–night variations in the brain expression of GnRH-1, GnRH-3 and several GnRH receptors (dlGnRHR-II-1c, -2a, which exhibited higher transcript levels at mid-light compared to mid-dark phase of the photocycle. Moreover, an inhibitory effect of melatonin on the nocturnal expression of GnRH-1, GnRH-3, and GnRH receptors subtypes 1c, 2a and 2b was also demonstrated. Interestingly, the inhibitory effect of melatonin affected the expression of hypophysiotrophic GnRH forms and GnRH receptors that exhibit day–night fluctuations, suggesting that exogenous melatonin reinforce physiological mechanisms already established. These interactions between melatoninergic and GnRH systems could be mediating photoperiod effects on reproductive and other rhythmic physiological events in the European sea bass.

  10. Melatonin Inhibits GnRH-1, GnRH-3 and GnRH Receptor Expression in the Brain of the European Sea Bass, Dicentrarchus labrax

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    Servili, Arianna; Herrera-Pérez, Patricia; del Carmen Rendón, María; Muñoz-Cueto, José Antonio

    2013-01-01

    Several evidences supported the existence of melatonin effects on reproductive system in fish. In order to investigate whether melatonin is involved in the modulation of GnRH systems in the European sea bass, we have injected melatonin (0.5 μg/g body mass) in male specimens. The brain mRNA transcript levels of the three GnRH forms and the five GnRH receptors present in this species were determined by real time quantitative PCR. Our findings revealed day–night variations in the brain expression of GnRH-1, GnRH-3 and several GnRH receptors (dlGnRHR-II-1c, -2a), which exhibited higher transcript levels at mid-light compared to mid-dark phase of the photocycle. Moreover, an inhibitory effect of melatonin on the nocturnal expression of GnRH-1, GnRH-3, and GnRH receptors subtypes 1c, 2a and 2b was also demonstrated. Interestingly, the inhibitory effect of melatonin affected the expression of hypophysiotrophic GnRH forms and GnRH receptors that exhibit day–night fluctuations, suggesting that exogenous melatonin reinforce physiological mechanisms already established. These interactions between melatoninergic and GnRH systems could be mediating photoperiod effects on reproductive and other rhythmic physiological events in the European sea bass. PMID:23567273

  11. Epigenetic control of GnRH neurons

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    Joseph Raymond Kurian

    2013-05-01

    Full Text Available Epigenetic modifications to the genome, including DNA methylation and histone modifications, occur in response to external stimuli. Reproductive function is highly sensitive to environmental conditions including season, diet, hormonal changes, and exposure to chemical contaminants. GnRH neurons, which play a key role in reproduction, are particularly sensitive to various environmental stimuli. We recently reported that the rhesus monkey GnRH gene exhibits distinct epigenetic differentiation during embryonic development. More recently, we further found that a similar epigenetic phenomenon occurs across puberty. In this article, we highlight recent findings, suggest implications of these findings (or potential mechanisms and then discuss current challenges as well as future work. Consequently, this review will provide background to understand the epigenetic control of GnRH neurons as a link between the environment and reproductive function.

  12. A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1 Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models.

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    Polly P Huang

    Full Text Available Gonadotropin-releasing hormone (GnRH, a neuropeptide released from a small population of neurons in the hypothalamus, is the central mediator of the hypothalamic-pituitary-gonadal axis, and is required for normal reproductive development and function. Evolutionarily conserved regulatory elements in the mouse, rat, and human Gnrh1 gene include three enhancers and the proximal promoter, which confer Gnrh1 gene expression specifically in GnRH neurons. In immortalized mouse hypothalamic GnRH (GT1-7 neurons, which show pulsatile GnRH release in culture, RNA sequencing and RT-qPCR revealed that expression of a novel long noncoding RNA at Gnrh1 enhancer 1 correlates with high levels of GnRH mRNA expression. In GT1-7 neurons, which contain a transgene carrying 3 kb of the rat Gnrh1 regulatory region, both the mouse and rat Gnrh1 enhancer-derived noncoding RNAs (GnRH-E1 RNAs are expressed. We investigated the characteristics and function of the endogenous mouse GnRH-E1 RNA. Strand-specific RT-PCR analysis of GnRH-E1 RNA in GT1-7 cells revealed GnRH-E1 RNAs that are transcribed in the sense and antisense directions from distinct 5' start sites, are 3' polyadenylated, and are over 2 kb in length. These RNAs are localized in the nucleus and have a half-life of over 8 hours. In GT1-7 neurons, siRNA knockdown of mouse GnRH-E1 RNA resulted in a significant decrease in the expression of the Gnrh1 primary transcript and Gnrh1 mRNA. Over-expression of either the sense or antisense mouse GnRH-E1 RNA in immature, migratory GnRH (GN11 neurons, which do not express either GnRH-E1 RNA or GnRH mRNA, induced the transcriptional activity of co-transfected rat Gnrh1 gene regulatory elements, where the induction requires the presence of the rat Gnrh1 promoter. Together, these data indicate that GnRH-E1 RNA is an inducer of Gnrh1 gene expression. GnRH-E1 RNA may play an important role in the development and maturation of GnRH neurons.

  13. Comparison of GnRH Agonist, GnRH Antagonist, and GnRH Antagonist Mild Protocol of Controlled Ovarian Hyperstimulation in Good Prognosis Patients

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    Martin Stimpfel

    2015-01-01

    Full Text Available The reports on how to stimulate the ovaries for oocyte retrieval in good prognosis patients are contradictory and often favor one type of controlled ovarian hyperstimulation (COH. For this reason, we retrospectively analyzed data from IVF/ICSI cycles carried out at our IVF Unit in good prognosis patients (aged <38 years, first and second attempts of IVF/ICSI, more than 3 oocytes retrieved to elucidate which type of COH is optimal at our condition. The included patients were undergoing COH using GnRH agonist, GnRH antagonist or GnRH antagonist mild protocol in combination with gonadotrophins. We found significant differences in the average number of retrieved oocytes, immature oocytes, fertilized oocytes, embryos, transferred embryos, embryos frozen per cycle, and cycles with embryo freezing between studied COH protocols. Although there were no differences in live birth rate (LBR, miscarriages, and ectopic pregnancies between compared protocols, pregnancy rate was significantly higher in GnRH antagonist mild protocol in comparison with both GnRH antagonist and GnRH agonist protocols and cumulative LBR per cycle was significantly higher in GnRH antagonist mild protocol in comparison to GnRH agonist protocol. Our data show that GnRH antagonist mild protocol of COH could be the best method of choice in good prognosis patients.

  14. Carbohydrate-Binding Non-Peptidic Pradimicins for the Treatment of Acute Sleeping Sickness in Murine Models

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    Castillo-Acosta, Víctor M.; Ruiz-Pérez, Luis M.; Reichardt, Niels C.; Igarashi, Yasuhiro; Liekens, Sandra; Balzarini, Jan

    2016-01-01

    Current treatments available for African sleeping sickness or human African trypanosomiasis (HAT) are limited, with poor efficacy and unacceptable safety profiles. Here, we report a new approach to address treatment of this disease based on the use of compounds that bind to parasite surface glycans leading to rapid killing of trypanosomes. Pradimicin and its derivatives are non-peptidic carbohydrate-binding agents that adhere to the carbohydrate moiety of the parasite surface glycoproteins inducing parasite lysis in vitro. Notably, pradimicin S has good pharmaceutical properties and enables cure of an acute form of the disease in mice. By inducing resistance in vitro we have established that the composition of the sugars attached to the variant surface glycoproteins are critical to the mode of action of pradimicins and play an important role in infectivity. The compounds identified represent a novel approach to develop drugs to treat HAT. PMID:27662652

  15. New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists.

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    Shore, N D; Abrahamsson, P-A; Anderson, J; Crawford, E D; Lange, P

    2013-03-01

    Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH

  16. Interaction of a non-peptide agonist with angiotensin II AT1 receptor mutants

    DEFF Research Database (Denmark)

    Costa-Neto, Claudio M; Miyakawa, Ayumi A; Pesquero, João B;

    2002-01-01

    To identify residues of the rat AT1A angiotensin II receptor involved with signal transduction and binding of the non-peptide agonist L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazol[4,5,6]-pyridine) we have performed ligand bindi...

  17. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.

    2014-01-01

    This thesis focuses on the optimisation of controlled ovarian stimulation for IVF using exogenous FSH and GnRH antagonist co-treatment, by studying the timing of the initiation of GnRH antagonist co-medication and the role of ovarian reserve markers in optimising ovarian response and reproductive ou

  18. Searching for the optimal GnRH antagonist regimen to compare with GnRH agonists in IVF

    NARCIS (Netherlands)

    Huirne, J.A.F.

    2007-01-01

    De zoektocht naar het optimale GnRH-antagonistschema voor de vergelijking met GnRH-agonisten tijdens IVF behandelingen. Ondanks het gegeven dat in meer dan 200 klinische studies gebruik gemaakt wordt van gonadotrophine releasing hormone (GnRH) antagonisten, is het optimale GnRH- antagonistschema n

  19. GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET

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    Depalo Raffaella

    2012-04-01

    Full Text Available Abstract Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in “in Vitro” Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed.

  20. GnRH agonist versus GnRH antagonist in in vitro fertilization and embryo transfer (IVF/ET).

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    Depalo, Raffaella; Jayakrishan, K; Garruti, Gabriella; Totaro, Ilaria; Panzarino, Mariantonietta; Giorgino, Francesco; Selvaggi, Luigi E

    2012-04-13

    Several protocols are actually available for in Vitro Fertilization and Embryo Transfer. The review summarizes the main differences and the clinic characteristics of the protocols in use with GnRH agonists and GnRH antagonists by emphasizing the major outcomes and hormonal changes associated with each protocol. The majority of randomized clinical trials clearly shows that in "in Vitro" Fertilization and Embryo Transfer, the combination of exogenous Gonadotropin plus a Gonadotropin Releasing Hormone (GnRH) agonist, which is able to suppress pituitary FSH and LH secretion, is associated with increased pregnancy rate as compared with the use of gonadotropins without a GnRH agonist. Protocols with GnRH antagonists are effective in preventing a premature rise of LH and induce a shorter and more cost-effective ovarian stimulation compared to the long agonist protocol. However, a different synchronization of follicular recruitment and growth occurs with GnRH agonists than with GnRH antagonists. Future developments have to be focused on timing of the administration of GnRH antagonists, by giving a great attention to new strategies of stimulation in patients in which radio-chemotherapy cycles are needed.

  1. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol

    DEFF Research Database (Denmark)

    Toftager, M.; Bogstad, J; Bryndorf, T

    2016-01-01

    and thus predict risk of OHSS, were not performed. Finally, the physicians were not blinded to GnRH treatment group after randomization. WIDER IMPLICATIONS OF THE FINDINGS: The short GnRH antagonist protocol should be the protocol of choice for patients undergoing their first ART cycle in females years...... between the two arms. None of the women had undergone previous ART treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: All infertile women referred for their first IVF/ICSI at two public fertility clinics, less than 40 years of age and with no uterine malformations were asked to participate. A total......STUDY QUESTION: Is the risk of severe ovarian hyperstimulation syndrome (OHSS) similar in a short GnRH antagonist and long GnRH agonist protocol in first cycle IVF/ICSI patients less than 40 years of age?. SUMMARY ANSWER: There is an increased risk of severe OHSS in the long GnRH agonist group...

  2. GnRH tandem peptides for inducing an immunogenic response to GnRH-I without cross-reactivity to other GnRH isoforms

    NARCIS (Netherlands)

    Turkstra, J.A.; Schaaper, W.M.M.; Oonk, H.B.; Meloen, R.H.

    2005-01-01

    Gonadotropin releasing hormone (GnRH) occurs in various isoforms in mammals, i.e. GnRH-I (mammalian GnRH), GnRH-II (chicken GnRH-II), GnRH-III (salmon GnRH) and two forms of lamprey GnRH. The function of the latter four molecules have only been partially investigated. Also not much is known about th

  3. Induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor RPR-115135: role of gene mutations.

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    Ottoboni, C; Crippa, A; Falugi, C; Russo, P

    2001-09-01

    To investigate the relationship between oncogene activation and induction of micronuclei by a new non-peptidic mimetic farnesyltransferase inhibitor, RPR-115135, two isogenic cell lines, human colon cancer line HCT-116, which harbors a K-ras mutation, and spontaneously immortalized human breast epithelial cell line MCF-10A, were utilized. HCT-116 cells were transfected with an empty control pCMV vector (clone CMV-2) or with a dominant negative mutated p53 transgene (clone Mu-p53-2) to disrupt p53 function. In both clones RPR-115135 induced a significant increase in the frequency of micronucleation at concentrations that did not affect cell membrane integrity. RPR-115135 produced a significant increase in the ratio of CREST+ to CREST- micronuclei. MCF-10A cells were stably transfected with either c-Ha-ras or c-erbB-2 or both H-ras + c-erbB-2. No induction of micronuclei was observed. No induction of micronuclei was reported in human lymphocytes and in primary spinal cells obtained from 7-day chick embryos. In conclusion, RPR-115135 acts as an aneugenic agent in a complex manner, dependent upon the complement of mutations in cell regulatory genes in tumour cells and this activity may be independent of ras genotype.

  4. Gonadotropin-releasing hormone (GnRH) variants in a lizard brain: is mammalian GnRH being expressed?

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    Montaner, A D; Gonzalez, O; Paz, D A; Affanni, J M; Somoza, G M

    2000-08-01

    In reptiles as in other vertebrates, multiple forms of gonadotropin-releasing hormone (GnRH) within a single brain have been identified. In this group the following GnRH molecular variants have been characterized either by direct or indirect methods: chicken GnRH I (cGnRH-I), chicken GnRH II (cGnRH-II), salmon GnRH (sGnRH) and several unidentified GnRH-like forms. In the present study GnRH variants were investigated in brain extracts of the lizard Tupinambis teguixin (= T. merinae) by combining high-performance liquid chromatography (RP-HPLC) followed by radioimmunoassays (RIA). Two peaks showing GnRH immunoreactivity with the elution position of synthetic mammalian GnRH (mGnRH) and cGnRH-II were detected. Both peaks were further analyzed with different radioimmunoassay systems specific for mGnRH, cGnRH-I, and cGnRH-II. Pooled fractions corresponding to the first eluting peak showed no crossreactivity when analyzed with a cGnRH-I specific assay and logit-log displacement curves were not significantly different from those of synthetic mGnRH with homologous RIA systems. The second peak showed immunological characteristics of cGnRH-II when analyzed with a specific antiserum. The first ir-GnRH peak was selected for further RP-HPLC purification showing similar chromatographic behavior as mGnRH synthetic standard. We demonstrated the absence of cGnRH-I in this lizard using well-characterized antisera.

  5. A structural feature of the non-peptide ligand interactions with mice mu-opioid receptors.

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    Noori, Hamid R; Mucksch, Christian; Urbassek, Herbert M

    2014-01-01

    By binding to and activating the G-protein coupled μ-, κ- and δ-opioid receptors in the central nervous system, opiates are known to induce analgesic and sedative effects. In particular, non-peptide opioid ligands are often used in clinical applications to induce these therapeutically beneficial effects, due to their superior pharmacokinetics and bioavailability in comparison to endogenous neuropeptides. However, since opioid alkaloids are highly addictive substances, it is necessary to understand the exact mechanisms of their actions, specifically the ligand-binding properties of the target receptors, in order to safely apply opiates for therapeutic purposes. Using an in silico molecular docking approach (AutoDock Vina) combined with two-step cluster analysis, we have computationally obtained the docking scores and the ligand-binding pockets of twelve representative non-peptide nonendogenous agonists and antagonists at the crystallographically identified μ-opioid receptor. Our study predicts the existence of two main binding sites that are congruently present in all opioid receptor types. Interestingly, in terms of the agonist or antagonist properties of the substances on the receptors, the clustering analysis suggests a relationship with the position of the ligand-binding pockets, particularly its depth within the receptor structure. Furthermore, the binding affinity of the substances is directly correlated to the proximity of the binding pockets to the extracellular space. In conclusion, the results provide further insights into the structural features of the functional pharmacology of opioid receptors, suggesting the importance of the binding position of non-peptide agonists and antagonists- specifically the distance and the level of exposure to the extracellular space- to their dissociation kinetics and subsequent potency.

  6. GnRH Analogues in the Prevention of Ovarian Hyperstimulation Syndrome

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    Alama, Pilar; Bellver, Jose; Vidal, Carmen; Giles, Juan

    2013-01-01

    The GnRH analogue (agonist and antagonist GnRH) changed ovarian stimulation. On the one hand, it improved chances of pregnancy to obtain more oocytes and better embryos. This leads to an ovarian hyper-response, which can be complicated by the ovarian hyperstimulation syndrome (OHSS). On the other hand, the GnRH analogue can prevent the incidence of OHSS: GnRH antagonist protocols, GnRH agonist for triggering final oocyte maturation, either together or separately, coasting, and the GnRH analogue may prove useful for avoiding OHSS in high-risk patients. We review these topics in this article. PMID:23825982

  7. Non-Peptide-based Small-Molecule Probe for Fluorogenic and Chromogenic Detection of Chymotrypsin.

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    Wu, Lei; Yang, Shu-Hou; Xiong, Hao; Yang, Jia-Qian; Guo, Jun; Yang, Wen-Chao; Yang, Guang-Fu

    2017-02-23

    We report herein a non-peptide-based small molecule probe for fluorogenic and chromogenic detection of chymotrypsin, and the primary application. This probe was rationally designed by mimicking the peptide substrate and optimized by adjusting the recognization group. The refined probe 2 exhibits good specificity toward chymotrypsin, producing about 25-fold higher enhancement in both the fluorescence intensity and absorbance upon the catalysis by chymotrypsin. Compared with the most widely used peptide substrate (AMC-FPAA-Suc) of chymotrypsin, probe 2 shows about 5-fold higher binding affinity, and comparable catalytical efficiency against chymotrypsin. Furthermore, it was successfully applied for the inhibitor characterization. To the best of our knowledge, probe 2 is the first non-peptide-based small-molecule probe for chymotrypsin, with the advantages of simple structure and high sensitivity compared to the widely used peptide-based substrates. This small-molecule probe is expected to be a useful molecular tool for drug discovery and chymotrypsin-related diseases diagnosis.

  8. Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility.

    Science.gov (United States)

    Hoffmann, Hanne M; Trang, Crystal; Gong, Ping; Kimura, Ikuo; Pandolfi, Erica C; Mellon, Pamela L

    2016-03-23

    Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates mammalian fertility. Herein we demonstrate a critical role for the homeodomain transcription factor ventral anterior homeobox 1 (VAX1) in GnRH neuron maturation and show that Vax1 deletion from GnRH neurons leads to complete infertility in males and females. Specifically, global Vax1 knock-out embryos had normal numbers of GnRH neurons at 13 d of gestation, but no GnRH staining was detected by embryonic day 17. To identify the role of VAX1 specifically in GnRH neuron development,Vax1(flox)mice were generated and lineage tracing performed in Vax1(flox/flox):GnRH(cre):RosaLacZ mice. This identified VAX1 as essential for maintaining expression of Gnrh1 The absence of GnRH staining in adult Vax1(flox/flox):GnRH(cre)mice led to delayed puberty, hypogonadism, and infertility. To address the mechanism by which VAX1 maintains Gnrh1 transcription, the capacity of VAX1 to regulate Gnrh1 transcription was evaluated in the GnRH cell lines GN11 and GT1-7. As determined by luciferase and electrophoretic mobility shift assays, we found VAX1 to be a direct activator of the GnRH promoter through binding to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P), and able to compete with the homeoprotein SIX6 for occupation of the identified ATTA sites in the GnRH promoter. We conclude that VAX1 is expressed in GnRH neurons where it is required for GnRH neuron expression of GnRH and maintenance of fertility in mice. Infertility classified as idiopathic hypogonadotropic hypogonadism (IHH) is characterized by delayed or absent sexual maturation and low sex steroid levels due to alterations in neuroendocrine control of the hypothalamic-pituitary-gonadal axis. The incidence of IHH is 1-10 cases per 100,000 births. Although extensive efforts have been invested in identifying genes giving rise to IHH, >50% of cases have unknown genetic origins

  9. Rapid direct action of estradiol in GnRH neurons: findings and implications

    Directory of Open Access Journals (Sweden)

    Ei eTerasawa

    2012-01-01

    Full Text Available Estradiol plays a pivotal role in the control of GnRH neuronal function and female reproduction. While positive and negative feedback actions of estradiol that enhance and suppress release of GnRH and LH are primarily mediated through estrogen receptor alpha (ERα located in interneurons, a series of recent studies in our laboratory indicate that rapid excitatory actions of estradiol also directly modify GnRH neuronal activity. We observed this phenomenon in cultured primate GnRH neurons, but similar rapid direct actions of estradiol are also described in cultured GnRH neurons and GFP-labeled GnRH neurons of mice. Importantly, rapid direct action of estradiol in GnRH neurons is mediated through membrane or membrane associated receptors, such as GPR30, STX-sensitive receptors, and ERβ. In this review, possible implications of this rapid estradiol action in GnRH neurons are discussed.

  10. Insulin receptor signaling in the GnRH neuron plays a role in the abnormal GnRH pulsatility of obese female mice.

    Directory of Open Access Journals (Sweden)

    Sara A DiVall

    Full Text Available Infertility associated with obesity is characterized by abnormal hormone release from reproductive tissues in the hypothalamus, pituitary, and ovary. These tissues maintain insulin sensitivity upon peripheral insulin resistance. Insulin receptor signaling may play a role in the dysregulation of gonadotropin-releasing hormone (GnRH secretion in obesity, but the interdependence of hormone secretion in the reproductive axis and the multi-hormone and tissue dysfunction in obesity hinders investigations of putative contributing factors to the disrupted GnRH secretion. To determine the role of GnRH insulin receptor signaling in the dysregulation of GnRH secretion in obesity, we created murine models of diet-induced obesity (DIO with and without intact insulin signaling in the GnRH neuron. Obese control female mice were infertile with higher luteinizing hormone levels and higher GnRH pulse amplitude and total pulsatile secretion compared to lean control mice. In contrast, DIO mice with a GnRH specific knockout of insulin receptor had improved fertility, luteinizing hormone levels approaching lean mice, and GnRH pulse amplitude and total secretion similar to lean mice. Pituitary responsiveness was similar between genotypes. These results suggest that in the obese state, insulin receptor signaling in GnRH neurons increases GnRH pulsatile secretion and consequent LH secretion, contributing to reproductive dysfunction.

  11. Effects of GnRH immunization in sexually mature pony stallions

    NARCIS (Netherlands)

    Turkstra, J.A.; Meer, F.J.U.M.; Knaap, J.; Rottier, P.J.M.; Teerds, K.J.; Colenbrander, B.; Meloen, R.H.

    2005-01-01

    Immunization against gonadotrophin releasing hormone (GnRH) was studied as an alternative for the commonly used surgical castration in stallions. Two GnRH vaccines comprising non-mineral oil adjuvants were evaluated for their potential to induce high antibody titers directed against GnRH and subsequ

  12. A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

    Science.gov (United States)

    Pastor-Cavada, Elena; Pardo, Leticia M.; Kandil, Dalia; Torres-Fuentes, Cristina; Clarke, Sarah L.; Shaban, Hamdy; McGlacken, Gerard P.; Schellekens, Harriet

    2016-11-01

    Loss of appetite in the medically ill and ageing populations is a major health problem and a significant symptom in cachexia syndromes, which is the loss of muscle and fat mass. Ghrelin is a gut-derived hormone which can stimulate appetite. Herein we describe a novel, simple, non-peptidic, 2-pyridone which acts as a selective agonist for the ghrelin receptor (GHS-R1a). The small 2-pyridone demonstrated clear agonistic activity in both transfected human cells and mouse hypothalamic cells with endogenous GHS-R1a receptor expression. In vivo tests with the hit compound showed significant increased food intake following peripheral administration, which highlights the potent orexigenic effect of this novel GHS-R1a receptor ligand.

  13. GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis

    OpenAIRE

    Youssef, M.A.F.; Abdelmoty, Hatem I; Ahmed, Mohamed A.S.; Maged Elmohamady

    2015-01-01

    Final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles can be triggered with HCG or a GnRH agonist. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of the final oocyte maturation trigger in GnRH antagonist co-treated cycles. Outcome measures were ongoing pregnancy rate (OPR) and ovarian hyperstimulation syndrome (OHSS) incidence. Searches: were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library, ...

  14. Pharmacological and toxicological assessment of a potential GnRH vaccine in young-adult male pigs

    NARCIS (Netherlands)

    Turkstra, J.A.; Staay, van der F.J.; Stockhofe-Zurwieden, N.; Woelders, H.; Meloen, R.H.; Schuurman, T.

    2011-01-01

    Active immunization against gonadotrophin-releasing hormone (GnRH) is successfully applied to prevent boar taint in pork. In men, GnRH immunization could be an alternative to hormone therapy in patients with prostate cancer. In this study, a new GnRH vaccine formulation (a modified GnRH peptide conj

  15. R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism.

    Directory of Open Access Journals (Sweden)

    Luigi Maione

    Full Text Available Normosmic congenital hypogonadotropic hypogonadism (nCHH is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative "hot spot". Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH.

  16. The role of GABA in the regulation of GnRH neurons

    Directory of Open Access Journals (Sweden)

    Miho eWatanabe

    2014-11-01

    Full Text Available Gonadotropin-releasing hormone (GnRH neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.

  17. GluVII:06--a highly conserved and selective anchor point for non-peptide ligands in chemokine receptors

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Schwartz, Thue W

    2006-01-01

    to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule...

  18. Regulation versus modulation in GnRH receptor function

    Energy Technology Data Exchange (ETDEWEB)

    Zolman, J.C.; Theodoropoulos, T.J.

    1985-03-01

    Serum luteinizing hormone (LH) concentration after exposure to gonadotropin-releasing hormone (GnRH) indicates that an instantaneous increase occurs in the rate of release of LH directly from the anterior pituitary, as measured dynamically during superfusion in vitro. On the other hand, estradiol-17 beta (E2) alone shows no such instantaneous effect on LH release rate (at least for the first four hours), in either physiologic or pharmacologic concentrations. At the same time, brief (ten to 30 minute) exposure of isolated anterior pituitary plasma membranes to physiologic concentrations of E2 significantly alters the binding of a fully biologically active /sup 125/I-GnRH to its plasma membrane receptor protein. In order to characterize the effect of E2 on GnRH binding further, dispersed bovine anterior pituitary cells were preincubated for six hours in the presence or absence of physiologic concentrations of E2 (10(-10)M). Following preincubation in the presence of E2, the cell suspension was incubated for 30 minutes with physiologic concentrations (5 x 10(-11) - 5 x 10(-10)M) of a fully biologically active /sup 125/I-GnRH. The treatment, at least, doubled the number of biologically important high affinity GnRH binding sites (Kd's . 7.5 x -10(-11) - 4.5 x 10(-10)M), and changed the binding capacity of some of the binding sites up to three fold, which altered the cooperativity of GnRH-receptor interaction. Thus, the interaction of E2 with GnRH at the level of GnRH receptor is mandatory for the short-term pituitary effect of E2 on LH release in vitro and in vivo.

  19. Estrogenic Regulation of the GnRH Neuron

    Directory of Open Access Journals (Sweden)

    Sally eRadovick

    2012-04-01

    Full Text Available Reproductive function is regulated by the secretion of luteinizing hormone (LH and follicle-stimulating hormone (FSH from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex characteristics, gametogenesis, cellular function and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common pathway for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about circadian, seasonal, behavioral, pheromonal and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dramatic increase in GnRH secretion (Sisk and others 2001; Clarke 1993; Moenter, Brand and Karsch 1992; Xia and others 1992. This is coupled with an increase in pituitary sensitivity to GnRH (Turzillo, DiGregorio and Nett 1995; Savoy-Moore and others 1980, which produces the massive surge in secretion of LH that triggers ovulation.

  20. Comparison between a GnRH Agonist and a GnRH Antagonist Protocol for the Same Patient Undergoing IVF

    Institute of Scientific and Technical Information of China (English)

    Yufeng LI; Yuan LI; Qiaohong LAI; Hanwang ZHANG; Guijin ZHU; Lei JIN; Jing YUE

    2008-01-01

    Summary: In order to compare GnRH agonist with antagonist protocol for the same patient during controlled ovarian stimulation cycles, the in vitro fertilization and embryo transfer (IVF-ET) outcome was retrospectively studied in 81 patients undergoing 105 agonist protocols and 88 antagonist protocols. The results showed that there was no statistically significant difference in duration of ovarian stimulation, number of ampoules, oocytes retrieved, serum estradiol (E2) and progesterone (P) levels,thickness of endometrium, the zygote-and blastocyst-developmcnt rate between GnRH agonist and antagonist protocols (P>0.05). High quality embryo rate was higher in antagonist protocols, but there was no significant difference between two protocols. Implantation rate and clinical pregnant rate were significantly higher in antagonist protocol (15.82% and 30.26%, respectively) than in agonist protocol (5.26% and 10.64% respectively (P<0.05). It was concluded GnRH antagonist protocol probably improved the outcome of pregnancy of older patients with a history of multiple failure of IVF-ET in a GnRH protocol.

  1. Rabconnectin-3α is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness

    OpenAIRE

    Tata, Brooke K.; Carole Harbulot; Zsolt Csaba; Stéphane Peineau; Sandrine Jacquier; Nicolas Roux

    2017-01-01

    A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show ...

  2. The non-peptidic part determines the internalization mechanism and intracellular trafficking of peptide amphiphiles.

    Directory of Open Access Journals (Sweden)

    Dimitris Missirlis

    Full Text Available BACKGROUND: Peptide amphiphiles (PAs are a class of amphiphilic molecules able to self-assemble into nanomaterials that have shown efficient in vivo targeted delivery. Understanding the interactions of PAs with cells and the mechanisms of their internalization and intracellular trafficking is critical in their further development for therapeutic delivery applications. METHODOLOGY/PRINCIPAL FINDINGS: PAs of a novel, cell- and tissue-penetrating peptide were synthesized possessing two different lipophilic tail architectures and their interactions with prostate cancer cells were studied in vitro. Cell uptake of peptides was greatly enhanced post-modification. Internalization occurred via lipid-raft mediated endocytosis and was common for the two analogs studied. On the contrary, we identified the non-peptidic part as the determining factor of differences between intracellular trafficking and retention of PAs. PAs composed of di-stearyl lipid tails linked through poly(ethylene glycol to the peptide exhibited higher exocytosis rates and employed different recycling pathways compared to ones consisting of di-palmitic-coupled peptides. As a result, cell association of the former PAs decreased with time. CONCLUSIONS/SIGNIFICANCE: Control over peptide intracellular localization and retention is possible by appropriate modification with synthetic hydrophobic tails. We propose this as a strategy to design improved peptide-based delivery systems.

  3. AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection.

    Science.gov (United States)

    da Costa Gonçalves, Andrey C; Fraga-Silva, Rodrigo A; Leite, Romulo; Santos, Robson A S

    2013-03-01

    The renin-angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1-7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetized Wistar rats, measured as the ratio between corpus cavernosum pressure and mean arterial pressure, upon electrical stimulation of the major pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991. We demonstrated that AVE 0991 potentiates the penile erectile response through Mas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction.

  4. Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment.

    Directory of Open Access Journals (Sweden)

    Tao Yang

    Full Text Available The p75 neurotrophin receptor (p75(NTR is expressed by neurons particularly vulnerable in Alzheimer's disease (AD. We tested the hypothesis that non-peptide, small molecule p75(NTR ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR signaling and Abeta pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Abeta-induced neuronal dystrophy and death.

  5. A conserved non-reproductive GnRH system in chordates.

    Directory of Open Access Journals (Sweden)

    Takehiro G Kusakabe

    Full Text Available Gonadotropin-releasing hormone (GnRH is a neuroendocrine peptide that plays a central role in the vertebrate hypothalamo-pituitary axis. The roles of GnRH in the control of vertebrate reproductive functions have been established, while its non-reproductive function has been suggested but less well understood. Here we show that the tunicate Ciona intestinalis has in its non-reproductive larval stage a prominent GnRH system spanning the entire length of the nervous system. Tunicate GnRH receptors are phylogenetically closest to vertebrate GnRH receptors, yet functional analysis of the receptors revealed that these simple chordates have evolved a unique GnRH system with multiple ligands and receptor heterodimerization enabling complex regulation. One of the gnrh genes is conspicuously expressed in the motor ganglion and nerve cord, which are homologous structures to the hindbrain and spinal cord of vertebrates. Correspondingly, GnRH receptor genes were found to be expressed in the tail muscle and notochord of embryos, both of which are phylotypic axial structures along the nerve cord. Our findings suggest a novel non-reproductive role of GnRH in tunicates. Furthermore, we present evidence that GnRH-producing cells are present in the hindbrain and spinal cord of the medaka, Oryzias latipes, thereby suggesting the deep evolutionary origin of a non-reproductive GnRH system in chordates.

  6. Gonadotropin-releasing hormone (Gn-RH) in striped mullet (Mugil cephalus), milkfish (Chanos chanos), and rainbow trout (Salmo gairdneri): comparison with salmon Gn-RH

    Energy Technology Data Exchange (ETDEWEB)

    Sherwood, N.M.; Harvey, B.; Brownstein, M.J.; Eiden, L.E.

    1984-08-01

    Immunoreactive gonadotropin-releasing hormone (Gn-RH) was extracted from brains of striped mullet, milkfish, rainbow trout, and chum salmon with acetone/HCl and petroleum ether. High pressure liquid chromatography and cross-reactivity studies show mullet, milkfish, and trout brains to contain a peptide chromatographically and immunologically identical to synthetic salmon Gn-RH, while the mammalian form of Gn-RH is detectable in none of these fishes. Gn-RH is present in immature 7-month-old and 4-year-old milkfish. A second immunoreactive peptide is separable by HPLC in all the fish studied. This early-eluting form of Gn-RH is unlikely to be a precursor; its cross-reactivity with antisera R-42 and number185 suggests that any modification is in the C-terminal region. Several possible roles for this peptide are advanced.

  7. Detection of Messenger RNA for Gonadotropin-Releasing Hormone (GnRH) but not for GnRH Receptors in Rat Pancreas

    Institute of Scientific and Technical Information of China (English)

    王雷; 谢莉萍; 黄威权; 张荣庆

    2001-01-01

    Although gonadotropin-releasing hormone (GnRH), GnRH-like molecule, and GnRH receptor (GnRH-R) have been reported to exist in several tissues other than brain or anterior pituitary, there are no reports concerning GnRH or GnRH-R gene expression in a normal pancreatic gland. In order to define the production of GnRH as well as GnRH-R in the pancreatic gland, we examined their gene expression in various developmental stages of rat pancreas using the reverse transcriptase-polymerase chain reaction (RT-PCR).GnRH mRNA transcripts were found in pancreas of male and female rats at different ages, expressing at about the same level, whereas GnRH-R mRNA transcripts could not be detected in any rat pancreatic gland samples. These results suggest a possible biological role of GnRH in rodent pancreas.

  8. Endogenous kisspeptin tone is a critical excitatory component of spontaneous GnRH activity and the GnRH response to NPY and CART

    Science.gov (United States)

    Verma, Saurabh; Kirigiti, Melissa; Millar, Robert P.; Grove, Kevin L.; Smith, M. Susan

    2014-01-01

    Background/Aims Kisspeptin is the major excitatory regulator of GnRH neurons and is responsible for basal GnRH/LH release and the GnRH/LH surge. Although it is widely assumed, based on mutations in kisspeptin and Kiss1R, that kisspeptin acts to sustain basal GnRH neuronal activity, there have been no studies to investigate whether endogenous basal kisspeptin tone plays a direct role in basal spontaneous GnRH neuronal excitability. It is also of interest to examine possible interactions between endogenous kisspeptin tone and other neuropeptides that have direct effects on GnRH neurons, such as NPY or CART, since the activity of all these neuropeptides changes during states of negative energy balance. Methods Loose cell-attached and whole cell current-clamp patch recordings were made from GnRH-GFP neurons in hypothalamic slices from female and male rats. Results Kisspeptin activated GnRH neurons in a concentration dependent manner with an EC50 of 3.32 ± 0.02 nM. Surprisingly, a kisspeptin antagonist, Peptide 347, suppressed spontaneous activity in GnRH neurons, demonstrating the essential nature of the endogenous kisspeptin tone. Furthermore, inhibition of endogenous kisspeptin tone blocked the direct activation of GnRH cells that occurs in response to antagonism of NPY Y5R or by CART. Conclusions Our electrophysiology studies suggest that basal endogenous kisspeptin tone is not only essential for spontaneous GnRH neuronal firing, but it is also required for the net excitatory effects of other neuropeptides, such as CART or NPY antagonism, on GnRH neurons. Therefore, endogenous kisspeptin tone could serve as the linchpin in GnRH activation or inhibition. PMID:25011649

  9. Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities.

    Science.gov (United States)

    Zhang, Heng; Kang, Dongwei; Huang, Boshi; Liu, Na; Zhao, Fabao; Zhan, Peng; Liu, Xinyong

    2016-05-23

    CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced.

  10. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats.

    Science.gov (United States)

    Ali, Quaisar; Hussain, Tahir

    2012-06-01

    Previously, we demonstrated that angiotensin II type 2 (AT(2)) receptors have a role in natriuresis in obese Zucker rats (OZR). In the present study, we investigated the role of a novel, non-peptide agonist, C21, in natriuresis via AT(2) receptor activation in OZR. Infusion of C21 (1 and 5 μg kg(-1) min(-1)) into rats under anesthesia caused a dose-dependent increase in urine flow (UF) and urinary Na volume (U(Na)V). These effects of C21 were blocked by pre-infusion of the AT(2) receptor antagonist, PD123319, (50 μg kg(-1) min(-1)), suggesting involvement of the AT(2) receptor. Infusion of C21 (5 μg kg(-1) min(-1)) significantly increased the fractional excretion of sodium without changing the glomerular filtration rate or blood pressure, suggesting a tubular effect. Similarly, C21 infusion increased the fractional excretion of lithium, suggesting a proximal tubular effect. Furthermore, we tested the effect of C21 on natriuresis after blocking two main, distal-nephron Na transporters, the epithelial Na channels (ENaC), with amiloride (AM, 3 mg kg(-1) body wt), and the NaCl cotransporters (NCC), with bendroflumethiazide (BFTZ, 7 mg kg(-1) body wt). Infusion of AM + BFTZ caused significant increases in both diuresis and natriuresis, which were further increased by infusion of C21 (5 μg kg(-1) min(-1)). Natriuresis in response to C21 was associated with increases in urinary NO and cGMP levels. The data indicate that the AT(2) receptor agonist, C21, promotes natriuresis via AT(2) receptor activation and that this effect is potentially based in the proximal tubules and linked to the nitric oxide/cyclic guanosine monophosphate pathway. The natriuretic response to C21 may have therapeutic significance by improving kidney function in obesity.

  11. Identification of the GnRH-(1-5) Receptor and Signaling Pathway

    Science.gov (United States)

    2013-03-22

    expression in immortalized GnRH neurons and to facilitate lordosis behavior in female rats. Interestingly, EP24.15 colocalizes with vii...expression in immortalized GnRH neurons (73) and facilitates lordosis behavior in female rats (72). Interestingly, EP24.15 is expressed along the...biologically active by facilitating lordosis behavior in ovariectomized estrogen-primed rats (72); and can increase the mRNA expression of GnRH in immortalized

  12. Cytotoxic effect of a non-peptidic small molecular inhibitor of the p53-HDM2 interaction on tumor cells

    Institute of Scientific and Technical Information of China (English)

    Wen-Dong Li; Mi-Juan Wang; Fang Ding; Da-Li Yin; Zhi-Hua Liu

    2005-01-01

    AIM: To investigate if non-peptidic small molecular inhibitors of the p53-HDM2 interaction could restore p53 function and kill tumor cells.METHODS: A series of non-peptidic small HDM2 inhibitors were designed by computer-aided model and synthesized by chemical method. Syl-155 was one of these inhibitors. Cytotoxic effect of syl-155 on three tumor cell lines with various states of p53, HT1080 (wild-type p53), KYSE510 (mutant p53), MG63 (p53 deficiency) was evaluated by MTT assay, Western blot and flow cytometry.RESULTS: Syl-155 stimulated the accumulation of p53 and p21 protein in HT1080 cells expressing wild-type p53, but not in KYSE510 and MG63 cells. Consequently, syl-155 induced cell cycle arrest and apoptosis in HT1080 cells.CONCLUSION: Non-peptidic small molecular inhibitors of the p53-HDM2 interaction show promise in treatment of tumors expressing wild-type p53.

  13. Expression Analysis of Gnrh1 and Gnrhr1 in Spermatogenic Cells of Rat

    Directory of Open Access Journals (Sweden)

    Vincenza Ciaramella

    2015-01-01

    Full Text Available Hypothalamic Gonadotropin Releasing Hormone (GnRH, via GnRH receptor (GnRHR, is the main actor in the control of reproduction, in that it induces the biosynthesis and the release of pituitary gonadotropins, which in turn promote steroidogenesis and gametogenesis in both sexes. Extrabrain functions of GnRH have been extensively described in the past decades and, in males, local GnRH activity promotes the progression of spermatogenesis and sperm functions at several levels. The canonical localization of Gnrh1 and Gnrhr1 mRNA is Sertoli and Leydig cells, respectively, but ligand and receptor are also expressed in germ cells. Here, we analysed the expression rate of Gnrh1 and Gnrhr1 in rat testis (180 days old by quantitative real-time PCR (qPCR and by in situ hybridization we localized Gnrh1 and Gnrhr1 mRNA in different spermatogenic cells of adult animals. Our data confirm the testicular expression of Gnrh1 and of Gnrhr1 in somatic cells and provide evidence that their expression in the germinal compartment is restricted to haploid cells. In addition, not only Sertoli cells connected to spermatids in the last steps of maturation but also Leydig and peritubular myoid cells express Gnrh1.

  14. Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH) neurons

    Science.gov (United States)

    Cortés-Campos, Christian; Letelier, Joaquín; Ceriani, Ricardo; Whitlock, Kathleen E.

    2015-01-01

    ABSTRACT Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons. PMID:26209533

  15. Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH neurons

    Directory of Open Access Journals (Sweden)

    Christian Cortés-Campos

    2015-09-01

    Full Text Available Gonadotropin-releasing hormone (GnRH is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons.

  16. GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis.

    Science.gov (United States)

    Youssef, M A F; Abdelmoty, Hatem I; Ahmed, Mohamed A S; Elmohamady, Maged

    2015-05-01

    Final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles can be triggered with HCG or a GnRH agonist. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of the final oocyte maturation trigger in GnRH antagonist co-treated cycles. Outcome measures were ongoing pregnancy rate (OPR) and ovarian hyperstimulation syndrome (OHSS) incidence. Searches: were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library, and databases of abstracts. There was a statistically significant difference against the GnRH agonist for OPR in fresh autologous cycles (n = 1024) with an odd ratio (OR) of 0.69 (95% CI: 0.52-0.93). In oocyte-donor cycles (n = 342) there was no evidence of a difference (OR: 0.91; 95% CI: 0.59-1.40). There was a statistically significant difference in favour of GnRH agonist regarding the incidence of OHSS in fresh autologous cycles (OR: 0.06; 95% CI: 0.01-0.33) and donor cycles respectively (OR: 0.06; 95% CI: 0.01-0.27). In conclusion GnRH agonist trigger for final oocyte maturation trigger in GnRH antagonist cycles is safer but less efficient than HCG.

  17. GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    M.A.F. Youssef

    2015-05-01

    Full Text Available Final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles can be triggered with HCG or a GnRH agonist. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of the final oocyte maturation trigger in GnRH antagonist co-treated cycles. Outcome measures were ongoing pregnancy rate (OPR and ovarian hyperstimulation syndrome (OHSS incidence. Searches: were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library, and databases of abstracts. There was a statistically significant difference against the GnRH agonist for OPR in fresh autologous cycles (n = 1024 with an odd ratio (OR of 0.69 (95% CI: 0.52–0.93. In oocyte-donor cycles (n = 342 there was no evidence of a difference (OR: 0.91; 95% CI: 0.59–1.40. There was a statistically significant difference in favour of GnRH agonist regarding the incidence of OHSS in fresh autologous cycles (OR: 0.06; 95% CI: 0.01–0.33 and donor cycles respectively (OR: 0.06; 95% CI: 0.01–0.27. In conclusion GnRH agonist trigger for final oocyte maturation trigger in GnRH antagonist cycles is safer but less efficient than HCG.

  18. Targeted Mutagenesis of the Hypophysiotropic Gnrh3 in Zebrafish (Danio rerio Reveals No Effects on Reproductive Performance.

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    Olivia Smith Spicer

    Full Text Available Gnrh is the major neuropeptide regulator of vertebrate reproduction, triggering a cascade of events in the pituitary-gonadal axis that result in reproductive competence. Previous research in mice and humans has demonstrated that Gnrh/GNRH null mutations result in hypogonadotropic hypogonadism and infertility. The goal of this study was to eliminate gnrh3 (the hypophysiotropic Gnrh form function in zebrafish (Danio rerio to determine how ontogeny and reproductive performance are affected, as well as factors downstream of Gnrh3 along the reproductive axis. Using the TALEN technology, we developed a gnrh3-/- zebrafish line that harbors a 62 bp deletion in the gnrh3 gene. Our gnrh3-/- zebrafish line represents the first targeted and heritable mutation of a Gnrh isoform in any organism. Using immunohistochemistry, we verified that gnrh3-/- fish do not possess Gnrh3 peptide in any regions of the brain. However, other than changes in mRNA levels of pituitary gonadotropin genes (fshb, lhb, and cga during early development, which are corrected by adulthood, there were no changes in ontogeny and reproduction in gnrh3-/- fish. The gnrh3-/- zebrafish are fertile, displaying normal gametogenesis and reproductive performance in males and females. Together with our previous results that Gnrh3 cell ablation causes infertility, these results indicate that a compensatory mechanism is being activated, which is probably primed early on upon Gnrh3 neuron differentiation and possibly confined to Gnrh3 neurons. Potential compensation factors and sensitive windows of time for compensation during development and puberty should be explored.

  19. The effect of peptidic and non-peptidic proteasome inhibitors on the biological properties of Acanthamoeba castellanii belonging to the T4 genotype.

    Science.gov (United States)

    Siddiqui, Ruqaiyyah; Saleem, Sahreena; Khan, Naveed Ahmed

    2016-09-01

    The treatment of Acanthamoeba infections remains problematic, suggesting that new targets and/or chemotherapeutic agents are needed. Bioassay-guided screening of drugs that are clinically-approved for non-communicable diseases against opportunistic eukaryotic pathogens is a viable strategy. With known targets and mode of action, such drugs can advance to clinical trials at a faster pace. Recently Bortezomib (proteasome inhibitor) has been approved by FDA in the treatment of multiple myeloma. As proteasomal pathways are well known regulators of a variety of eukaryotic cellular functions, the overall aim of the present study was to study the effects of peptidic and non-peptidic proteasome inhibitors on the biology and pathogenesis of Acanthamoeba castellanii of the T4 genotype, in vitro. Zymographic assays revealed that inhibition of proteasome had detrimental effects on the extracellular proteolytic activities of A. castellanii. Proteasome inhibition affected A. castellanii growth (using amoebistatic assays), but not viability of A. castellanii. Importantly, proteasome inhibitors affected encystation as determined by trophozoite transformation into the cyst form, as well as excystation, as determined by cyst transformation into the trophozoite form. The ability of proteasome inhibitor to block Acanthamoeba differentiation is significant, as it presents a major challenge in the successful treatment of Acanthamoeba infection. As these drugs are used clinically against non-communicable diseases, the findings reported here have the potential to be tested in a clinical setting against amoebic infections.

  20. Genetics of Isolated Hypogonadotropic Hypogonadism: Role of GnRH Receptor and Other Genes

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    Karges Beate

    2012-01-01

    Full Text Available Hypothalamic gonadotropin releasing hormone (GnRH is a key player in normal puberty and sexual development and function. Genetic causes of isolated hypogonadotropic hypogonadism (IHH have been identified during the recent years affecting the synthesis, secretion, or action of GnRH. Developmental defects of GnRH neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/FGF8, PROKR2/PROK2, or CHD7. Impaired GnRH secretion in normosmic patients with IHH may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself. Normosmic IHH is predominantly caused by inactivating mutations in the pituitary GnRH receptor inducing GnRH resistance, while mutations of the β-subunits of LH or FSH are very rare. Inheritance of GnRH deficiency may be oligogenic, explaining variable phenotypes. Future research should identify additional genes involved in the complex network of normal and disturbed puberty and reproduction.

  1. Regulation of Endogenous Conductances in GnRH neurons by Estrogens

    Science.gov (United States)

    Rønnekleiv, Oline K.; Bosch, Martha A.; Zhang, Chunguang

    2010-01-01

    17β-estradiol (E2) regulates the activity of the gonadotropin-releasing hormone (GnRH) neurons through both presynaptic and postsynaptic mechanisms, and this ovarian steroid hormone is essential for cyclical GnRH neuronal activity and secretion. E2 has significant actions to modulate the mRNA expression of numerous ion channels in GnRH neurons and/or to enhance (suppress) endogenous conductances (currents) including potassium (KATP, A-type) and calcium low voltage T-type and high voltage L-type currents. Also, it is well documented that E2 can alter the excitability of GnRH neurons via direct action, but the intracellular signaling cascades mediating these actions are not well understood. As an example, KATP channels are critical ion channels needed for maintaining GnRH neurons in a hyperpolarized state for recruiting T-type calcium channels that are important for burst firing in GnRH neurons. E2 modulates the activity of KATP channels via a membrane-initiated signaling pathway in GnRH neurons. Obviously there are other channels, including the small conductance activated K+ (SK) channels, that maybe modulated by this signaling pathway, but the ensemble of mER-, ERα-, and ERβ-mediated effects both pre- and post-synaptic will ultimately dictate the excitability of GnRH neurons. PMID:20816765

  2. Dynamic GnRH- and hCG-testing

    DEFF Research Database (Denmark)

    Bang, A Kirstine; Nordkap, Loa; Almstrup, Kristian

    2017-01-01

    was illustrated by results from 45 patients suspected of disordered hypothalamic-pituitary-gonadal axis. 3. METHODS: Baseline, stimulated, relative and absolute changes in serum FSH and LH were determined by ultrasensitive TRIFMA, and testosterone was determined by LC-MS/MS. 4. RESULTS: For the reference group LH...... insufficiency, compared to the relative increase. 5. CONCLUSIONS: We provide novel reference ranges for GnRH and hCG test in healthy men, which allows future diagnostic evaluation of hypothalamic-pituitary-gonadal disorders in men....

  3. Characterization of the cDNAs encoding three GnRH forms in the pejerrey fish Odontesthes bonariensis (Atheriniformes) and the evolution of GnRH precursors.

    Science.gov (United States)

    Guilgur, Leonardo G; Ortí, Guillermo; Strobl-Mazzulla, Pablo H; Fernandino, Juan I; Miranda, Leandro A; Somoza, Gustavo M

    2007-06-01

    Most vertebrates express two gonadotropin releasing hormone (GnRH) variants in brain tissue but there is an increasing number of fish species for which a third GnRH form has been detected. We characterized the precursors (cDNAs) of all three forms expressed in the brain of the pejerrey (silverside) fish, Odontesthes bonariensis (Atheriniformes): type I (GnRH-I; 440 bp), type II (GnRH-II; 529 bp), and type III (GnRH-III; 515 bp). The expression of these GnRHs precursors was also observed in peripheral tissues related to reproduction (gonads), visual and chemical senses (eye and olfactory epithelium), and osmoregulation (gill), suggesting that in teleost fish and possibly other vertebrates GnRH mediates directly or indirectly many other functions besides reproduction. We also present a comprehensive phylogenetic analysis including representatives of all chordate GnRH precursors characterized to date that supports the idea of two main paralogous GnRH lineages with different function. A "forebrain lineage" separates evolutionarily from the "midbrain lineage" as a result of an ancient duplication (ca. 600 million years ago). A third, fish-only clade of GnRH genes seems to have originated before the divergence of fish and tetrapods but retained only in fish. Phylogenetic analyses of GnRH precursors (DNA and protein sequences) under different optimality criteria converge on this result. Although alternative scenarios could not be statistically rejected in this study due to the relatively short size of the analyzed molecules, this hypothesis also receives support from chromosomal studies of synteny around the GnRH genes in vertebrates.

  4. GnRH antagonist in in vitro fertilization: where we are now.

    Science.gov (United States)

    Shapiro, D B; Mitchell-Leef, D

    2003-10-01

    This review focuses on the recent literature concerning the use of GnRH antagonists in ovulation induction for in vitro fertilization (IVF). The GnRH antagonists, ganirelix acetate (Orgalutran/Antagon) and cetrorelix (Cetrotide), have come into increasingly common use since their release in the last 3 years. This class of GnRH analogue has several potential advantages over GnRH agonists. Among these advantages are: 1) shorter duration of injectable drug treatment, 2) decreased gonadotropin requirement per cycle, 3) improved patient convenience and 4) lower overall treatment cost. As clinicians gain experience with these drugs, optimal treatment paradigms will likely emerge. This review will discuss current strategies and potential applications for the GnRH antagonists.

  5. Cumulus cells gene expression profiling in terms of oocyte maturity in controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist.

    Directory of Open Access Journals (Sweden)

    Rok Devjak

    Full Text Available In in vitro fertilization (IVF cycles controlled ovarian hyperstimulation (COH is established by gonadotropins in combination with gonadotropin-releasing hormone (GnRH agonists or antagonists, to prevent premature luteinizing hormone (LH surge. The aim of our study was to improve the understanding of gene expression profile of cumulus cells (CC in terms of ovarian stimulation protocol and oocyte maturity. We applied Affymetrix gene expression profiling in CC of oocytes at different maturation stages using either GnRH agonists or GnRH antagonists. Two analyses were performed: the first involved CC of immature metaphase I (MI and mature metaphase II (MII oocytes where 359 genes were differentially expressed, and the second involved the two GnRH analogues where no differentially expressed genes were observed at the entire transcriptome level. A further analysis of 359 differentially genes was performed, focusing on anti-Müllerian hormone receptor 2 (AMHR2, follicle stimulating hormone receptor (FSHR, vascular endothelial growth factor C (VEGFC and serine protease inhibitor E2 (SERPINE2. Among other differentially expressed genes we observed a marked number of new genes connected to cell adhesion and neurotransmitters such as dopamine, glycine and γ-Aminobutyric acid (GABA. No differential expression in CC between the two GnRH analogues supports the findings of clinical studies where no significant difference in live birth rates between both GnRH analogues has been proven.

  6. Flexible, Multi-dose GnRH Antagonist versus Long GnRH Agonist Protocol in Poor Responders: A Randomized Controlled Trial

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    Ensieh Shahrokh Tehraninejad

    2009-01-01

    Full Text Available Background: To compare a flexible, multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders.Materials and Methods: A randomized clinical trial of 70 poor responder patients (35 patients in GnRH antagonist protocol and 35 patients in long GnRH agonist protocol was performed at Royan Institute, Tehran, Iran. Both groups were given a fixed dose of human menopausal gonadotropin (HMG for stimulation and oral contraceptive pre-treatment. Data analyzed by student’s group t-test or Chi square test.Results: Stimulation duration, total gonadotrophins consumption, mean numbers of oocytes retrieved, formed embryos, cycle cancellation rate, and clinical pregnancy rate were similar between both groups. Although the miscarriage rate was higher in the agonist protocol group, the rate of miscarriage was not statistically significant between both groups.Conclusion: A flexible, multi-dose GnRH antagonist protocol appears as effective as the long GnRH agonist protocol in poor responders. More (larger randomized controlled trials for better statistical analysis are recommended.

  7. The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

    Science.gov (United States)

    Moon, Ho-Sang; Kim, Mi-Kyung; Son, Moon-Ho

    2011-07-01

    Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

  8. Pro-Cognitive Effects of Non-Peptide Analogues of Soluble Amyloid Peptide Precursor Fragment sAPP.

    Science.gov (United States)

    Tiunova, A A; Komissarova, N V; Nenaidenko, V G; Makhmutova, A A; Beznosko, B K; Bachurin, S O; Anokhin, K V

    2016-08-01

    We studied pro-cognitive effect of two heterocyclic low-molecular-weight compounds that serve as non-peptide analogues of soluble fragment of amyloid peptide precursor (sAPP). Intracerebroventricular and systemic administration of peptide mimetics P2 and P5 improved weak memory on the model of passive avoidance in chicks and in the object location task in mice. Both compounds were effective if administered close to the moment of training or 4 h after it. The time windows and dose range for the pro-cognitive effects of the mimetics were similar to those observed in previous studies with sAPP peptide fragments.

  9. In vitro fertilization outcome in patients with polycystic ovary syndrome treated with GnRH analogue

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    Marzieh Mehrafza

    2013-11-01

    Full Text Available Background: Polycystic ovarian syndrome (PCOS is the most common endocrinological disorders that affect approximately 5-7% of women in reproductive age. There is not any consensus about the efficient in vitro fertilization (IVF protocol for patients with PCOS. The aim of the present study was to compare the half and one-third dose depot gonadotropin-releasing hormone (GnRH agonist protocols versus the GnRH antagonist protocol in PCOS patients.Methods: In the present study, we retrospectively evaluated 119 infertile women with PCOS. The patients entered in the study in accordance with Rotterdam criteria. According to GnRH analogue used for pituitary suppression, patients were divided into three groups: half and one-third dose depot GnRH agonist protocols and GnRH antagonist protocol. In GnRH agonist protocol, half or one-third dose depot Decapeptyl (1.875 mg, 1.25 mg was injected on 21st day of previous cycle. In GnRH antagonist cycles, cetrotide 0.25 mg were administered daily when the leading follicles reached 14 mm. All basal and controlled ovarian hyperstimulation (COH characteristics were analyzed. Results: Basal characteristics including: age, FBS, prolactin, hirsutism, length of menstrual cycle were similar between 3 groups. Statically significant decreases in days of stimulation, number of gonadotrophin ampoules and metaphase II (MII oocytes were found in GnRH antagonist protocol (P<0.001, P<0.001 and P=0.045, while the decrease in biochemical pregnancy (P=0.083 and live birth rate (P=0.169 wasn't significant. Number of embryos transferred were similar in the half and one-third dose depot GnRH agonist and GnRH antagonist cycles (P=0.881. The incidence of OHSS weren't significantly different between 3 groups (5%, 4.9% and 12.8%, P=0.308. Conclusion: Our study suggest that one-third dose depot GnRH agonist protocol could be a suitable choice for treatment of PCOS because of lower incidence of ovarian hyperstimulation syndrome (OHSS as

  10. Dynamic evolution of the GnRH receptor gene family in vertebrates.

    Science.gov (United States)

    Williams, Barry L; Akazome, Yasuhisa; Oka, Yoshitaka; Eisthen, Heather L

    2014-10-25

    Elucidating the mechanisms underlying coevolution of ligands and receptors is an important challenge in molecular evolutionary biology. Peptide hormones and their receptors are excellent models for such efforts, given the relative ease of examining evolutionary changes in genes encoding for both molecules. Most vertebrates possess multiple genes for both the decapeptide gonadotropin releasing hormone (GnRH) and for the GnRH receptor. The evolutionary history of the receptor family, including ancestral copy number and timing of duplications and deletions, has been the subject of controversy. We report here for the first time sequences of three distinct GnRH receptor genes in salamanders (axolotls, Ambystoma mexicanum), which are orthologous to three GnRH receptors from ranid frogs. To understand the origin of these genes within the larger evolutionary context of the gene family, we performed phylogenetic analyses and probabilistic protein homology searches of GnRH receptor genes in vertebrates and their near relatives. Our analyses revealed four points that alter previous views about the evolution of the GnRH receptor gene family. First, the "mammalian" pituitary type GnRH receptor, which is the sole GnRH receptor in humans and previously presumed to be highly derived because it lacks the cytoplasmic C-terminal domain typical of most G-protein coupled receptors, is actually an ancient gene that originated in the common ancestor of jawed vertebrates (Gnathostomata). Second, unlike previous studies, we classify vertebrate GnRH receptors into five subfamilies. Third, the order of subfamily origins is the inverse of previous proposed models. Fourth, the number of GnRH receptor genes has been dynamic in vertebrates and their ancestors, with multiple duplications and losses. Our results provide a novel evolutionary framework for generating hypotheses concerning the functional importance of structural characteristics of vertebrate GnRH receptors. We show that five

  11. Enhancers of GnRH Transcription Embedded in an Upstream Gene Use Homeodomain Proteins to Specify Hypothalamic Expression

    OpenAIRE

    Iyer, Anita K.; MILLER, NICHOL L. G.; Yip, Kathleen; Tran, Brian H.; Mellon, Pamela L.

    2010-01-01

    GnRH, the central regulator of reproductive function, is produced by only approximately 800 highly specialized hypothalamic neurons. Previous studies identified a minimal promoter [GnRH minimal promoter (GnRH-P)] (−173/+1) and a neuron-specific enhancer [GnRH-enhancer (E)1] (−1863/−1571) as regulatory regions in the rat gene that confer this stringent specificity of GnRH expression to differentiated GnRH neurons. In transgenic mice, these two elements target only GnRH neurons but fail to driv...

  12. Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.

    Science.gov (United States)

    Stepniewski, Tomasz M; Filipek, Slawomir

    2015-07-15

    Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His102(3.29) and Phe257(6.51), for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Chemotaxis of human and rat leukocytes by the delta-selective non-peptidic opioid SNC 80.

    Science.gov (United States)

    Ordaz-Sánchez, Iván; Weber, Richard J; Rice, Kenner C; Zhang, Xiaoyan; Rodríguez-Padilla, C; Tamez-Guerra, R; Méndez-Vázquez, José L; Gómez-Flores, R

    2003-01-01

    Opioids like morphine, represent a major source of relief for most chronic moderate to severe nonmalignant pain. However, opioid abuse may lead to infections such as hepatitis and AIDS because opioids have been associated with suppressing various parameters of immune function including antimicrobial resistance, antibody production, monocyte-mediated phagocytosis, and both neutrophil and monocyte chemotaxis. We have previously reported immunopotentiating properties of non-peptidic opioid receptor selective agonists and antagonists. In this study, we evaluated the effects of the nonpeptidic delta-opioid receptor agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC 80) on chemotaxis of rat thymic and human peripheral blood mononuclear cells by using a modified Wilkinson chamber. Cell recruitment is an essential process in acute and chronic inflammatory responses. We observed that SNC 80 at concentrations of 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) M, significantly (p SNC 80 on chemotaxis of rat and human leukocytes were antagonized by naloxone, indicating that the modulation of chemotaxis by SNC 80 is via a classic opioid receptor. The development and use of non-peptidic opioids like SNC 80 could have an immediate impact not only as potent analgesics, but in immunoregulation.

  14. Delayed cardioprotection is mediated via a non-peptide delta opioid agonist, SNC-121, independent of opioid receptor stimulation.

    Science.gov (United States)

    Patel, Hemal H; Hsu, Anna; Gross, Garrett J

    2004-01-01

    Acute cardioprotection is mediated primarily through delta opioid receptor stimulation independent of micro or kappa opioid receptor stimulation. Delayed cardioprotection is mediated by delta opioid receptor agonists but ambiguity remains about direct receptor involvement. Therefore, we investigated the potential of SNC-121, a non-peptide delta opioid agonist, to produce delayed cardioprotection and characterized the role of opioid receptors in this delayed response. All rats underwent 30 minutes of ischemia followed by 2 hours of reperfusion. SNC-121 induced a significant delayed cardioprotective effect. To determine the nature of this SNC-121-induced delayed cardioprotection, rats were treated with specific opioids receptor antagonists and underwent pertussis toxin (PT) treatment prior to opioid agonist stimulation. Control rats were injected with saline and allowed to recover for 24 hours. Pretreatment and early treatment with opioid receptor antagonists failed to inhibit the delayed protective effects of SNC-121, as did pretreatment with PT. Treatment with a free radical scavenger, 2-mercaptopropionyl glycine, at the time of opioid stimulation attenuated the delayed cardioprotective effects of SNC-121. These data suggest that delayed cardioprotection is stimulated via non-peptide delta opioid agonists by a mechanism unrelated to opioid receptor activation. The mechanism appears to be a non-opioid receptor mediated production of reactive oxygen species that triggers the signaling cascade leading to delayed cardioprotection.

  15. Gliotransmission by Prostaglandin E2: a prerequisite for GnRH neuronal function?

    Directory of Open Access Journals (Sweden)

    Jerome eClasadonte

    2011-12-01

    Full Text Available Over the past four decades it has become clear that prostaglandin E2 (PGE2, a phospholipid-derived signaling molecule, plays a fundamental role in modulating the GnRH neuroendocrine system and in shaping the hypothalamus. In this review, after a brief historical overview, we highlight studies revealing that PGE2 released by glial cells such as astrocytes and tanycytes is intimately involved in the active control of GnRH neuronal activity and neurosecretion. Recent evidence suggests that hypothalamic astrocytes surrounding GnRH neuronal cell bodies may respond to neuronal activity with an activation of the erbB receptor tyrosine-kinase signaling, triggering the release of PGE2 as a chemical transmitter from the glia themselves, and, in turn, leading to the feedback regulation of GnRH neuronal activity. At the GnRH neurohemal junction, in the median eminence of the hypothalamus, PGE2 is released by tanycytes in response to cell-cell signaling initiated by glial cells and vascular endothelial cells. Upon its release, PGE2 causes the retraction of the tanycyte end feet enwrapping the GnRH nerve terminals, enabling them to approach the adjacent pericapillary space and thus likely facilitating neurohormone diffusion from these nerve terminals into the pituitary portal blood. In view of these new insights, we suggest that synaptically-associated astrocytes and perijunctional tanycytes are integral modulatory elements of GnRH neuronal function at the cell soma/dendrite and nerve terminal levels, respectively.

  16. Social status, breeding state, and GnRH soma size in convict cichlids (Cryptoheros nigrofasciatus).

    Science.gov (United States)

    Chee, San-San Amy; Espinoza, Walter A S; Iwaniuk, Andrew N; Pakan, Janelle M P; Gutiérrez-Ibáñez, Cristian; Wylie, Douglas R; Hurd, Peter L

    2013-01-15

    Gonadotropin-releasing hormone (GnRH) expressing neurons in the preoptic area (POA) of the hypothalamus plays a key role in regulating reproductive function through the control of gonadotropin release. Several studies have illustrated the importance of the social environment in modulating the size of GnRH expressing neurons. In the African cichlid fish Astatotilapia burtoni, the size of the soma of GnRH expressing neurons in the POA varies with social status in males, and with breeding state in females. Territorial males have larger GnRH+ cells than non-territorial males, while brooder females have smaller GnRH+ cells than control females. The lek-like breeding system of A. burtoni is, however, only one type of social system within the diverse assemblage of cichlids. To gain a better understanding of GnRH neuronal plasticity in response to the changes in the social environment, we tested whether similar effects occur in the monogamous New World cichlid, the convict cichlid (Cryptoheros nigrofasciatus), a model species for the study of social behaviour. Our results indicate that, indeed GnRH expressing neuron soma size, and not cell number, varies with both male territorial status, and manipulations of female breeding state in this monogamous, biparental, New World cichlid.

  17. GnRH Protein Levels in Atrazine-Treated Axolotls (Ambystoma mexicanum

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    Sarah Leupen

    2008-01-01

    Full Text Available Atrazine is the most widely used agricultural herbicide in the United States and a known endocrine disruptor. In amphibians, it has been shown to cause gonadal malformations, feminization of males, behavioral changes, and immune suppression; however, its mechanism ofaction is unknown. We hypothesized that atrazine reduces the production of gonadotropin releasing hormone (GnRH in the hypothalamus. Axolotls (Ambystoma mexicanum were exposed to atrazine, 10-8 M ß-estradiol-3-benzoate, or no treatment and were sacrificed at 6, 8, and 10 months of age. GnRH neurons were labeled using immunocytochemistry, and labeled neurons were then counted using confocal microscopy. Although no significant difference wasfound in the total number of GnRH neurons, ectopic GnRH expression was seen in some brains. A significant negative correlation was found between presence of ectopic GnRH and number of normal GnRH neurons. Atrazine-treated animals were more likely than control or estrogentreated animals to have ectopic GnRH expression. The data implicate a central site of action of atrazine.

  18. Origins of gonadotropin-releasing hormone (GnRH) in vertebrates: identification of a novel GnRH in a basal vertebrate, the sea lamprey.

    Science.gov (United States)

    Kavanaugh, Scott I; Nozaki, Masumi; Sower, Stacia A

    2008-08-01

    We cloned a cDNA encoding a novel (GnRH), named lamprey GnRH-II, from the sea lamprey, a basal vertebrate. The deduced amino acid sequence of the newly identified lamprey GnRH-II is QHWSHGWFPG. The architecture of the precursor is similar to that reported for other GnRH precursors consisting of a signal peptide, decapeptide, a downstream processing site, and a GnRH-associated peptide; however, the gene for lamprey GnRH-II does not have introns in comparison with the gene organization for all other vertebrate GnRHs. Lamprey GnRH-II precursor transcript was widely expressed in a variety of tissues. In situ hybridization of the brain showed expression and localization of the transcript in the hypothalamus, medulla, and olfactory regions, whereas immunohistochemistry using a specific antiserum showed only GnRH-II cell bodies and processes in the preoptic nucleus/hypothalamus areas. Lamprey GnRH-II was shown to stimulate the hypothalamic-pituitary axis using in vivo and in vitro studies. Lamprey GnRH-II was also shown to activate the inositol phosphate signaling system in COS-7 cells transiently transfected with the lamprey GnRH receptor. These studies provide evidence for a novel lamprey GnRH that has a role as a third hypothalamic GnRH. In summary, the newly discovered lamprey GnRH-II offers a new paradigm of the origin of the vertebrate GnRH family. We hypothesize that due to a genome/gene duplication event, an ancestral gene gave rise to two lineages of GnRHs: the gnathostome GnRH and lamprey GnRH-II.

  19. Identification of non-peptidic cysteine reactive fragments as inhibitors of cysteine protease rhodesain.

    Science.gov (United States)

    McShan, Danielle; Kathman, Stefan; Lowe, Brittiney; Xu, Ziyang; Zhan, Jennifer; Statsyuk, Alexander; Ogungbe, Ifedayo Victor

    2015-10-15

    Rhodesain, the major cathepsin L-like cysteine protease in the protozoan Trypanosoma brucei rhodesiense, the causative agent of African sleeping sickness, is a well-validated drug target. In this work, we used a fragment-based approach to identify inhibitors of this cysteine protease, and identified inhibitors of T. brucei. To discover inhibitors active against rhodesain and T. brucei, we screened a library of covalent fragments against rhodesain and conducted preliminary SAR studies. We envision that in vitro enzymatic assays will further expand the use of the covalent tethering method, a simple fragment-based drug discovery technique to discover covalent drug leads.

  20. A prospective study of GnRH long agonist versus flexible GnRH antagonist protocol in PCOS: Indian experience

    Directory of Open Access Journals (Sweden)

    Harpreet Kaur

    2012-01-01

    Full Text Available Background: Polycystic ovarian syndrome is a common endocrine disorder of reproductive age women. Many controlled ovarian stimulation (COS strategies have been offered for the treatment of patients with PCOS undergoing in vitro fertilization, but the optimal protocol is still a controversy. There is no compelling evidence for the advantage of one stimulation protocol over the other. Materials and Methods: This is a single-center prospective controlled study comparing long agonist and antagonist protocol in PCOS women. Results: There was no significant difference in live birth rate and clinical pregnancy rate. Rate of ovarian hyperstimulation syndrome was significantly higher in the agonist group. Number of oocytes retrieved, number of follicles and peak estradiol levels were significantly more in the agonist group. Conclusion: The GnRH antagonist protocol is an equally effective but safer protocol in PCOS patients compared with the long agonist protocol.

  1. Peripheral kisspeptin reverses short photoperiod-induced gonadal regression in Syrian hamsters by promoting GNRH release

    DEFF Research Database (Denmark)

    Ansel, L; Bentsen, A H; Ancel, C;

    2011-01-01

    stimulators of GNRH neurons. Both central and peripheral acute injections of Kp have been reported to activate the gonadotropic axis in mammals. The aim of this study was to determine if and how peripheral administration of Kp54 could restore gonadal function in photo-inhibited hamsters. Testicular activity...... of hamsters kept in SD was reactivated by two daily i.p. injections of Kp54 but not by chronic subcutaneous delivery of the same peptide via mini-pumps. Acute i.p. injection of Kp54-induced FOS (c-Fos) expression in a large number of GNRH neurons and pituitary gonadotrophs together with a strong increase...... in circulating testosterone. The activation of pituitary cells by Kp was inhibited by preadministration of the GNRH receptor antagonist acyline. Altogether, our results demonstrate that peripheral Kp54 activates the gonadotropic axis by stimulating GNRH release and indicate that an appropriate protocol of long...

  2. Mathematical modeling of the GnRH pulse and surge generator

    CERN Document Server

    Clement, Frederique

    2007-01-01

    We propose a mathematical model allowing for the alternating pulse and surge pattern of GnRH (Gonadotropin Releasing Hormone) secretion. The model is based on the coupling between two systems running on different time scales. The faster system corresponds to the average activity of GnRH neurons, while the slower one corresponds to the average activity of regulatory neurons. The analysis of the slow/fast dynamics exhibited within and between both systems allows to explain the different patterns (slow oscillations, fast oscillations and periodical surge) of GnRH secretion. Specifications on the model parameter values are derived from physiological knowledge in terms of amplitude, frequency and plateau length of oscillations. The behavior of the model is finally illustrated by numerical simulations reproducing natural ovarian cycles and either direct or indirect actions of ovarian steroids on GnRH secretion.

  3. Fgf8-deficient mice compensate for reduced GnRH neuronal population and exhibit normal testicular function

    Directory of Open Access Journals (Sweden)

    Wei eZhang

    2015-09-01

    Full Text Available Gonadotropin-releasing hormone (GnRH is critical for the onset and maintenance of reproduction in vertebrates. The development of GnRH neurons is highly dependent on fibroblast growth factor (Fgf signaling. Mice with a hypomorphic Fgf8 allele (Fgf8 Het exhibited a ~50% reduction in GnRH neuron number at birth. Female Fgf8 Het mice were fertile but showed significantly delayed puberty. However, it was unclear if these mice suffered additional loss of GnRH neurons after birth, and if male Fgf8 Het mice had normal pubertal transition and testicular function. In this study, we examined postnatal GnRH neuron number and hypothalamic GnRH content in Fgf8 Het mice from birth to 120 days of age. Further, we examined seminal vesicle and testicular growth, testicular histology, and circulating luteinizing hormone (LH around and after pubertal transition. Our results showed that GnRH neuron numbers were significantly and consistently reduced in Fgf8 Het mice of both sexes in all ages examined, suggesting these animals were born with an inherently defective GnRH system, and no further postnatal loss of GnRH neurons had occurred. Despite an innately compromised GnRH system, male and female Fgf8 mice exhibited normal levels of immunoassayable hypothalamic GnRH peptide at all ages examined except on 60 days of age, suggesting increased GnRH synthesis or reduced turnover as a compensatory mechanism. Fgf8 Het males also had normal seminal vesicle and testicular mass/body mass ratios, testicular histology, and circulating LH. Overall, our data speak to the extraordinary ability of a GnRH system permanently compromised by developmental defect to overcome pre-existing deficiencies to ensure pubertal progression and reproduction.

  4. GnRH neuron firing and response to GABA in vitro depend on acute brain slice thickness and orientation.

    Science.gov (United States)

    Constantin, Stephanie; Piet, Richard; Iremonger, Karl; Hwa Yeo, Shel; Clarkson, Jenny; Porteous, Robert; Herbison, Allan E

    2012-08-01

    The GnRH neurons exhibit long dendrites and project to the median eminence. The aim of the present study was to generate an acute brain slice preparation that enabled recordings to be undertaken from GnRH neurons maintaining the full extent of their dendrites or axons. A thick, horizontal brain slice was developed, in which it was possible to record from the horizontally oriented GnRH neurons located in the anterior hypothalamic area (AHA). In vivo studies showed that the majority of AHA GnRH neurons projected outside the blood-brain barrier and expressed c-Fos at the time of the GnRH surge. On-cell recordings compared AHA GnRH neurons in the horizontal slice (AHAh) with AHA and preoptic area (POA) GnRH neurons in coronal slices [POA coronal (POAc) and AHA coronal (AHAc), respectively]. AHAh GnRH neurons exhibited tighter burst firing compared with other slice orientations. Although α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) excited GnRH neurons in all preparations, γ-aminobutyric acid (GABA) was excitatory in AHAc and POAc but inhibitory in AHAh slices. GABA(A) receptor postsynaptic currents were the same in AHAh and AHAc slices. Intriguingly, direct activation of GABA(A) or GABA(B) receptors respectively stimulated and inhibited GnRH neurons regardless of slice orientation. Subsequent experiments indicated that net GABA effects were determined by differences in the ratio of GABA(A) and GABA(B) receptor-mediated effects in "long" and "short" dendrites of GnRH neurons in the different slice orientations. These studies document a new brain slice preparation for recording from GnRH neurons with their extensive dendrites/axons and highlight the importance of GnRH neuron orientation relative to the angle of brain slicing in studying these neurons in vitro.

  5. In vitro regulation of LH biosynthesis and release by GnRH and estradiol

    Energy Technology Data Exchange (ETDEWEB)

    Ramey, J.W.

    1986-01-01

    Anterior pituitaries were taken from female rats at random stages of the estrous cycle, enzymatically dispersed, and cultured for 48h in steroid-free ..cap alpha..-modified Eagles medium followed by 24h in fresh medium +/- estradiol (E/sub 2/). The pituitary cells were then incubated in fresh medium containing radiolabeled precursors +/- gonadotropin releasing hormone (GnRH). Radioactive precursor incorporation into LH was determined by immuno-precipitation. The dose-dependent effects of E/sub 2/(10/sup -11/ to 10/sup -8/M) on /sup 3/H-glucosamine (/sup 3/H-Gln) and /sup 35/S-methionine (/sup 35/S-Met) incorporation into LH +/- 1 nM GnRH (4h) were investigated. GnRH (10/sup -9/M) and E/sub 2/ (all doses) significantly increased total /sup 3/H-Gln LH. Moreover, E/sub 2/ at 10/sup -9/M and 10/sup -8/M significantly enhanced GnRH stimulated LH glycosylation. In contrast, addition of GnRH and/or E/sub 2/ did not significantly increase /sup 35/S-Met incorporation into LH over a 4h period. The effects of various GnRH concentrations (10/sup -11/ to 10/sup -9/M; 8h) +/- E/sub 2/ (0.05 nM) on /sup 3/H-Gln LH and /sup 35/S-Met LH production were also investigated. In the absence of E/sub 2/, only 10/sup -9/M GnRH was effective in increasing total /sup 3/H-Gln LH and /sup 35/S-Met LH synthesis. However, in the presence of E/sub 2/, all concentrations of GnRH stimulated LH synthesis with /sup 3/H-Gln LH production responding in a dose related manner whereas /sup 35/S-Met LH production was maximally stimulated at all doses of GnRH. In the final series of experiments, pituitary cells previously exposed to estradiol were incubated for 4 h in normal calcium or low calcium medium containing /sup 3/H-Gln or /sup 35/S-Met +/- GnRH. Removal of extracellular calcium completely inhibited GnRH stimulated /sup 3/H-Gln LH and /sup 35/S-Met LH production.

  6. Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone (GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  7. Highly immunogenic and fully synthetic peptide-carrier constructs targetting GnRH

    DEFF Research Database (Denmark)

    Beekman, N.J.C.M.; Schaaper, W.M.M.; Turkstra, J.A.;

    1999-01-01

    using a tandem GnRH peptide as a branched polylysine construct, a lipo-thioester, a lipo-amide or a KLH conjugate in CFA, and the lipoamide peptide in an immuno-stimulating complex (ISCOM). We found the lipo-thioester and the branched polylysine constructs to be the most effective carrier molecules...... for the induction of antibodies against GnRH and immunocastration of pigs....

  8. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  9. Kisspeptin and GnRH Neuronal Excitability: Molecular Mechanisms Driven by 17β-Estradiol

    Science.gov (United States)

    Rønnekleiv, Oline K.; Zhang, Chunguang; Bosch, Martha A.; Kelly, Martin J.

    2014-01-01

    Kisspeptin is a neuropeptide that signals via a Gαq-coupled receptor, GPR54, in gonadotropin-releasing hormone (GnRH) neurons and is essential for pubertal maturation and fertility. Kisspeptin depolarizes and excites GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels and inhibition of K+ channels. The gonadal steroid 17β-estradiol (E2) up-regulates not only kisspeptin (Kiss1) mRNA, but also increases the excitability of the rostral forebrain Kiss1 neurons. In addition, a primary postsynaptic action of E2 on GnRH neurons is to up-regulate the expression of channel transcripts that orchestrate the downstream signaling of kisspeptin in GnRH neurons. These include not only TRPC4 channels, but also low voltage-activated T-type calcium channels and high voltage-activated L-, N- and R-type calcium channel transcripts. Moreover, E2 has direct membrane-initiated actions to alter the excitability of GnRH neurons by enhancing ATP-sensitive potassium (KATP) channel activity, which is critical for maintaining GnRH neurons in a hyperpolarized state for recruitment of T-type calcium channels that are important for burst firing. Therefore, E2 modulates the excitability of GnRH neurons as well as Kiss1 neurons by altering the expression and/or function of ion channels; and kisspeptin provides critical excitatory input to GnRH neurons to facilitate burst firing activity and peptide release. PMID:25612870

  10. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  11. Gonadotropin-releasing hormone (GnRH) receptors of cattle aggregate on the surface of gonadotrophs and are increased by elevated GnRH concentrations.

    Science.gov (United States)

    Kadokawa, Hiroya; Pandey, Kiran; Nahar, Asrafun; Nakamura, Urara; Rudolf, Faidiban O

    2014-11-30

    The presence of gonadotropin-releasing hormone (GnRH) receptors (GnRHRs) on gonadotrophs in the anterior pituitary (AP) is an important factor for reproduction control. However, little is known regarding GnRHR gene expression in gonadotrophs of cattle owing to the lack of an appropriate anti-GnRHR antibody. Therefore, an anti-GnRHR antibody for immunohistochemistry, flow cytometry, and immunocytochemistry assays was developed to characterize GnRHR gene expression in gonadotrophs. The anti-GnRHR antibody could suppress GnRH-induced LH secretion from cultured AP cells of cattle. The GnRHR, luteinizing hormone (LH), and follicle stimulating hormone (FSH) in the AP tissue was analyzed by fluorescence immunohistochemistry. The GnRHRs were aggregated on a limited area of the cell surface of gonadotrophs, possibly localized to lipid rafts. The LH secretion was stimulated with increasing amounts of GnRH; however, excessive concentrations (> 1 nM) resulted in a decrease in LH secretion. A novel method to purify gonadotrophs was developed using the anti-GnRHR antibody and fluorescence-activated cell sorting. Flow cytometric analysis using the anti-GnRHR antibody for cultured bovine AP cells, however, failed to support the hypothesis that GnRH induces GnRHR internalization and decreases GnRHR on the surface of GnRHR-positive AP cells. In contrast, immunocytochemistry using primary antibodies for cultured bovine AP cells showed that 10 nM (P < 0.05) and 100 nM (P < 0.01) GnRH, but not 0.01-1 nM GnRH, increased GnRHR in the cytoplasm of LH-positive cells. In conclusion, these data suggested that GnRHRs were aggregated on the surface of gonadotrophs and GnRHR inside gonadotrophs increased with elevated concentrations of GnRH.

  12. Controle sobre GnRH durante o anestro pós-parto em bovinos GnRH control during bovine postpartum anestrous

    Directory of Open Access Journals (Sweden)

    João Francisco Coelho de Oliveira

    2010-12-01

    Full Text Available O pós-parto em bovinos é caracterizado como um momento em que as fêmeas bovinas não ovulam, principalmente devido a uma inadequada liberação de gonadotrofinas. Os conceitos e os mecanismos regulatórios do hormônio liberador de gonadotrofinas (GnRH têm sido descritos isoladamente. Esta revisão aborda a influência da nutrição e amamentação, com enfoque na regulação do GnRH, e fornece conceitos atuais do controle neuroendocrinológico da secreção de GnRH durante o pós-parto em bovinos. Conhecimentos atuais das funções do hormônio inibitório de gonadotrofinas (GnIH, da leptina, dos estrógenos, da kisspeptina e da adiponectina, bem como suas complexas inter-relações durante este período estão detalhados para melhor entendimento do assunto.The bovine postpartum period is characterized as a moment when the ovulation is suppressed, mainly in consequence of insufficient release of gonadotropins. Concepts and regulatory mechanisms of gonadotropin-releasing hormone (GnRH had been described independently. This review covers the influence of nutrition and suckling with emphasis on GnRH regulation, and provides up to date concepts of neuroendocrine control of GnRH secretion during postpartum in cattle. Current knowledge of gonadotropin-inhibitory hormone (GnIH, leptin, estrogens and kisspeptin during this period are presented in order to provide a better understanding of the subject.

  13. Gonadotropin-releasing hormone: regulation of the GnRH gene.

    Science.gov (United States)

    Lee, Vien H Y; Lee, Leo T O; Chow, Billy K C

    2008-11-01

    As the key regulator of reproduction, gonadotropin-releasing hormone (GnRH) is released by neurons in the hypothalamus, and transported via the hypothalamo-hypophyseal portal circulation to the anterior pituitary to trigger gonadotropin release for gonadal steroidogenesis and gametogenesis. To achieve appropriate reproductive function, mammals have precise regulatory mechanisms; one of these is the control of GnRH synthesis and release. In the past, the scarcity of GnRH neurons and their widespread distribution in the brain hindered the study of GnRH gene expression. Until recently, the development of GnRH-expressing cell lines with properties similar to those of in vivo GnRH neurons and also transgenic mice facilitated GnRH gene regulation research. This minireview provides a summary of the molecular mechanisms for the control of GnRH-I and GnRH-II gene expression. These include basal transcription regulation, which involves essential cis-acting elements in the GnRH-I and GnRH-II promoters and interacting transcription factors, and also feedback control by gonadotropins and gonadal sex steroids. Other physiological stimuli, e.g. insulin and melatonin, will also be discussed.

  14. GnRH analogue attenuated apoptosis of rat hippocampal neuron after ischemia-reperfusion injury.

    Science.gov (United States)

    Chu, Chenyu; Xu, Bainan; Huang, Weiquan

    2010-12-01

    The expression and new functions of reproductive hormones in organs beyond hypothalamus-pituitary-gonad axis have been reported. So far, there is no report about the protective effects of GnRH analogue to hippocampal neurons suffering from ischemia-reperfusion injury. Middle cerebral artery occlusion model together with TUNEL staining were made in vivo and oxygen-glucose deprivation model together with double staining of Annexin V/PI with flow cytometer were made in vitro to observe the anti-apoptotic effects of GnRH analogue to hippocampal neurons after ischemia-reperfusion injury. The results found that the number of TUNEL positive pyramidal neurons in CA1 region in GnRH analogue experiment group was less than that in control group in vivo; the percentage of apoptotic neurons in GnRH analogue experiment group was less than that in control group in vitro. These findings suggested that pretreatment with certain concentration of GnRH analogue could attenuate apoptosis of hippocampal neurons. GnRH analogue has the protective effects to neurons.

  15. Evaluation of GnRH analogue testing in diagnosis and management of children with pubertal disorders

    Directory of Open Access Journals (Sweden)

    Hemchand K Prasad

    2012-01-01

    Full Text Available Context: Gonadotrophin releasing hormone (GnRH stimulation test is pivotal in the assessment of children with pubertal disorders. However, lack of availability and high cost often result in the test falling into disfavor. We routinely use the GnRH analogue stimulation test as an alternative at our center. Aim: To present the data on children with endocrine disorders who underwent GnRH agonist stimulation test in pediatric endocrine clinic of a tertiary care referral hospital. Setting and Design: Pediatric endocrine clinic of a tertiary care referral hospital. Retrospective analysis of case records. Materials and Methods: The details pertaining to clinical and radiological parameters and hormonal tests were retrieved from case records of 15 children who underwent GnRH agonist stimulation test from May 2010 to April 2011. Results: Indications for testing with GnRH analogue were evaluation of delayed puberty, diagnosis of precocious puberty, assessment of hormonal suppression in treatment of precocious puberty and micropenis in two, nine, three and one cases, respectively. The results of the test and clinical and radiological parameters were in concordance. The test was also crucial in diagnosing the onset of central precocious puberty in two children with congenital adrenal hyperplasia. Conclusion: GnRH agonist test is a convenient, safe test that can be performed on an out-patient basis and can help the clinicians in the correct diagnosis and appropriate treatment of various puberty-related disorders.

  16. Comparisons of GnRH antagonist versus GnRH agonist protocol in supposed normal ovarian responders undergoing IVF: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jin-song Xiao

    Full Text Available OBJECTIVE: To evaluate the effectiveness and safety of GnRH antagonist and GnRH agonist in supposed normal ovarian responders undergoing IVF. METHODS: Data from 6 databases were retrieved for this study. The RCTs of GnRH agonist and GnRH antagonist use during IVF-EF therapy for patients with supposed normal ovarian response were included. A meta-analysis was performed with Revman 5.1software. RESULTS: Twenty-three RCTs met the inclusion criteria. The number of stimulation days (mean difference (MD: -0.66, 95% confidence interval (CI: -1.04∼-0.27, Gn amount (MD: -2.92, 95% CI: -5.0∼-0.85, E2 values on the day of HCG (MD: -330.39, 95% CI: -510.51∼-150.26, Number of oocytes retrieved (MD: -1.33, 95% CI: -2.02∼-0.64, clinical pregnancy rate (odds ratio (OR: 0.87, 95% CI: 0.75-1.0, and ovarian hyperstimulation syndrome (OHSS incidence (OR: 0.59, 95% CI: 0.42∼0.82 were significantly lower in GnRH antagonist protocol than GnRH agonist protocol. However, the endometrial thickness on the day of HCG (MD: -0.04, 95% CI: -0.23∼0.14, the ongoing pregnancy rate (OR: 0.87, 95% CI: 0.74∼1.03, live birth rate (OR: 0.89, 95% CI: 0.64∼1.24, miscarriage rate (OR: 1.17, 95% CI: 0.85∼1.61, and cycle cancellation rate (OR: 1.11, 95% CI: 0.90∼1.37 did not significantly differ between the 2 groups. CONCLUSIONS: During IVF treatment for patients with supposed normal responses, the incidence of OHSS were significantly lower, whereas the ongoing pregnancy and live birth rates were similar in the GnRH antagonist compared with the standard long GnRH agonist protocols.

  17. The type of GnRH analogue used during controlled ovarian stimulation influences early embryo developmental kinetics

    DEFF Research Database (Denmark)

    Muñoz, Manuel; Cruz, María; Humaidan, Peter

    2013-01-01

    OBJECTIVE: To explore if the GnRH analogue used for controlled ovarian stimulation (COS) and the ovulation triggering factor (GnRH agonist+hCG triggering versus GnRH antagonist+GnRH agonist triggering) affect embryo development and kinetics. STUDY DESIGN: In a retrospective cohort study in the In......OBJECTIVE: To explore if the GnRH analogue used for controlled ovarian stimulation (COS) and the ovulation triggering factor (GnRH agonist+hCG triggering versus GnRH antagonist+GnRH agonist triggering) affect embryo development and kinetics. STUDY DESIGN: In a retrospective cohort study...... in the Instituto Valenciano de Infertilidad (IVI) Alicante and the Instituto Universitario-IVI Valencia, Spain, 2817 embryos deriving from 400 couples undergoing oocyte donation were analysed. After controlled ovarian stimulation and IVF/intracytoplamic sperm injection, the timing of embryonic cleavages...

  18. Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

    Directory of Open Access Journals (Sweden)

    Guo S

    2017-03-01

    Full Text Available Song Guo,1,* Xiaowei Lu,1,* Ruihuan Gu,2 Di Zhang,3 Yijuan Sun,2 Yun Feng1 1Department of Obstetrics and Gynecology, Reproductive Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Gynecology, Shanghai Ji Ai Genetics & In Vitro Fertilization Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Gynecology and Obstetrics, Jinan Military General Hospital, Jinan, People’s Republic of China *These authors contributed equally to this work Purpose: Adenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis.Methods: Neonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each. The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR.Results: The litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; P<0.05. However, the average live litter

  19. Feedback actions of estradiol on GnRH secretion during the follicular phase of the estrous cycle.

    Science.gov (United States)

    Karsch, F J; Evans, N P

    1996-01-01

    The pattern of GnRH secretion during the follicular phase of the estrous cycle of sheep is characterized by an initial marked change in episodic secretion (increased frequency and decreased amplitude) followed by a massive and sustained discharge-the preovulatory GnRH surge. Studies employing a physiological model for the follicular phase have revealed that estradiol has profound and complex feedback effects on GnRH release during the preovulatory period. These include both quantitative effects on pulses (stimulation of frequency, inhibition of amplitude) and qualitative effects (altering pulse shape, stimulating interpulse secretion), in addition to inducing a preovulatory GnRH surge. In stimulating the surge, estradiol causes a highly characteristic change in the minute-to-minute pattern of GnRH in hypophyseal portal blood. Initially, a strictly episodic pattern gives way to one in which GnRH is consistently elevated between pulses. Then, following enhancement of both pulsatile and interpulse components, GnRh becomes extremely high and variable for the majority of the surge. From this point, a regular and well organized pulse pattern is not apparent. The characteristic time course of GnRH at surge onset provides insight into possible mechanistic changes in the GnRH neurosecretory system. Such changes include quantitative and qualitative alterations in the pulse generating mechanism, recruitment of a surge specific population of GnRH neurones, morphologic alterations in GnRH neurones and neighboring cells, and changes in efficiency or route of delivery of GnRH from its site of release to the portal vasculature. These possibilities, while untested and speculative, provide a conceptual framework for future research.

  20. Rabconnectin-3α is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness.

    Science.gov (United States)

    Tata, Brooke K; Harbulot, Carole; Csaba, Zsolt; Peineau, Stéphane; Jacquier, Sandrine; de Roux, Nicolas

    2017-02-17

    A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show that brain expression levels of Dmxl2, which encodes the vesicular protein rabconnectin-3α, determine the capacity of GnRH neurons to be activated by kisspeptin and estradiol. We also demonstrate that Dmxl2 expression levels control the pruning of GnRH dendrites, highlighting an unexpected role for a vesicular protein in the maturation of GnRH neuronal network. This effect is mediated by rabconnectin-3α in neurons or glial cells afferent to GnRH neurons. The widespread expression of Dmxl2 in several brain areas raises the intriguing hypothesis that rabconnectin-3α could be involved in the maturation of other neuronal populations.

  1. [GnRH analogues for the treatment of fibroids].

    Science.gov (United States)

    Murillo, Ester Ortiz; Cano, Antonio

    2013-07-01

    Uterine fibroids are benign tumors that are very common in women and may present significant symptoms in 20%-50% of cases. When they require action, their traditional management has been surgery (hysterectomy or fibroidectomy); however medical alternatives have been proposed, given that surgery is associated with a certain morbidity and mortality and involves healthcare costs. Within the pharmacological management of uterine fibroids, GnRH analogues are the best known and most commonly used drugs, although their indications are limited by the side effects associated with long-term treatment. Their primary indication is based on preoperative treatment (to hysterectomy or fibroidectomy) and in selected cases of patients close to menopause or who want more conservative management. These analogues are able to significantly reduce the uterine volume, the size of the fibroid and their accompanying symptoms. Their main disadvantage, however, lies in the reversibility of their effect when treatment is discontinued, along with the side effects associated with hypoestrogenism, such as climacteric symptoms and loss of bone mass. "Add-back" therapies, which associate low-dose estrogens to aGnRH, allow for extended use thanks to decreased side effects without affecting the benefits. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  2. Local duplication of gonadotropin-releasing hormone (GnRH receptor before two rounds of whole genome duplication and origin of the mammalian GnRH receptor.

    Directory of Open Access Journals (Sweden)

    Fatemeh Ameri Sefideh

    Full Text Available Gonadotropin-releasing hormone (GnRH and the GnRH receptor (GnRHR play an important role in vertebrate reproduction. Although many GnRHR genes have been identified in a large variety of vertebrate species, the evolutionary history of GnRHR in vertebrates is unclear. To trace the evolutionary origin of GnRHR we examined the conserved synteny of chromosomes harboring GnRHR genes and matched the genes to linkage groups of reconstructed vertebrate ancestor chromosomes. Consistent with the phylogenetic tree, three pairs of GnRHR subtypes were identified in three paralogous linkage groups, indicating that an ancestral pair emerged through local duplication before two rounds of whole genome duplication (2R. The 2R then led to the generation of six subtypes of GnRHR. Some subtypes were lost during vertebrate evolution after the divergence of teleosts and tetrapods. One subtype includes mammalian GnRHR and a coelacanth GnRHR that showed the greatest response to GnRH1 among the three types of GnRH. This study provides new insight into the evolutionary relationship of vertebrate GnRHRs.

  3. Mathematical modeling of perifusion cell culture experiments on GnRH signaling.

    Science.gov (United States)

    Temamogullari, N Ezgi; Nijhout, H Frederik; C Reed, Michael

    2016-06-01

    The effects of pulsatile GnRH stimulation on anterior pituitary cells are studied using perifusion cell cultures, where constantly moving culture medium over the immobilized cells allows intermittent GnRH delivery. The LH content of the outgoing medium serves as a readout of the GnRH signaling pathway activation in the cells. The challenge lies in relating the LH content of the medium leaving the chamber to the cellular processes producing LH secretion. To investigate this relation we developed and analyzed a mathematical model consisting of coupled partial differential equations describing LH secretion in a perifusion cell culture. We match the mathematical model to three different data sets and give cellular mechanisms that explain the data. Our model illustrates the importance of the negative feedback in the signaling pathway and receptor desensitization. We demonstrate that different LH outcomes in oxytocin and GnRH stimulations might originate from different receptor dynamics and concentration. We analyze the model to understand the influence of parameters, like the velocity of the medium flow or the fraction collection time, on the LH outcomes. We show that slow velocities lead to high LH outcomes. Also, we show that fraction collection times, which do not divide the GnRH pulse period evenly, lead to irregularities in the data. We examine the influence of the rate of binding and dissociation of GnRH on the GnRH movement down the chamber. Our model serves as an important tool that can help in the design of perifusion experiments and the interpretation of results. Published by Elsevier Inc.

  4. ART Outcomes in GnRH Antagonist Protocol (Flexible) and Long GnRH Agonist Protocol during Early Follicular Phase in Patients with Polycystic Ovary Syndrome: A Randomized Clinical Trial

    Science.gov (United States)

    Mokhtar, Sara; Sadeghi, Mohammad Reza; Akhondi, Mohammad Mehdi; Zafardoust, Simin; Badenush, Bita; Fatemi, Farnaz; Nazari, Fattane; Kamali, Koorosh; Mohammadzade, Afsaneh

    2015-01-01

    Background: Since increased LH in the early follicular phase in PCOS patients especially in GnRH antagonist protocol could be associated with reduced oocyte quality and pregnancy and impared implantation. The current study was conducted to determine ART outcomes in GnRH antagonist protocol (flexible) and long GnRH agonist protocol and compare them with adding GnRH antagonist in GnRH antagonist (flexible) protocol during early follicular phase in patients with polycystic ovary syndrome undergoing ICSI. Methods: In this randomized clinical trial, 150 patients with polycystic ovary syndrome undergoing ICSI were enrolled from 2012 to 2014 and randomly assigned to receive either GnRH antagonist protocol during early and late follicular phase or GnRH antagonist protocol (flexible) or long GnRH agonist protocol. The clinical and laboratory pregnancy in three groups was determined and compared. In this context, the chi-square and Fisher's exact test and ANOVA were used for data analysis. Statistical significance was defined as p<0.05. Results: There was no statistically significant difference with respect to chemical pregnancy and clinical pregnancy between the three groups. Also, other indices such as number and quality of oocytes and embryos were alike. Conclusion: Totally, according to our results, GnRH antagonist protocol during early and late follicular phase and GnRH antagonist protocol (flexible) and long GnRH agonist protocol in patients with polycystic ovary syndrome undergoing ICSI are similarly effective and use of each one based on patients' condition and physicians' opinion could be considered. PMID:26913233

  5. GnRH agonist versus GnRH antagonist in IVF/ICSI cycles with recombinant LH supplementation: DNA fragmentation and apoptosis in granulosa cells.

    Science.gov (United States)

    Lavorato, Heloisa L; Oliveira, Joao Batista A; Petersen, Claudia G; Vagnini, Laura; Mauri, Ana L; Cavagna, Mario; Baruffi, Ricardo L R; Franco, Jose G

    2012-11-01

    To compare the level of apoptosis and DNA fragmentation in the human granulosa cell (GC) layer exposed to an agonist or antagonist of GnRH in intracytoplasmic sperm injection (ICSI) cycles supplemented with recombinant LH (rLH). Patients without ovulatory dysfunction, aged ≤37 years and in their first ICSI cycle were prospectively randomised to receive either a long GnRH agonist protocol or a multi-dose antagonist protocol. In both groups, recombinant FSH supplemented with rLH was used for ovarian stimulation, and the GCs were collected during oocyte denudation. The GCs were then analysed for DNA fragmentation by TUNEL assay and for apoptosis using the annexin-V assay. The outcomes were given as the percentage of GCs with DNA fragmentation and apoptosis out of the total number of GCs analysed. Comparison of the agonist versus the antagonist group was performed using the Mann-Whitney test. DNA fragmentation: 32 patients were included in either the GnRH agonist group (n=16) or the antagonist group (n=16). The percentage of GCs with positive DNA fragmentation did not differ significantly (P=0.76) between the agonist group (15.5 ± 9.4%) and the antagonist group (18.8 ± 13.3%). Apoptosis: 28 patients were included in either the GnRH agonist group (n=14) or the antagonist group (n=14). The percentage of GCs positive for apoptosis did not differ significantly (P=0.78) between the agonist group (34.6 ± 14.7%) and the antagonist group (36.5 ± 22%). The results suggest that therapy with either an agonist or antagonist of GnRH is associated with comparable levels of DNA fragmentation and apoptosis in granulosa cells in ICSI cycles supplemented with rLH. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  6. Central effects of some peptide and non-peptide opioids and naloxone on thermoregulation in the rabbit

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The effects of several peptide and non-peptide opiods and naloxone on induced hyperthermia is studied in rabbits. The effect of tyical mu, kappa, and sigma receptor antagonists (morphine, ketocyclazcine and SKF 10,0 10, 047) and some opioid peptides (Beta-endorphin /BE/, methionine-enkaphalin /ME/, and D-Ala2-methionine-enkaphalin-amide /DAME/ are determined. The role of prostaglandins (PG), cAMP, and norepinephrine (NE) in morphine, BE, and DAME induced hyperthermia is investigated. In addition, the effect of naloxone on pyrogen, arachidonic acid, PGE2, prostacyclin, dibutyryl cAMP, and NE induced hyperthermia is determined. Among other results, it is found that the three receptor antagonists induced hyperthermia in rabbits. BE, ME, and DAME were also found to cause hyperthermia, and it is suggested that they act on the same type of receptor. It is also determined that neither NE nor cAMP is involved in the hyperthermia due to morphine, BE, and DAME. It is suggested that an action of endogenous peptides on naloxone sensitive receptors plays little role in normal thermoregulation or in hyperthermia.

  7. Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1.

    Directory of Open Access Journals (Sweden)

    Adeline Gasser

    Full Text Available Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI.

  8. Combined ovulation triggering with GnRH agonist and hCG in IVF patients.

    Science.gov (United States)

    Kasum, Miro; Kurdija, Kristijan; Orešković, Slavko; Čehić, Ermin; Pavičić-Baldani, Dinka; Škrgatić, Lana

    2016-11-01

    The aim of the review is to analyse the combination of a gonadotrophin releasing hormone (GnRH) agonist with a human chorionic gonadotrophin (hCG) trigger, for final oocyte maturation in in vitro fertilisation (IVF) cycles. The concept being a ''dual trigger'' combines a single dose of the GnRH agonist with a reduced or standard dosage of hCG at the time of triggering. The use of a GnRH agonist with a reduced dose of hCG in high responders demonstrated luteal phase support with improved pregnancy rates, similar to those after conventional hCG and a low risk of ovarian hyperstimulation syndrome (OHSS). The administration of a GnRH agonist and a standard hCG in normal responders, demonstrated significantly improved live-birth rates and a higher number of embryos of excellent quality, or cryopreserved embryos. The concept of the ''double trigger" represents a combination of a GnRH agonist and a standard hCG, when used 40 and 34 h prior to ovum pick-up, respectively. The use of the ''double trigger" has been successfully offered in the treatment of empty follicle syndrome and in patients with a history of immature oocytes retrieved or with low/poor oocytes yield. Further prospective studies are required to confirm the aforementioned observations prior to clinical implementation.

  9. Effect of GnRH analogs in postnatal domestic cats.

    Science.gov (United States)

    Carranza, A; Faya, M; Merlo, M Lopez; Batista, P; Gobello, C

    2014-07-01

    The aim of this study was to reproductively assess the clinical and hormonal effects of a GnRH agonist (AG) and an antagonist (AN) administered during the postnatal period in domestic cats. Forty-eight male and female postnatal kittens were randomly assigned to deslorelin acetate 1.6 mg subcutaneous (AG; n = 16), acyline 33 μg/100 g subcutaneous weekly for 3 months (AN; n = 16), or control (CO; n = 16) which remained untreated. The cats were followed up (behavioral observation, physical examination, fecal sexual steroid determinations, mating test, and pregnancy diagnosis) up to puberty. Puberty was delayed (weeks) in the AG animals (62.9 ± 3.5; P  0.05) when they were compared with CO kittens (13.4 ± 0.4). Fifteen (15/16) of the AN and CO animals, and only 11 of 16 cats of the AG group were fertile (P > 0.1). No differences were found in body weight (P > 0.1) and measurements (P > 0.1), libido (P > 0.1) and in the appearance of side effects (P > 0.1; except a pyometra in an AG female) among groups. In both AG- and AN-treated males (testosterone; P < 0.01) and females (estradiol-17β; P < 0.01) fecal hormone concentrations were lower than in CO group during the first five postnatal weeks but not later. It is concluded that the neonatal administration of these AG and AN decreased fecal sexual steroids during the first postnatal weeks causing, the agonists but not the antagonist, a significant, reversible delay in puberty appearance.

  10. Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Müllerian hormone

    NARCIS (Netherlands)

    Hamdine, O.; Eijkemans, M. J C; Lentjes, E. W G; Torrance, H. L.; Macklon, N. S.; Fauser, B. C J M; Broekmans, F. J.

    2015-01-01

    STUDY QUESTION What is the clinical value of anti-Müllerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment? SUMMARY ANSWER AMH as a single test has substantial accuracy for ovarian response prediction in GnRH

  11. Effect of epinephrine, norepinephrine and(or) GnRH on serum LH in prepuberal beef heifers.

    Science.gov (United States)

    Hardin, D R; Randel, R D

    1983-09-01

    Forty prepuberal Simmental X Brahman-Hereford heifers were utilized to determine the effects of epinephrine (E), norepinephrine (NE), gonadotropin releasing hormone (GnRH) or combinations of GnRH + E and GnRH + NE on serum luteinizing hormone (LH) concentrations. Animals were assigned randomly to one of five treatments with four replicates/treatment. Treatments consisted of I) 100 micrograms GnRH at time 0 (n = 8); II) 50 mg NE at time -15 and 0 (n = 8); III) 50 mg E at time -15 and 0 (n = 8); IV) 100 micrograms GnRH at time 0, plus 50 mg NE at time -15 and 0 (n = 8) and V) 100 micrograms GnRH at time 0, plus 50 mg E at time -15 and 0 (n = 8). All treatment compounds were administered im in 2 ml physiological saline and blood samples were collected via tail vessel puncture at -30, -15, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min from GnRH injection. Treatment with NE or E alone had no effect (P greater than .10) on serum LH during the sampling period. The initial LH release to GnRH was altered (P less than .05) by concomitant treatment with NE (treatment IV) or E (treatment V). Magnitude of the LH release was reduced (P less than .01) by treatment V. Area under the LH surge was reduced (P less than .05) by treatment IV (NE) and V (E).

  12. EFFECTS OF GONADOTROPIN RELEASING HORMONE (GnRH) ANGONIST ON OVARIAN GnRH RECEPTORS OF RATS

    Institute of Scientific and Technical Information of China (English)

    SUFang-Ming; LUXiang-Yun; GONGYue-Ting

    1989-01-01

    A potent D-Trp6-GnRH iodinated by the lactoperoxidase glucose oxidase method was used as a ligand to bind specifically to the rat ovarian membrane, The ovariu GnRH receptor has a binding affinity with the agonist similar to that of the pituiary receptor, Ka

  13. Repeat Breeder ineklerde GnRH uygulaması ve döl verimi

    OpenAIRE

    Ata, Ayhan

    1997-01-01

    Bu çalışma Repeat Breeder ineklerde değişik gonadotropin releasing hormon (GnRH) uygulamalarının reprodüktif performans üzerine etkisini tespit etmek amacıyla yapıldı. Araştırmada materyal olarak bakım ve barınma koşulları yeterli olan Repeat Breeder özelliği gösteren 30 inek kullanıldı. Bu inekler üç gruba ayrıldı. I. gruptaki ineklere 0,02 mg GnRH analoğu, II. gruptaki ineklere 0,01 mg GnRH analoğu uygulanırken, IH. gruptaki 10 inek kontrol grubu olarak tutuldu. Çalışma...

  14. [Synthesis of GnRH analogs and their application in targeted gene delivery systems].

    Science.gov (United States)

    Iablokova, T V; Chelushkin, P S; Dorosh, M Iu; Efremov, A M; Orlov, S V; Burov, S V

    2012-01-01

    A set of GnRH analogues containing nuclear localization signal (NLS) of SV-40 virus large T-antigen have been synthesized using solid phase peptide synthesis and chemical ligation technique. Selective chemical ligation was achieved as a result of hydrazone formation in the course of interaction between NLS hydrazide and GnRH analog modified by pyruvic acid. The efficiency of synthesized peptide carriers was demonstrated in experiments with human cancer cells transfected by reporter luciferase and beta-galactosidase genes or suicide HSV-1 thymidine kinase gene. It was shown that selectivity of action on cancer cells can be achieved as a result of peptide/DNA complex penetration through the cell membrane by GnRH receptor-mediated endocytosis pathway.

  15. Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

    Science.gov (United States)

    Guo, Song; Lu, Xiaowei; Gu, Ruihuan; Zhang, Di; Sun, Yijuan; Feng, Yun

    2017-01-01

    Purpose Adenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH) agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis. Methods Neonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each). The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR). Results The litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; Ppregnancy outcome of adenomyosis in a mouse model. Besides pituitary down-regulation, other possible mechanisms such as the regulation of cell proliferation may play a role in this. These new insights into GnRH agonist mechanisms will be useful for future adenomyosis treatment. PMID:28331289

  16. Endocannabinoids and Endovanilloids: A Possible Balance in the Regulation of the Testicular GnRH Signalling

    Directory of Open Access Journals (Sweden)

    Rosanna Chianese

    2013-01-01

    Full Text Available Reproductive functions are regulated both at central (brain and gonadal levels. In this respect, the endocannabinoid system (eCS has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH. Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed.

  17. A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities.

    Science.gov (United States)

    He, Min; Guan, Ni; Gao, Wei-wei; Liu, Qing; Wu, Xiao-yan; Ma, Da-wei; Zhong, Da-fang; Ge, Guang-bo; Li, Chuan; Chen, Xiao-yan; Yang, Ling; Liao, Jia-yu; Wang, Ming-wei

    2012-02-01

    Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes. However, there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development. This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R). Here, we briefly review the discovery, characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R, including Boc5 and its newly discovered analogue WB4-24. Although the oral bioavailability of such compounds still poses great challenges, the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

  18. A continued saga of Boc5, the first non-peptidic glucagon-like peptide-1 receptor agonist with in vivo activities

    Institute of Scientific and Technical Information of China (English)

    Min HE; Xiao-yan CHEN; Ling YANG; Jia-yu LIAO; Ming-wei WANG; Ni GUAN; Wei-wei GAO; Qing LIU; Xiao-yan WU; Da-wei MA; Da-fang ZHONG; Guang-bo GE; Chuan LI

    2012-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy presents a promising option for treating type 2 diabetes.However,there are several limitations relative to the peptidic GLP-1 mimetics currently on the market or under development.This concern has led to a continued interest in the search for non-peptidic agonists for GLP-1 receptor (GLP-1R).Here,we briefly review the discovery,characterization and current status of a novel class of cyclobutane-derivative-based non-peptidic agonists for GLP-1R,including Boc5 and its newly discovered analogue WB4-24.Although the oral bioavailability of such compounds still poses great challenges,the progress made so far encourages us to identify a truly 'druggable' small molecule agonist for GLP-1R.

  19. Repeated use of the GnRH analogue deslorelin to down-regulate reproduction in male cheetahs (Acinonyx jubatus).

    Science.gov (United States)

    Bertschinger, H J; Jago, M; Nöthling, J O; Human, A

    2006-10-01

    The GnRH analogue deslorelin, as a subcutaneous implant, was initially developed in Australia as an ovulation-inducing agent in mares. Its uses, for the suppression of reproduction in the domestic dog and cat and in other species, including humans, have been developed subsequently. Such implants have been used as a contraceptive modality in a variety of wild carnivores, both males and females. This paper describes the use of deslorelin implants as a contraceptive agent for cheetah males maintained in a semi-captive environment and housed in various camps together with females. Annually, male cheetahs were treated for 1 (n = 2), 2 (n = 7), 3 (n = 9), 4 (n = 3) or 5 (n = 1) consecutive years with an implant containing 4.7, 5.0 or 6.0 mg of deslorelin. On the first day of treatment and then on an annual basis, blood testosterone concentrations were analysed, testicular measurements were taken, appearance of penile spikes was determined, and semen was collected and evaluated. Pregnancy rates of mated or inseminated females were determined. A dose of 6 mg of deslorelin suppressed reproduction for at least 1 year, whereas with 4.7 and 5 mg of deslorelin, 3 of 17 males had a few non-motile spermatozoa in their ejaculates. All testosterone concentrations were basal at 1 year post-implant and no side effects were observed. We concluded that deslorelin implantation, at a dose of 6 mg, was a safe and reliable method of annual contraception in male cheetahs.

  20. Receptor-mediated binding and uptake of GnRH agonist and antagonist by pituitary cells

    Energy Technology Data Exchange (ETDEWEB)

    Jennes, L.; Stumpf, W.E.; Conn, P.M.

    1984-01-01

    The intracellular pathway of an enzyme resistant GnRH agonist (D- Lys6 -GnRH) conjugated to ferritin or to colloidal gold was followed in cultured pituitary cells. After an initial uniform distribution over the cell surface of gonadotropes, the electrondense marker was internalized, either individually or in small groups. After longer incubation times, the marker appeared in the lysosomal compartment and the Golgi apparatus, where it could be found in the vesicular as well as cisternal portion. In addition, the receptor-mediated endocytosis of the GnRH antagonist D-p-Glu1-D-Phe2-D-Trp3-D- Lys6 -GnRH was studied by light and electron microscopic autoradiography after 30 and 60 min of incubation to ensure uptake. At both time points, in in vitro as well as in vivo studies, silver grains were localized over cytoplasmic organelles of castration cells, including dilated endoplasmic reticulum, lysosomes, and clear vesicles. No consistent association with cell nuclei, mitochondria, or secretory vesicles could be observed. The results suggest that both agonist and antagonist are binding selectively to the plasma membrane of gonadotropes and subsequently are taken up via receptor-mediated endocytosis for degradation or possible action on synthetic processes.

  1. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

    DEFF Research Database (Denmark)

    Humaidan, P; Kol, Stefan; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...

  2. Regulation of GnRH receptors by progesterone and inhibin in ovine pituitary cell culture

    Energy Technology Data Exchange (ETDEWEB)

    Laws, S.C.

    1988-01-01

    The effects of progesterone (P{sub 4}) and the gonadal protein, inhibin, on gonadotropin-releasing hormone (GnRH) receptor number and binding affinity were investigated in vitro, using ovine pituitary cells in culture. Changes in GnRH binding were correlated with GnRH-stimulated luteinizing hormone (LH) release following pretreatment with P{sub 4} and inhibin. Ovine pituitary cells in culture were preincubated with P{sub 4} or porcine inhibin (I{sub P}) for 24 or 48 hours (h). Cells were collected and analyzed for GnRH binding using a radioligand-receptor assay. des-Gly{sup 10}-(D-Ala{sup 6})-LHRH-ethyl-amide was used as the radiolabeled GnRh superagonist analog (mono-{sup 125}I-GnRH-A) and as competing ligand. Treatment with P{sub 4} progressively decreased GnRH-A binding capacity by 44.3% and 71.8% of the control following pretreatment for 24 or 48 h, respectively. When P{sub 4} was removed from the cultures, GnRH-A binding capacity partially returned to control levels within 24 h. Decreased GnRH-A binding was closely correlated with the reduction in GnRH-stimulated LH release which was observed following 24 or 48 h pretreatment with P{sub 4}.

  3. Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Mullerian hormone

    NARCIS (Netherlands)

    Hamdine, O.; Eijkemans, M.J.; Lentjes, E.W.; Torrance, H.L.; Macklon, N.S.; Fauser, B.C.; Broekmans, F.J.

    2015-01-01

    STUDY QUESTION: What is the clinical value of anti-Mullerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment? SUMMARY ANSWER: AMH as a single test has substantial accuracy for ovarian response prediction in Gn

  4. SELECTIVE ACTIONS OF OPIOID PEPTIDES ON GnRH RELEASE FROM THE MEDIAN EMINENCE OF RATS

    Institute of Scientific and Technical Information of China (English)

    ZHAOBai-Ge; LUOLu--Guang; BICKNELLR.J.; CHAPMANC.; HEAVENSR.P.

    1989-01-01

    It has been known that morphine inhibits the secretion of pituitary gonadotrophins[1l and the inhibition may be mediated by preventing GnRH release from hypothalamus[2]. In the present study, We examined the direct and selective effects of a series of opioid

  5. Sirt1-deficient mice have hypogonadotropic hypogonadism due to defective GnRH neuronal migration.

    Science.gov (United States)

    Di Sante, Gabriele; Wang, Liping; Wang, Chenguang; Jiao, Xuanmiao; Casimiro, Mathew C; Chen, Ke; Pestell, Timothy G; Yaman, Ismail; Di Rocco, Agnese; Sun, Xin; Horio, Yoshiyuki; Powell, Michael J; He, Xiaohong; McBurney, Michael W; Pestell, Richard G

    2015-02-01

    Hypogonadatropic hypogonadism (HH) can be acquired through energy restriction or may be inherited as congenital hypogonadotropic hypogonadism and its anosmia-associated form, Kallmann's syndrome. Congenital hypogonadotropic hypogonadism is associated with mutations in a group of genes that impact fibroblast growth factor 8 (FGF8) function. The Sirt1 gene encodes a nicotinamide adenine dinucleotide-dependent histone deacetylase that links intracellular metabolic stress to gene expression. Herein Sirt1(-/-) mice are shown to have HH due to failed GnRH neuronal migration. Sirtuin-1 (Sirt1) catalytic function induces GnRH neuronal migration via binding and deacetylating cortactin. Sirt1 colocalized with cortactin in GnRH neurons in vitro. Sirt1 colocalization with cortactin was regulated in an FGF8/fibroblast growth factor receptor-1 dependent manner. The profound effect of Sirt1 on the hormonal status of Sirt1(-/-) mice, mediated via defective GnRH neuronal migration, links energy metabolism directly to the hypogonadal state. Sirt1-cortactin may serve as the distal transducer of neuronal migration mediated by the FGF8 synexpression group of genes that govern HH.

  6. Sirt1-Deficient Mice Have Hypogonadotropic Hypogonadism due to Defective GnRH Neuronal Migration

    Science.gov (United States)

    Di Sante, Gabriele; Wang, Liping; Wang, Chenguang; Jiao, Xuanmiao; Casimiro, Mathew C.; Chen, Ke; Pestell, Timothy G.; Yaman, Ismail; Di Rocco, Agnese; Sun, Xin; Horio, Yoshiyuki; Powell, Michael J.; He, Xiaohong; McBurney, Michael W.

    2015-01-01

    Hypogonadatropic hypogonadism (HH) can be acquired through energy restriction or may be inherited as congenital hypogonadotropic hypogonadism and its anosmia-associated form, Kallmann's syndrome. Congenital hypogonadotropic hypogonadism is associated with mutations in a group of genes that impact fibroblast growth factor 8 (FGF8) function. The Sirt1 gene encodes a nicotinamide adenine dinucleotide-dependent histone deacetylase that links intracellular metabolic stress to gene expression. Herein Sirt1−/− mice are shown to have HH due to failed GnRH neuronal migration. Sirtuin-1 (Sirt1) catalytic function induces GnRH neuronal migration via binding and deacetylating cortactin. Sirt1 colocalized with cortactin in GnRH neurons in vitro. Sirt1 colocalization with cortactin was regulated in an FGF8/fibroblast growth factor receptor-1 dependent manner. The profound effect of Sirt1 on the hormonal status of Sirt1−/− mice, mediated via defective GnRH neuronal migration, links energy metabolism directly to the hypogonadal state. Sirt1-cortactin may serve as the distal transducer of neuronal migration mediated by the FGF8 synexpression group of genes that govern HH. PMID:25545407

  7. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

    DEFF Research Database (Denmark)

    Humaidan, P; Kol, Stefan; Papanikolaou, E G

    2011-01-01

    GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase...

  8. Familial idiopathic gonadotropin deficiency not linked to gene for gonadotropin-releasing hormone (GnRH) in Brazilian kindred

    Energy Technology Data Exchange (ETDEWEB)

    Faraco, J.; Francke, U.; Toledo, S. [Stanford Univ. School of Medicine, CA (United States)

    1994-09-01

    Familial idiopathic gonadotropin deficiency (FIGD) is an autosomal recessive disorder which results in failure to develop secondary sexual characteristics. The origin is a hypothalamic defect resulting in insufficient secretion of gonadotropin-releasing hormone GnRH (also called LHRH, luteinizing hormone releasing hormone) and follicle-stimuating hormone (FSH). FIGD has been determined to be a separate entity from Kallmann syndrome which presents with hypogonadism as well as anosmia. The FIGD phenotype appears to be analogous to the phenotype of the hpg (hypogonadal) mouse. Because the hpg phenotype is the result of a structurally abnormal GnRH gene, we have studied the GnRH gene in individuals from a previously reported Brazilian FIGD family. An informative dimorphic marker in the signal peptide sequence of the GnRH gene allowed assessment of linkage between the disease gene and the GnRH locus in this pedigree. We have concluded that the GnRH locus is not linked to the disease-causing mutation in these hypogonadal individuals. Recent evidence suggests that neuropeptide Y (NPY) may play a role in the initiation of puberty. We hypothesize that mutations in NPY may result in failure to secrete GnRH. We have characterized three diallelic frequent-cutter restriction fragment length polymorphisms within the human NPY locus, and are currently using these markers to determine if the NPY gene is linked to, and possibly the site of the disease mutation in this kindred.

  9. VEGF signalling controls GnRH neuron survival via NRP1 independently of KDR and blood vessels.

    Science.gov (United States)

    Cariboni, Anna; Davidson, Kathryn; Dozio, Elena; Memi, Fani; Schwarz, Quenten; Stossi, Fabio; Parnavelas, John G; Ruhrberg, Christiana

    2011-09-01

    Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells that are born in the nasal placode during embryonic development and migrate through the nose and forebrain to the hypothalamus, where they regulate reproduction. Many molecular pathways that guide their migration have been identified, but little is known about the factors that control the survival of the migrating GnRH neurons as they negotiate different environments. We previously reported that the class 3 semaphorin SEMA3A signals through its neuropilin receptors, NRP1 and NRP2, to organise the axons that guide migrating GnRH neurons from their birthplace into the brain. By combining analysis of genetically altered mice with in vitro models, we show here that the alternative neuropilin ligand VEGF164 promotes the survival of migrating GnRH neurons by co-activating the ERK and AKT signalling pathways through NRP1. We also demonstrate that survival signalling relies on neuronal, but not endothelial, NRP1 expression and that it occurs independently of KDR, the main VEGF receptor in blood vessels. Therefore, VEGF164 provides survival signals directly to developing GnRH neurons, independently of its role in blood vessels. Finally, we show that the VEGF164-mediated neuronal survival and SEMA3A-mediated axon guidance cooperate to ensure that migrating GnRH neurons reach the brain. Thus, the loss of both neuropilin ligands leads to an almost complete failure to establish the GnRH neuron system.

  10. Afferent neuronal control of type-I gonadotropin releasing hormone (GnRH neurons in the human

    Directory of Open Access Journals (Sweden)

    Erik eHrabovszky

    2013-09-01

    Full Text Available Understanding the regulation of the human menstrual cycle represents an important ultimate challenge of reproductive neuroendocrine research. However, direct translation of information from laboratory animal experiments to the human is often complicated by strikingly different and unique reproductive strategies and central regulatory mechanisms that can be present in even closely related animal species. In all mammals studied so far, type-I gonadotropin releasing hormone (GnRH synthesizing neurons form the final common output way from the hypothalamus in the neuroendocrine control of the adenohypophysis. Under various physiological and pathological conditions, hormonal and metabolic signals either regulate GnRH neurons directly or act on upstream neuronal circuitries to influence the pattern of pulsatile GnRH secretion into the hypophysial portal circulation. Neuronal afferents to GnRH cells convey important metabolic-, stress-, sex steroid-, lactational- and circadian signals to the reproductive axis, among other effects. This article gives an overview of the available neuroanatomical literature that described the afferent regulation of human GnRH neurons by peptidergic, monoaminergic and amino acidergic neuronal systems. Recent studies of human genetics provided evidence that central peptidergic signaling by kisspeptins and neurokinin B play particularly important roles in puberty onset and later, in the sex steroid-dependent feedback regulation of GnRH neurons. This review article places special emphasis on the topographic distribution, sexual dimorphism, aging-dependent neuroanatomical changes and plastic connectivity to GnRH neurons of the critically important human hypothalamic kisspeptin and neurokinin B systems.

  11. Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study.

    Science.gov (United States)

    Weiss, A; Beck-Fruchter, R; Golan, J; Lavee, M; Geslevich, Y; Shalev, E

    2016-03-23

    In-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger. We conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015. Significant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section. Excessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

  12. Morphological Characterization of the Action Potential Initiation Segment in GnRH Neuron Dendrites and Axons of Male Mice.

    Science.gov (United States)

    Herde, Michel K; Herbison, Allan E

    2015-11-01

    GnRH neurons are the final output neurons of the hypothalamic network controlling fertility in mammals. In the present study, we used ankyrin G immunohistochemistry and neurobiotin filling of live GnRH neurons in brain slices from GnRH-green fluorescent protein transgenic male mice to examine in detail the location of action potential initiation in GnRH neurons with somata residing at different locations in the basal forebrain. We found that the vast majority of GnRH neurons are bipolar in morphology, elaborating a thick (primary) and thinner (secondary) dendrite from opposite poles of the soma. In addition, an axon-like process arising predominantly from a proximal dendrite was observed in a subpopulation of GnRH neurons. Ankyrin G immunohistochemistry revealed the presence of a single action potential initiation zone ∼27 μm in length primarily in the secondary dendrite of GnRH neurons and located 30 to 140 μm distant from the cell soma, depending on the type of process and location of the cell body. In addition to dendrites, the GnRH neurons with cell bodies located close to hypothalamic circumventricular organs often elaborated ankyrin G-positive axon-like structures. Almost all GnRH neurons (>90%) had their action potential initiation site in a process that initially, or ultimately after a hairpin loop, was coursing in the direction of the median eminence. These studies indicate that action potentials are initiated in different dendritic and axonal compartments of the GnRH neuron in a manner that is dependent partly on the neuroanatomical location of the cell body.

  13. Characterization of 12 GnRH peptide agonists – a kinetic perspective

    Science.gov (United States)

    Nederpelt, Indira; Georgi, Victoria; Schiele, Felix; Nowak‐Reppel, Katrin; Fernández‐Montalván, Amaury E.; IJzerman, Adriaan P.

    2015-01-01

    Background and Purpose Drug‐target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin‐releasing hormone (GnRH) receptor for the treatment of hormone‐dependent diseases. Surprisingly, the kinetic receptor‐binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor‐binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. Experimental Approach A novel radioligand‐binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [125I]‐triptorelin. In addition to radioligand‐binding studies, a homogeneous time‐resolved FRET Tag‐lite™ method was developed as an alternative assay for the same purpose. Key Results Two novel competition association assays were successfully developed and applied to determine the kinetic receptor‐binding characteristics of 12 high‐affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). Conclusions and Implications Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor. PMID:26398856

  14. Effects of GnRH administration on ovulation and fertility in ewes subjected to estrous synchronization

    Directory of Open Access Journals (Sweden)

    Amanda dos Santos Cavalcanti

    2012-06-01

    Full Text Available The objective of this study was to verify the effects of GnRH on ovulation and pregnancy of ewes subjected to a short-term synchronization of estrus. Santa Inês and crossbred Santa Inês/Dorper ewes received 60 mg MAP sponges during 6 days plus 300 IU eCG and 30 µg d-cloprostenol 24 h prior to sponge withdrawal (SW. Ewes were assigned to receive 0.9% NaCl solution (Tcontrol; n = 32 or 25 µg GnRH (licerelin, T GnRH; n = 34 24 hours after SW. Each group was assigned to intrauterine insemination by laparoscopy (n = 25 or to natural mating (n = 41. Artificial insemination was performed with a single dose of fresh semen. For controlled mating, females were exposed to males 12, 24, 36 and 48 hours after SW. Ten females per treatment were subjected to transrectal ultrasound examination at 12-hour intervals (SW to 60 hours after. Estrous response (100.0% vs 95.2%, interval from SW to estrus (32.9±7.4 vs 29.8±6.9 hours, estrous length (37.4±9.0 vs 31.5±10.4 hours, pregnancy rates (57.0% vs 41.0%, ovulation rate (100.0% vs 90.0%, number of ovulations/ewe (1.1±0.3 vs 1.2±0.4, maximum follicular diameter (6.4±0.7 vs 6.1±0.6 mm, interval from SW to ovulation (59.1±3.5 vs 58.4±3.5 hours did not differ between Tcontrol and T GnRH, respectively. Administration of GnRH 24 hours after SW does not improve ovulation or pregnancy rate in estrous synchronization in ewes.

  15. Netrin-1 stimulates developing GnRH neurons to extend neurites to the median eminence in a calcium- dependent manner.

    Directory of Open Access Journals (Sweden)

    Victoria F Low

    Full Text Available Hypothalamic gonadotropin-releasing hormone (GnRH neurons are required for fertility in all mammalian species studied to date. In rodents, GnRH neuron cell bodies reside in the rostral hypothalamus, and most extend a single long neuronal process in the caudal direction to terminate at the median eminence (ME, the site of hormone secretion. The molecular cues that GnRH neurites use to grow and navigate to the ME during development, however, remain poorly described. Reverse transcription-PCR (RT-PCR identified mRNAs encoding Netrin-1, and its receptor, DCC, in the fetal preoptic area (POA and mediobasal hypothalamus (MBH, respectively, from gestational day 12.5 (GD12.5, a time when the first GnRH neurites extend toward the MBH. Moreover, a subpopulation of GnRH neurons from GD14.5 through GD18.5 express the Netrin-1 receptor, DCC, suggesting a role for Netrin-1/DCC signaling in GnRH neurite growth and/or guidance. In support of this notion, when GD15.5 POA explants, containing GnRH neurons actively extending neurites, were grown in three-dimensional collagen gels and challenged with exogenous Netrin-1 (100 ng/ml or 400 ng/ml GnRH neurite growth was stimulated. In addition, Netrin-1 provided from a fixed source was able to stimulate outgrowth, although it did not appear to chemoattract GnRH neurites. Finally, the effects of Netrin-1 on the outgrowth of GnRH neurites could be inhibited by blocking either L-type voltage-gated calcium channels (VGCCs with nifedipine (10 µM, or ryanodine receptors with ryanodine (10 µM. This is consistent with the role of Ca2+ from extra- and intracellular sources in Netrin-1/DCC-dependent growth cone motility in other neurons. These results indicate that Netrin-1 directly stimulates the growth of a subpopulation of GnRH neurites that express DCC, provide further understanding of the mechanisms by which GnRH nerve terminals arrive at their site of hormone secretion, and identify an additional neuronal population

  16. Circadian control of kisspeptin and a gated GnRH response mediate the preovulatory luteinizing hormone surge

    DEFF Research Database (Denmark)

    Williams, Wilbur P; Jarjisian, Stephan G; Mikkelsen, Jens D;

    2011-01-01

    linking the SCN to the GnRH system to stimulate ovulation in Syrian hamsters (Mesocricetus auratus). Kisspeptin neurons exhibit an estrogen-dependent, daily pattern of cellular activity consistent with a role in the circadian control of the LH surge. The SCN targets kisspeptin neurons via vasopressinergic...... (AVP), but not vasoactive intestinal polypeptide-ergic, projections. Because AVP administration can only stimulate the LH surge during a restricted time of day, we examined the possibility that the response to AVP is gated at the level of kisspeptin and/or GnRH neurons. Kisspeptin and GnRH activation...... were assessed after the administration of AVP during the morning (when AVP is incapable of initiating the LH surge) and the afternoon (when AVP injections stimulate the LH surge). Kisspeptin, but not GnRH, cellular activity was up-regulated after morning injections of AVP, suggesting that time...

  17. Do GnRH analogues directly affect human endometrial epithelial cell gene expression?

    KAUST Repository

    Zhang, Xiaomei

    2010-03-04

    We examined whether Gonadotrophin-releasing hormone (GnRH) analogues [leuprolide acetate (LA) and ganirelix acetate (GA)] modulate gene expression in Ishikawa cells used as surrogate for human endometrial epithelial cells in vitro. The specific aims were: (i) to study the modulatory effect of GnRH analogues by RT-PCR [in the absence and presence of E2 and P4, and cyclic adenosine monophos-phate (cAMP)] on mRNA expression of genes modulated during the window of implantation in GnRH analogues/rFSH-treated assisted reproductive technology cycles including OPTINEURIN (OPTN), CHROMATIN MODIFYING PROTEIN (CHMP1A), PROSAPOSIN (PSAP), IGFBP-5 and SORTING NEXIN 7 (SNX7), and (ii) to analyze the 5\\'-flanking regions of such genes for the presence of putative steroid-response elements [estrogen-response elements (EREs) and P4-response element (PREs)]. Ishikawa cells were cytokeratin+/vimentin2 and expressed ERa,ERb, PR and GnRH-R proteins. At 6 and 24 h, neither LA nor GA alone had an effect on gene expression. GnRH analogues alone or following E2 and/or P4 co-incubation for 24 h also had no effect on gene expression, but P4 significantly increased expression of CHMP1A.E2 + P4 treatment for 4 days, alone or followed by GA, had no effect, but E2 + P4 treatment followed by LA significantly decreased IGFBP-5 expression. The addition of 8-Br cAMP did not modify gene expression, with the exception of IGFBP-5 that was significantly increased. The GnRH analogues did not modify intracellular cAMP levels. We identified conserved EREs for OPN, CHMP1A, SNX7 and PSAP and PREs for SNX7. We conclude that GnRH analogues appear not to have major direct effects on gene expression of human endo-metrial epithelial cells in vitro. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

  18. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice.

    Science.gov (United States)

    Roa, Juan; Herbison, Allan E

    2012-11-01

    Hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons act to sense and coordinate the brain's responses to metabolic cues. One neuronal network that is very sensitive to metabolic status is that controlling fertility. In this study, we investigated the impact of neuropeptides released by NPY and POMC neurons on the cellular excitability of GnRH neurons, the final output cells of the brain controlling fertility. The majority (∼70%) of GnRH neurons were activated by α-melanocyte-stimulating hormone, and this resulted from the direct postsynaptic activation of melanocortin receptor 3 and melanocortin receptor 4. A small population of GnRH neurons (∼15%) was excited by cocaine and amphetamine-regulated transcript or inhibited by β-endorphin. Agouti-related peptide, released by NPY neurons, was found to have variable inhibitory (∼10%) and stimulatory (∼25%) effects upon subpopulations of GnRH neurons. A variety of NPY and pancreatic polypeptide analogs was used to examine potential NPY interactions with GnRH neurons. Although porcine NPY (Y1/Y2/Y5 agonist) directly inhibited the firing of approximately 45% of GnRH neurons, [Leu(31),Pro(34)]-NPY (Y1/Y4/Y5 agonist) could excite (56%) or inhibit (19%). Experiments with further agonists indicated that Y1 receptors were responsible for suppressing GnRH neuron activity, whereas postsynaptic Y4 receptors were stimulatory. These results show that the activity of GnRH neurons is regulated in a complex manner by neuropeptides released by POMC and NPY neurons. This provides a direct route through which different metabolic cues can regulate fertility.

  19. Immunization of Male Mice with a New Recombinant GnRH Fusion Protein Reduces the Testicular Function

    Institute of Scientific and Technical Information of China (English)

    FANG Fu-gui; YANG Ya-ping; LIU Ya; ZHANG Yun-hai; TAO Yong; WANG Suo-lu; PU Yong; ZHANG Xiao-rong

    2009-01-01

    The objective of the present study was to evaluate the effect of an immunogenie maltose-binding protein-gonadotropin releasing hormone (GnRH-6-MBP) using genetic engineering. The synthetic mammalian tandem repeated GnRH hexamer gene was inserted into the expression plasmid pMAL-c2x. Recombinant GnRH-6-MBP protein was over-expressed in E.coli strain BL21. Amylose resin with affinity chromatograph was used to purify target protein. The reaetiongenicity of fusion protein was identified by indirect enzyme linked immunosorbent assay (ELISA), and the antigenicity and biological effects of GnRH-6-MBP were tested in mice. In the experiment, 20 male Kunming white mice of 20 d old were randomly divided into treatment and control group. Ten mice were immunized with 100 μgGnRH-6-MBP administered subcutaneously (s.c.) thrice at 2-week intervals with GnRH-6-MBP. Mice were sacrificed after 3 weeks following the booster injection, the testis was removed, weighed and measured, and the histological structure was observed. The reactiongenieity of fusion protein to GnRH antibody was much higher than the control.Active immunization against GnRH-6-MBP reduced remarkably (P < 0.01) the length and weight of the testis, and shortened the girth and width of the testis (P < 0.05), and suppressed testieular spermatogenesis compared to the control mice. These results indicate that the recombinant GnRH-6-MBP acted as a strong immunogen and caused atrophy of the testis.

  20. Effect of GnRH and D-Chloprostenol application on pregnancy and prolificacy rates on Pelibuey ewes

    Directory of Open Access Journals (Sweden)

    Jaime Martínez T.

    2013-10-01

    Full Text Available Objective. Was to evaluate the effect of GnRH and D-Chloprostenol application on pregnancy and prolificacy rates on Pelibuey ewes. Materials and methods. Forty five ewes were randomly allocated to one of three treatments: T1(n=15, day 0: sponges with 65 mg medroxyprogesterone acetate (MPA + 200 IU equine chorionic gonadotropin (eCG and sponge removal (day 12 + breeding by natural mating (days 12-15; T2 (n=15, day 0: 50 μg gonadotropin releasing hormone (GnRH + 7.5 mg D-Chloprostenol (day 5 + 50 μg GnRH (day 7 + insemination at fixed time (AIFT 12 to 14 h after last injection of GnRH; T3 (n=15, 100 μg GnRH (day 0 + 7.5 mg D-Chloprostenol (day 5 + 100 μg GnRH (day 7 + AIFT 12 to 14 h after last injection of GnRH. Results. The average concentration of progesterone (P4 in blood was 1.22 ± 0.74 ng/mL, which was used to verify ovarian activity at the beginning of the treatments. 100% of the T1 ewes presented estrus, beginning at 38.4±9.56 h after sponge removal. There were differences (p0.05 among the treatments where the values were 1.2, 1.4 and 1.4 lambs/ewe for T1, T2 and T3, Conclusions. The results of this study show that the use of GnRH and D-Chloprostenol did improve pregnancy rates but did not improve prolificacy in tropical ewes.

  1. The Effect of GnRH Given on Day of Mating on Ovarian Function and Reproductive Performance in Lohi Sheep

    Directory of Open Access Journals (Sweden)

    Mushtaq H. Lashari* and Zahida Tasawar

    2010-01-01

    Full Text Available The present study was conducted to investigate the effects of GnRH (Dalmeralin treatment given on the day of mating on reproductive performance in Lohi sheep. Seventy six ewes 3-5 year old, weighing 44 ± 0.4 Kg were put to rams at synchronized estrus using two intramuscular injections of 2 ml PGF2α analogue (Dalmazin 11 days apart. These animals were divided into two equal groups through random stratification by body weight and were given either saline (group 1 or 2 ml GnRH (group 11 on day of mating. A total of 16 ewes were slaughtered on day 25 of pregnancy (eight ewes from each treatment group. GnRH administration on the day of mating increased (P0.05. Pregnancy rate was higher in GnRH treated group (83.3% than control (60% group (P<0.05. The ewes in GnRH administered group had more twins (P<0.05 than those in control group (28 v 10. In conclusion, GnRH administration improved reproductive performance of ewes when administered on the day of mating, probably through its beneficial effect on embryo survival by enhancing luteal function.

  2. Enhanced incorporation of nonhydrolyzable tritium in GnRH and TRF by catalytic exchange labeling

    Energy Technology Data Exchange (ETDEWEB)

    Oehlke, J.; Bienert, M.; Niedrich, H.; Mittag, E.; Toth, G.

    1987-12-01

    Gonadotropin releasing hormone (GnRH), D-Phe/sub 6/-GnRH and thyro-tropin releasing factor (TRF) were tritiated by direct catalytic exchange using RhA1/sub 2/O/sub 3/ + HT under conditions which lead in model deuterations of N..cap alpha..-acetylhistidine amide to a high incorporation of deuterium into position 5 of the histidine ring. Specific activities up to a range of 400 GBqmmol in form of nonhydrolyzable tritium are attainable after removal of the label incorporated into position 2 of the histidine ring. A crucial reason for diminished specific activities was found to be a catalyst mediated hydrogen transfer between the peptides and traces of water, contained in the reaction mixture, competing with the tritiation.

  3. GnRH receptors in human granulosa cells: Anatomical localization and characterization by autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Latouche, J.; Crumeyrolle-Arias, M.; Jordan, D.; Kopp, N.; Augendre-Ferrante, B.; Cedard, L.; Haour, F. (Institut Pasteur, Paris (France))

    1989-09-01

    The presence of receptors for GnRH in human ovary has been investigated by quantitative autoradiography. Simultaneous visualization and characterization of specific receptors on frozen sections were obtained on six pairs of human ovaries. Among them only one exhibited a large preovulatory follicle. This dominant follicle exhibited a specific and high affinity binding capacity for {sup 125}I-GnRHa exclusively localized on the granulosa cell layer. Analysis of saturation curve indicates a Kd value of 0.22 nM and Bmax of 9.6 fmol/mg protein. In contrast LH-hCG binding sites were present in all antral follicles. These data demonstrate for the first time the presence of high affinity GnRH receptors in human granulosa cells at a late stage of follicular maturation.

  4. [GnRH analogues containing SV-40 virus T-antigen nuclear localization sequence].

    Science.gov (United States)

    Burov, S V; Iablokova, T V; Dorosh, M Iu; Kriviziuk, E V; Efremov, A M; Orlov, S V

    2010-01-01

    To improve the efficiency of anticancer drugs due to their delivery to intracellular targets a set of GnRH analogues containing nuclear localization signal (NLS) of SV-40 virus large T-antigen have been synthesized. NLS was attached to the parent molecule via ε-amino group of D-Lysine in position 1 or 6 of peptide sequence using orthogonal protection strategy. The biological activity studies revealed that incorporation of NLS moiety significantly increases cytotoxic activity of palmitoyl-containing GnRH analogues in vitro. The influence of tested peptides on tumor cells does not accompanied by the destruction of cell membrane, as confirmed in experiments with normal fibroblasts, used as a control.

  5. Chronic administration of the metastin/kisspeptin analog KISS1-305 or the investigational agent TAK-448 suppresses hypothalamic pituitary gonadal function and depletes plasma testosterone in adult male rats.

    Science.gov (United States)

    Matsui, Hisanori; Tanaka, Akira; Yokoyama, Kotaro; Takatsu, Yoshihiro; Ishikawa, Kaori; Asami, Taiji; Nishizawa, Naoki; Suzuki, Atsuko; Kumano, Satoshi; Terada, Michiko; Kusaka, Masami; Kitada, Chieko; Ohtaki, Tetsuya

    2012-11-01

    Metastin/kisspeptin, a hypothalamic peptide, plays a pivotal role in controlling GnRH neurons. Here we studied the effect of chronic sc administration of two kisspeptin analogs, KISS1-305 and TAK-448, on hypothalamic-pituitary-gonadal function in male rats in comparison with a GnRH analogue leuprolide or bilateral orchiectomy (ORX). The prototype polypeptide, KISS1-305 (1-4 nmol/h), caused substantial elevations of plasma LH and testosterone, followed by abrupt reductions of both hormone levels. Notably, testosterone levels were reduced to castrate levels within 3 d and remained depleted throughout the 4-wk dosing period, an effect that was faster and more pronounced than leuprolide (1 nmol/h) dosing. KISS1-305 also reduced genital organ weight more profoundly than leuprolide. In mechanistic studies, chronic KISS1-305 administration only transiently induced c-Fos expression in GnRH neurons, suggesting that GnRH-neural response was attenuated over time. Hypothalamic GnRH content was reduced to 10-20% of control at 3 wk without any changes in Gnrh mRNA expression. Dosing with the investigational peptide TAK-448 was also studied to extend our understanding of hypothalamic-pituitary functions. Similar to ORX, TAK-448 (0.1 nmol/h) depleted testosterone and decreased GnRH content by 4 wk. However, in contrast to ORX, TAK-448 decreased gonadotropin levels in pituitary and plasma samples, implying the suppression of GnRH pulses. These results suggest that chronic administration of kisspeptin analogs disrupts endogenous kisspeptin signals to suppress intrinsic GnRH pulses, perhaps by attenuating GnRH-neural response and inducing continuous GnRH leakage from the hypothalamus. The potential utility of kisspeptin analogs as novel agents to treat hormone-related diseases, including prostate cancer, is discussed.

  6. Computational Studies of Difference in Binding Modes of Peptide and Non-Peptide Inhibitors to MDM2/MDMX Based on Molecular Dynamics Simulations

    Directory of Open Access Journals (Sweden)

    Yuxin Zhang

    2012-02-01

    Full Text Available Inhibition of p53-MDM2/MDMX interaction is considered to be a promising strategy for anticancer drug design to activate wild-type p53 in tumors. We carry out molecular dynamics (MD simulations to study the binding mechanisms of peptide and non-peptide inhibitors to MDM2/MDMX. The rank of binding free energies calculated by molecular mechanics generalized Born surface area (MM-GBSA method agrees with one of the experimental values. The results suggest that van der Waals energy drives two kinds of inhibitors to MDM2/MDMX. We also find that the peptide inhibitors can produce more interaction contacts with MDM2/MDMX than the non-peptide inhibitors. Binding mode predictions based on the inhibitor-residue interactions show that the π–π, CH–π and CH–CH interactions dominated by shape complimentarity, govern the binding of the inhibitors in the hydrophobic cleft of MDM2/MDMX. Our studies confirm the residue Tyr99 in MDMX can generate a steric clash with the inhibitors due to energy and structure. This finding may theoretically provide help to develop potent dual-specific or MDMX inhibitors.

  7. GnRH agonist trigger versus hCG trigger in GnRH antagonist in IVF/ICSI cycles: A review article

    Science.gov (United States)

    Alyasin, Ashraf; Mehdinejadiani, Shayesteh; Ghasemi, Marzieh

    2016-01-01

    Routinely, a bolus of 5.000-10.000 IU human chorionic gonadotropin (hCG) is used for the final follicular maturation and ovulation as a standard method. HCG has the same effect of luteinizing hormone (LH) with long half-life. It has the long lutheotrophic effect which increases the risk of ovarian hyper stimulation syndrome (OHSS). Recently, gonadotropin-releasing hormone agonist (GnRH-a) trigger has been used for the induction of final follicular maturation and ovulation with the aim of reducing the OHSS risk. Several studies have shown that the releases of endogenous follicular stimulating hormone (FSH) and LH after administration of GnRH agonist in in vitro fertilization (IVF) cycles are able to precede the final follicular maturation leading to removal of fertile oocyte with normal development of the embryo and ultimately pregnancy. But based on the results of some studies, using GnRH-a trigger leads to defect luteal-phase resulting to reduce the implantation and clinical pregnancy rates and also increase abortion in fresh embryo transfer cycles compared to routine IVF cycle with hCG triggering . Also, in recent years, studies have continued to modify the luteal phase support, so that the fresh embryo transfer is possible too. In this review, we examined the benefits, problems, and also ways to reform GnRH agonist triggering complications. PMID:27738657

  8. Study of Positive and Negative Consequences of Using GnRH Antagonist in Intrauterine Insemination Cycles

    Directory of Open Access Journals (Sweden)

    Maryam Bagheri

    2009-01-01

    Full Text Available Background: To assess the usefulness of premature luteinization hormone (LH surge preventionin an intrauterine insemination (IUI cycle by GnRH antagonist administration.Materials and Methods: Sixty patients with unexplained or mild male infertility or minimalto mild endometriosis were enrolled in this prospective randomized controlled trial. There weretwenty patients in group A (with GnRH antagonist and 40 patients in group B (without GnRHantagonist.In all of the participants, clomiphene citrate and human menopausal gonadotropin (CC+HMG wereused for ovarian stimulation. When at least one follicle with ≥ 16 mm diameter was seen, LH surgewas checked by a urinary LH kit. In patients with negative results, human chorionic gonadotropinwas continued in both groups, but in group A 0.25 mg Ganirelix SQ was administered for two days,,then in both groups human chorionic gonadotropin (HCG was injected on the third day and IUIwas done 36-40 hours later. Ongoing pregnancy was the primary outcome.Results: Baseline characters and clinical parameters were similar in both groups with the exceptionof ≥14 mm follicles which were higher in group A (p value= 0.003. The pregnancy rate in bothgroups was not significantly different, although it was higher in group B (10% in group A and 15%in group B.Conclusion: At least in CC+HMG stimulated cycles for IUI, the occurrence of premature LHsurge could have a useful rule and GnRH antagonist administration could be an inappropriateintervention.

  9. Self-assembled nanostructures of long-acting GnRH analogs modified at position 7.

    Science.gov (United States)

    Zhou, Ning; Gao, Xing; Lv, Yujian; Cheng, Junping; Zhou, Wenxia; Liu, Keliang

    2014-11-01

    It is well known that GnRH analogs can self-assemble into amyloid fibrils and that the duration of action of GnRH analogs depends on the ability of the amyloid to slowly release active peptides. The aim of this study was to investigate the influence of the amino acid residues at position 7 of GnRH analogues on peptide self-assembly. It was found that the dominant shape of the nanostructure can be changed when the structures of the residues at position 7 differ significantly from that of leucine in Degarelix. When the backbone length was extended (peptide 9), or the side chain of the residue at position 7 was replaced by an aromatic ring (peptide 6), or the rotation of the amide bond was restricted (peptide 8), the nanostructure changed from fibrils to vesicles. The results also indicate that the increasing hydrophilicity had little influence on the nanostructure morphology. In addition, a suitable release rate was found to play a more important role for the duration of the peptide action by maintaining the equilibrium between the drug concentration and the persistent release time, while the nanostructure shape was found to exert little influence on the duration of the peptide action.

  10. The lack of gonadotrophin-releasing hormone (GnRH) receptor desensitisation in alphaT3-1 cells is not due to GnRH receptor reserve or phosphatidylinositol 4,5-bis-phosphate pool size.

    Science.gov (United States)

    Forrest-Owen, W; Willars, G B; Nahorski, S R; Assefa, D; Davidson, J S; Hislop, J; McArdle, C A

    1999-01-25

    The phospholipase C (PLC)-activating gonadotrophin-releasing hormone (GnRH) receptor is thought not to rapidly desensitise in alphaT3-1 cells. This extremely unusual characteristic raises the concern that it might be a feature of the cell type, rather than the receptor per se. Here we have used video imaging to establish whether the effects of endogenous PLC-activating G-protein coupled receptors (GPCRs) on Ca2+ ion concentration [Ca2+]i desensitise in these cells. Oxytocin, endothelin-1, methacholine, and UTP all caused [Ca2+]i increases which underwent rapid homologous desensitisation in that they were transient and responses to repeat stimuli were attenuated whereas subsequent responses to GnRH were not. To test whether receptor reserve obscures functional desensitisation of GnRH receptors, a photoaffinity antagonist (Pant-1), was used to effect a partial and irreversible receptor blockade. UV crosslinking in medium with 1000 nM Pant-1 reduced GnRH receptor number to 20 +/- 5% and reduced maximal buserelin-stimulated [3H]IP(X) accumulation to 57 +/- 5%, demonstrating removal of receptor reserve. In control alphaT3-1 cells the initial rate of GnRH-stimulated [3H]IP(X) accumulation was maintained for at least 5 min and GnRH caused a sustained increase in Ins(1,4,5)P3 mass (confirming the resistance of GnRH receptors to desensitisation) and Pant-1 pre-treatment reduced the magnitude of these responses without altering their temporal profiles. In alphaT3-1 cells stably transfected with recombinant human muscarinic receptors (alphaT3-1/M3), responses to methacholine were characteristic of desensitising GPCRs (transient Ins(1,4,5)P3 and curvilinear [3H]IP(X) responses) and were unaltered by Pant-1. To test the relevance of phospholipid pool size, alphaT3-1/M3 cells were pre-treated with GnRH or methacholine in medium with LiCl (to deplete PtdIns(4,5)P2 pools). These pre-treatments reduced subsequent responses to methacholine and GnRH comparably, indicating access to a

  11. The GnRH receptor and the response of gonadotrope cells to GnRH pulse frequency code. A story of an atypical adaptation of cell function relying on a lack of receptor homologous desensitization.

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    Christian Bleux

    2010-01-01

    Full Text Available Brain control of the reproductive system is mediated through hypothalamic gonadotropin-releasing hormone (GnRH which activates specific receptors (GnRHR present at the surface of the pituitary gonadotropes to trigger secretion of the two gonadotropins LH and FSH. A unique feature of this system is the high dependence on the secretion mode of GnRH, which is basically pulsatile but undergoes considerable fluctuations in pulse frequency pattern in response to endogenous or external factors. How the physiological fluctuations of GnRH secretion that orchestrate normal reproduction are decoded by the gonadotrope cell machinery to ultimately control gonadotropin release and/or subunit gene transcription has been the subject of intensive studies during the past decades. Surprisingly, the mammalian GnRHR is unique among G protein-coupled receptor family as it lacks the carboxy-terminal tail usually involved in classical endocytotic process. Accordingly, it does not desensitize properly and internalizes very poorly. Both this atypical intrinsic property and post-receptor events may thus contribute to decode the GnRH signal. This includes the participation of a network of signaling pathways that differently respond to GnRH together with a growing amount of genes differentially sensitive to pulse frequency. Among these are two pairs of genes, the transcription factors EGR-1 and NAB, and the regulatory factors activin and follistatin, that function as intracellular autoregulatory feedback loops controlling respectively LHbeta and FSHbeta gene expression and hence, LH and FSH synthesis. Pituitary gonadotropes thus represent a unique model of cells functionally adapted to respond to a considerably fluctuating neuroendocrine stimulation, from short individual pulses to sustained GnRH as observed at the proestrus of ovarian cycle. Altogether, the data emphasize the adaptative reciprocal complementarity of hypothalamic GnRH neurones and pituitary gonadotropes to

  12. Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat.

    Science.gov (United States)

    Goericke-Pesch, Sandra; Georgiev, Plamen; Fasulkov, Ivan; Vodenicharov, Angel; Wehrend, Axel

    2013-07-01

    Slow-release GnRH agonist implants are considered an effective, reversible alternative to surgical castration in male tom cats. Individual differences exist regarding the onset of efficacy and might be delayed in some animals. Single measurements of testosterone (T) might result in basal concentrations also in intact male cats. Consequently, GnRH stimulation tests are performed to measure T increase in intact animals and to differentiate castrated from intact male cats. In this study, five tom cats were treated with a 4.7-mg deslorelin implant and GnRH stimulation tests using buserelin were performed before treatment and at 4-week intervals afterward until Week 20. After the last test in Week 20 all animals were castrated. Four of five animals had basal T after 4 weeks and-in contrast to pretreatment-application of buserelin did not result in any further T increase. In one animal, T was low after implant insertion, but not basal; however, a GnRH stimulation test induced a slight increase of T in Week 8 and 16 only and no response in Weeks 4, 12, and 20. Testicular volume was significantly decreased and penile spines disappeared in all cats. Testicular histology showed mixed atrophy, but also fully elongated spermatids in three of five male cats making infertility questionable. Because of the loss of the stimulatory effect of short-term GnRH application (buserelin), it can be assumed that long-term GnRH agonists also act by some mechanisms of downregulation of pituitary GnRH receptors in the tom cat. Copyright © 2013 Elsevier Inc. All rights reserved.

  13. The novel actions of the metabolite GnRH-(1-5 are mediated by a G protein-coupled receptor (GPCR

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    Darwin Omar Larco

    2013-07-01

    Full Text Available The gonadotropin-releasing hormone (GnRH was originally isolated from the mammalian hypothalamus for its role as the primary regulator of reproductive function. Since its discovery, GnRH has also been shown to be located in non-hypothalamic tissues and is known to have diverse functions. Although the regulation of GnRH synthesis and release has been extensively studied, there is additional evidence to suggest that the processing of GnRH to the metabolite GnRH-(1-5 represents another layer of regulation. The focus of this review will be on the current evidence for the action of the pentapeptide metabolite GnRH-(1-5 in regulating cellular migration. We discuss the potential role of GnRH-(1-5 in regulating GnRH neuronal migration during development. Furthermore, we demonstrate these actions are mediated by the activation of a G protein-coupled receptor (GPCR. Our findings suggest that GnRH-(1-5 may play a developmental function in addition to regulating developing cells.

  14. In silico and in situ characterization of the zebrafish (Danio rerio gnrh3 (sGnRH gene

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    Husebye Harald

    2002-08-01

    Full Text Available Abstract Background Gonadotropin releasing hormone (GnRH is responsible for stimulation of gonadotropic hormone (GtH in the hypothalamus-pituitary-gonadal axis (HPG. The regulatory mechanisms responsible for brain specificity make the promoter attractive for in silico analysis and reporter gene studies in zebrafish (Danio rerio. Results We have characterized a zebrafish [Trp7, Leu8] or salmon (s GnRH variant, gnrh3. The gene includes a 1.6 Kb upstream regulatory region and displays the conserved structure of 4 exons and 3 introns, as seen in other species. An in silico defined enhancer at -976 in the zebrafish promoter, containing adjacent binding sites for Oct-1, CREB and Sp1, was predicted in 2 mammalian and 5 teleost GnRH promoters. Reporter gene studies confirmed the importance of this enhancer for cell specific expression in zebrafish. Interestingly the promoter of human GnRH-I, known as mammalian GnRH (mGnRH, was shown capable of driving cell specific reporter gene expression in transgenic zebrafish. Conclusions The characterized zebrafish Gnrh3 decapeptide exhibits complete homology to the Atlantic salmon (Salmo salar GnRH-III variant. In silico analysis of mammalian and teleost GnRH promoters revealed a conserved enhancer possessing binding sites for Oct-1, CREB and Sp1. Transgenic and transient reporter gene expression in zebrafish larvae, confirmed the importance of the in silico defined zebrafish enhancer at -976. The capability of the human GnRH-I promoter of directing cell specific reporter gene expression in zebrafish supports orthology between GnRH-I and GnRH-III.

  15. Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation.

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    Carol Taylor-Burds

    Full Text Available A developmental "switch" in chloride transporters occurs in most neurons resulting in GABAA mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABAA receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABAA receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABAA receptor activation. Anion exchangers (AEs are also potential modulators of responses to GABAA activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s underlying GABAA mediated depolarization, GnRH neurons were analyzed for 1 expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2 responses to GABAA receptor activation in NKCC1-/- mice and 3 function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1-/- mice retained relatively normal responses to the GABAA agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO3- mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABAA mediated transmission in GnRH neurons.

  16. Effect of GnRH antagonist on follicular development and uterine biophysical profile in controlled ovarian stimulation

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    Bhawana Tiwary

    2015-02-01

    Full Text Available Background: Objective of current study was to assess the effect of GnRH antagonist on follicular development, premature luteinization, uterine biophysical profile and pregnancy rate in controlled ovarian stimulation with clomiphene and gonadotropins for intrauterine insemination in women with unexplained infertility. Methods: Randomised controlled trial. Minimal stimulation protocol with or without GnRH antagonist was compared. Setting: Infertility clinic, PGIMER, Chandigarh. Patients: Couples with unexplained infertility, age of female partner between 20-39 years. Intervention: GnRH antagonist 0.25 mg since follicle size 14 mm till hCG administration. Main outcome measures: Follicle characteristics, premature luteinisation, uterine biophysical profile and pregnancy rate. Results: The mean number of follicles recruited in group A was 2.32 +/- 1.01 while that in group B (receiving GnRH antagonist it was 4.10 +/- 1.69. Statistically significant increase in total biophysical profile score was observed in periovulatory phase in the antagonist group. 40% women in group A had premature luteinization whereas only 4% women in group B suffered from premature luteinization. 20% women who received GnRH antagonist conceived against only 6% in group A, this difference however was not statistically significant Conclusions: GnRH antagonist has a role in increasing the number of follicles recruited. Furthermore, GnRH antagonist can improve the total uterine biophysical profile score by improving the endometrial thickness, endometrial pattern, blood flow and decreasing the impedance to the blood flow in uterine artery. The drug can potentially help in improving pregnancy rates by decreasing the rate of premature luteinisation. [Int J Reprod Contracept Obstet Gynecol 2015; 4(1.000: 157-163

  17. Photoaffinity labeling of pituitary GnRH receptors: significance of the position of photolabel on the ligand

    Energy Technology Data Exchange (ETDEWEB)

    Nikolics, K.; Szonyi, E.; Ramachandran, J.

    1988-03-08

    Photoreactive derivatives of GnRH and its analogues were prepared by incorporation of the 2-nitro-4(5)-azidophenylsulfenyl (2,4(5)-NAPS) group into amino acid residues at position 1, 3, 6, or 8 of the decapeptide sequence. The modification of Trp/sup 3/ by the 2,4-NAPS group led to a complete loss of the luteinizing hormone (LH) releasing as well as LH-release-inhibiting activity of the peptide. The (D-Lys(2,4-NAPS))/sup 6/ analog was a very potent agonist that, after covalent attachment by photoaffinity labeling, caused prolonged LH secretion at a submaximal rate. (Orn(2,4-NAPS))/sup 8/-GnRH, a full agonist with a relative potency of 7% of GnRH, after photoaffinity labeling caused prolonged maximal LH release from cultured pituitary cells. In contrast, (Orn(2,5-NAPS))/sup 8/-GnRH, although being equipotent with the 2,4-NAPS isomer in terms of LH releasing ability, was unable to cause prolonged LH release after photoaffinity labeling. Thus, (Orn(2,4-NAPS))/sup 8/GnRH is very effective photolabeling ligand of the functionally significant pituitary GnRH receptor. Based on this compound, a pituitary peptidase resistant derivative, D-Phe/sup 6/, (Orn(2,4-NAPS))/sup 8/-GnRH-(1-9)-ethylamide, was synthesized. This derivative showed high-affinity binding to pituitary membranes with a K/sub d/ comparable to those of other GnRH analogues. A radioiodinated form of this peptide was used for pituitary GnRH-receptor labeling. This derivative labeled 59- and 57-kDa proteins in rat and 58- and 56-kDa proteins in bovine pituitary membrane preparations, respectively. This peptide also labeled pituitary GnRH receptors in the solubilized state and therefore appears to be a suitable ligand for the isolation and further characterization of the receptor.

  18. Expression of Vesicular Glutamate Transporter 2 (vGluT2 on Large Dense-Core Vesicles within GnRH Neuroterminals of Aging Female Rats.

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    Weiling Yin

    Full Text Available The pulsatile release of GnRH is crucial for normal reproductive physiology across the life cycle, a process that is regulated by hypothalamic neurotransmitters. GnRH terminals co-express the vesicular glutamate transporter 2 (vGluT2 as a marker of a glutamatergic phenotype. The current study sought to elucidate the relationship between glutamate and GnRH nerve terminals in the median eminence--the site of GnRH release into the portal capillary vasculature. We also determined whether this co-expression may change during reproductive senescence, and if steroid hormones, which affect responsiveness of GnRH neurons to glutamate, may alter the co-expression pattern. Female Sprague-Dawley rats were ovariectomized at young adult, middle-aged and old ages (~4, 11, and 22 months, respectively and treated four weeks later with sequential vehicle + vehicle (VEH + VEH, estradiol + vehicle (E2 + VEH, or estradiol + progesterone (E2+P4. Rats were perfused 24 hours after the second hormone treatment. Confocal microscopy was used to determine colocalization of GnRH and vGluT2 immunofluorescence in the median eminence. Post-embedding immunogold labeling of GnRH and vGluT2, and a serial electron microscopy (EM technique were used to determine the cellular interaction between GnRH terminals and glutamate signaling. Confocal analysis showed that GnRH and vGluT2 immunofluorescent puncta were extensively colocalized in the median eminence and that their density declined with age but was unaffected by short-term hormone treatment. EM results showed that vGluT2 immunoreactivity was extensively associated with large dense-core vesicles, suggesting a unique glutamatergic signaling pathway in GnRH terminals. Our results provide novel subcellular information about the intimate relationship between GnRH terminals and glutamate in the median eminence.

  19. Effects of a GnRH administration on testosterone profile, libido and semen parameters of dromedary camel bulls.

    Science.gov (United States)

    Monaco, Davide; Fatnassi, Meriem; Padalino, Barbara; Aubé, Lydiane; Khorchani, Touhami; Hammadi, Mohamed; Lacalandra, Giovanni Michele

    2015-10-01

    GnRH treatment has been suggested to increase testosterone levels temporarily and to stimulate libido in stallions, but its use has not fully ascertained in dromedary camels. The aim of this work was to study the effects of administering 100 μg of GnRH on testosterone profile, libido and semen parameters in dromedary camels. The same bulls were used as self-controls and experimental group. Blood samples were collected every 20 min (T0-T12) for 4h, and semen collections were performed over a 2-hour period after T12. GnRH was administered immediately after T0. In GnRH-treated bulls, testosterone levels showed an upward trend, peaking after 140 min, and then slowly decreasing. GnRH administration also led to a decrease in mating time and an increase in spermatozoa concentration. Overall, it seems that administration of 100 μg GnRH might increase testosterone levels temporarily and enhance camel reproduction performance.

  20. Discovery of 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives as non-peptidic selective SUMO-sentrin specific protease (SENP)1 inhibitors.

    Science.gov (United States)

    Uno, Masaharu; Koma, Yosuke; Ban, Hyun Seung; Nakamura, Hiroyuki

    2012-08-15

    We developed 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivative 4 (GN6958) as a non-peptidic selective SUMO-sentrin specific protease (SENP)1 protease inhibitor based on the hypoxia inducible factor (HIF)-1α inhibitor 1 (GN6767). The direct interaction of compound 1 with SENP1 protein in cells was observed by the pull-down experiments using the biotin-tagged compound 2 coated on the streptavidin affinity column. Among the various 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives tested, compounds 3 and 4 suppressed HIF-1α accumulation in a concentration-dependent manner without affecting the expression level of tubulin protein in HeLa cells. Both compounds inhibited SENP1 protease activity in a concentration-dependent manner, and compound 4 exhibited more potent inhibition than compound 3. Compound 4 exhibited selective inhibition against SENP1 protease activity without inhibiting other protease enzyme activities in vitro.

  1. Topical non-peptide antagonists of sensory neurotransmitters substance P and CGRP do not modify patch test and prick test reactions

    DEFF Research Database (Denmark)

    Wallengren, Joanna; Edvinsson, Lars

    2014-01-01

    developed. Their effect on the skin barrier was measured in terms of transepidermal water loss (TEWL) while permeation was calculated using permeation coefficients. Patch tests in patients allergic to nickel and prick test reactions to histamine were used as models. None of the treatments increased TEWL...... vasoconstriction in the skin but did not change the infiltration of nickel reactions. None of the treatments influenced the nickel patch test induced pruritus. The data suggest that the topical application of non-peptide antagonists penetrates the skin but does not inhibit contact dermatitis or pruritus.......Immunologic responses in the skin can be modulated by such neurotransmitters of sensory nerve fibers as substance P (SP) and calcitonin gene-related peptide (CGRP). The first-generation receptor antagonists were peptides with large molecules and had to be injected intracutaneously. The aim...

  2. Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists.

    Science.gov (United States)

    Meini, Stefania; Cucchi, Paola; Bellucci, Francesca; Catalani, Claudio; Faiella, Angela; Rotondaro, Luigi; Quartara, Laura; Giolitti, Alessandro; Maggi, Carlo Alberto

    2004-02-15

    Combining site-directed mutagenesis with information obtained from molecular modelling of the bradykinin (BK) human B2 receptor (hB2R) as derived from the bovine rhodopsin crystal structure [Science 289 (2000) 739], we previously defined a putative binding mode for the non-peptide B2 receptor antagonists, FR173657 and LF16-0687 [Can J Physiol Pharmacol 80 (2002) 303]. The present work is aimed to define the specific role of the quinoline moiety in the pharmacophore of these non-peptide antagonists. The effect of the mutations I110A, L114A (TM, transmembrane 3), W256A (TM6), F292A, Y295A and Y295F (TM7) was evaluated. None of the mutations affected the binding interaction of peptide ligands: the agonist BK and the peptide antagonist MEN 11270. The affinities in competing for [3H]-BK binding and in blocking the BK-induced IP production by the non-peptide antagonists LF16-0687 and FR173657 at the wild type and mutant receptors were analysed. While the affinities of LF16-0687 and FR173657 were crucially decreased at the I110A, Y295A, and Y295F mutants, the W256A mutation affected the affinity of the LF16-0687 only. The important contribution of the quinoline moiety was shown by the inability of an analogue of LF16-0687, lacking this moiety, to affect BK binding at the wild type receptor. On the other hand, the benzamidine group did not interact with mutated residues, since LF16-0687 analogues without this group or with an oxidated benzamidine displayed pairwise loss of affinity on wild type and mutated receptors. Further differences between FR173657 and LF16-0687 were highlighted at the I110 and Y295 mutants when comparing binding (pK(i)) and functional antagonist (pKB) affinity. First, the I110A mutation similarly impaired their binding affinity (250-fold), but at a less extent the antagonist potency of FR173657 only. Second, both the hydroxyl and the phenyl moieties of the Y295 residue had a specific role in the LF16-0687 interaction with the receptor, as

  3. CGRP receptors mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with 'Compound 1' (WO98/11128), a non-peptide antagonist

    DEFF Research Database (Denmark)

    Hasbak, P; Sams, A; Schifter, S

    2001-01-01

    1. Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that the calcitonin (CT) receptor, the CT receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) form the basis of all the recept......1. Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that the calcitonin (CT) receptor, the CT receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) form the basis of all....... The partial porcine mRNA sequences shared 82 - 92% nucleotide identity with human sequences. 3. The human peptides alphaCGRP, betaCGRP, AM and amylin induced relaxation with pEC(50) values of 8.1, 8.1, 6.7 and 6.1 M respectively. 4. The antagonistic properties of a novel non-peptide CGRP antagonist 'Compound...

  4. Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery.

    Science.gov (United States)

    Zafar, Atif; Ahmad, Sabahuddin; Rizvi, Asim; Ahmad, Masood

    2015-01-01

    Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in the digestion of host proteins for growth and development of Schistosoma mansoni. Inhibiting the function of SmCL1 could control the wide spread of infections caused by S. mansoni in humans. With this objective, a homology modeling approach was used to obtain theoretical three-dimensional (3D) structure of SmCL1. In order to find the potential inhibitors of SmCL1, a plethora of in silico techniques were employed to screen non-peptide inhibitors against SmCL1 via structure-based drug discovery protocol. Receiver operating characteristic (ROC) curve analysis and molecular dynamics (MD) simulation were performed on the results of docked protein-ligand complexes to identify top ranking molecules against the modelled 3D structure of SmCL1. MD simulation results suggest the phytochemical Simalikalactone-D as a potential lead against SmCL1, whose pharmacophore model may be useful for future screening of potential drug molecules. To conclude, this is the first report to discuss the virtual screening of non-peptide inhibitors against SmCL1 of S. mansoni, with significant therapeutic potential. Results presented herein provide a valuable contribution to identify the significant leads and further derivatize them to suitable drug candidates for antischistosomal therapy.

  5. Treatment of Ovarian Cysts in Dairy Cows with Simultaneous Administration of GnRH and PGF2α has no Clear Advantage Over the Use of GnRH Alone

    Directory of Open Access Journals (Sweden)

    Rudowska Małgorzata

    2015-04-01

    Full Text Available The aim of the study was to determine the therapeutic efficacy o f simultaneous administration of GnRH and PGF2α in dairy cows with ovarian cysts. Ovarian cyst-affected dairy cows were divided into two experimental groups: 54 cows treated with GnRH and PGF2α, and 42 cows treated with GnRH alone, whereas 22 untreated cows served as the control group. Clinical response and reproductive performance were evaluated. The cumulative disappearance was better in treated cows than in the control group; however, there were no differences between the treatment groups (92.6; 95.2% vs. 72.3%. The mean interval from calving to conception was not significantly shorter (being so by 29 d in the GnRH/PGF2α group than in the cows treated with GnRH alone (P > 0.05. The intervals from treatment to conception were also similar in these groups. The pregnancy rate in both treated groups was similar (62% and higher than in the control cows (53%. In the cows with luteal cysts, the total pregnancy rate was higher in all experimental groups; however, only in GnRH-treated cows was this difference statistically significant (77.8% vs. 50.0%, P < 0.05. With time after parturition, the pregnancy rate decreased in all groups. In general, the cows treated with GnRH and PGF2α simultaneously displayed a good clinical response and slight improvement in reproductive performance compared to the single-therapy GnRH group; however, this was not fully convincing.

  6. The Interrelationship of Estrogen Receptor and GnRH in a Basal Vertebrate, the Sea Lamprey

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    Stacia A Sower

    2011-10-01

    Full Text Available The hypothalamic-pituitary system is considered to be a vertebrate innovation and seminal event that emerged prior to or during the differentiation of the ancestral agnathans. Lampreys are the earliest evolved vertebrates for which there is a demonstrated neuroendocrine system. Lampreys have three hypothalamic GnRHs (lGnRH-I, -II, and –III and two and possibly three pituitary GnRH receptors involved in mediating reproductive processes. Estradiol is considered to be a major reproductive steroid in both male and female lampreys. The purpose of this study was to investigate estrogen receptor (ER expression in the lamprey brain in adult sea lampreys. Expression of ER mRNA was confirmed in the adult lamprey brain using RT-PCR. Using digoxigenin (DIG-labeled probes, ER expression was shown to yield moderate, but distinct reaction products in specific neuronal nuclei of the lamprey brain, including the olfactory lobe, hypothalamus, habenular area, and hindbrain. Expression of ER in the hypothalamic area of the brain provides evidence of potential interaction between estradiol and GnRH(s, and is consistent with previous evidence showing estrogen feedback on GnRH in adult lamprey brain. Earlier studies have reported that there is a close distribution of GAD (GABA and lamprey GnRH in the preoptic region in adult lampreys. The establishment of a direct estradiol-kisspeptin-GABA-GnRH interaction in lamprey has yet to be determined and will require future functional and co-localization studies. The phylogenetic position of lampreys as a basal vertebrate allows lampreys to be a basis for understanding the molecular evolution of the neuroendocrine system that arose in the vertebrates.

  7. Corifollitropin alfa followed by rFSH in a GnRH antagonist protocol for poor ovarian responder patients

    DEFF Research Database (Denmark)

    Polyzos, Nikolaos P; Devos, Michel; Humaidan, Peter;

    2013-01-01

    OBJECTIVE: To identify whether women with poor ovarian response may benefit from treatment with corifollitropin alfa in a GnRH antagonist protocol. DESIGN: Retrospective pilot study. SETTING: University-based tertiary care center. PATIENT(S): Poor ovarian responders fulfilling the Bologna criteria...... developed by European Society for Human Reproduction and Embryology Consensus Group. INTERVENTION(S): Corifollitropin alfa (150 μg) followed by 300 IU rFSH in a GnRH antagonist protocol. MAIN OUTCOME MEASURE(S): Endocrinologic profile and ongoing pregnancy rates. RESULT(S): Among 43 women treated...... compared with a cohort of patients treated during 2011 with the standard protocol for poor responders in our center (short agonist-hMG) (7% vs. 6.3%). CONCLUSION(S): Treatment of poor ovarian responders, as described by the Bologna criteria, with corifollitropin alfa in a GnRH antagonist protocol results...

  8. Random-start GnRH antagonist for emergency fertility preservation: a self-controlled trial

    Directory of Open Access Journals (Sweden)

    Checa MA

    2015-02-01

    Full Text Available Miguel A Checa,1,2 Mario Brassesco,2 Margalida Sastre,1 Manuel Gómez,2 Julio Herrero,3 Laura Marque,3 Arturo Brassesco,2 Juan José Espinós3 1Department of Obstetrics and Gynecology, Parc de Salut Mar, Universitat Autònoma de Barcelona, 2Centro de Infertilidad y Reproducción Humana (CIRH, 3Centro de Reproducción Asistida Sagrada Familia, Clínica Sagrada Familia, Barcelona, Spain Abstract: The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332 was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B or on day 20 (protocol C of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A. The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3±4.6 in the standard protocol versus 13.0±9.1 and 13.2±5.2 in protocols B and C, respectively; values expressed as mean ± standard deviation. The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase and C (stimulation on luteal phase were compared with protocol A (standard stimulation. GnRH antagonists can be effectively used for random-start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency

  9. GnRH treatment at artificial insemination in beef cattle fails to increase plasma progesterone concentrations or pregnancy rates.

    Science.gov (United States)

    Perry, G A; Perry, B L

    2009-03-15

    Treatment with GnRH at the onset of standing estrus increased pregnancy percentages and circulating concentrations of progesterone in repeat breeder dairy cows. The objective of this study was to determine the effect of treatment with GnRH at AI on concentrations of progesterone and conception rates in beef cattle that exhibited estrus. Two hundred ninety-three heifers at four locations were synchronized with the Select Synch plus CIDR protocol (given GnRH and a CIDR was placed into the vagina, and 7 d later, given PGF(2alpha) and CIDR removed; n=253) or the 14-19 melengestrol acetate (MGA) protocol (MGA fed at 0.5mg/head/d for 14 d, with PGF(2alpha) 19 d after MGA withdrawal n=40) and AI was done after detection of estrus. At Location 1, blood samples were collected on Day 2, 4, 6, 10, 15, and 18 after AI (Day 0=AI). Two hundred and fifty postpartum cows at two locations were synchronized with the Select Synch plus CIDR protocol, and AI was performed after detection of estrus. At AI, cattle were alternately assigned to one of two treatments: (1) treatment with GnRH (100microg) at AI (n=127 heifers and n=108 cows); or (2) non-treated control (n=120 heifers and n=119 cows). Concentrations of progesterone tended to be greater in control heifers compared to GnRH-treated heifers on Days 6 (P=0.08), 10 (P=0.07), and 15 (P=0.11). Overall conception rates were 68% and 66% for GnRH treated and control, respectively, and were not different between treatments (P=0.72). In summary, treatment with GnRH at time of AI had no influence on conception rates in cattle that had exhibited estrus.

  10. Hyperthermic responses to central injections of some peptide and non-peptide opioids in the guinea-pig

    Science.gov (United States)

    Kandasamy, S. B.; Williams, B. A.

    1983-01-01

    The intracerebroventricular administration of prototype nonpeptide opioid receptor (mu, kappa, and sigma) agonists, morphine, ketocyclazocine, and N-allyl normetazocine and an agonist at both kappa and sigma receptors, pentazocine, was found to induce hyperthermia in guinea pigs. The similar administration of peptide opioids like beta endorphin, methionine endkephalin, leucine endkephaline, and several of their synthetic analogues was also found to cause hyperthermia. Only the liver-like transport system of the three anion transport systems (iodide, hippurate, and liver-like) present in the choroid plexus was determined to be important to the central inactivation of beta-endorphin and two synthetic analogues. Prostaglandins and norepinephrine (NE) as well as cAMP were not involved in peptide and nonpeptide opioid-induced hyperthermia. Naloxone-sensitive receptors were found to be involved in the induction of hyperthermia by morphine and beta-endorphin, while hyperthermic responses to ketocyclazocine, N-allyl normetazocine, pentazocine, Met-enkephalin, Leu-enkephalin, and two of the synthetic analogues were not antagonized by nalozone. The lack of antagonism of naloxone on pyrogen, arachidonic acid, PGE2, dibutyryl cAMP, and NE-induced hyperthermia shows that endogenous opioid peptides are not likely to be central mediators of the hyperthermia induced by these agents.

  11. Melanin-concentrating hormone (MCH) and gonadotropin-releasing hormones (GnRH) in Atlantic cod, Gadus morhua: tissue distributions, early ontogeny and effects of fasting.

    Science.gov (United States)

    Tuziak, Sarah M; Volkoff, Hélène

    2013-12-01

    Melanin-concentrating hormone (MCH) is classically known for its role in regulating teleost fish skin color change for environmental adaptation. Recent evidence suggests that MCH also has appetite-stimulating properties. The gonadotropin-releasing hormone (GnRH) peptide family has dual roles in endocrine control of reproduction and energy status in fish. Atlantic cod (Gadus morhua) are a commercially important aquaculture species inhabiting the shores of Atlantic Canada. In this study, we examine MCH and GnRH transcript expression profiles during early development as well as in central and peripheral tissues and quantify juvenile Atlantic cod MCH and GnRH hypothalamic mRNA expressions following food deprivation. MCH and GnRH3 cDNAs are maternally deposited into cod eggs, while MCH has variable expression throughout early development. GnRH2 and GnRH3 mRNAs "turn-on" during mid-segmentation once the brain is fully developed. For both MCH and GnRH, highest expression appears during the exogenous feeding stages, perhaps supporting their functions as appetite regulators during early development. MCH and GnRH transcripts are found in brain regions related to appetite regulation (telencephalon/preoptic area, optic tectum/thalamus, hypothalamus), as well as the pituitary gland and the stomach, suggesting a peripheral function in food intake regulation. Atlantic cod MCH mRNA is upregulated during fasting, while GnRH2 and GnRH3 transcripts do not appear to be influenced by food deprivation. In conclusion, MCH might be involved in stimulating food intake in juvenile Atlantic cod, while GnRHs may play a more significant role in appetite regulation during early development.

  12. A minimalist model of calcium-voltage coupling in GnRH cells

    Energy Technology Data Exchange (ETDEWEB)

    Rennie, Martin; Chan, Rossanna; Duan Wen; Sneyd, James [Department of Mathematics, University of Auckland, Auckland 1142 (New Zealand); Schneider, David, E-mail: schneide@tandar.cnea.gov.ar [Departamento de Fisica, Comision Nacional de Energia Atomica. Av. del Libertador 8250, 1429 Buenos Aires (Argentina)

    2011-03-01

    We present a minimalist model to describe the interplay between burst firing and calcium dynamics in Gonadotropin-releasing hormone (GnRH) cells. This model attempts to give a qualitative representation of Duan's model [3], and it comprises two FithzHugh-Nagumo (FHN) coupled systems describing the dynamics of the membrane potential and calcium concentration in the GnRH cells. Within the framework of our minimalist model, we find that the calcium subsystem drives burst firing by making the voltage subsystem to undergo a Hopf bifurcation. Specifically, fast relaxation oscillations occur in a specific region of the c-z plane (c being the calcium concentration, and z a calcium-dependent gating variable). Slow calcium oscillations, instead, are carried by the voltage subsystem by successive shifts of the calcium steady state, and have the net effect of an external perturbation. The full comprehension of the phase-plane of the voltage subsystem and the 3-dimensional phase-space of the calcium subsystem ultimately allows us to study the behaviours of the entire model under the change of certain parameters. Those special parameters do not necessarily follow realistic assumptions, but merely intend to mimic some pharmacological tests which have been performed experimentally and also simulated by Duan's model under the corresponding physiological considerations.

  13. Protective Role of GnRH Antagonist on Chemotherapy-induced Spermatogenesis Disorder: A Morphological Study

    Directory of Open Access Journals (Sweden)

    Daryosh Mohammadnejad

    2013-08-01

    Full Text Available Purpose: Anti cancer drugs is one of the most important chemotherapeutic factors which can influence spermatogenesis process and germinal epithelium. Since dividing cells are mainly affected by anticancer drugs, the aim of the present study is to investigate thepreventive effect of GnRH antagonist on spermatogenic defect produced by anticancer drugs. Methods: In the present study thirty adult male mice aging 6-8 weeks were divided into 3 groups as: Control, Experimental 1 and Experimental 2. Experimental 1 group received Cisplatin for 5 days as 2.5 mg/kg intraperitoneally and Experimental 2group received 0.25 mg/kg cetrorelix (GnRH antagonist one week before cisplatin treatment and continued for 3 weeks. The mice in all groups were sacrificed 35 days after the last injection and testis specimens were fixed in boueins, formaldehyde fixativeand 2.5% Glutaraldehide then prepared for light and electron microscopic examination. Results: Light microscopy (LM study showed that the number of spermatogonial cells, thickness of germinal epithelium, was decreased in Experimental 1group. Electronmicroscopy revealed that in this group several intercellular spaces appeared between spermatogenic cells and secretory granules in interstitial cells was increased. There were several vacuolated mitochondria and destroyed organelles in spermatogonial cells but inExperimental 2 group condition was similar to control group. Conclusion: These results indicate that the cetrorelix administration before cancer treatment may protect germinal epithelium against side effects of cisplatin.

  14. Treatment of central precocious puberty by GnRH analogs:long-term outcome in men

    Institute of Scientific and Technical Information of China (English)

    Silvano Bertelloni; Dick Mul

    2008-01-01

    In boys, central precocious puberty (CPP) is the appearance of secondary sex characteristics driven by pituitary gonadotropin secretion before the age of 9 years. In the last years, relevant improvements in the treatment of CPP have been achieved. Because CPP is rare in boys, the majority of papers on this issue focus on girls and do not address specific features of male patients regarding end results and safety. In the present paper, recent advances of CPP management with GnRH analogs in men are summarized. End results in untreated and treated patients are also reviewed by an analysis of the recently published literature on treatment of CPP in men. The available data indicate that therapy with GnRH analogs can improve final height into the range of target height without significant adverse short-term and long-term effects, but longer follow-up of larger series of patients is still required to draw definitive conclusions. (Asian J Androl 2008 Jul; 10: 525-534)

  15. The control of reproduction in finfish species through GnRH treatments

    Directory of Open Access Journals (Sweden)

    Simona Rainis

    2010-01-01

    Full Text Available Fish in captivity can show some dysfunctions, at different levels, in the physiological processes of reproduction, due to  the lack of synthesis or release of gonadotropins (GtHs by hypophysis. As a consequence, a worsening of quality and  quantity of spawned gametes, or a lack of egg and sperm spawning, can be observed. The farmers can act on fish repro-  ductive cycle manipulating the environmental parameters of rearing, the diet, the genetics or using GnRH treatments.  Nowadays, they are used mainly GnRH, synthesized in laboratory as analogues. These releasing factors, naturally pro-  duced by hypothalamus, let to overcome the technological and biological limits of the “traditional” hormonal treatments  with hCG, being more effective, cheaper and easily available on market. This article makes a historical survey of the con-  ditioning treatments for fish reproduction and also considers the future perspectives of these treatments, examining the  topics that research will have to focus, in order to make these treatments common worldwide, in any hatchery and for  each farmed  species of finfish. 

  16. Development of a Ga-68 labeled triptorelin analog for GnRH receptor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Zoghi, Masoumeh; Niazi, Ali [Islamic Azad Univ., Arak (Iran, Islamic Republic of). Dept. of Chemistry; Jalilian, Amir R.; Johari-daha, Fariba; Alirezapour, Behrouz [Nuclear Science and Technology Research Institute (NSTRI) (Iran, Islamic Republic of). Radiation Application Research School; Ramezanpour, Sorour [K.N. Toosi Univ. of Technology, Tehran (Iran, Islamic Republic of). Peptide Chemistry Research Center

    2016-08-01

    Optimized total synthesis, radiolabeling and quality control of [{sup 68}Ga]-DOTA-Hyd-TRP as an efficient and possible PET radiotracer for GnRH receptor imaging in various tumors is of great interest. DOTA-Hyd-TRP was synthesized using solid phase peptide synthesis followed by conjugation to DOTA using pSCN-Bn-DOTA. [{sup 68}Ga]-DOTA-Hyd-TRP was prepared using generator-based [{sup 68}Ga]GaCl{sub 3} and DOTA-Hyd-TRP under optimized conditions for time, temperature, ligand amount, gallium content and column cartridge purification followed by proper formulation. The biodistribution of the tracer in rats was studied using tissue counting up to 120 min. [{sup 68}Ga]-DOTA-Hyd-TRP was prepared at optimized conditions in 5-7 min at 95 C followed by separation using C{sub 18} cartridge (radiochemical purity ∼99 ± 0.88% ITLC, > 99% HPLC, specific activity: 300 ± 15 MBq/nM). The biodistribution of the tracer demonstrated high kidney uptake of the tracer in 10-20 min as well as significant testicular uptake consistent with reported GnRH receptor mappings. Block test studies by triptorelin pretreatment of the animals prior to tracer administration demonstrated significant specific uptake in receptor rich organs including testes and stomach.

  17. Prostate cancer: what are the news in hormonal therapy? The role of GnRH antagonists.

    Science.gov (United States)

    Zattoni, Filiberto

    2012-09-01

    The latest EAU guidelines on the evidence based-management of prostate cancer (P.Ca.), with regard to pharmacological androgen deprivation therapy (ADT), reiterate that the primary objective of hormonal therapy is to slow down the progression of the disease to the greatest possible extent. Degarelix a new product for the treatment of hormone-dependent P.Ca. has recently become available in Italy. This product is classified as a GnRH antagonist and provides safe and effective ADT. It completely blocks the synthesis and release of gonadotropins (LH and FSH), thus rapidly reducing the testosterone levels without causing clinical flare. The results of the clinical trials (36 months) demonstrate that degarelix, compared to high-dose leuprorelin (7.5 mg), suppresses levels of testosterone and PSA (Prostate-Specific Antigen) more rapidly and reduces levels of FSH and musculoskeletal events associated with treatment (pain, muscle weakness, spasms, oedema/joint stiffness, arthralgia, osteoporosis and osteopoenia) to a greater extent. In addition, these results demonstrate a significant increase in the probability of PSA progression-free survival, suggesting a possible delay in the onset of the "castration-resistant" stage. The information available to date supports the use of this new molecule as a valid alternative to GnRH agonists in the treatment of hormone-sensitive P.Ca.

  18. Combined therapy with GnRH analog plus growth hormone in central precocious puberty.

    Science.gov (United States)

    Pucarelli, I; Segni, M; Ortore, M; Moretti, A; Iannaccone, R; Pasquino, A M

    2000-07-01

    GnRH analogues (GnRHa) arrest pubertal development, and slow growth velocity (GV) and bone maturation, thus improving adult height in central precocious puberty (CPP). In some patients, however, GV decreases to such an extent that it compromises the improvement in predicted adult height (PAH) and therefore the addition of GH is suggested. Of 20 patients with idiopathic CPP (treated with GnRHa [depot-triptorelin] at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 yr) whose GV fell below the 25th percentile for chronological age (CA), ten received, in addition to the GnRHa, GH at a dose of 0.3 mg/kg/wk, s.c. 6 days weekly, for 2-4 yr. Ten patients matched for BA, CA, and duration of GnRHa treatment who showed the same growth pattern but refused GH treatment, served to evaluate the efficacy of the addition of GH. No patient showed classical GH deficiency. Both groups discontinued treatment at a comparable BA (mean +/- SEM): 13.2 +/- 0.2 yr in GnRHa + GH vs 13.0 +/- 0.1 yr in the control group. At the conclusion of the study all the patients had achieved adult height. Adult height was considered to be attained when the growth during the preceding year was less than 1 cm, with a BA of over 15 yr. Patients of the group treated with GH + GnRHa showed an adult height significantly higher (p<0.001) than pretreatment PAH (160.6 +/- 1.3 vs 152.7 +/- 1.7 cm). Height SDS for BA significantly increased from -1.5 +/- 0.2 at start of GnRHa to -0.21 +/- 0.2 at adult height (p<0.001). Target height was significantly exceeded. The GnRH alone treated group reached an adult height not significantly higher than pretreatment PAH (157.1 +/- 2.5 vs 155.5 +/- 1.9 cm). Height SDS for BA did not change (from -1.0 +/- 0.3 at start of GnRHa to -0.7 +/- 0.4 at adult height). Target height was just reached but not significantly exceeded. The gain in centimeters obtained calculated between pretreatment PAH and final height was 7.9 +/- 1.1 cm in patients treated with GH combined with GnRH

  19. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization

    NARCIS (Netherlands)

    B.C.J.M. Fauser (Bart); D. de Jong (Danielle); F. Olivennes; H. Wramsby; C. Tay; J. Itskovitz-Eldor; H.G. van Hooren

    2002-01-01

    textabstractIn a randomized multicenter study, the efficacies of two different GnRH agonists were compared with that of hCG for triggering final stages of oocyte maturation after ovarian hyperstimulation for in vitro fertilization. Ovarian stimulation was conducted by recombinant F

  20. Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

    Directory of Open Access Journals (Sweden)

    Min He

    Full Text Available BACKGROUND: Glucagon-like peptide-1 (GLP-1 is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg for 12 weeks. Body weight, body mass index (BMI, food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various

  1. Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats

    DEFF Research Database (Denmark)

    Nellemann, Christine Lydia; Lefevre, P. A.; Ashby, J.

    2003-01-01

    BACKGROUND: The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology...

  2. FSH inhibits the augmentation by oestradiol of the pituitary responsiveness to GnRH in the female rat

    NARCIS (Netherlands)

    Schuiling, GA; Valkhof, N; Koiter, TR

    1999-01-01

    The effect of follicle stimulating hormone (FSH) treatment on the pituitary response to gonadotrophin-releasing hormone (GnRH) was studied in rats in various reproductive conditions. A 3-day treatment of cycling rats with FSH (Metrodin(R); 10 IU/injection) lowered the spontaneous pre-ovulatory LH-su

  3. Active immunization against GnRH in ovine (Ovis aries: testicular morphometry, histopathology and endocrine responses in prepubertal ram lambs

    Directory of Open Access Journals (Sweden)

    Gutierrez-Reinoso MA

    2017-08-01

    Full Text Available The main objective of the present research was to assess the effects of an active immunization against GnRH on male reproductive function as an alternative to surgical sterilization evaluating testicular morphometry, histopathological alterations and plasma gonadotropin levels in prepubertal ram lambs. Dorper ram lambs (age= 2 months; control group, n= 5; treatment group, n=15 were immunised by using an anti-GnRH vaccine (two administrations spaced 15d developed by linking a GnRH homologous molecule to tetanus toxoid (clostridial toxoid with aluminum hydroxide as coadjuvant. To determine the effectiveness of the vaccination protocol, testicular morphometry was evaluated (length, width, mean volume and total volume together with histopathological alterations in testicular tissue samples (seminiferous tubule diameters, spermatogonia per testis and sperm presence and endocrine responses (ELISA from blood samples (FSH, LH, testosterone and cortisol plasma levels. Morphometric parameters (testicular length, width and volume were significantly reduced in vaccinated animals with respect to the control group (p0.05. In conclusion, prepubertal active immunization against GnRH led to marked differences on testes morphometry and activity in ovine species, however, it did not affect endocrine levels nor spermatogenesis in all individuals studied showing a partial vaccination effect in some of them. Thus, taking into account the heterogeneous dysfunctional responses obtained, different vaccination assays and strategies should be tested before active immunization against GnRH is considered as a viable alternative to conventional surgical sterilization.

  4. Cumulative live birth rate after GnRH agonist trigger and elective cryopreservation of all embryos in high responders.

    Science.gov (United States)

    Vlaisavljević, Veljko; Kovačič, Borut; Knez, Jure

    2017-07-01

    Elective embryo cryopreservation after using gonadotrophin-releasing hormone (GnRH) antagonist protocols and GnRH agonist triggering is becoming an increasingly important part of medically assisted reproduction. We designed a single-centre retrospective study to assess the cumulative probability of achieving a live birth through consecutive transfers of vitrified-warmed blastocysts after elective embryo cryopreservation in high-responding patients. Hence, 123 women identified to be at high risk for developing ovarian hyperstimulation syndrome were included. They were stimulated using GnRH antagonist protocol, and GnRH agonist was used to trigger final oocyte maturation. All embryos were vitrified at the blastocyst stage and transferred in the subsequent menstrual cycles. Using the Kaplan-Meier survival analysis, a total of 65.9% (95% CI 57.5 to 74.3) women achieved a live birth after a maximum of six embryo transfer cycles using the 'conservative' approach. Applying the 'optimistic' approach, presuming that women who still had cryopreserved embryos and did not return for embryo transfer had the same chance of achieving a live birth as those returning for transfer, the cumulative live birth rate estimated in six embryo transfer cycles was 76.6% (95% CI 69.1 to 84.1). No cases of severe ovarian hyperstimulation syndrome were recorded. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Serum inhibin A and inhibin B in central precocious puberty before and during treatment with GnRH agonists

    DEFF Research Database (Denmark)

    Sehested, A; Andersson, A M; Müller, J

    2000-01-01

    Serum levels of the gonadal hormones inhibin A and inhibin B are undetectable or low in prepubertal girls, and rise during puberty. In girls with central precocious puberty (CPP) the hypothalamic-pituitary-gonadal axis is prematurely activated, if the girl is thereafter treated with GnRH agonists...

  6. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist

    NARCIS (Netherlands)

    Oostdijk, W; Rikken, B; Schreuder, S; Otten, B; Odink, R; Rouwe, C; Jansen, M; Gerver, WJ; Waelkens, J; Drop, S

    1996-01-01

    Objective-To study the resumption of puberty and the final height achieved in children with central precocious puberty (CPP) treated with the GnRH agonist triptorelin. Patients-31 girls and five boys with CPP who were treated with triptorelin 3.75 mg intramuscularly every four weeks. Girls were trea

  7. Foliation-Based Parameter Tuning in a Model of the GnRH Pulse and Surge Generator

    Science.gov (United States)

    Clement, Frederique; Vidal, Alexandre

    2009-01-01

    We investigate a model of the GnRH pulse and surge generator, with the definite aim of constraining the model GnRH output with respect to a physiologically relevant list of specifications. The alternating pulse and surge pattern of secretion results from the interaction between a GnRH secreting system and a regulating system exhibiting slow-fast dynamics. The mechanisms underlying the behavior of the model are reviewed from the study of the Boundary-Layer System according to the dissection method principle. Using singular perturbation theory, we describe the sequence of bifurcations undergone by the regulating (FitzHugh-Nagumo) system, encompassing the rarely investigated case of homoclinic connection. Based on pure dynamical considerations, we restrict the space of parameter search for the regulating system and describe a foliation of this restricted space, whose leaves define constant duration ratios between the surge and the pulsatility phase in the whole system. We propose an algorithm to fix the parameter values also to meet the other prescribed ratios dealing with amplitude and frequency features of the secretion signal. We finally apply these results to illustrate the dynamics of GnRH secretion in the ovine species and the rhesus monkey.

  8. Regulation of luteinizing hormone (LH) subunit biosynthesis in cultured male anterior pituitary cells: effects of GnRH and testosterone

    Energy Technology Data Exchange (ETDEWEB)

    Krummen, L.A.

    1988-01-01

    The purpose of this study was to evaluate the direct effects of testosterone (T) on LH subunit apoprotein synthesis, glycosylation and release by the male pituitary. Cells from 1 wk castrate rats were cultured for 48 h in steroid-free medium followed by 48h in media /+-/10nM T. The cells were then incubated for 2, 4, 6, 8, or 12h in media containing (/sup 35/S)-methionine (/sup 35/S-Met) or (/sup 3/H)-glucosamine (/sup 3/H-Gln), /+-/1nM GnRH (exp 1) or in media containing precursors /+-/ 10nM T and/or 1nM GnRH (exp 2). Radiolabeled precursor incorporation into LH subunits was determined by immunoprecipitation followed by SDS-PAGE. In experiment 1, precursor incorporation into total protein (TP) and LH subunits increased linearly with time for at least 8h. GnRH did not effect precursor incorporation in to TP or /sup 35/S-Met labeling of LH subunits, but stimulated a linear, time-dependent accumulation of /sup 3/H-Gln into total LH subunits and the release of RIA-LH and radiolabeled subunits into media. Based on these results, the effects of T on LH subunit biosynthesis were studied during an 8h incubation. In experiment 2, GnRH enhanced the total /sup 3/H-Gln incorporation (but not /sup 35/S-Met incorporation) into both LH subunits. GnRH stimulated the release of /sup 35/S-Met LH..cap alpha.. and /sup 3/H-Gln LH subunits into media and increased the relative glycosylation of secreted LH subunits without altering the relative glycosylation of intracellular LH subunits. T inhibited RIA-LH release and incorporation of both precursors into total and secreted LH subunits (/+-/GnRH). However, only the relative glycosylation of secreted LH..cap alpha.. was reduced by T (/+-/GnRh).

  9. Pulsatile GnRH Is Superior to hCG in Therapeutic Efficacy in Adolescent Boys With Hypogonadotropic Hypogonadodism.

    Science.gov (United States)

    Gong, Chunxiu; Liu, Ying; Qin, Miao; Wu, Di; Wang, Xiaoling

    2015-07-01

    We investigated the efficacy and safety of two different treatments that have not been evaluated in peripuberty boys with hypogonadotropic hypogonadism (HH). The objective of the study was to assess the effectiveness and safety of GnRH or human chorionic gonadotropin (hCG) treatment in adolescent boys with HH. Twelve patients received 8-10 μg of GnRH, sc injected every 90 minutes using a pump. Another 22 patients received hCG, injected im as follows: for the first 3 months, 1000 IU of hCG was injected two times per week and then once every other day for the next 3 months. The dose of hCG was increased to 2000 IU after a 6-month treatment and the above cycle was repeated for another 6 months. All patients were treated for 12-14 months and followed up every 3 months. Thirty-five participants were chosen from Beijing Children's Hospital from 2008 to 2014. Twenty-three patients with Kallmann syndrome and 12 with normosmic idiopathic hypogonadotropic hypogonadism. The age ranged from 10 to 16 years. Twelve patients were treated with pulsatile pump GnRH (group 1), and 22 patients were treated with im hCG (group 2). One patient was treated successively with hCG and GnRH, which was removed in data analysis. Testicular volume was measured by an orchidometer. The levels of T, LH, and FSH serum were measured with a chemiluminesent immunoassay. Bone age was measured by x-ray. Patients treated with GnRH showed larger testes than those treated with hCG. Patients in both groups showed a significantly increased length of penis and T levels. But the difference of the two groups was not statistically significant. There was no significant difference in side effects in both groups. Boys with HH may be effectively treated with GnRH. We suggested that GnRH exhibits higher efficacy in treating adolescent boys with HH than hCG.

  10. Effect of GnRH and hCG on progesterone concentration and ovarian and luteal blood flow in diestrous mares.

    Science.gov (United States)

    Brito, L F C; Baldrighi, J M; Wolf, C A; Ginther, O J

    2017-01-01

    The objective of the present study was to investigate the effect of reproductive hormones (GnRH, hCG, LH and progesterone) on the regulation of corpus luteum (CL) and ovarian blood flow. Diestrous mares received a single treatment of saline, 100μg gonadorelin (GnRH), or 1500IU hCG 10days after ovulation. Plasma LH and progesterone concentrations, resistance index (RI) for ovarian artery blood-flow, and percentage of corpus luteum (CL) with color-Doppler signals of blood flow were determined immediately before treatment (hour 0) and at hours 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, and 6. In the GnRH group, LH increased (Pblood-flow signals was greater at hour 0.5 in the GnRH group than in the saline group and was intermediate in the hCG group. The similarity among groups in progesterone concentration indicated that changes in progesterone were not involved in the GnRH and hCG stimulation of ovarian vascular perfusion. Effects of treatment might have been mediated through LH; however, since hCG biological activity is primarily LH-like, the differences in timing and degree of ovarian and luteal blood flow changes after GnRH or hCG administration in the present study suggest that GnRH might have a direct effect on ovarian blood vessels and vascular control.

  11. The type of GnRH analogue used during controlled ovarian stimulation influences early embryo developmental kinetics: a time-lapse study.

    Science.gov (United States)

    Muñoz, Manuel; Cruz, María; Humaidan, Peter; Garrido, Nicolás; Pérez-Cano, Inmaculada; Meseguer, Marcos

    2013-06-01

    To explore if the GnRH analogue used for controlled ovarian stimulation (COS) and the ovulation triggering factor (GnRH agonist + hCG triggering versus GnRH antagonist + GnRH agonist triggering) affect embryo development and kinetics. In a retrospective cohort study in the Instituto Valenciano de Infertilidad (IVI) Alicante and the Instituto Universitario-IVI Valencia, Spain, 2817 embryos deriving from 400 couples undergoing oocyte donation were analysed. After controlled ovarian stimulation and IVF/intracytoplamic sperm injection, the timing of embryonic cleavages was assessed by a video time-lapse system. The results were analysed using Student's t test for comparison of timings (hours) and Chi-squared test for comparison of proportions. A p-value < 0.05 was considered to be statistically significant. Embryos from cycles co-treated with GnRH antagonist + GnRH agonist (n = 2101) cleaved faster than embryos deriving from patients co-treated with GnRH agonist + hCG (n = 716): these differences were significant at the first stages of development but they disappeared as long as the embryo developed. Assessing embryo quality in terms of morphokinetic characteristics, we did not find significant differences between the two groups. By adopting a time-lapse video system, we can suggest that the type of protocol used for controlled ovarian stimulation influences embryo kinetics of development but these variations are not reflected in embryo quality. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Dopamine-dependent behavioural stimulation by non-peptide delta opioids BW373U86 and SNC 80: 1. Locomotion, rearing and stereotypies in intact rats.

    Science.gov (United States)

    Spina, L; Longoni, R; Mulas, A; Chang, K J; Di Chiara, G

    1998-02-01

    The unconditioned behavioural effects of two non-peptide delta-opioid receptor agonists, BW 373U86 and SNC 80, were studied in the intact rat. BW 373U86 (0.1-2.5 mg/kg s.c.) and SNC 80 (2.5-10 mg/kg s.c.) dose-dependently elicited locomotion, rearing, stereotyped sniffing, licking and gnawing. These effects were abolished by pretreatment with the delta-opioid receptor antagonist naltrindole (5.0 mg/kg s.c.). In view of the phenomenological similarities between this syndrome and that elicited by dopamine-receptor agonists, the role played by dopamine receptors was investigated. The specific dopamine D1 receptor antagonist SCH 23390 and the specific dopamine D2/D3 receptor antagonist raclopride reduced or even abolished the behavioural stimulation induced by lower doses of BW 373U86 and SNC 80. When higher doses of BW 373U86 were used (2.5 mg/kg), however, raclopride, even at high cataleptic doses (6.0 mg/kg), only partly prevented the behavioural stimulation induced by the delta-opioid receptor agonist. The behavioural stimulation remaining after high doses of raclopride was abolished by the administration of SCH 23390. These results show that delta-opioid receptor stimulation elicits dopamine-dependent behavioural activation in the rat that depends on dopamine receptors, particularly of the D1 subtype.

  13. Kisspeptin is a component of the pulse generator for GnRH secretion in female sheep but not the pulse generator.

    Science.gov (United States)

    Ezzat, Ahmed; Pereira, Alda; Clarke, Iain J

    2015-05-01

    We tested the hypothesis that kisspeptin cells constitute the "pulse generator" for GnRH secretion. In ewes, we determined whether iv administered kisspeptin elicits a secretory pulse of LH in anaesthetized, sex-steroid suppressed ovariectomized ewes. A response was seen in both anaesthetized and conscious animals, which was not associated with induction of c-Fos labeling in GnRH cells, supporting the notion that kisspeptin acts on the neurosecretory GnRH terminals. Response was lower in the anaesthetized animals, suggesting that some nonkisspeptin elements may be involved in GnRH responses. Microinjection of kisspeptin (100 nmol) into the median eminence of conscious ewes elicited a pulse of LH, indicating that kisspeptin acts at this level to cause GnRH secretion. To determine which cells are activated at the time of GnRH secretion, we blood sampled 18 ewes during the luteal phase of the estrous cycle and harvested brains after 3 hours. Three of these ewes displayed a pulse of LH within 30 minutes of euthanasia. An increase in c-Fos labeling was seen in kisspeptin and glutamate cells of the arcuate nucleus but not in GnRH neurons, preoptic kisspeptin neurons, or preoptic glutamate neurons. Immunohistochemistry in 4 hypothalami showed that 72% of arcuate kisspeptin cells receive glutamatergic input. These data support the concept that the kisspeptin cells of the arcuate nucleus drive pulsatile secretion of GnRH at the level of the median eminence, but this may involve "upstream" input from glutamate cells. We conclude that the pulse generator for GnRH secretion involves more than 1 element.

  14. Ghrelin action on GnRH neurons and pituitary gonadotropes might be mediated by GnIH-GPR147 system.

    Science.gov (United States)

    Celik, Onder; Celik, Nilufer; Aydin, Suleyman; Aygun, Banu Kumbak; Haberal, Esra Tustas; Kuloglu, Tuncay; Ulas, Mustafa; Aktun, Lebriz Hale; Acet, Mustafa; Celik, Sudenaz

    2016-02-01

    Acylated ghrelin (AG) effect on GnRH secretion is mediated, at least in part, by GH secreta-gogue receptor (GHS-R) which is present in the GnRH neurons. As the acylation is mandatory for binding to GHS-R, unacylated isoform of ghrelin (UAG) action on gonadotropin secretion is likely to be mediated by other receptors or mediators that have not been identified yet. UAG, therefore, may act partially via a GHS-R-independent mechanism and inhibitory impact of UAG on GnRH neurons may be executed via modulation of other neuronal networks. Ghrelin and gonadotropin inhibitory hormone (GnIH), two agonistic peptides, have been known as important regulators of reproductive events. Potential impact of ghrelin on the activity of GnIH neurons is not exactly known. Both GnIH and ghrelin are potent stimulators of food intake and inhibitors of gonadotropin release. By binding G-protein coupled GnIH receptor (GnIH-R), GPR147, which is located in the human gonadotropes and GnRh neurons, GnIH exerts an inhibitory effect on both GnRH neurons and the gonadotropes. The GnIH-GPR147 system receives information regarding the status of energy reservoir of body from circulating peptides and then transfers them to the kisspeptin-GnIH-GnRH network. Due to wide distribution of this network in brain GnIH neurons may project on ghrelin neurons in the arcuate nucleus and contribute to the regulation of UAG's central effects or vice versa. Together, the unidentified ghrelin receptor in the hypothalamus and hypophysis may be GnIH-R. Therefore, it is reasonable that ghrelin may act on both hypothalamus and hypophysis via GnIH-GPR147 system to block gonadotropin synthesis and secretion.

  15. Withania somnifera aqueous extract facilitates the expression and release of GnRH: In vitro and in vivo study.

    Science.gov (United States)

    Kataria, Hardeep; Gupta, Muskan; Lakhman, Sukhwinder; Kaur, Gurcharan

    2015-10-01

    Ashwagandha (Withania somnifera) has a long history in traditional medicines as an aphrodisiac. It has been known to influence sexual behaviour in animal models but mechanism of action is still unknown. The present study was aimed to investigate the mechanisms by which Ashwagandha extract exert its gonadotropic activities. Due to the complexity of neuroendocrine pathways, there are limited in vitro models available despite the strong demand for such systems to study and predict neuroendocrine effects of chemicals or natural products. Immortalized rat hypothalamic GnV-3 cell line was investigated as a model to screen for neuroendocrine effects of Ashwagandha extract. GnV-3 cells were cultured under different media conditions and evaluated after treatment with Ashwagandha water extract, for GnRH expression and release by immunostaining and ELISA respectively. These cells acquired differentiated morphology, characteristic shape displayed by preoptic GnRH neurons in vivo. In addition, GnV-3 cells exhibited upregulation of plasticity related polysialylated neural cell adhesion molecule (PSA-NCAM) and mature dendrite marker microtubule associated protein (MAP2) as well as GnRH expression and release. Chloroform fraction of the extract proved to exhibit all the bioactive properties as it induced differentiation and upregulated GnRH and MAP2 expression in GnV-3 cells, similar to Ashwagandha extract. Withanone and Withaferin A were found to be present in ASH-WEX and chloroform fraction while Withanone came out to be the major constituent of chloroform fraction. The preliminary in vivo studies in adult male animals showed that ASH-WEX was able to upregulate the GnRH levels although non-significantly. Taken together, this data demonstrate significant morphological and physiological changes in GnV-3 cells after treatment with Ashwagandha extract and may suggest the potential beneficial effects of Ashwagandha on reproductive functions in vivo.

  16. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment

    NARCIS (Netherlands)

    N.S. Macklon (Nick); M.J.C. Eijkemans (René); M. Ludwig (Michael); R.E. Felberbaum; K. Diedrich; S. Bustion; E. Loumaye; B.C.J.M. Fauser (Bart); N.G.M. Beckers (Nicole)

    2003-01-01

    textabstractReplacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because o

  17. Efficiency of fixed-time artificial insemination using a progesterone device combined with GnRH or estradiol benzoate in Nellore heifers

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    Vinícius Antônio Pelissari Poncio

    2015-10-01

    Full Text Available he use of estrogens in artificial insemination protocols for cattle is the least expensive and most efficient method currently available. However, the trend to prohibit the use of estrogens for this purpose has made it necessary to find alternatives that replace estrogens without compromising the reproductive performance of the animals. The objective of this study was to evaluate conception rates in Bos indicus beef heifers treated with a progesterone device (P4 combined with GnRH or an estradiol ester. On day 0, pubertal Nellore heifers (n = 100 received an intravaginal device containing 1 g P4 and were randomly divided into two groups. The GnRH group (n = 49 received an intramuscular injection of 100 µg GnRH, while the E2 group (n = 51 received 2 mg estradiol benzoate (EB. The P4 device was removed after 5 (GnRH group or 8 days (E2 group, followed by an injection of 125 µg of the PGF2α, analog cloprostenol. On that occasion, the E2 group received an additional injection of 300 IU eCG. Twenty-four hours later, the GnRH group received a second injection of 125 µg cloprostenol, while the E2 group received 1 mg EB. The heifers were inseminated 72 (GnRH group or 54 hours (E2 group after removal of the P4 device. At the time of insemination, the GnRH group received additionally an injection of 100 µg GnRH. Estrus was monitored during the period of cloprostenol injection until the time of artificial insemination and pregnancy was diagnosed 40 days after insemination by transrectal ultrasonography. The data were analyzed by Fisher’s exact test. The pregnancy rate was 38.8% and 31.4% in the GnRH and E2 groups, respectively (P>0.05. The ovarian condition of the heifers (estrus or anestrus tended to influence (P=0.07 pregnancy rates in the GnRH group, but not in the E2 group. At the time of artificial insemination, 33.3% of heifers in the GnRH group showed signs of estrus versus 88.2% in the E2 group (P<0.05. However, the time of estrus

  18. A comparative therapeutic management of anoestrus in buffaloes using insulin and GnRH

    Science.gov (United States)

    Purkayastha, R. D.; Shukla, S. N.; Shrivastava, O. P.; Kumar, P. R.

    2015-01-01

    Aim: Anoestrus is one of the most common functional disorders of the reproductive cycle in buffaloes. In spite of technical advancement, there is no single cure for the management of anoestrus. Therefore, the aim of this study was to find out the efficacy of gonadotropic releasing hormone (GnRH) and metabolic hormone for the management of true anoestrus in buffaloes. Materials and Methods: The experimental animals were selected on the basis of history, gyneco-clinical examinations and progesterone estimation. Deworming was done with Fenbendazole and thereafter mineral mixture was given @ 50 g per animal per day for 10 days in all the selected buffaloes before the start of treatment. The selected buffaloes were randomly divided into four groups (n=25). In Group I, buffaloes were administered 20 µg of buserelin intramuscularly. Buffaloes of Group II were administered long-acting insulin @ 0.25 IU/Kg body weight subcutaneously for 5 consecutive days. In Group III, buffaloes were treated with a combination of insulin and buserelin in the above-mentioned doses whereas buffaloes of Group IV were kept as untreated control. Results: The higher oestrus induction (64% vs. 28%) was found in Group III and differed significantly (p<0.05) as compared to control group. The conception rate (69.23% vs. 66.66%) was also found higher in Group III but did not differ significantly among the treated groups. The mean time taken for the onset of oestrus was recorded significantly shorter in insulin (8.80±0.69) and GnRH (7.60±0.92 days) alone and as compared to other (Group III, 14.43±0.83 and Group IV, 20.57±1.69 days) groups. Conclusion: The results of this study indicated better fertility response using Insulin plus Buserelin in true anoestrus buffaloes under field conditions. PMID:27065651

  19. EFFECT OF GnRH AND PHOSPHORUS IN DELAYED PUBERTAL SURTI BUFFALO HEIFERS

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    H.B. Dhamsaniya

    2016-06-01

    Full Text Available The study was conducted on eighteen delayed pubertal Surti buffalo heifers, divided into three equal groups (6 in each to evaluate the efficacy of GnRH alone and in combination of phosphorus. The buffalo heifers in Group-I and Group-II were treated with Buserelin acetate (5 ml, IM. Buffalo heifers in Group-II also received additional injection of Toldimphos sodium (10 ml, IM at 3 day interval for 4 times, while buffalo heifers in Group-III served as control. The percentage of induced estrus was highest (83.33% in each treated groups as compared to control group (50%. The mean estrus induction intervals were significantly (P<0.05 shorter in Group-I (20.20 ± 2.18 days and Group-II (18.80 ± 2.32 days as compared to control group (30.24 ± 0.81 days. The conception rate at induced estrus was highest in Group-II (50% followed by Group-I (33.33%. The plasma progesterone levels being significantly lowest on the day of estrus (less than 0.5 ng/ml as compared to pre-treatment days in all groups. The mean total protein and triglycerides levels were differed significantly between the groups on the day of estrus and being significantly higher in Group-II as compared to Group-I and III on that day. A significantly higher level of cholesterol in both treatment groups as compared to the control group during different intervals and also being higher on the day of estrus as compared to pre-treatment days. The mean plasma glucose levels were differed nonsignificantly between and within the treatment and control groups. It is concluded that estrus can be successfully induced in delayed pubertal heifers with the use of GnRH alone and in combination with phosphorus.

  20. Behavior of feral horses in response to culling and GnRH immunocontraception

    Science.gov (United States)

    Ransom, Jason I.; Powers, Jenny G.; Garbe, Heidi M.; Oehler, Michael W.; Nett, Terry M.; Baker, Dan L.

    2014-01-01

    Wildlife management actions can alter fundamental behaviors of individuals and groups,which may directly impact their life history parameters in unforeseen ways. This is especially true for highly social animals because changes in one individual’s behavior can cascade throughout its social network. When resources to support populations of social animals are limited and populations become locally overabundant, managers are faced with the daunting challenge of decreasing population size without disrupting core behavioral processes. Increasingly, managers are turning to fertility control technologies to supplement culling in efforts to suppress population growth, but little is quantitatively known about how either of these management tools affects behavior. Gonadotropin releasing hormone (GnRH) is a small neuropeptide that performs an obligatory role in mammalian reproduction and has been formulated into the immunocontraceptive GonaCon-BTM. We investigated the influences of this vaccine on behavior of feral horses (Equus caballus) at Theodore Roosevelt National Park, North Dakota, USA, for a year preceding and a year following nonlethal culling and GnRH-vaccine treatment. We observed horses during the breeding season and found only minimal differences in time budget behaviors of free-ranging female feral horses treated with GnRH and those treated with saline. The differences observed were consistent with the metabolic demands of pregnancy and lactation. We observed similar social behaviors between treatment groups, reflecting limited reproductive behavior among control females due to high rates of pregnancy and suppressed reproductive behavior among treated females due to GnRH-inhibited ovarian activity. In the treatment year, band stallion age was the only supported factor influencing herding behavior (P decreased 50.7% following treatment and culling (P decreasing energetically expensive competitive behaviors, but further investigation is needed to explicitly test

  1. A comparative therapeutic management of anoestrus in buffaloes using insulin and GnRH

    Directory of Open Access Journals (Sweden)

    R. D. Purkayastha

    2015-06-01

    Full Text Available Aim: Anoestrus is one of the most common functional disorders of the reproductive cycle in buffaloes. In spite of technical advancement, there is no single cure for the management of anoestrus. Therefore, the aim of this study was to find out the efficacy of gonadotropic releasing hormone (GnRH and metabolic hormone for the management of true anoestrus in buffaloes. Materials and Methods: The experimental animals were selected on the basis of history, gyneco-clinical examinations and progesterone estimation. Deworming was done with Fenbendazole and thereafter mineral mixture was given @ 50 g per animal per day for 10 days in all the selected buffaloes before the start of treatment. The selected buffaloes were randomly divided into four groups (n=25. In Group I, buffaloes were administered 20 μg of buserelin intramuscularly. Buffaloes of Group II were administered long-acting insulin @ 0.25 IU/Kg body weight subcutaneously for 5 consecutive days. In Group III, buffaloes were treated with a combination of insulin and buserelin in the above-mentioned doses whereas buffaloes of Group IV were kept as untreated control. Results: The higher oestrus induction (64% vs. 28% was found in Group III and differed significantly (p<0.05 as compared to control group. The conception rate (69.23% vs. 66.66% was also found higher in Group III but did not differ significantly among the treated groups. The mean time taken for the onset of oestrus was recorded significantly shorter in insulin (8.80±0.69 and GnRH (7.60±0.92 days alone and as compared to other (Group III, 14.43±0.83 and Group IV, 20.57±1.69 days groups. Conclusion: The results of this study indicated better fertility response using Insulin plus Buserelin in true anoestrus buffaloes under field conditions.

  2. The GnRH analogue triptorelin confers ovarian radio-protection to adult female rats

    Energy Technology Data Exchange (ETDEWEB)

    Camats, N. [Institut de Biotecnologia i de Biomedicina (I.B.B.), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Garcia, F. [Institut de Biotecnologia i de Biomedicina (I.B.B.), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Parrilla, J.J. [Servicio de Ginecologia y Obstetricia, Hospital Universitario Virgen de la Arrixaca, 30120 El Palmar, Murcia (Spain); Calaf, J. [Servei de Ginecologia i Obstetricia, Hospital Universitari de la Santa Creu i Sant Pau, 08025 Barcelona (Spain); Martin-Mateo, M. [Departament de Pediatria, d' Obstetricia i Ginecologia i de Medicina Preventiva, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Caldes, M. Garcia, E-mail: Montserrat.Garcia.Caldes@uab.es [Institut de Biotecnologia i de Biomedicina (I.B.B.), Universitat Autonoma de Barcelona, 08193 Barcelona (Spain); Departament de Biologia Cel.lular, Fisiologia i Immunologia, Universitat Autonoma de Barcelona, 08193 Barcelona (Spain)

    2009-10-02

    There is a controversy regarding the effects of the analogues of the gonadotrophin-releasing hormone (GnRH) in radiotherapy. This has led us to study the possible radio-protection of the ovarian function of a GnRH agonist analogue (GnRHa), triptorelin, in adult, female rats (Rattus norvegicus sp.). The effects of the X-irradiation on the oocytes of ovarian primordial follicles, with and without GnRHa treatment, were compared, directly in the female rats (F{sub 0}) with reproductive parameters, and in the somatic cells of the resulting foetuses (F{sub 1}) with cytogenetical parameters. In order to do this, the ovaries and uteri from 82 females were extracted for the reproductive analysis and 236 foetuses were obtained for cytogenetical analysis. The cytogenetical study was based on the data from 22,151 metaphases analysed. The cytogenetical parameters analysed to assess the existence of chromosomal instability were the number of aberrant metaphases (2234) and the number (2854) and type of structural chromosomal aberrations, including gaps and breaks. Concerning the reproductive analysis of the ovaries and the uteri, the parameters analysed were the number of corpora lutea, implantations, implantation losses and foetuses. Triptorelin confers radio-protection of the ovaries in front of chromosomal instability, which is different, with respect to the single and fractioned dose. The cytogenetical analysis shows a general decrease in most of the parameters of the triptorelin-treated groups, with respect to their controls, and some of these differences were considered to be statistically significant. The reproductive analysis indicates that there is also radio-protection by the agonist, although minor to the cytogenetical one. Only some of the analysed parameters show a statistically significant decrease in the triptorelin-treated groups.

  3. Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders.

    Science.gov (United States)

    Datta, Adrija Kumar; Eapen, Abey; Birch, Heidi; Kurinchi-Selvan, Anitha; Lockwood, Gillian

    2014-11-01

    All IVF-ICSI cycles carried out between October 2009 and October 2012 using GnRH agonist (GnRHa) ovulation trigger (n = 62) followed by a single dose of HCG plus progesterone and oestradiol in the luteal phase because of anticipated ovarian hypertsimulation were retrospectively compared with historic control cycles using HCG trigger (n = 29) and standard luteal phase support. Women's mean age, body mass index, anti-Müllerian hormone, FSH, LH, starting and total stimulation dose, number of follicles, oocytes, embryos, fertilization, implantation, polycystic ovary syndrome, ICSI, live birth and ongoing pregnancy rates per embryo transfer were similar (GnRHa 40.7% versus HCG 35.0%). For each started cycle, GnRHa resulted in 11.4% higher (statistically non-significant) live birth and ongoing pregnancy rate (OR 1.73, CI 0.64 to 4.69), with a similar difference for double-embryo transfers (OR 1.62, CI 0.44 to 6.38) and less need for freezing all embryos (9.7% versus 27.6%; P = 0.04). Incidence of mild-to-moderate OHSS was 16.2% with GnRHa trigger and 31.0% with HCG trigger) and no severe OHSS in the former. The addition of single low-dose HCG in the luteal phase after GnRHa trigger for suspected high-responders reduced the incidence of OHSS with good clinical outcomes, compared with HCG trigger. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  4. Impact of Mid-Luteal Phase GnRH Agonist Administration on Reproductive Outcomes in GnRH Agonist-Triggered Cycles: A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Abdelhamid Benmachiche

    2017-06-01

    Full Text Available ObjectiveTo explore whether the addition of a mid-luteal bolus of GnRH agonist (GnRHa improves the implantation rate (IR in in vitro fertilization (IVF cycles.DesignA randomized controlled trial.SettingPrivate IVF center.Patients328 IVF/intracytoplasmic sperm injection patients were triggered with GnRHa and received 1,500 IU HCG on the day of oocyte pick-up (OPU in addition to a standard luteal phase support (LPS.Intervention(sIn addition, the study group received a bolus of GnRHa 6 days after OPU, whereas the control group did not.Main outcome measureImplantation rate.Secondary outcome measure(sOngoing pregnancy (OP and live birth (LB rates.ResultsAlthough serum concentrations of FSH, LH, E2, and P on day OPU + 7 were significantly higher in the study group compared to the control group, the IR was not statistically different between the treatment group (27% and the control group (23% [odds ratio (OR 1.2 (95% CI 0.9–1.7, P < 0.27]. Similarly, the OP rate was 37% in the treatment group and 31% in the control group [OR 1.3 (95% CI 0.8–2.0, P < 0.23]. The LB rate was 36% in the treatment group and 31% in the control group [OR: 1.3 (95% CI 0.8–2.0, P < 0.27].ConclusionAlthough a trend toward a higher IR and pregnancy rate was observed in the treatment group, this difference was not statistically significant. However, the absolute risk difference of 5% found for LB is clinically relevant, warranting further investigation.NCT02053779.

  5. Rational design and identification of a non-peptidic aggregation inhibitor of amyloid-β based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-].

    Science.gov (United States)

    Arai, Tadamasa; Araya, Takushi; Sasaki, Daisuke; Taniguchi, Atsuhiko; Sato, Takeshi; Sohma, Youhei; Kanai, Motomu

    2014-07-28

    Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small-molecule aggregation inhibitors of Alzheimer's amyloid-β (Aβ) are extremely scarce, however, and are mainly restricted to dye- and polyphenol-type compounds that lack drug-likeness. Based on the structure-activity relationship of cyclic Aβ16-20 (cyclo-[KLVFF]), we identified unique pharmacophore motifs comprising side-chains of Leu(2), Val(3), Phe(4), and Phe(5) residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non-peptidic, small-molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non-peptidic, small-molecule aggregation inhibitors of amyloids based on rational molecular design.

  6. Dopamine-dependent behavioural stimulation by non-peptide delta opioids BW373U86 and SNC 80: 2. Place-preference and brain microdialysis studies in rats.

    Science.gov (United States)

    Longoni, R; Cadoni, C; Mulas, A; Di Chiara, G; Spina, L

    1998-02-01

    The motivational properties of the non-peptide delta-opioid receptor agonists BW373U86 and SNC 80 were investigated using the place-conditioning paradigm. BW373U86 (0.5-1.0 mg/kg s.c.) and SNC 80 (1.25-5.0 mg/kg s.c.) elicited significant preference for the drug-paired compartment, in a dose-related fashion. Naltrindole (5.0 mg/kg s.c.) pretreatment, while failing to modify preference when given alone, completely prevented place-preference induced by BW373U86 (1.0 mg/kg s.c.) and SNC 80 (1.25 mg/kg s.c.). The dopamine D1 receptor antagonist SCH23390, given at doses that do not affect place-preference (0.012 mg/kg s.c.), completely prevented the place-preference induced by BW373U86 and SNC 80. At the doses effective in eliciting place-preference, BW373U86 and SNC 80 failed to modify extracellular dopamine in the medial nucleus accumbens, while in the dorso-lateral caudate-putamen BW373U86 (1.0 and 2.5 mg/kg s.c.) reduced extracellular dopamine, and this effect was prevented by naltrindole (5.0 mg/kg s.c.). SNC 80, only at the dose of 5 mg/kg s.c., significantly reduced extracellular DA in the dorso-lateral caudate-putamen. The results indicate that stimulation of delta-opioid receptors has incentive properties that might be related to an indirect amplification of post-synaptic dopamine transmission.

  7. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Senderovitz, Thomas;

    2007-01-01

    Aims To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin...... and the GnRH receptor blocker degarelix. Methods Fifty-eight healthy subjects received single subcutaneous or intramuscular injections of 3.75 mg of triptorelin and 170 prostate cancer patients received multiple subcutaneous doses of degarelix of between 120 and 320 mg. All subjects were pooled...... for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system....

  8. Serum levels of antimüllerian hormone in early maturing girls before, during, and after suppression with GnRH agonist

    DEFF Research Database (Denmark)

    Hagen, Casper P; Sørensen, Kaspar; Anderson, Richard A

    2012-01-01

    To evaluate whether serum antimüllerian hormone (AMH) levels are affected in early maturing girls, and whether pituitary suppression by long-acting GnRH agonist (GnRH-a) affects AMH.......To evaluate whether serum antimüllerian hormone (AMH) levels are affected in early maturing girls, and whether pituitary suppression by long-acting GnRH agonist (GnRH-a) affects AMH....

  9. Progesterone treatment inhibits and dihydrotestosterone (DHT) treatment potentiates voltage-gated calcium currents in gonadotropin-releasing hormone (GnRH) neurons.

    Science.gov (United States)

    Sun, Jianli; Moenter, Suzanne M

    2010-11-01

    GnRH neurons are central regulators of fertility, and their activity is modulated by steroid feedback. In normal females, GnRH secretion is regulated by estradiol and progesterone (P). Excess androgens present in hyperandrogenemic fertility disorders may disrupt communication of negative feedback signals from P and/or independently stimulate GnRH release. Voltage-gated calcium channels (VGCCs) are important in regulating excitability and hormone release. Estradiol alters VGCCs in a time-of-day-dependent manner. To further elucidate ovarian steroid modulation of GnRH neuron VGCCs, we studied the effects of dihydrotestosterone (DHT) and P. Adult mice were ovariectomized (OVX) or OVX and treated with implants containing DHT (OVXD), estradiol (OVXE), estradiol and DHT (OVXED), estradiol and P (OVXEP), or estradiol, DHT, and P (OVXEDP). Macroscopic calcium current (I(Ca)) was recorded in the morning or afternoon 8-12 d after surgery using whole-cell voltage-clamp. I(Ca) was increased in afternoon vs. morning in GnRH neurons from OVXE mice but this increase was abolished in cells from OVXEP mice. I(Ca) in cells from OVXD mice was increased regardless of time of day; there was no additional effect in OVXED mice. P reduced N-type and DHT potentiated N- and R-type VGCCs; P blocked the DHT potentiation of N-type-mediated current. These data suggest P and DHT have opposing actions on VGCCs in GnRH neurons, but in the presence of both steroids, P dominates. VGCCs are targets of ovarian steroid feedback modulation of GnRH neuron activity and, more specifically, a potential mechanism whereby androgens could activate GnRH neuronal function.

  10. Impact of GnRH analogues on oocyte/embryo quality and embryo development in in vitro fertilization/intracytoplasmic sperm injection cycles: a case control study

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    Rigó János

    2009-09-01

    Full Text Available Abstract Background Despite the clinical outcomes of ovarian stimulation with either GnRH-agonist or GnRH-antagonist analogues for in vitro fertilization (IVF being well analysed, the effect of analogues on oocyte/embryo quality and embryo development is still not known in detail. The aim of this case-control study was to compare the efficacy of a multiple-dose GnRH antagonist protocol with that of the GnRH agonist long protocol with a view to oocyte and embryo quality, embryo development and IVF treatment outcome. Methods Between October 2001 and December 2008, 100 patients were stimulated with human menopausal gonadotrophin (HMG and GnRH antagonist in their first treatment cycle for IVF or intracytoplasmic sperm injection (ICSI. One hundred combined GnRH agonist + HMG (long protocol cycles were matched to the GnRH antagonist + HMG cycles by age, BMI, baseline FSH levels and by cause of infertility. We determined the number and quality of retrieved oocytes, the rate of early-cleavage embryos, the morphology and development of embryos, as well as clinical pregnancy rates. Statistical analysis was performed using Wilcoxon's matched pairs rank sum test and McNemar's chi-square test. P Results The rate of cytoplasmic abnormalities in retrieved oocytes was significantly higher with the use of GnRH antagonist than in GnRH agonist cycles (62.1% vs. 49.9%; P Conclusion Antagonist seemed to influence favourably some parameters of early embryo development dynamics, while other morphological parameters seemed not to be altered according to GnRH analogue used for ovarian stimulation in IVF cycles.

  11. Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3

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    Lund Eiliv

    2009-07-01

    Full Text Available Abstract Background Gonadotropin releasing hormone (GNRH1 triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3. Methods We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs were genotyped and used to identify haplotype-tagging SNPs (htSNPS in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II, European Prospective Investigation on Cancer and Nutrition (EPIC, Multiethnic Cohort (MEC, Nurses' Health Study (NHS, and Women's Health Study (WHS. Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone were also measured in 4713 study subjects. Results Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. Conclusion Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.

  12. 17β-Estradiol Rapidly Increases KATP Activity in GnRH via a Protein Kinase Signaling Pathway

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    Zhang, Chunguang; Kelly, Martin J.; Rønnekleiv, Oline K.

    2010-01-01

    17β-Estradiol (E2) both inhibits and excites GnRH neurons via presynaptic as well as postsynaptic mechanisms. Although it has been demonstrated that E2 can alter the excitability of GnRH neurons via direct actions, the intracellular signaling cascades mediating these actions are not well understood. Previously we have shown that the activity of one of the critical ion channels needed for maintaining GnRH neurons in a hyperpolarized state, the ATP-sensitive potassium channel (KATP) channel, is augmented by E2 in ovariectomized females. However, the mRNA expression of the KATP channel subunits Kir6.2 and SUR1 are unchanged with in vivo E2 treatment. Therefore, to elucidate the cellular signaling mechanism(s) modulating the channel activity, we did whole-cell patch-clamp recording of enhanced green fluorescent protein-GnRH neurons from ovariectomized female mice to study the acute effects of E2. E2 dose-dependently (EC50 = 0.6 nM) enhanced the diazoxide (channel opener)-activated KATP channel currents by 1.2- to 2.0-fold, which was antagonized by ICI 182,780. E2-BSA was equally as effective as E2, whereas E2 had no effect. The protein kinase A (PKA) activator forskolin mimicked the effects of E2, whereas the PKA inhibitor H89 and the protein kinase C (PKC) inhibitor bisindolylmaleimide I blocked the effects of E2. Similar to E2, STX, a membrane estrogen receptor (ER) agonist that does not bind to ERα or ERβ, also potentiated the diazoxide-induced KATP channel current by 1.5-fold. Therefore, E2 can potentiate KATP channel activity in GnRH neurons through a membrane ER-activated PKC-PKA signaling pathway. PMID:20660067

  13. Histidine residues in the peptide D-Lys(6)-GnRH: potential for copolymerization in polymeric nanoparticles.

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    Kafka, Alexandra P; Kleffmann, Torsten; Rades, Thomas; McDowell, Arlene

    2009-01-01

    Poly(ethylcyanoacrylate) (PECA) nanoparticles containing the bioactive d-Lys(6)-GnRH were manufactured by an in situ interfacial polymerization process using a w/o-microemulsion template containing the peptide in the dispersed aqueous pseudophase of the microemulsion. Polymeric nanoparticles were characterized using PCS, RP-HPLC (bulk level) and MALDI TOF mass spectrometry (molecular level). The peptide d-Lys(6)-GnRH was reactive with the alkylcyanoacrylate monomer, resulting in some of the peptide copolymerizing with the monomer. MALDI TOF/TOF (tandem) analysis revealed that the histidine residue in position 2 of d-Lys(6)-GnRH interacts covalently in the polymerization process. A reaction mechanism for this nucleophilic interference is suggested. The copolymerization reaction appeared to occur within seconds after the addition of the monomer to the microemulsion. The surface charge of resulting nanoparticles was less negative (-3 mV) compared with the zeta potential of empty nanoparticles (-27.5 mV). The copolymerization yielded high entrapment rates of 95 +/- 4% of peptide, but showed limited release ( approximately 11%) of free peptide over 5 days. A separate experiment demonstrated that the addition of d-Lys(6)-GnRH to preformed empty PECA nanoparticles (ex situ) also yielded fractions of copolymerized peptide suggesting a certain proportion of polymer remains available for copolymerization possibly through an unzipping depolymerization/repolymerization process. Therefore, the reactivity of histidine residues in bioactives needs to be considered whenever using the bioactive in situ or ex situ with polymeric PECA nanoparticles.

  14. Vaccination against GnRH may suppress aggressive behaviour and musth in African elephant (Loxodonta africana bulls - a pilot study

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    H. M. De Nys

    2010-05-01

    Full Text Available Aggressive behaviour and musth are constant problems in captive and sometimes in free-ranging African elephant bulls. Aggressive bulls are difficult and musth bulls almost impossible to manage without severely restricting their movement either by leg-chaining or using tranquillisers. This study investigated the relationship between faecal androgen metabolites (FAM and faecal cortisol metabolites (FCM concentrations and aggressive behaviour and tested a GnRH vaccine as a means of down-regulating aggressive behaviour and musth in 1 free-ranging and 5 captive elephant bulls. The bulls were non-aggressive (n = 3, aggressive (n = 2 or in musth (n = 1 at the onset of the study. The bulls were injected with a GnRH vaccine-adjuvant combination 3 or 4 times at 3- to 7-week intervals. Behaviour, FAM and FCM concentrations were measured during every week prior to vaccination until 4 months after the last vaccination. FAM concentrations were positively correlated with aggressive behaviour before the 1st vaccination. Androgen production, as reflected by FAM concentrations, was down-regulated in 3 of the 6 immunised bulls. At least 2 bulls and possibly a 3rd showed behavioural improvement following GnRH vaccination and in all 3 temporal gland secretion ceased. No further aggressive behaviour was observed until the end of the study in any of the bulls. The results of this 1st GnRH immunisation study suggest that it could be a useful method to control aggressive behaviour and musth in African elephant bulls.

  15. Circadian Control of the Estrogenic Circuits Regulating GnRH Secretion and the Preovulatory Luteinizing Hormone Surge

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    Lance J Kriegsfeld

    2012-05-01

    Full Text Available Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG axis functioning. In mammals, the master circadian pacemaker in the suprachaismatic nucleus (SCN of the anterior hypothalamus coordinates reproductively-relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the GnRH system in control of the preovulatory LH surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.

  16. A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH

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    Reed Michael C

    2004-09-01

    Full Text Available Abstract In a previous study, a model was developed to investigate the release of luteinizing hormone (LH from pituitary cells in response to a short pulse of gonadotropin-releasing hormone (GnRH. The model included: binding of GnRH to its receptor (R, dimerization and internalization of the hormone receptor complex, interaction with a G protein, production of inositol 1,4,5-trisphosphate (IP3, release of calcium from the endoplasmic reticulum (ER, entrance of calcium into the cytosol via voltage gated membrane channels, pumping of calcium out of the cytosol via membrane and ER pumps, and release of LH. The extended model, presented in this paper, also includes the following physiologically important phenomena: desensitization of calcium channels; internalization of the dimerized receptors and recycling of some of the internalized receptors; an increase in Gq concentration near the plasma membrane in response to receptor dimerization; and basal rates of synthesis and degradation of the receptors. With suitable choices of the parameters, good agreement with a variety of experimental data of the LH release pattern in response to pulses of various durations, repetition rates, and concentrations of GnRH were obtained. The mathematical model allows us to assess the effects of internalization and desensitization on the shapes and time courses of LH response curves.

  17. Leptin facilitates lordosis behavior through GnRH-1 and progestin receptors in estrogen-primed rats.

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    García-Juárez, Marcos; Beyer, Carlos; Soto-Sánchez, Alfonso; Domínguez-Ordoñez, Raymundo; Gómora-Arrati, Porfirio; Lima-Hernández, Francisco Javier; Eguibar, José R; Etgen, Anne M; González-Flores, Oscar

    2011-02-01

    Dose response curves for leptin facilitation of estrous behavior (lordosis and proceptivity) were made by infusing the peptide into the lateral ventricle (icv) of ovariectomized (ovx), ad libitum-fed rats injected 40h previously with 5μg of estradiol benzoate. Leptin doses of 1 and 3μg produced significant lordosis quotient at 60min post-injection, with maximal lordosis being displayed at 120min. Yet the intensity of lordosis was weak, and a high incidence of rejection behaviors was found. Moreover, leptin did not induce significant proceptive behaviors at any dose. The leptin doses of 1 and 3μg were selected for determining whether antide, a GnRH-1 receptor antagonist, or the progestin receptor antagonist RU486 could modify the lordosis response to leptin. Icv injection of either antide or RU486 1h before leptin significantly depressed leptin facilitation of lordosis. The results suggest that leptin stimulates lordosis by releasing GnRH, which in turn activates GnRH-1 and progestin receptors. The physiological role of leptin in the control of estrous behavior remains to be determined. Copyright © 2010 Elsevier Ltd. All rights reserved.

  18. Improvement of chloride transport defect by gonadotropin-releasing hormone (GnRH in cystic fibrosis epithelial cells.

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    Nathalie Benz

    Full Text Available Cystic fibrosis (CF, the most common autosomal recessive disease in Caucasians, is due to mutations in the CFTR gene. F508del, the most frequent mutation in patients, impairs CFTR protein folding and biosynthesis. The F508del-CFTR protein is retained in the endoplasmic reticulum (ER and its traffic to the plasma membrane is altered. Nevertheless, if it reaches the cell surface, it exhibits a Cl(- channel function despite a short half-life. Pharmacological treatments may target the F508del-CFTR defect directly by binding to the mutant protein or indirectly by altering cellular proteostasis, and promote its plasma membrane targeting and stability. We previously showed that annexine A5 (AnxA5 directly binds to F508del-CFTR and, when overexpressed, promotes its membrane stability, leading to the restoration of some Cl(- channel function in cells. Because Gonadotropin-Releasing Hormone (GnRH increases AnxA5 expression in some cells, we tested it in CF cells. We showed that human epithelial cells express GnRH-receptors (GnRH-R and that GnRH induces an AnxA5 overexpression and an increased Cl(- channel function in F508del-CFTR cells, due to an increased stability of the protein in the membranes. Beside the numerous physiological implications of the GnRH-R expression in epithelial cells, we propose that a topical use of GnRH is a potential treatment in CF.

  19. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons

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    Qiu, Jian; Nestor, Casey C; Zhang, Chunguang; Padilla, Stephanie L; Palmiter, Richard D

    2016-01-01

    Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1ARH) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1ARH neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1ARH neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1ARH neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1ARH neurons. We propose that Kiss1ARH neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function. DOI: http://dx.doi.org/10.7554/eLife.16246.001 PMID:27549338

  20. Molecular modeling of interactions of the non-peptide antagonist YM087 with the human vasopressin V1a, V2 receptors and with oxytocin receptors.

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    Giełdoń, Artur; Kaźmierkiewicz, Rajmund; Ślusarz, Rafał; Ciarkowski, Jerzy

    2001-12-01

    The nonapeptide hormones arginine vasopressin (CYFQNCPRG-NH2, AVP) and oxytocin (CYIQNCPLG-NH2, OT), control many essential functions in mammals. Their main activities include the urine concentration (via stimulation of AVP V2 receptors, V2R, in the kidneys), blood pressure regulation (via stimulation of vascular V1a AVP receptors, V1aR), ACTH control (via stimulation of V1b receptors, V1bR, in the pituitary) and labor and lactation control (via stimulation of OT receptors, OTR, in the uterus and nipples, respectively). All four receptor subtypes belong to the GTP-binding (G) protein-coupled receptor (GPCR) family. This work consists of docking of YM087, a potent non-peptide V1aR and V2R - but not OTR - antagonist, into the receptor models based on relatively new theoretical templates of rhodopsin (RD) and opiate receptors, proposed by Mosberg et al. (Univ. of Michigan, Ann Arbor, USA). It is simultaneously demonstrated that this RD template satisfactorily compares with the first historical GPCR structure of bovine rhodopsin (Palczewski et al., 2000) and that homology-modeling of V2R, V1aR and OTR using opiate receptors as templates is rational, based on relatively high (20-60%) sequence homology among the set of 4 neurophyseal and 4 opiate receptors. YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA). From about 80 diverse configurations, sampled for each of the three ligand/receptor systems, 3 best energy-relaxed complexes were selected for mutual comparisons. Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data.

  1. Maternal undernutrition alters triiodothyronine concentrations and pituitary response to GnRH in fetal sheep.

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    Rae, M T; Rhind, S M; Kyle, C E; Miller, D W; Brooks, A N

    2002-06-01

    The aims of this study were to determine which hormones may have a role in the expression of maternal undernutrition effects on reproductive function, in both the developing fetus and the adult offspring. This was undertaken by measuring the effects of long-term maternal undernutrition on metabolic hormone profiles and pituitary responses to single doses of GnRH and GH-releasing factor (GRF) in fetal sheep. From mating, groups of ewes were fed rations providing either 100% (HIGH) or 50% (LOW) of estimated metabolisable energy requirements for pregnancy throughout the experiment until slaughter at approximately 119 days of gestation. Fetal and maternal blood samples were collected from 113 until 119 days of gestation, via carotid and jugular catheters respectively, and assayed for insulin, IGF-I, GH, thyroxine and triiodothyronine (T(3)). Undernutrition had no effects on fetal weight, fetal gonad weight of either sex, fetal insulin or IGF-I concentrations. Male LOW fetuses exhibited a significantly attenuated response (Psheep, fetal gonadal abnormalities and reductions in reproductive capacity in adult life which are associated with fetal undernutrition are unlikely to be attributable to altered pituitary function. Additionally, these studies raise the possibility that thyroid hormones may have a role in the expression of maternal undernutrition effects on fetal development.

  2. In Vitro Characterization of Six Month Dosage Forms for a GnRH Antagonist

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    Susan D’Souza

    2014-01-01

    Full Text Available The objective of this study was to develop long-acting injectable dosage forms of Orntide, a peptide GnRH antagonist, to provide tailored release for 6-month duration. Using a polylactide homopolymer and the solvent extraction/evaporation method, three microsphere formulations (Formulations A, B, and C were prepared at various drug loadings (11.85–15.79%. The microspheres were characterized for particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM, and bulk density by tapping, as well as long-term in vitro drug release, mass loss and hydration at 37°C, and short-term in vitro drug release at elevated temperatures (51–59°C. Experiments at 37°C revealed that drug release was triphasic and occurred due to slow degradation of the polylactide polymer. Short-term in vitro release results indicated that drug release was diffusional. Application of the Higuchi equation to short-term release confirmed the temperature dependency of the diffusional rate constant. Using the rate constant and the Arrhenius equation, an Ea value of 45 kcal/mol (Formulation A and approximately 25 kcal/mol (Formulations B and C was obtained for diffusional release. Study results suggest that by selection of an appropriate biodegradable polymer, injectable dosing forms that release drug for 6 months or longer can be developed.

  3. FXYD1, a modulator of Na+,K+-ATPase activity, facilitates female sexual development by maintaining GnRH neuronal excitability

    Science.gov (United States)

    Garcia-Rudaz, Cecilia; Deng, Vivianne; Matagne, Valerie; Ronnekleiv, Oline; Bosch, Martha; Han, Victor; Percy, Alan K.; Ojeda, Sergio R.

    2009-01-01

    The excitatory tone to GnRH neurones is a critical component underlying the pubertal increase in GnRH secretion. However, the homeostatic mechanisms modulating the response of GnRH neurones to excitatory inputs remain poorly understood. A basic mechanism of neuronal homeostasis is the Na+, K+-ATPase-dependent restoration of Na+ and K+ transmembrane gradients after neuronal excitation. This activity is reduced in a mouse model of Rett syndrome (RTT), a neurodevelopmental disorder in which expression of FXYD1, a modulator of Na+, K+-ATPase activity, is increased. We now report that the initiation, but not the completion of puberty, is advanced in girls with RTT, and that in rodents FXYD1 may contribute to the neuroendocrine regulation of female puberty by modulating GnRH neuronal excitability. Fxyd1 mRNA abundance reaches maximal levels in the female rat hypothalamus by the fourth postnatal week of life, i.e., around the time when the mode of GnRH secretion acquires an adult pattern of release. Although Fxyd1 mRNA expression is low in the hypothalamus, about 50% of GnRH neurones contain Fxyd1 transcripts. Whole-cell patch recording of GnRH-EGFP neurones revealed that the neurones of Fxyd1-null female mice respond to somatic current injections with a lower number of action potentials than wild-type cells. Both the age at vaginal opening and at first oestrous were delayed in Fxyd1-/- mice, but adult reproductive capacity was normal. These results suggest that FXYD1 contributes to facilitating the advent of puberty by maintaining GnRH neuronal excitability to incoming transsynaptic stimulatory inputs. PMID:19187398

  4. Conditional Viral Tract Tracing Delineates the Projections of the Distinct Kisspeptin Neuron Populations to Gonadotropin-Releasing Hormone (GnRH) Neurons in the Mouse.

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    Yip, Siew Hoong; Boehm, Ulrich; Herbison, Allan E; Campbell, Rebecca E

    2015-07-01

    Kisspeptin neurons play an essential role in the regulation of fertility through direct regulation of the GnRH neurons. However, the relative contributions of the two functionally distinct kisspeptin neuron subpopulations to this critical regulation are not fully understood. Here we analyzed the specific projection patterns of kisspeptin neurons originating from either the rostral periventricular nucleus of the third ventricle (RP3V) or the arcuate nucleus (ARN) using a cell-specific, viral-mediated tract-tracing approach. We stereotaxically injected a Cre-dependent recombinant adenovirus encoding farnesylated enhanced green fluorescent protein into the ARN or RP3V of adult male and female mice expressing Cre recombinase in kisspeptin neurons. Fibers from ARN kisspeptin neurons projected widely; however, we did not find any evidence for direct contact with GnRH neuron somata or proximal dendrites in either sex. In contrast, we identified RP3V kisspeptin fibers in close contact with GnRH neuron somata and dendrites in both sexes. Fibers originating from both the RP3V and ARN were observed in close contact with distal GnRH neuron processes in the ARN and in the lateral and internal aspects of the median eminence. Furthermore, GnRH nerve terminals were found in close contact with the proximal dendrites of ARN kisspeptin neurons in the ARN, and ARN kisspeptin fibers were found contacting RP3V kisspeptin neurons in both sexes. Together these data delineate selective zones of kisspeptin neuron inputs to GnRH neurons and demonstrate complex interconnections between the distinct kisspeptin populations and GnRH neurons.

  5. Intraovarian expression of GnRH-1 and gonadotropin mRNA and protein levels in Siberian hamsters during the estrus cycle and photoperiod induced regression/recrudescence.

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    Shahed, Asha; Young, Kelly A

    2011-01-15

    The hypothalamic-pituitary-gonadal (HPG) axis is the key reproductive regulator in vertebrates. While gonadotropin releasing hormone (GnRH), follicle stimulating (FSH), and luteinizing (LH) hormones are primarily produced in the hypothalamus and pituitary, they can be synthesized in the gonads, suggesting an intraovarian GnRH-gonadotropin axis. Because these hormones are critical for follicle maturation and steroidogenesis, we hypothesized that this intraovarian axis may be important in photoperiod-induced ovarian regression/recrudescence in seasonal breeders. Thus, we investigated GnRH-1 and gonadotropin mRNA and protein expression in Siberian hamster ovaries during (1) the estrous cycle; where ovaries from cycling long day hamsters (LD;16L:8D) were collected at proestrus, estrus, diestrus I, and diestrus II and (2) during photoperiod induced regression/recrudescence; where ovaries were collected from hamsters exposed to 14 weeks of LD, short days (SD;8L:16D), or 8 weeks post-transfer to LD after 14 weeks SD (PT). GnRH-1, LHβ, FSHβ, and common α subunit mRNA expression was observed in cycling ovaries. GnRH-1 expression peaked at diestrus I compared to other stages (p 0.05). SD exposure decreased ovarian mass and plasma estradiol concentrations (p<0.05) and increased GnRH-1, LHβ, FSHβ, and α subunit mRNA expression as compared to LD and, except for LH, compared to PT (p < 0.05). GnRH and gonadotropin protein was also dynamically expressed across the estrous cycle and photoperiod exposure. The presence of cycling intraovarian GnRH-1 and gonadotropin mRNA suggests that these hormones may be locally involved in ovarian maintenance during SD regression and/or could potentially serve to prime ovaries for rapid recrudescence.

  6. Effect of short-term and prolonged stress on the biosynthesis of gonadotropin-releasing hormone (GnRH) and GnRH receptor (GnRHR) in the hypothalamus and GnRHR in the pituitary of ewes during various physiological states.

    Science.gov (United States)

    Ciechanowska, M; Łapot, M; Antkowiak, B; Mateusiak, K; Paruszewska, E; Malewski, T; Paluch, M; Przekop, F

    2016-11-01

    Using an ELISA assay, the levels of GnRH and GnRHR were analysed in the preoptic area (POA), anterior (AH) and ventromedial hypothalamus (VM), stalk/median eminence (SME); and GnRHR in the anterior pituitary gland (AP) of non-breeding and breeding sheep subjected to short-term or prolonged stress. The ELISA study was supplemented with an analysis of plasma LH concentration. Short-term footshock stimulation significantly increased GnRH levels in hypothalamus in both seasons. Prolonged stress elevated or decreased GnRH concentrations in the POA and the VM, respectively during anoestrus, and lowered GnRH amount in the POA-hypothalamus of follicular-phase sheep. An up-regulation of GnRHR levels was noted in both, anoestrous and follicular-phase animals. In the non-breeding period, a prolonged stress procedure increased GnRHR biosynthesis in the VM and decreased it in the SME and AP, while in the breeding time the quantities of GnRHR were significantly lower in the whole hypothalamus. In follicular-phase ewes the fluctuations of GnRH and GnRHR levels under short-term and prolonged stress were reflected in the changes of LH secretion, suggesting the existence of a direct relationship between GnRH and GnRH-R biosynthesis and GnRH/LH release in this period. The study showed that stress was capable of modulating the biosynthesis of GnRH and GnRHR; the pattern of changes was dependent upon the animal's physiological state and on the time course of stressor application. The obtained results indicate that the disturbances of gonadotropin secretion under stress conditions in sheep may be due to a dysfunction of GnRH and GnRHR biosynthetic pathways. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Magnetic resonance guided focused ultrasound surgery of uterine fibroids-The tissue effects of GnRH agonist pre-treatment

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    Smart, O.C. [Department of Academic Obstetrics and Gynaecology, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Department of Magnetic Resonance Imaging, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Hindley, J.T. [Department of Academic Obstetrics and Gynaecology, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Regan, L. [Department of Academic Obstetrics and Gynaecology, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom); Gedroyc, W.M.W. [Department of Magnetic Resonance Imaging, St. Mary' s Hospital and Imperial College School of Medicine, Praed Street, London W2 1NY (United Kingdom)]. E-mail: w.gedroyc@imperial.ac.uk

    2006-08-15

    Objective: The purpose of this study was to determine the ablative effect of magnetic resonance guided focused ultrasound (MRgFUS) on fibroid tissue following the administration of gonadotrophin releasing hormone (GnRH) agonist. Study design: Fifty women with clinically symptomatic uterine fibroids were treated. Those with uterine diameter of 10 cm or greater were given 3 months pre-treatment with GnRH agonists. Data regarding number of ultrasound sonications, Joules of energy delivered and volume of thermal destruction was recorded. Results: Twenty-seven subjects were given GnRH agonist therapy before MRgFUS and 23 women underwent MRgFUS without pre-treatment. All patients in both study groups completed MR guided FUS as an outpatient procedure with no device related adverse events reported. In the group of women who received GnRH agonists, the volume of ablation was significantly larger than that in the control group (0.06 cm{sup 3} versus 0.03 cm{sup 3}, P < 0.05), per Joule of energy applied. Conclusion: The use of GnRH agonists potentiates the thermal effects of MRgFUS in women undergoing treatment of uterine fibroids.

  8. mRNA Expression of Ion Channels in GnRH Neurons: Subtype-Specific Regulation by 17β-Estradiol

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    Bosch, Martha A.; Tonsfeldt, Karen J.; Rønnekleiv, Oline K.

    2013-01-01

    Burst firing of neurons optimizes neurotransmitter release. GnRH neurons exhibit burst firing activity and T-type calcium channels, which are vital for burst firing activity, are regulated by 17β-estradiol (E2) in GnRH neurons. To further elucidate ion channel expression and E2 regulation during positive and negative feedback on GnRH neurosecretion, we used single cell RT-PCR and real-time qPCR to quantify channel mRNA expression in GnRH neurons. GFP-GnRH neurons expressed numerous ion channels important for burst firing activity. E2-treatment sufficient to induce an LH surge increased mRNA expression of HCN1 channels, which underlie the pacemaker current, the calcium-permeable CaV1.3, CaV2.2, CaV2.3 channels, and TRPC4 channels, which mediate the kisspeptin excitatory response. E2 also decreased mRNA expression of SK3 channels underlying the medium AHP current. Therefore, E2 exerts fundamental changes in ion channel expression in GnRH neurons, to prime them to respond to incoming stimuli with increased excitability at the time of the surge. PMID:23305677

  9. Impact of gonadotropin type on progesterone elevation during ovarian stimulation in GnRH antagonist cycles.

    Science.gov (United States)

    Lawrenz, B; Beligotti, F; Engelmann, N; Gates, D; Fatemi, H M

    2016-11-01

    Does hormonal stimulation with corifollitropin alpha (CFA) only, mimicking a step down protocol, result in lower incidence of progesterone elevation on the day of hCGtrigger as compared to sustained stimulation with recombinant FSH (rFSH)? The current findings support the concept that sustained FSH stimulus contributes to premature progesterone elevation in stimulated IVF cycles. Serum progesterone rise during the follicular phase of ovarian stimulation for IVF treatment seems to be related to a poorer reproductive outcome. However, the mechanism by which the rise in progesterone is caused is not yet fully understood. This study was a post hoc analysis of data from two multi-center, randomized, double-blind, double-dummy, active-controlled, non-inferiority trials, ENGAGE and PURSUE, conducted from June 2006 to January 2008 and from July 2010 to October 2012 respectively. In the ENGAGE-study, 1506 women, aged 18-36 years, were allocated to either a single injection of 150 mg CFA or daily injections of 200 IU rFSH in the first week of stimulation, using a standard GnRH antagonist protocol. In the PURSUE-study, a total of 1390 women, aged 35-42 years, were allocated to either a single injection of 150 mg of CFA or daily 300 IU of rFSH for the first week, again using a standard GnRH antagonist protocol. In both trials, daily rFSH was continued until three follicles reached >17 mm in size. All women had a body weight of between 50 and 90 kg, regular menstrual cycles and an indication for ovarian stimulation before IVF. The incidence of progesterone elevation on day of hCG-trigger in patients with CFA only or rFSH stimulation, and triggered on Day 8 of stimulation, was analyzed. Of patients with CFA only stimulation, 5.4% (13/239 patients) showed a progesterone elevation above 1.5 ng/ml on day of hCG-trigger, whereas patients with rFSH stimulation had a significant higher incidence of progesterone elevation (18.3%; 62/339 patients) (P towards the end of the follicular

  10. Predicting the effect of gonadotropin-releasing hormone (GnRH) analogue treatment on uterine leiomyomas based on MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Matsuno, Y.; Yamashita, Y.; Takahashi, M. [Dept. of Radiology, Kumamoto Univ. School of Medicine, Kumamoto (Japan); Katabuchi, H.; Okamura, H. [Dept. of Gynecology and Obstetrics, Kumamoto Univ. School of Medicine, Kumamoto (Japan); Kitano, Y.; Shimamura, T. [Dept. of Gynecology and Obstetrics, Amakusa Chuou General Hospital, Hondo (Japan)

    1999-11-01

    Purpose: To test the hypothesis that the simple assessment of signal intensity on T2-weighted MR images is predictive of the effect of hormonal treatment with gonadotropin-releasing hormone (GnRH) analogue. Material and methods: The correlation between T2-weighted MR imaging of uterine leiomyomas and histologic findings was evaluated using 85 leiomyomas from 62 females who underwent myomectomy or hysterectomy. We also correlated the pretreatment MR images features obtained in 110 women with 143 leiomyomas with the effect of GnRH analogue treatment. The size (length x width x depth) of the leiomyoma was evaluated before and at 6 months after treatment by ultrasound. Results: The proportion of leiomyoma cell fascicles and that of extracellular matrix affected signal intensities of uterine leiomyomas on T2-weighted MR images. The amount of extracellular matrix was predominant in hypointense leiomyomas on T2-weighted images, while diffuse intermediate signal leiomyomas were predominantly composed of leiomyoma cell fascicles. Marked degenerative changes were noted in leiomyomas with heterogenous hyperintensity. The homogeneously intermediate signal intensity leiomyomas showed significant size reduction after treatment (size ratio; posttreatment volume/pretreatment volume 0.29{+-}0.11). The size ratio for the hypointense tumors was 0.82{+-}0.14, and 0.82{+-}0.18 for the heterogeneously hyperintense tumors. There was a significant difference in the response to treatment between the homogeneously intermediate signal intensity leiomyomas and the hypointense or heterogeneously hyperintense leiomyomas (both p<0.01). Conclusion: Signal intensity on T2-weighted MR images depends on the amount of leiomyoma cell fascicles and extracellular matrix. Simple assessment of the MR signal intensity is useful in predicting the effect of GnRH analogue on uterine leiomyomas. (orig.)

  11. Lactobacillus rhamnosus accelerates zebrafish backbone calcification and gonadal differentiation through effects on the GnRH and IGF systems.

    Directory of Open Access Journals (Sweden)

    Matteo A Avella

    Full Text Available Endogenous microbiota play essential roles in the host's immune system, physiology, reproduction and nutrient metabolism. We hypothesized that a continuous administration of an exogenous probiotic might also influence the host's development. Thus, we treated zebrafish from birth to sexual maturation (2-months treatment with Lactobacillus rhamnosus, a probiotic species intended for human use. We monitored for the presence of L. rhamnosus during the entire treatment. Zebrafish at 6 days post fertilization (dpf exhibited elevated gene expression levels for Insulin-like growth factors -I and -II, Peroxisome proliferator activated receptors -α and -β, VDR-α and RAR-γ when compared to untreated-10 days old zebrafish. Using a gonadotropin-releasing hormone 3 GFP transgenic zebrafish (GnRH3-GFP, higher GnRH3 expression was found at 6, 8 and 10 dpf upon L. rhamnosus treatment. The same larvae exhibited earlier backbone calcification and gonad maturation. Noteworthy in the gonad development was the presence of first testes differentiation at 3 weeks post fertilization in the treated zebrafish population -which normally occurs at 8 weeks- and a dramatic sex ratio modulation (93% females, 7% males in control vs. 55% females, 45% males in the treated group. We infer that administration of L. rhamnosus stimulated the IGF system, leading to a faster backbone calcification. Moreover we hypothesize a role for administration of L. rhamnosus on GnRH3 modulation during early larval development, which in turn affects gonadal development and sex differentiation. These findings suggest a significant role of the microbiota composition on the host organism development profile and open new perspectives in the study of probiotics usage and application.

  12. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Senderovitz, Thomas

    2007-01-01

    for the population PK/PD data analysis. A systematic population PK/PD model-building framework using stochastic differential equations was applied to the data to identify nonlinear dynamic dependencies and to deconvolve the functional feedback interactions of the HPG axis. Results In our final PK/PD model of the HPG......Aims To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin...... for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system....

  13. Efectos reproductivos, endocrinologicos e histologicos del antagonista de GnRH acyline en caninos y felinos machos

    OpenAIRE

    García Romero, Guadalupe

    2012-01-01

    Con el objetivo de contribuir al desarrollo del control farmacológico de la reproducción en caninos y felinos machos, el presente Trabajo de Tesis consistió en describir los efectos endocrinos e histológicos reproductivos de un antagonista de tercera generación del factor liberador de gonadotrofinas (GnRH), acyline, en estas especies. En el primer capítulo, con un diseño aleatorizado y con grupo control, se utilizaron un total de 13 perr...

  14. Synchronisation of the follicular wave with GnRH and PGF2α analogue for a timed breeding programme in dromedary camels (Camelus dromedarius).

    Science.gov (United States)

    Manjunatha, B M; Al-Bulushi, Samir; Pratap, N

    2015-09-01

    This study was conducted to develop a hormone protocol that precisely synchronises follicular development for a timed breeding (TB) programme in dromedary camels. To examine the effect of GnRH treatment at four known stages of follicular development, animals were treated with GnRH when the largest follicle of the wave was 4-7, 8-11, 12-17 and 18-27 mm in diameter. Transrectal ultrasonography was carried out daily up to 20 days after treatment. A hormone protocol (FWsynch) for the synchronisation of follicular wave and TB consisting of GnRH-1 (GnRH) on Day 0, PG-1 (PGF2α) on Day 7, GnRH-2 on Day 10 and PG-2 on Day 17 was initiated at four known stages of follicular development. Ovarian structures were monitored by ultrasonography. The FWsynch protocol was initiated at random stages of follicle development and animals were bred by natural mating at a fixed time at the research facility and in field. The pregnancy was diagnosed by ultrasonography. GnRH treatment in animals with a dominant follicle (DF) of ≥ 11 mm in diameter resulted in synchronous new follicular wave emergence, whereas in animals with a DF ≤ 10 mm, the treatment did not alter the development of the existing follicular wave. The FWsynch protocol was effective in synchronising the follicular wave for TB irrespective of the stage of follicular development at the beginning of the protocol. TB using FWsynch protocol resulted in a pregnancy rate of 60.2% in a research facility and 53.6% and 45.6% in normal and infertile camels respectively under field conditions.

  15. Schistocephalus solidus infections increase gonadotropins and gonadotropin releasing hormone (GnRH3) mRNA levels in the three-spined stickleback, Gasterosteus aculeatus.

    Science.gov (United States)

    Shao, Yi Ta; Tseng, Yung Che; Trombley, Susanne; Hwang, Pung Pung; Schmitz, Monika; Borg, Bertil

    2012-09-01

    Parasites often impair the reproduction of their hosts, one well known case being the cestode Schistocephalus solidus which is a common parasite in three-spined sticklebacks, Gasterosteus aculeatus. One of the possible ways that this could be exerted is by suppression on the brain-pituitary-gonadal (BPG) axis. In this study, mRNA levels of FSH-β and LH-β and of GnRH2 (cGnRH II) and GnRH3 (sGnRH) were measured via Q-PCR in infected and uninfected fish sampled from the field a few weeks before the onset of breeding. The pituitary mRNA levels of both FSH-β and LH-β were higher in infected males than in uninfected males. Also in females, FSH-β mRNA levels were higher in infected individuals than in others, whereas there was no significant difference found in LH-β expression. Brain mRNA levels of GnRH3 were higher in infected fish than in uninfected fish in both sexes, but no difference was found in GnRH2 mRNA levels. Thus, infection by S. solidus was able to alter the expressions not only of gonadotropins (GtHs), but also of GnRH which has not been observed previously. However, the effects are opposite to what should be expected if the parasite suppressed reproduction via actions on the brain-pituitary level. The gonads are perhaps more likely to be impaired by the parasites in other ways, and changed feedbacks on the BPG axis could then lead to the increases in GtHs and GnRH.

  16. Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome

    DEFF Research Database (Denmark)

    Iliodromiti, Stamatina; Lan, Vuong Thi Ngoc; Tuong, Ho Manh;

    2013-01-01

    Conventional luteal support packages are inadequate to facilitate a fresh transfer after GnRH agonist (GnRHa) trigger in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). By providing intensive luteal-phase support with oestradiol and progesterone satisfactory implanta......Conventional luteal support packages are inadequate to facilitate a fresh transfer after GnRH agonist (GnRHa) trigger in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). By providing intensive luteal-phase support with oestradiol and progesterone satisfactory...

  17. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH neurons in an estrous cycle and endocannabinoid signaling dependent manner.

    Directory of Open Access Journals (Sweden)

    Imre Farkas

    Full Text Available The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+-imaging revealed a ghrelin-triggered increase of the Ca(2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM suggesting direct action of ghrelin. Estradiol (1nM eliminated the ghrelin-evoked rise of Ca(2+-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1 antagonist AM251 (1µM and the intracellularly applied DAG-lipase inhibitor THL (10 µM, indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

  18. Regulative Actions of the Chinese Drugs for Tonifying the Kidney on Gene Expression of the Hypothalamic GnRH, Pituitary FSH, LH and Osteoblastic BGP

    Institute of Scientific and Technical Information of China (English)

    蔡德培; 张炜

    2005-01-01

    It is found that the drugs for nourishing yin to reduce pathogenic fire can significantly down-regulate, and the drags for tonifying the kidney to replenish essence can up-regulate mRNA expression of the hypothalamic GnRH, pituitary FSH, LH and osteoblastic BGP, indicating that the Chinese drugs for tonifying the kidney can regulate gene expression of the hypothalamic GnRH, pituitary FSH, LH, and osteoblastic BGP, which is possibly one of the main mechanisms of the Chinese drug for tonifying the kidney, regulating ephebic development process and improving skeletal development in sexual precocity children.

  19. Expression of Two Gonadotropin-Releasing Hormone (GnRH) Precursor Genes in Various Tissues of the Japanese Eel and Evolution of GnRH(Endocrinology)

    OpenAIRE

    Kataaki, Okubo; Hiroaki, Suetake; KATSUMI, AIDA; Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University of Tokyo

    1999-01-01

    We isolated and characterized two distinct cDNAs for mammalian gonadotropin-releasing hormone (mGnRH) and chicken GnRH-ll (cGnRH-ll) precursors from the Japanese eel by rapid amplification of cDNA ends. Each GnRH precursors were composed of a signal peptide, a GnRH decapeptide, a processing site and a GnRH-associated peptide. Northern blot and reverse transcription-polymerase chain reaction analysis revealed that the mGnRH precursor gene is expressed in all tissues tested including the brain,...

  20. Developmental exposure to ethinylestradiol affects reproductive physiology, the GnRH neuroendocrine network and behaviors in female mouse

    Directory of Open Access Journals (Sweden)

    Lyes eDerouiche

    2015-12-01

    Full Text Available During development, environmental estrogens are able to induce an estrogen mimetic action that may interfere with endocrine and neuroendocrine systems. The present study investigated the effects on the reproductive function in female mice following developmental exposure to pharmaceutical ethinylestradiol (EE2, the most widespread and potent synthetic steroid present in aquatic environments. EE2 was administrated in drinking water at environmentally relevant (ENVIR or pharmacological (PHARMACO doses (0.1 and 1 µg/kg (body weight/day respectively, from embryonic day 10 until postnatal day 40. Our results show that both groups of EE2-exposed females had advanced vaginal opening and shorter estrus cycles, but a normal fertility rate compared to CONTROL females. The hypothalamic population of GnRH neurons was affected by EE2 exposure with a significant increase in the number of perikarya in the preoptic area of the PHARMACO group and a modification in their distribution in the ENVIR group, both associated with a marked decrease in GnRH fibers immunoreactivity in the median eminence. In EE2-exposed females, behavioral tests highlighted a disturbed maternal behavior, a higher lordosis response, a lack of discrimination between gonad-intact and castrated males in sexually experienced females, and an increased anxiety-related behavior. Altogether, these results put emphasis on the high sensitivity of sexually dimorphic behaviors and neuroendocrine circuits to disruptive effects of EDCs.

  1. The fetal hypothalamus has the potential to generate cells with a gonadotropin releasing hormone (GnRH phenotype.

    Directory of Open Access Journals (Sweden)

    Roberto Salvi

    Full Text Available BACKGROUND: Neurospheres (NS are colonies of neural stem and precursor cells capable of differentiating into the central nervous system (CNS cell lineages upon appropriate culture conditions: neurons, and glial cells. NS were originally derived from the embryonic and adult mouse striatum subventricular zone. More recently, experimental evidence substantiated the isolation of NS from almost any region of the CNS, including the hypothalamus. METHODOLOGY/FINDINGS: Here we report a protocol that enables to generate large quantities of NS from both fetal and adult rat hypothalami. We found that either FGF-2 or EGF were capable of inducing NS formation from fetal hypothalamic cultures, but that only FGF-2 is effective in the adult cultures. The hypothalamic-derived NS are capable of differentiating into neurons and glial cells and most notably, as demonstrated by immunocytochemical detection with a specific anti-GnRH antibody, the fetal cultures contain cells that exhibit a GnRH phenotype upon differentiation. CONCLUSIONS/SIGNIFICANCE: This in vitro model should be useful to study the molecular mechanisms involved in GnRH neuronal differentiation.

  2. Estrus synchronization in sheep and goats using combinations of GnRH, progestagen and prostaglandin F2alpha.

    Science.gov (United States)

    Titi, H H; Kridli, R T; Alnimer, M A

    2010-08-01

    The objective of this experiment was to evaluate the effect of GnRH, progestagen and prostaglandin F(2alpha) on estrus synchronization in sheep and goats. Sixty Awassi ewes and 53 Damascus does were used in the study. The experiment started at the beginning of the breeding season (June/July). The same treatments were applied to sheep and goats as follows: no treatment (CON), 14-day progestagen sponges and 600 IU equine chorionic gonadotropin (S), gonadotropin releasing hormone followed 5 days later by prostaglandin F(2alpha) (GP) and gonadotropin releasing hormone, progestagen sponges for 5 days and prostaglandin F(2alpha) on the day of sponge removal (GSP). None of the ewes in the S group lambed from mating during the induced cycle. A greater lambing rate (p synchronizing estrus and improving fecundity in sheep and goats. Although the use of GnRH-PGF(2alpha) was effective, the addition of progestagen sponges at the time of GnRH administration appeared to improve reproductive parameters.

  3. Non-peptidic thrombospondin-1 mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds.

    Science.gov (United States)

    Colombo, Giorgio; Margosio, Barbara; Ragona, Laura; Neves, Marco; Bonifacio, Silvia; Annis, Douglas S; Stravalaci, Matteo; Tomaselli, Simona; Giavazzi, Raffaella; Rusnati, Marco; Presta, Marco; Zetta, Lucia; Mosher, Deane F; Ribatti, Domenico; Gobbi, Marco; Taraboletti, Giulia

    2010-03-19

    Endogenous inhibitors of angiogenesis, such as thrombospondin-1 (TSP-1), are promising sources of therapeutic agents to treat angiogenesis-driven diseases, including cancer. TSP-1 regulates angiogenesis through different mechanisms, including binding and sequestration of the angiogenic factor fibroblast growth factor-2 (FGF-2), through a site located in the calcium binding type III repeats. We hypothesized that the FGF-2 binding sequence of TSP-1 might serve as a template for the development of inhibitors of angiogenesis. Using a peptide array approach followed by binding assays with synthetic peptides and recombinant proteins, we identified a FGF-2 binding sequence of TSP-1 in the 15-mer sequence DDDDDNDKIPDDRDN. Molecular dynamics simulations, taking the full flexibility of the ligand and receptor into account, and nuclear magnetic resonance identified the relevant residues and conformational determinants for the peptide-FGF interaction. This information was translated into a pharmacophore model used to screen the NCI2003 small molecule databases, leading to the identification of three small molecules that bound FGF-2 with affinity in the submicromolar range. The lead compounds inhibited FGF-2-induced endothelial cell proliferation in vitro and affected angiogenesis induced by FGF-2 in the chicken chorioallantoic membrane assay. These small molecules, therefore, represent promising leads for the development of antiangiogenic agents. Altogether, this study demonstrates that new biological insights obtained by integrated multidisciplinary approaches can be used to develop small molecule mimics of endogenous proteins as therapeutic agents.

  4. [Uricosuric agent].

    Science.gov (United States)

    Ohno, Iwao

    2008-04-01

    Urate lowering treatment is indicated in patients with recurrent acute attacks, tophi, gouty arthropathy, radiographic changes of gout, multiple joint involvement, or associated uric acid nephrolithiasis. Uricosuric agents like benzbromarone and probenecid are very useful to treat hyperuricemia as well as allopurinol (xanthine oxidase inhibitor). Uricosuric agents act the urate lowering effect through blocking the URAT1, an urate transporter, in brush border of renal proximal tubular cells. In order to avoid the nephrotoxicity and urolithiasis due to increasing of urinary urate excretion by using uricosuric agents, the proper urinary tract management (enough urine volume and correction of aciduria) should be performed.

  5. Vasoactive Agents

    OpenAIRE

    Husedzinovic, Ino; Bradic, Nikola; Goranovic, Tanja

    2006-01-01

    This article is a short review of vasoactive drugs which are in use in todays clinical practice. In the past century, development of vasoactive drugs went through several phases. All of these drugs are today divided into several groups, depending on their place of action, pharmacological pathways and/or effects on target organ or organ system. Hence, many different agents are today in clinical practice, we have shown comparison between them. These agents provide new directions in the treatmen...

  6. GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study

    DEFF Research Database (Denmark)

    Kol, Shahar; Humaidan, Peter; Itskovitz-Eldor, Joseph

    2011-01-01

    BACKGROUND It is now well established that a GnRH agonist (GnRHa) ovulation trigger completely prevents ovarian hyperstimulation syndrome. However, early studies, using conventional luteal support, showed inferior clinical results following a GnRHa trigger compared with a conventional hCG trigger...

  7. Testing the synergistic effects of GnRH and testosterone on the reproductive physiology of pre-adult pink salmon Oncorhynchus gorbuscha.

    Science.gov (United States)

    Crossin, G T; Hinch, S G; Cooke, S J; Patterson, D A; Lotto, A G; Van Der Kraak, G; Zohar, Y; Klenke, U; Farrell, A P

    2010-01-01

    To test the hypothesis that the hypothalmic gonadotropin-releasing hormone (GnRH) and testosterone (T) co-treatment stimulates both the hypothalmo-pituitary-gonadal (HPG) and hypothalmo-pituitary-interrenal axes, the reproductive and osmoregulatory responses of pre-adult pink salmon Oncorhynchus gorbuscha were compared after GnRH and T administration either alone or in combination. Relative to controls, neither GnRH nor T treatment resulted in significantly greater ovarian or testicular growth, but co-treatment significantly increased ovarian growth after 5 months. Interestingly, the stimulation was undetectable after 3 months. However, once daily photoperiod began shortening after the summer solstice, c. 2 months before the natural spawning date, GnRH+T-treated females were stimulated to produce larger ovaries. Final fish body length and the size of individual eggs did not differ among treatment groups. GnRH+T eggs, however, showed signs of advanced vitellogenesis relative to GnRH-treated and control eggs, whereas T-treated eggs became atretic. Testis size increased significantly from initial values and most males were spermiating, but this growth and development were independent of hormone treatments. Final plasma ion, metabolite and cortisol concentrations did not differ among treatment groups. It is concluded that GnRH+T co-treatment was effective in stimulating female but not male maturation. GnRH and T treatment, however, presumably had little effect on the hypothalmo-pituitary-interrenal axis as observed by ionoregulatory status.

  8. Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus.

    Science.gov (United States)

    Georgopoulos, N A; Markou, K B; Pappas, A P; Protonatariou, A; Vagenakis, G A; Sykiotis, G P; Dimopoulos, P A; Tzingounis, V A

    2001-12-01

    Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge, while thyroid-stimulating hormone (TSH) response to TRH was diminished, and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus, with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.

  9. Synchrony of ovulation and follicular dynamics in merino ewes treated with GnRH in the breeding and non-breeding seasons.

    Science.gov (United States)

    Reyna, J; Thomson, P C; Evans, G; Maxwell, W M C

    2007-08-01

    The effect of gonadotropin releasing hormone (GnRH) treatment on the time of ovulation and the occurrence of follicular dominance during the non-breeding and breeding seasons (experiment 1), and on fertility after artificial insemination (AI) in the non-breeding season (experiment 2), was examined in Merino ewes. Oestrus was synchronized in 40 nulliparous ewes (experiment 1; n = 20, in the non-breeding and breeding seasons) and in 79 multiparous ewes (experiment 2) using intravaginal sponges and pregnant mare serum gonadotropin. Thirty six hours after sponge removal (SR), half the ewes were injected (i.m.) with 40 microg of synthetic GnRH and the remainder used as controls. GnRH improved the synchrony of ovulation compared with the controls in the breeding (SD = 2.8 vs 5.7 days, p = 0.04) but not the non-breeding season (SD = 3.8 vs 4.4 days, p = 0.69), with ewes ovulating from 42 to 54 h (mean 50.4 +/- 4.08 h) and 42-60 h (mean 54.4 +/- 5.47 h) after SR for GnRH and control, respectively. For both treated and control ewes, ovulation occurred earlier in the non-breeding than the breeding season (50.1 vs 54.6 h; p = 0.002). GnRH had no effect on follicular dominance, as assessed by divergence (D: the time the ovulatory follicle exceeded the average size of the other non-ovulating follicles) or on the interval from D to ovulation (IDO). However, follicular dynamics differed between seasons. The mean follicle diameter increased at a faster rate up to 36 h after SR in the non-breeding compared with the breeding season and then rapidly declined, compared with a later peak (42 h after SR) in mean follicular size during the breeding season. IDO was shorter in the non-breeding than in the breeding season (26.7 +/- 4.30 h vs 39.6 +/- 4.53 h; p = 0.05). In experiment 2, ewes (n = 38 GnRH-treated, n = 40 controls) were inseminated in the uterus by laparoscopy 42 h or 48 h after SR with frozen-thawed sperm. The fertility of ewes treated with GnRH (nine of 39, 23%) was not

  10. Chronic immune thrombocytopenic purpura. New agents.

    Science.gov (United States)

    Rodeghiero, F; Ruggeri, M

    2009-01-01

    First generation thrombopoietic growth factors (rhTPO and PEG-rHuMGDF), investigated in the early 2000s, proved effective in increasing platelet count in normal volunteers, in thrombocytopenia due to chemotherapy and also in a few cases of immune thrombocytopenic purpura (ITP). These agents did not complete their clinical development since one of them induced antibodies in the recipients that cross reacted with endogenous thrombopoietin (TPO), thus causing thrombocytopenia. This promoted the ingenious design of a new generation of thrombopoietic growth factors having no sequence homology with natural TPO. The two main agents are romiplostim, a peptibody already approved for clinical use in USA and eltrombopag, a non-peptide, orally active small molecule. In open label and placebo-controlled trials both agents proved to predictably increase platelet count in normal volunteers and in patients with ITP. With appropriate dosages (1-10 microg/kg weekly sub cutaneously for romiplostim; 50-75 mg/die per os for eltrombopag ) a platelet increase becomes significant after 7-10 days and peaks between 10-14 days. By discontinuing treatment, platelet count returns to baseline level in 10-15 days. The response rate with both agents is above 70-80%, also in patients that had undergone several lines of treatment, or that have failed splenectomy. The response is maintained during the treatment, but is almost invariably lost even after several months of successful administration. Due to the lack of a curative potential and to the incomplete knowledge of long-term side effects, the place of these new drugs in the management of ITP is still unsettled and their use is best restricted to refractory patients or in preparation of splenectomy. It seems however that a new paradigm in the treatment of ITP has been established where the focus is not on reducing platelet consumption but on increasing platelet production.

  11. [Inotropic agents].

    Science.gov (United States)

    Sasayama, Shigetake

    2003-05-01

    Depression of myocardial contractility plays an important role in the development of heart failure and many inotropic agents were developed to improve the contractile function of the failing heart. Agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exerted dramatic short-term hemodynamic benefits, but these acute effects were not extrapolated into long-term improvement of the clinical outcome of heart failure patients. Administration of these agents to an energy starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, however, the recent large scale clinical trial has ironically proved that digoxin reduced the rate of hospitalization both overall and for worsening heart failure. More recently, attention was paid to other inotropic agents that have a complex and diversified mechanism. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including cytokine inhibitors, immunomodulators, or calcium sensitizers. In the Western Societies these agents were again shown to increase mortality of patients with severe heart failure in a dose dependent manner with the long-term administration. However, it may not be the case in the Japanese population in whom mortality is relatively low. Chronic treatment with inotropic agent may be justified in Japanese, as it allows optimal care in the context of relief of symptoms and an improved quality of life. Therefore, each racial group should obtain specific evidence aimed at developing its own guidelines for therapy rather than translating major guidelines developed for other populations.

  12. Peripherally Administered Non-peptide Oxytocin Antagonist, L368,899®, Accumulates in Limbic Brain Areas: A New Pharmacological Tool for the Study of Social Motivation in Non-Human Primates

    Science.gov (United States)

    Boccia, Maria L.; Goursaud, Anne-Pierre S.; Bachevalier, Jocelyne; Anderson, Kenneth D.; Pedersen, Cort A.

    2009-01-01

    Central administration of oxytocin (OT) antagonists inhibits maternal and sexual behavior in non-primates, providing the strongest experimental evidence that endogenous OT facilitates these behaviors. While there have been a few reports that ICV administration of OT increases social behaviors in monkeys, no studies to date have assessed the effects of OT antagonists. Therefore, we studied in rhesus monkeys whether L368,899®, a non-peptide antagonist produced by Merck that selectively blocks the human uterine OT receptor, penetrates the CNS after peripheral administration and alters female maternal and sexual behavior. In two studies in four male monkeys, L368,899 was injected iv (1 mg/kg) after which (1) CSF samples were collected at intervals over 4 h and (2) brains were collected at 60 min. Assay of samples confirmed that iv-administered L368,899 entered CSF and accumulated in the hypothalamus, septum, orbitofrontal cortex, amygdala and hippocampus, but not other areas. An adult female monkey was tested for interest in either an infant or sexual behavior, receiving a different iv treatment prior to each test (1 or 3 mg/kg of L368,899 or saline) OT antagonist treatment reduced or eliminated interest in the infant and sexual behavior. These results, although preliminary, are the first to directly implicate endogenous OT in activation of primate maternal interest and sexual behavior. While it remains to be empirically demonstrated that peripherally administered L368,899 blocks central OT receptors, our behavioral findings suggest that this non-peptide antagonist may facilitate testing OT involvement in a variety of social and other behaviors in primates. PMID:17583705

  13. Sunscreening Agents

    Science.gov (United States)

    Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B.R.

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents. PMID:23320122

  14. Mobile Agents

    Science.gov (United States)

    Satoh, Ichiro

    Mobile agents are autonomous programs that can travel from computer to computer in a network, at times and to places of their own choosing. The state of the running program is saved, by being transmitted to the destination. The program is resumed at the destination continuing its processing with the saved state. They can provide a convenient, efficient, and robust framework for implementing distributed applications and smart environments for several reasons, including improvements to the latency and bandwidth of client-server applications and reducing vulnerability to network disconnection. In fact, mobile agents have several advantages in the development of various services in smart environments in addition to distributed applications.

  15. Anti Mullerian Hormone: Ovarian response indicator in young patients receiving Long GnRH Agonist Protocol for Ovarian Stimulation

    Science.gov (United States)

    Jamil, Zehra; Fatima, Syeda Sadia; Rehman, Rehana; Alam, Faiza; Arif, Sara

    2016-01-01

    Objective: Anti Mullerian hormone (AMH) is gaining place as ovarian marker, chiefly in infertility assistance. We explored its correlation with oocytes retrieval after long GnRH agonist protocol for stimulation, in younger and older infertile population. Methods: This retrospective analysis compiled data of 166 females, receiving ICSI treatment from June 2014 to March 2015. Serum FSH, LH, Estadiol, AMH and antral follicle count were assessed. Outcomes were measured as good (5 to 19 oocytes) and bad responders. Results: Higher discriminatory power of AMH (AUROC; 0.771; p 35 year (r=0.169; p>0.05). Conclusion: Our study reaffirms that serum AMH correlates well with oocytes retrieved, particularly in females younger than 35 years. We suggest incorporation of AMH in baseline assessment of infertile females, who are falsely advised to postpone interventions based on their age and normal FSH levels. PMID:27648045

  16. GnRH receptor activation competes at a low level with growth signaling in stably transfected human breast cell lines

    Directory of Open Access Journals (Sweden)

    Morgan Kevin

    2011-11-01

    Full Text Available Abstract Background Gonadotrophin releasing hormone (GnRH analogs lower estrogen levels in pre-menopausal breast cancer patients. GnRH receptor (GnRH-R activation also directly inhibits the growth of certain cells. The applicability of GnRH anti-proliferation to breast cancer was therefore analyzed. Methods GnRH-R expression in 298 primary breast cancer samples was measured by quantitative immunofluorescence. Levels of functional GnRH-R in breast-derived cell lines were assessed using 125I-ligand binding and stimulation of 3H-inositol phosphate production. Elevated levels of GnRH-R were stably expressed in cells by transfection. Effects of receptor activation on in vitro cell growth were investigated in comparison with IGF-I and EGF receptor inhibition, and correlated with intracellular signaling using western blotting. Results GnRH-R immunoscoring was highest in hormone receptor (triple negative and grade 3 breast tumors. However prior to transfection, functional endogenous GnRH-R were undetectable in four commonly studied breast cancer cell lines (MCF-7, ZR-75-1, T47D and MDA-MB-231. After transfection with GnRH-R, high levels of cell surface GnRH-R were detected in SVCT and MDA-MB-231 clones while low-moderate levels of GnRH-R occurred in MCF-7 clones and ZR-75-1 clones. MCF-7 sub-clones with high levels of GnRH-R were isolated following hygromycin phosphotransferase transfection. High level cell surface GnRH-R enabled induction of high levels of 3H-inositol phosphate and modest growth-inhibition in SVCT cells. In contrast, growth of MCF-7, ZR-75-1 or MDA-MB-231 clones was unaffected by GnRH-R activation. Cell growth was inhibited by IGF-I or EGF receptor inhibitors. IGF-I receptor inhibitor lowered levels of p-ERK1/2 in MCF-7 clones. Washout of IGF-I receptor inhibitor resulted in transient hyper-elevation of p-ERK1/2, but co-addition of GnRH-R agonist did not alter the dynamics of ERK1/2 re-phosphorylation. Conclusions Breast cancers

  17. Prostate specific antigen in boys with precocious puberty before and during gonadal suppression by GnRH agonist treatment

    DEFF Research Database (Denmark)

    Juul, A; Müller, J; Skakkebaek, N E

    1997-01-01

    In healthy boys, the pituitary-gonadal axis exhibits diurnal variation in early puberty. Serum testosterone levels are higher during the night and low or immeasurable during the day. These fluctuating levels of circulating androgens in early pubertal boys are difficult to monitor. Prostate specific...... antigen (PSA) is a marker of the androgen-dependent prostatic epithelial cell activity and it is used in the diagnosis and surveillance of adult patients with prostatic cancer. We have measured PSA concentrations in serum from boys with precocious puberty before and during gonadal suppression with Gn......RH agonists to evaluate the effect of normal and precocious puberty on PSA levels and to study the correlation between testosterone and PSA in boys....

  18. In vitro fertility rate of 129 strain is improved by Buserelin (GnRH) administration prior to superovulation

    Science.gov (United States)

    Vasudevan, K; Sztein, J M

    2012-01-01

    The 129 mice are well recognized for their low fertility and it is speculated that this lack of fertility may be due to oocyte condition. In this study we investigated superovulation regimens for 129S1/SvImJ mouse strain to improve the oocyte quality and fertility rate of in vitro fertilization (IVF). Female mice were divided into four groups based on hormone and timing of injection. Group 1 received pregnant mare serum gonatotropin (PMSG) and 48 hours later human chorionic gonadotropin (hCG); using the same dose, group 2 received hCG 52 hours post PMSG and group 3, 55 hours post PMSG. Group 4 received Buserelin (gonadotropin releasing hormone agonist [GnRH]) followed 24 hours later by PMSG and then hCG 55 hours post PMSG. IVF was performed using 129S1/SvImJ oocytes and sperm; C57BL/6J sperm with 129S1/SvImJ oocytes was used as fertility control. The IVF fertility rate was 1% (Groups 1 & 2), 17% (Group 3) and 55% (Group 4) for 129 oocytes fertilized with 129 sperm. For 129 oocytes fertilized with C57BL/6J sperm, the fertility rate was 5% (Group 1) 10% (Group 2) 40% (Group 3) and 59% (Group 4).-These results suggest that extending the interval time between PMSG and hCG and giving GnRH in addition to the standard PMSG and hCG treatment can improve IVF fertility rate of 129S1/SvImJ strain mice significantly. PMID:23097563

  19. Potential roles for GNIH and GNRH-II in reproductive axis regulation of an opportunistically breeding songbird.

    Science.gov (United States)

    Perfito, Nicole; Zann, Richard; Ubuka, Takayoshi; Bentley, George; Hau, Michaela

    2011-08-01

    The ability to breed at any time of year enables opportunistically breeding species to respond to good conditions whenever they occur. We investigate the neuroendocrine basis for this relatively unusual reproductive pattern in the avian world. One proposed mechanism for year-round breeding ability is tonic activation of gonadotropin-releasing hormone-I (GnRH-I) production that is flexibly modified by gonadotropin-inhibitory hormone (GnIH) production during unfavorable conditions. GnIH could inhibit GnRH secretion from the hypothalamus and/or inhibit GnRH action on the anterior pituitary gland. We studied neuroendocrine patterns in wild Australian zebra finches (Taeniopygia guttata) sampled during a breeding period in Southern Australia, a non-breeding period in central Australia, and in juvenile males in the latter location. We asked whether patterns in immunoreactivity of three neuropeptides important for reproductive axis regulation, GnRH-I, GnRH-II and GnIH, during periods of breeding and non-breeding reflect this flexibility. We found that the numbers and sizes of immunoreactive (-ir) GnRH-I cells did not vary between breeding stages and ages. Contrary to our predictions, irGnIH cell number and size, as well as the synthesis of GnIH mRNA were similar in breeding and non-breeding conditions. However, breeding males had more and larger irGnRH-II cells in the midbrain compared to non-breeding males. Hence, while changes in irGnIH cells are not associated with fluctuations in gonadotropin secretion or gonad volume, the regulation of irGnRH-II cells might represent a previously-unidentified mechanism by which reproductive flexibility can be achieved; namely via behavioral neurotransmitter actions of GnRH-II rather than through the typical sensory-CNS integration-GnRH-I route.

  20. GNRH-agonist or antagonist in the treatment of prostate cancer: a comparision based on oncological results.

    Science.gov (United States)

    Salciccia, Stefano; Gentilucci, Alessandro; Cattarino, Susanna; Sciarra, Alessandro

    2016-11-18

    On the basis of the trials available, are we ready to consider GnRH antagonists better than agonists? Is there a population of patients who may benefit from antagonists more than agonists?We specifically focused our analysis on the significance of oncological results obtained in phase III trials directly comparing Degarelix with GnRH agonists. Oncological results were evaluated only in 1 trial (CS21) with some subanalysis and they were not the primary endpoints of the study. The follow-up duration was 364 days, and therefore, the number of events (all causes deaths and prostate cancer (PC), Prostate Specific Antigen (PSA), Hazard ratio (HR)-related deaths) was very low in both groups and this aspect strongly reduces the significance of overall survival evaluation. In our opinion, the CS21A open-label extension does not consent to obtain useful clinical data and the design of the study loses the possibility to have a longer randomized comparison between degarelix and agonist. Moreover, the fact that the crossover from leuprolide to degarelix was pre-defined at 12 months and not at agonist failure does not allow to gather data also on the effect of sequential treatment.The answer to the question whether we are ready to consider antagonists better than agonists, based on oncological results, is probably no. We have data in terms of testosterone suppression and PSA control rather than overall survival or clinical progression free survival. A PSA progression-free survival is a secondary endpoint that in our opinion is not sufficient. Large prospective comparative trials with long-term follow-up are needed to clarify this critical clinical question.

  1. A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep.

    Science.gov (United States)

    Hough, D; Bellingham, M; Haraldsen, I R; McLaughlin, M; Robinson, J E; Solbakk, A K; Evans, N P

    2017-03-01

    Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (Plong lasting effects on other brain areas and aspects of cognitive function. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Antibiotic Agents

    Science.gov (United States)

    ... agents. A recent survey reported that 76% of liquid soaps from 10 states in the US contained triclosan ... regulated depends upon its intended use and its effectiveness. The US Food and Drug Administration (FDA) regulates antibacterial soaps and antibacterial substances that will either be used ...

  3. Therapeutic Utility of Non-Peptidic CRF1 Receptor Antagonists in Anxiety, Depression, and Stress-Related Disorders: Evidence from Animal Models

    Science.gov (United States)

    Kehne, John H.; Cain, Christopher K.

    2012-01-01

    Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF1) receptors in stress response system pathways is linked to stress-related psychopathology and CRF1 receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders. CRAs have a distinct phenotype in animals that has similarities to, and differences from, those of classic antidepressants and anxiolytics. CRAs are generally behaviorally silent, indicating that CRF1 receptors are normally in a state of low basal activation. CRAs reduce stressor-induced HPA axis activation by blocking pituitary and possibly brain CRF1 receptors which may ameliorate chronic stress-induced pathology. In animal models sensitive to anxiolytics and/or antidepressants, CRAs are generally more active in those with high stress levels, conditions which may maximize CRF1 receptor hyperactivation. Clinically, CRAs have demonstrated good tolerability and safety, but have thus far lacked compelling efficacy in major depressive disorder, generalized anxiety disorder, or irritable bowel syndrome. CRAs may be best suited for disorders in which stressors clearly contribute to the underlying pathology (e.g. posttraumatic stress disorder, early life trauma, withdrawal/abstinence from addictive substances), though much work is needed to explore these possibilities. An evolving literature exploring the genetic, developmental and environmental factors linking CRF1 receptor dysfunction to stress-related psychopathology is discussed in the context of improving the translational value of current animal models. PMID:20826181

  4. Radioprotective Agents

    Science.gov (United States)

    1982-01-01

    claimed to be effective are gallic acid derivatives, eg, sodium gallate 12053-21-61 (295-297) and propyl gallate 1121-79-91 (298). p...inhibition of a-adrenergic receptors can be achieved through the use of the antiradiation agents 2-(5-aminopentylamino)ethanephos- phorothioic acid ...tissue was ap- preciated immediately as a potential medical set, and they were put to use en- thusiastically. Early workers did notice an erythematous

  5. Advances in research of non-peptide small-molecule CCR5 antagonists%非肽类小分子趋化因子受体5拮抗剂的研究进展

    Institute of Scientific and Technical Information of China (English)

    姚虎; 冯建科; 韦弢; 刘瑞江

    2011-01-01

    趋化因子受体5(CCR5)属于G蛋白偶联受体超家族,是HIV感染早期介导病毒进入机体的主要辅助受体.CCR5拮抗剂已经成为一类重要的抗HIV病毒药物,主要包括趋化因子衍生物、非肽类小分子化合物、单克隆抗体、肽类化合物等4类.目前,全世界各大医药公司和研究机构纷纷研发了许多高选择性、活性强、生物利用度高的非肽类小分子CCR5拮抗剂,其中Maraviroc在2007年被FDA批准上市,还有一些目前已经进入临床试验阶段.文中对1999年到2009年10年间文献报道的相关非肽类小分子CCR5拮抗剂进行了综述.%CCR5, a membrane protein on cell surface, is a member of the G protein-coupled receptor superfamily and one of the major co-receptors for HIV-1 infection.CCR5 antagonists as viral entry inhibitors have recently emerged as an important class of anti-HIV medicines.Antagonists of CCR5 include following 4 types: chemokine derivatives, small molecule non-peptide compounds, monoclonal antibodies and peptides.In recent years,the major pharmaceutical companies and research institutions have developed a number of CCR5 antagonists with high selectivity, strong activity and a good bioavailability.Maraviroc was approved by FDA in 2007.The others have been under clinical trials.In this article, the literature from 1999 to 2009 related to non-peptide small-molecule CCR5 antagonists is reviewed.

  6. In vitro effect of octyl - methoxycinnamate (OMC) on the release of Gn-RH and amino acid neurotransmitters by hypothalamus of adult rats.

    Science.gov (United States)

    Carbone, S; Szwarcfarb, B; Reynoso, R; Ponzo, O J; Cardoso, N; Ale, E; Moguilevsky, J A; Scacchi, P

    2010-05-01

    OMC (octyl-methoxycinnamate), an endocrine disruptor having estrogenic activity, is used in sunscreen creams as UV filter. We studied its "in vitro" effects on the hypothalamic release of Gn-RH as well as on the amino acid neurotransmitter system. OMC significantly decreased Gn-RH release in normal male and female rats as well as in castrated rats with substitutive therapy. No effects were observed in castrated rats without substitutive therapy. In males OMC increases the release of GABA, decreasing the production of glutamate (GLU) while in the female decreases the excitatory amino acid aspartate (ASP) and GLU without modifications in the hypothalamic GABA release. These results suggest that OMC acting as endocrine disruptor could alter the sex hormone-neurotransmitter-Gn-RH axis relationships in adult rats.

  7. Parity Differences in Heat Expression of Dairy Cows Synchronized with GnRH, CIDR and PGF2α during Dry Season in Zambia

    Directory of Open Access Journals (Sweden)

    E. S. Mwaanga*, K. Choongo, H. Simukoko and C. Chama1

    2012-01-01

    Full Text Available A study was conducted to investigate parity differences in heat expression of dairy cows heat-synchronized during the dry season when feed scarcity is common. Cyclic cows (n=65 aged 2 to 10 years with parity range of 0 to 7 were selected from small-holder dairy farms around Lusaka. Cows were divided into 3 groups of nulliparous, primiparous and pluriparous. Heat-was synchronized using gonadotrophin releasing hormone (GnRH and controlled intra-vaginal drug releasing device (CIDR. Heat detection was observed after CIDR withdraw. The study showed a significantly (P<0.05 lower number of primiparous cows (68% coming into heat compared to nulliparous (81.8% and pluriparous cows (83.3%. It was concluded that parity influences estrus expression rate in dairy cows following synchronization with GnRH, CIDR and PGF2α during the dry season in the sub-tropics.

  8. Effect of different gonadorelin (GnRH) products used for the first or resynchronized timed artificial insemination on pregnancy rates in postpartum dairy cows.

    Science.gov (United States)

    Poock, S E; Lamberson, W R; Lucy, M C

    2015-09-01

    Different GnRH products are used for timed artificial insemination (AI) in postpartum dairy cows. Previous studies reported greater LH release and increased ovulation percentage for gonadorelin diacetate tetrahydrate compared with gonadorelin hydrochloride but pregnancies per AI (P/AI) were not evaluated. The objective, therefore, was to compare P/AI for cows treated with either gonadorelin hydrochloride or gonadorelin diacetate tetrahydrate before the first timed AI or resynchronized timed AI. Holstein cows (n = 3938) in a confinement dairy in northeast Missouri were assigned to weekly cohorts (n = 22) on the basis of calving date. Cows were treated with "Presynch Ovsynch" (PGF2α, 14 days; PGF2α, 14 days; GnRH, 7 days; PGF2α, 56 hours; GnRH, 16 hours; timed AI) so that the first timed AI was 70 to 76 days postpartum. The PGF2α was Lutalyse (5 mL; 25 mg; Zoetis). The GnRH product was either gonadorelin hydrochloride (2 mL; 100 μg; n = 1945) or gonadorelin diacetate tetrahydrate (2 mL; 100 μg; n = 1993) and alternated weekly for cows assigned to cohorts. There were first timed AI (n = 1790) and resynchronized timed AI (n = 2148) cows within each cohort. The resynchronization began 32 days after timed AI (GnRH, 6 days; ultrasound pregnancy diagnosis, 1 day; and then for nonpregnant cows: PGF2α, 56 hours; GnRH, 16 hours; timed AI). The trial was conducted from January to February 2012 (n = 1203) and July to October 2012 (n = 2735). Cows were fed a total mixed ration, milked thrice daily, and milk tested monthly for volume, somatic cell count (SCC), fat percentage, protein percentage, and milk urea nitrogen. Data were analyzed by fitting the binary response data to a generalized linear mixed model for repeated measures. There was no effect of the GnRH product (treatment) on P/AI (38.4 ± 1.2 vs. 35.7 ± 1.3; gonadorelin diacetate tetrahydrate vs. gonadorelin hydrochloride). Treatment interactions with parity, month of breeding

  9. Day-night and reproductive cycle profiles of melatonin receptor, kiss, and gnrh expression in orange-spotted grouper (Epinephelus coioides).

    Science.gov (United States)

    Chai, Ke; Liu, Xiaochun; Zhang, Yong; Lin, Haoran

    2013-07-01

    It is suggested that the MT1 melatonin receptor mediates the effects of melatonin on reproduction in rodents. Three melatonin receptor types, MT1, MT2, and Mel1c, have been identified in fish. To understand the potential roles of each type of melatonin receptor on reproduction, we explored the day-night and reproductive cycle profiles of melatonin receptor, kiss, and gnrh expression in the orange-spotted grouper (Epinephelus coioides). cDNAs encoding melatonin receptors (MT1, MT2, and Mel1c) were first isolated from the brain of the orange-spotted grouper. Quantitative real-time PCR analysis demonstrated that the expression levels of MT1 and MT2 were higher in most of the brain areas and pituitary, while mel1c mRNA was mainly distributed in some peripheral tissues and the pituitary. The expression levels of MT1 were much higher than those of MT2 and mel1c in most of the brain regions, and the day-night expression variations of MT1 were counter to those of kiss2 and gnrh1. Reproductive cycle variations in MT1 daytime expression were different from those for kiss2 and gnrh1, and contrary to ovarian fecundity. Our results suggest that MT1 may modulate gnrh1 expression through kiss2, or may directly influence it. Together, these signal cascades may regulate the seasonal breeding of the orange-spotted grouper. As the day-length variations were consistent with the ovarian fecundity variation observed during the reproductive cycle, we infer that photoperiod affects ovarian development of the orange-spotted grouper through MT1.

  10. Effects of single dose GnRH agonist as luteal support on pregnancy outcome in frozen-thawed embryo transfer cycles: an RCT

    Directory of Open Access Journals (Sweden)

    Robab Davar

    2015-08-01

    Full Text Available Background: There is no doubt that luteal phase support is essential to enhance the reproductive outcome in IVF cycles. In addition to progesterone and human chorionic gonadotropin, several studies have described GnRH agonists as luteal phase support to improve implantation rate, pregnancy rate and live birth rate, whereas other studies showed dissimilar conclusions. All of these studies have been done in fresh IVF cycles. Objective: To determine whether an additional GnRH agonist administered at the time of implantation for luteal phase support in frozen-thawed embryo transfer (FET improves the embryo developmental potential. Materials and Methods: This is a prospective controlled trial study in 200 FET cycles, patients were randomized on the day of embryo transfer into group 1 (n=100 to whom a single dose of GnRH agonist (0.1 mg triptorelin was administered three days after transfer and group 2 (n=100, who did not receive agonist. Both groups received daily vaginal progesterone suppositories plus estradiol valerate 6 mg daily. Primary outcome measure was clinical pregnancy rate. Secondary outcome measures were implantation rate, chemical, ongoing pregnancy rate and abortion rate. Results: A total of 200 FET cycles were analyzed. Demographic data and embryo quality were comparable between two groups. No statistically significant difference in clinical and ongoing pregnancy rates was observed between the two groups (26% versus 21%, p=0.40 and 21% versus 17%, p=0.37, respectively. Conclusion: Administration of a subcutaneous GnRH agonist at the time of implantation does not increase clinical or ongoing pregnancy.

  11. EFFECT OF POST-MATING GNRH TREATMET ON SERUM PROGESTERONE, LUTEINIZING HORMONE LEVELS, DURATION OF ESTROUS CYCLE AND PREGNANCY RATES IN COWS

    Directory of Open Access Journals (Sweden)

    H. YILDIZ, E. KAYGUSUZOĞLU, M. KAYA1 AND M. ÇENESIZ1

    2009-07-01

    Full Text Available Pregnancy rate, estrous cycle lenght, serum progesterone and luteinizing hormone (LH concentrations were determined in gonadotropin releasing hormone (GnRH; 10.5 μg synthetic gonadotrophin releasing hormone agonist, receptal administered cows on day 12 post-mating (n=9 compared to control cows (n=8. Their oestrous cycles were synchronised by intramuscular administration of prostaglandin F2 alpha (its analog, cloprostenol twice at 11 days interval. Estrous exhibited cows were mated naturally. Blood samples were collected every two days from all animals. Serum progesterone and LH concentrations were measured by ELISA method. GnRH administration significantly increased serum LH concentration which reached peak levels 2-3 h after treatment. However, serum progesterone concentration was not affected. There were no differences in mean progesterone concentrations on days 12 to 24 post-mating between GnRH administrated and control pregnant cows. However, in non pregnant animals, progesterone concentrations on days 16 in the treated group were lower than control group (P<0.01. Pregnancy diagnosis in animals made by B-mode ultrasonography between the 30th and 35th day showed that 77.7% of treated cows were pregnant compared to 50% in control group. Duration of the estrous cycle in the non-pregnant animals was not affected by the treatment (control, 21.3 ± 0.8 days; treated, 22.5 ± 0.5 days. In conclusion, this study supports the use of GnRH on day 12 post-mating as a method for enhancing pregnancy rates in lactating dairy cattle.

  12. Trading Agents

    CERN Document Server

    Wellman, Michael

    2011-01-01

    Automated trading in electronic markets is one of the most common and consequential applications of autonomous software agents. Design of effective trading strategies requires thorough understanding of how market mechanisms operate, and appreciation of strategic issues that commonly manifest in trading scenarios. Drawing on research in auction theory and artificial intelligence, this book presents core principles of strategic reasoning that apply to market situations. The author illustrates trading strategy choices through examples of concrete market environments, such as eBay, as well as abst

  13. Ovulation and conception rates according intravaginal progesterone device and hCG or GnRH to induce ovulation in buffalo during the off breeding season

    Directory of Open Access Journals (Sweden)

    P.S. Baruselli

    2010-02-01

    Full Text Available The objective of this study was to evaluate the effect of intravaginal progesterone device (P4; first or second use of different ovulatory inductors on ovulation and conception rates in buffaloes during the off breeding season. Two hundred and forty two buffaloes were allocated in four groups and received P4 device of first or second use plus estradiol benzoate on Day 0 (D0. The P4 device was removed and a dose of PGF2α and eCG was administered on D9. On D11, buffaloes received hCG or GnRH and 16hs after the animals were inseminated. The ultrasound examination was performed on D0 to verify the ovarian status, from D9 to D14 to establish the moment of ovulation and on D40 for pregnancy diagnosis. Data were analyzed by ANOVA and Chi-square test. There was no effect of interaction. The ovulation and conception rate were similar for P4 device of first and second use, for hCG and GnRH. Results indicate that the use of P4 device for two times and the use of GnRH instead of hCG provide satisfactory ovulation and conception rate in buffalo during the off breeding season and might reduce the cost of the protocol for artificial insemination.

  14. In Search of the Molecular Mechanisms Mediating the Inhibitory Effect of the GnRH Antagonist Degarelix on Human Prostate Cell Growth

    Science.gov (United States)

    Sakai, Monica; Martinez-Arguelles, Daniel B.; Patterson, Nathan H.; Chaurand, Pierre; Papadopoulos, Vassilios

    2015-01-01

    Degarelix is a gonadrotropin-releasing hormone (GnRH) receptor (GnRHR) antagonist used in patients with prostate cancer who need androgen deprivation therapy. GnRHRs have been found in extra-pituitary tissues, including prostate, which may be affected by the GnRH and GnRH analogues used in therapy. The direct effect of degarelix on human prostate cell growth was evaluated. Normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH)-1 cells, androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells, as well as VCaP cells derived from a patient with castration-resistant prostate cancer were used. Discriminatory protein and lipid fingerprints of normal, hyperplastic, and cancer cells were generated by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The investigated cell lines express GNRHR1 and GNRHR2 and their endogenous ligands. Degarelix treatment reduced cell viability in all prostate cell lines tested, with the exception of the PC-3 cells; this can be attributed to increased apoptosis, as indicated by increased caspase 3/7, 8 and 9 levels. WPE1-NA22, BPH-1, LNCaP, and VCaP cell viability was not affected by treatment with the GnRH agonists leuprolide and goserelin. Using MALDI MS, we detected changes in m/z signals that were robust enough to create a complete discriminatory profile induced by degarelix. Transcriptomic analysis of BPH-1 cells provided a global map of genes affected by degarelix and indicated that the biological processes affected were related to cell growth, G-coupled receptors, the mitogen-activated protein kinase (MAPK) pathway, angiogenesis and cell adhesion. Taken together, these data demonstrate that (i) the GnRH antagonist degarelix exerts a direct effect on prostate cell growth through apoptosis; (ii) MALDI MS analysis provided a basis to fingerprint degarelix-treated prostate cells; and (iii) the clusters of genes affected by degarelix suggest that

  15. In search of the molecular mechanisms mediating the inhibitory effect of the GnRH antagonist degarelix on human prostate cell growth.

    Directory of Open Access Journals (Sweden)

    Monica Sakai

    Full Text Available Degarelix is a gonadrotropin-releasing hormone (GnRH receptor (GnRHR antagonist used in patients with prostate cancer who need androgen deprivation therapy. GnRHRs have been found in extra-pituitary tissues, including prostate, which may be affected by the GnRH and GnRH analogues used in therapy. The direct effect of degarelix on human prostate cell growth was evaluated. Normal prostate myofibroblast WPMY-1 and epithelial WPE1-NA22 cells, benign prostatic hyperplasia (BPH-1 cells, androgen-independent PC-3 and androgen-dependent LNCaP prostate cancer cells, as well as VCaP cells derived from a patient with castration-resistant prostate cancer were used. Discriminatory protein and lipid fingerprints of normal, hyperplastic, and cancer cells were generated by matrix-assisted laser desorption/ionization (MALDI mass spectrometry (MS. The investigated cell lines express GNRHR1 and GNRHR2 and their endogenous ligands. Degarelix treatment reduced cell viability in all prostate cell lines tested, with the exception of the PC-3 cells; this can be attributed to increased apoptosis, as indicated by increased caspase 3/7, 8 and 9 levels. WPE1-NA22, BPH-1, LNCaP, and VCaP cell viability was not affected by treatment with the GnRH agonists leuprolide and goserelin. Using MALDI MS, we detected changes in m/z signals that were robust enough to create a complete discriminatory profile induced by degarelix. Transcriptomic analysis of BPH-1 cells provided a global map of genes affected by degarelix and indicated that the biological processes affected were related to cell growth, G-coupled receptors, the mitogen-activated protein kinase (MAPK pathway, angiogenesis and cell adhesion. Taken together, these data demonstrate that (i the GnRH antagonist degarelix exerts a direct effect on prostate cell growth through apoptosis; (ii MALDI MS analysis provided a basis to fingerprint degarelix-treated prostate cells; and (iii the clusters of genes affected by degarelix

  16. Photoperiod-independent changes in immunoreactive brain gonadotropin-releasing hormone (GnRH) in a free-living, tropical bird.

    Science.gov (United States)

    Moore, Ignacio T; Bentley, George E; Wotus, Cheryl; Wingfield, John C

    2006-01-01

    Timing of seasonal reproduction in high latitude vertebrates is generally regulated by photoperiodic cues. Increasing day length in the spring is associated with changes in the brain that are responsible for mediating reproductive activities. A primary example of this is the increased content of gonadotropin-releasing hormone (GnRH) in the preoptic area of the hypothalamus in birds as they enter the spring breeding season. Increased GnRH activity stimulates the release of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary. These gonadotropins induce growth of the gonads and release of sex steroids which act on the brain to mediate reproductive behaviors. By contrast, seasonal breeding in the tropics can occur in the absence of significant changes in photoperiod. To our knowledge, no studies have investigated whether seasonal breeding in free-living tropical vertebrates is associated with seasonal changes in the GnRH system. We studied two populations of rufous-collared sparrows (Zonotrichia capensis) at the equator, separated by only 25 km, but with asynchronous reproductive phenologies associated with local climate and independent of photoperiodic cues. We collected brains and measured GnRH immunoreactivity (GnRH-ir) during each population's breeding and non-breeding periods. Breeding males had larger, but not more, GnRH-ir cells than non-breeding birds. The plasticity of the GnRH system was associated with local climate, such that the two populations exhibited asynchronous changes in GnRH-ir despite experiencing identical photoperiod conditions. Our results demonstrate that tropical birds can exhibit neural changes similar to those exhibited in higher latitude birds. However, these tropical populations appear to be using supplementary cues (e.g., rainfall, temperature, food availability) in a similar way to higher latitude species using an initial predictive cue (photoperiod). These results raise questions about the evolution of

  17. Evaluation of Pre and Post Artificial Insemination effect of GnRH Hormone on conception of repeat breeder Deoni Cows

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    S.D. Awati

    2010-10-01

    Full Text Available Twenty four Deoni repeat breeder cows were randomly allocated into 4 groups of six each. The animals of groups I, II and III were injected with 250 µg of buserelin acetate (Receptal® on two occasions i.e. once on day of estrus and second dose on days 10 or 12 or14 respectively in I, II and III groups following breeding, while the animals of group IV served as control. Among the physical characters of estrual cervico-vaginal mucous, typical arborization pattern (80.95 % in pregnant vs. 55.56 % in non-pregnant cows and marginally high spinnbarkeit readings (24.67+2.7cms in pregnant and 22.21+1.32 cms in non-pregnant cows favored better fertility, although the differences between the groups were statistically insignificant. However, the pH of estrual cervico-vaginal mucous did not indicate any effect on fertility and it ranged between 8.00 to 9.00. The cows of treatment groups I, II and III registered a considerably higher conception rate of 83.33 percent each, while in control group cows had only 33.33 percent. To conclude GnRH therapy irrespective of days of administration resulted in an overall enhancement in conception rate of 83.33 as against 33.33 percent in control groups of cows. [Vet. World 2010; 3(5.000: 209-211

  18. Comparison of efficacy of bromocriptine and cabergoline to GnRH agonist in a rat endometriosis model.

    Science.gov (United States)

    Ercan, Cihangir Mutlu; Kayaalp, Oya; Cengiz, Mehmet; Keskin, Ugur; Yumusak, Nihat; Aydogan, Umit; Ide, Tayfun; Ergun, Ali

    2015-05-01

    To determine the effect of dopamine agonists in a surgically induced endometriosis model on rats. In this prospective randomized experimental study, surgical induction of endometriosis was performed by autotransplantation technique on 52 adult female Wistar-Albino rats. Endometriosis formation was confirmed by a second-look laparotomy (n:48) 1 month later. Four study groups were randomly generated according to their treatment regimens: group 1 (leuprolide acetate, n = 12), group 2 (bromocriptine, n = 12), group 3 (cabergoline, n = 12) and group 4 (control, n = 12). Endometriotic implants were excised for histopathological examination after treatment at the setting of laparotomy. The mean surface areas and histopathological glandular tissue (GT) and stromal tissue (ST) scores of endometriotic implants were studied and compared among groups. After 30 days of treatment, the mean surface area of the endometriotic implants of leuprolide acetate, bromocriptine and cabergoline groups was significantly decreased. The regression of endometriotic foci size in comparison to control was highest in group 1, followed by group 2, then group 3. In the histopathological evaluation both the ST and GT scores of group 1, 2 and 3 were significantly decreased in comparison to controls without a statistically significant difference between the groups. Dopamine agonists are as effective as GnRH agonists in the regression of experimental endometriotic implants in rats. Further trials are needed to elucidate the pathways affected by dopamine agonists.

  19. Semaphorin Signaling in the Development and Function of the Gonadotropin Hormone-Releasing Hormone (GnRH System

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    Andrea eMessina

    2013-09-01

    Full Text Available The semaphorin proteins are among the best-studied families of guidance cues, contributing to morphogenesis and homeostasis in a wide range of tissue types. The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors are capable to mediate signaling by semaphorins. These guidance proteins were originally identified as growth cone collapsing factors or as inhibitory signals, crucial for nervous system development. Since those seminal discoveries, the list of functions of semaphorins has rapidly grown. Over the past few years, a growing body of data indicates that semaphorins are involved in the regulation of the immune and vascular systems, in tumor growth/cancer cell metastasis and in neural circuit formation. Recently there has been increasing emphasis on research to determine the potential influence of semaphorins on the development and homeostasis of hormone systems and how circulating reproductive hormones regulate their expression and functions. Here, we focus on the emerging role of semaphorins in the development, differentiation and plasticity of unique neurons that secrete gonadotropin-releasing hormone (GnRH, which are essential for the acquisition and maintenance of reproductive competence in all vertebrates. Genetic evidence is also provided showing that insufficient semaphorin signaling contributes to some forms of reproductive disorders in humans, characterized by the reduction or failure of sexual competence.Finally, we will review some studies with the goal of highlighting how the expression of semaphorins and their receptors might be regulated by gonadal hormones in physiological and pathological conditions.

  20. Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles: a meta-analysis

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    Oliveira João

    2010-09-01

    Full Text Available Abstract Background The effects of gonadotrophin-releasing hormone agonist (GnRH-a administered in the luteal phase remains controversial. This meta-analysis aimed to evaluate the effect of the administration of a single-dose of GnRH-a in the luteal phase on ICSI clinical outcomes. Methods The research strategy included the online search of databases. Only randomized studies were included. The outcomes analyzed were implantation rate, clinical pregnancy rate (CPR per transfer and ongoing pregnancy rate. The fixed effects model was used for odds ratio. In all trials, a single dose of GnRH-a was administered at day 5/6 after ICSI procedures. Results All cycles presented statistically significantly higher rates of implantation (P Conclusions These findings demonstrate that the luteal-phase single-dose GnRH-a administration can increase implantation rate in all cycles and CPR per transfer and ongoing pregnancy rate in cycles with GnRH antagonist ovarian stimulation protocol. Nevertheless, by considering the heterogeneity between the trials, it seems premature to recommend the use of GnRH-a in the luteal phase. Additional randomized controlled trials are necessary before evidence-based recommendations can be provided.

  1. Protein Disulfide Isomerase Chaperone ERP-57 Decreases Plasma Membrane Expression of the Human GnRH Receptor

    Science.gov (United States)

    Yánez, Rodrigo Ayala; Conn, P. Michael

    2012-01-01

    Retention of misfolded proteins by the endoplasmic reticulum (ER) is a quality control mechanism involving the participation of endogenous chaperones such as calnexin (CANX) which interact and restrict plasma membrane expression of gonadotropin releasing hormone receptor (GnRHR), a G protein coupled receptor. CANX also interacts with ERP-57, a thiol oxidoreductase chaperone present in the ER. CANX along with ERP-57, promotes the formation of disulfide bond bridges in nascent proteins. The human GnRH receptor (hGnRHR) is stabilized by two disulfide bond bridges (Cys14-Cys200 and Cys114-Cys196), that, when broken, its expression at plasma membrane decreases. To determine if the presence of chaperones CANX and ERP-57 exert an influence over membrane routing and second messenger activation, we assessed the effect of various mutants including those with broken bridges (Cys→Ala) along with the wild type hGnRHR. The effect of chaperones on mutants was insignificant, whereas the overexpression of ERP-57 led to a wild type hGnRHR retention which was further enhanced by cotransfection with CANX cDNA disclosing receptor retention by ERP-57 augmented by CANX, suggesting a quality control mechanism. PMID:20029959

  2. Effect of Administration of Single Dose GnRH Agonist in Luteal Phase on Outcome of ICSI-ET Cycles in Women with Previous History of IVF/ICSI Failure: A Randomized Controlled Trial

    Science.gov (United States)

    Zafardoust, Simin; Jeddi-Tehrani, Mahmood; Akhondi, Mohammad Mehdi; Sadeghi, Mohammad Reza; Kamali, Koroush; Mokhtar, Sara; Badehnoosh, Bita; Arjmand-Teymouri, Fatemeh; Fatemi, Farnaz; Mohammadzadeh, Afsaneh

    2015-01-01

    Background GnRH agonist administration in the luteal phase has been suggested to beneficially affect the outcome of intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles. This blind randomized controlled study evaluates the effect of GnRH (Gonadotropine Releasing Hormone) agonist administration on ICSI outcome in GnRH antagonist ovarian stimulation protocol in women with 2 or more previous IVF/ICSI-ET failures. Methods One hundred IVF failure women who underwent ICSI cycles and stimulated with GnRH antagonist ovarian stimulation protocol, were included in the study. Women were randomly assigned to intervention (received a single dose injection of GnRH agonist (0.1 mg of Decapeptil) subcutaneously 6 days after oocyte retrieval) and control (did not receive GnRH agonist) groups. Implantation and clinical pregnancy rates were the primary outcome measures. Results Although the age of women, the number of embryos transferred in the current cycle and the quality of the transferred embryos were similar in the two groups, there was a significantly higher rate of implantation (Mann Whitney test, p = 0.041) and pregnancy (32.6% vs. 12.5%, p = 0.030, OR = 3.3, 95%CI, 1.08 to 10.4) in the intervention group. Conclusion Our results suggested that, in addition to routine luteal phase support using progesterone, administration of 0.1 mg of Decapeptil 6 days after oocyte retrieval in women with previous history of 2 or more IVF/ICSI failures led to a significant improvement in implantation and pregnancy rates after ICSI following ovarian stimulation with GnRH antagonist protocol. PMID:25927026

  3. Response to GnRH on day 6 of the estrous cycle is diminished as the percentage of Bos indicus breeding increases in Angus, Brangus, and Brahman x Angus heifers.

    Science.gov (United States)

    Portillo, Germán E; Bridges, G Allen; de Araujo, Jennifer W; Shaw, Mary-Karen V; Schrick, F Neal; Thatcher, William W; Yelich, Joel V

    2008-01-15

    Angus (n=6), Brangus (5/8 Angus x 3/8 Brahman, n=6), and Brahman x Angus (3/8 Angus x 5/8 Brahman, n=6) heifers exhibiting estrous cycles at regular intervals were used to determine if the percentage of Bos indicus breeding influenced the secretory patterns of LH in response to a GnRH treatment on Day 6 of the estrous cycle. Heifers were pre-synchronized with a two-injection PGF(2 alpha) protocol (25 mg i.m. Day -14 and 12.5 mg i.m. Day -3 and -2 of experiment). Heifers received 100 microg GnRH i.m. on Day 6 of the subsequent estrous cycle. Blood samples were collected at -60, -30, and -1 min before GnRH and 15, 30, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min after GnRH to determine concentrations of serum LH. Estradiol concentrations were determined at -60, -30, and -1 min before GnRH. On Day 6 and 8, ovaries were examined by ultrasonography to determine if ovulation occurred. On Day 13, heifers received 25 mg PGF(2 alpha) i.m. and blood samples were collected daily until either the expression of estrus or Day 20 for heifers not exhibiting estrus to determine progesterone concentrations. There was no effect (P>0.10) of breed on ovulation rate to GnRH as well as size of the largest follicle, mean estradiol, and mean corpus luteum volume at GnRH. Mean LH was greater (PBrahman x Angus (2.9+/-0.8 ng/mL), which were similar (P>0.10). Mean LH peak-height was similar (P>0.10) for Brangus (13.9+/-3.4 ng/mL) compared to Angus (21.9+/-3.4 ng/mL) and Brahman x Angus (8.0+/-3.4 ng/mL), but was greater (PBrahman x Angus. Interval from GnRH to LH peak was similar (P>0.10) between breeds. As the percentage of Bos indicus breeding increased the amount of LH released in response to GnRH on Day 6 of the estrous cycle decreased.

  4. Radioimmunoassay for GnRH agonist analogue in serum of patients with prostate cancer treated with D-Ser (tBu)/sup 6/AZA gly/sup 10/ GnRH

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    Clayton, R.N.; Bailey, L.C.; Cottam, J.; Arkell, D.; Perren, T.J.; Blackledge, G.R.P. (Birmingham Univ. (UK). Dept. of Medicine; Dudley Road Hospital, Birmingham (UK))

    1985-04-01

    A radioimmunoassay is described for D-Ser (tBu)/sup 6/ AZA Gly/sup 10/ GnRH (ICI 118630) in serum of prostate cancer patients treated chronically with this peptide to produce castration. With /sup 125/I-118630 as the label, and an anti-GnRH serum, the specificity of the assay is directed to the N-terminal end of the peptide, and putative degradation products have <6% cross-reactivity. The assay appears specific for intact 118630 which, after subcutaneous administration of 250 ..mu..g, has a half-time of disappearance from the serum of 4.9 +- 0.4 h and a volume of distribution of 13.7 +- 0.8 litres. Continuous subcutaneous infusion of 120 ..mu..g 118630/d gave stable serum concentrations of between 2-3 ng/ml for up to 63 d which were very similar to values predicted from pharmacokinetic analysis of the analogue clearance rate. This contrasts with the 'peak and trough' pattern of serum 118630 levels measured in two subjects after 118630 administration from a subcutaneous implant containing 3.6 mg of peptide in a biodegradable formulation. Serum 118630 levels peaked between 6-8 ng/ml 15 d after the implant, falling to <1 ng/ml at 29 d, immediately before the next implant. Serum 118630 levels following a second 3.6 mg implant were almost identical with respect to absolute concentration and time to peak value.

  5. Substituted cyclobutane derivatives as non-peptidic GLP-1 receptor agonists%取代环丁烷结构的非肽类胰高血糖素样肽-1受体激动剂

    Institute of Scientific and Technical Information of China (English)

    刘青; 何敏; 周彩红; 王明伟

    2012-01-01

    应用胰高血糖素样肽-l (glucagon-like peptide-1,GLP-1)及其类似物治疗2型糖尿病是代谢性疾病研究领域近年来的热点,尤其是胰高血糖素样肽-1独特的作用机制倍受业界的关注.它能同时作用于2型糖尿病的多个发病环节,在有效降低血糖的同时,避免低血糖的发生并能减轻体重.但这类药物因其多肽性质而存在诸多的使用限制(如需反复注射).简要介绍一类取代环丁烷结构的新型非肽类胰高血糖素样肽-1受体小分子激动剂的发现过程、基本药理学特征和体内抗糖尿病和抗肥胖症效应.%Application of glucagon-like peptide-1 (GLP-1) to treat type 2 diabetes has become a focal point in the study of metabolic diseases in recent years. Of particular interest is the unique mechanisms of action relative to GLP-1. It exerts multiple effects on the pathogenesis of type 2 diabetes. While effectively lowering blood glucose levels, it does not cause hypoglycemia but reduces body weight. However, GLP-1 and its peptidic mimetics require frequent injections that limits their wide use. This paper briefly reviews the discovery and pharmacological characterization of a class of novel cyclobutane derivatives as non-peptidic GLP-1 receptor agonists including in vivo efficacies on diabetes and obesity.

  6. The effect of GnRH or oestradiol injected at pro-oestrus on luteal function and follicular dynamics of the subsequent oestrous cycle in non-lactating cycling Holstein cows

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    B.V.E. Segwagwe

    2006-09-01

    Full Text Available Oestrous synchronization involves synchronization of ovarian follicular turnover, new wave emergence, and finally induction of ovulation. The final step can be synchronized by the parenteral administration of either GnRH or oestradiol benzoate. This study investigated corpus luteum and follicular emergence after ovulation had been induced by the administration of either GnRH or oestradiol benzoate. The injection of oestradiol benzoate may have delayed the emergence of the first follicular wave subsequent to the induced ovulation; administration of oestradiol benzoate or GnRH lowered the progesterone rise so that the maximum dioestrous concentration of progesterone on Day 9 was lower when cows were treated during pro-oestrus compared to the spontaneously ovulating controls. One implication of findings from the present study is that induction of ovulation with either oestradiol benzoate or GnRH, administered 24 or 36 h after withdrawal of the CIDR device, respectively, may lower fertility. Future studies must identify the timing of administration relative to the time of CIDR device withdrawal and the optimum concentration of oestradiol benzoate or GnRH that would not have untoward effects on the development of the corpus lutea, particularly within the first week of dioestrus.

  7. Administration of a GnRH analog on day 9 of a 14-day controlled internal drug release insert with timed artificial insemination in lactating beef cows.

    Science.gov (United States)

    Giles, R L; Ahola, J K; Whittier, J C; French, J T; Repenning, P E; Kruse, S G; Seidel, G E; Peel, R K

    2013-04-01

    Many estrus synchronization protocols aim to induce a new follicular wave to improve response and enhance pregnancy rate. Our objectives were to determine the effectiveness of GnRH analog administered d 0 and 9 during an extended controlled internal drug release (CIDR) protocol to produce 2 follicular waves, induce cyclicity in anestrus cows, and evaluate the efficacy of a single 50-mg dose of PGF2α to initiate luteal regression on CIDR removal. Lactating beef cows (n = 779) at 3 locations (n = 247, location 1; n = 395, location 2; n = 137, location 3) were randomly assigned to 1 of 3 treatments. Cows in the 14-d 50 PG treatment received a CIDR (1.38 g progesterone) with 100 μg GnRH analog intramuscularly (i.m.) on d 0, 100 μg GnRH analog i.m. on d 9, and CIDR removal concurrent with 50 mg PGF2α i.m. on d 14. Cows in the 14-d 6-h PG treatment were assigned the same protocol as the 14-d 50 PG treatment except that 25 mg PGF2α i.m. was given on d 14 plus 25 mg PGF2α i.m. 6 ± 1 h later. Cows in the control treatment, 5-d CO-Synch + CIDR (5-d CO-Synch), received a CIDR concurrent with 100 μg GnRH analog i.m. on d 9, CIDR removal concurrent with 25 mg PGF2α i.m. on d 14, and 25 mg PGF2α i.m. 6 ± 1 h after first F2α injection. Cows in all treatments received 100 μg GnRH analog i.m. and timed AI (TAI) 72 ± 3 h after CIDR removal. Pregnancy status to TAI was determined by ultrasonography 37 to 40 d after TAI. Averaged over all locations, pregnancy rates to TAI for 14-d 50 PG, 14-d 6-h PG, and 5-d CO-Synch treatments were 58.2%, 46.8%, and 41.9%, respectively. Pregnancy rates to TAI were greater (P 1 ng/mL at either (or both) bleeding date were considered cyclic. Averaged over the 2 locations, there was a tendency (P = 0.06) for a greater number of cyclic animals to become pregnant to TAI in the 14-d 50 PG treatment (64.4%) than 5-d CO-Synch treatment (50.2%). The 14-d CIDR with GnRH analog on d 0 and 9 and a single 50-mg dose of PG i.m. at CIDR removal was a

  8. Comparison of early versus late initiation of GnRH antagonist co-treatment for controlled ovarian stimulation in IVF: a randomized controlled trial.

    Science.gov (United States)

    Hamdine, O; Macklon, N S; Eijkemans, M J C; Laven, J S E; Cohlen, B J; Verhoeff, A; van Dop, P A; Bernardus, R E; Lambalk, C B; Oosterhuis, G J E; Holleboom, C A G; van den Dool-Maasland, G C; Verburg, H J; van der Heijden, P F M; Blankhart, A; Fauser, B C J M; Broekmans, F J

    2013-12-01

    What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P

  9. MOBILE AGENT: EMERGING TECHNOLOGY

    OpenAIRE

    RAJGURU P. V. DR. DESHMUKH S. D

    2011-01-01

    Mobile agent technology has been promoted as an emerging technology that makes it much easier to design, implement, and maintain distributed systems, introduction to basic concepts of mobile agents like agent mobility, agent types and places and agent communication. Then benefits of the usage of mobile agents are summarized and illustrated by selected applications. The next section lists requirements and desirable properties for mobile agent languages and systems. We study the main features, ...

  10. Molecular cloning, sequencing, and distribution of feline GnRH receptor (GnRHR) and resequencing of canine GnRHR.

    Science.gov (United States)

    Samoylov, Alexandre M; Napier, India D; Morrison, Nancy E; Martin, Douglas R; Cox, Nancy R; Samoylova, Tatiana I

    2015-01-15

    GnRH receptors play vital roles in mammalian reproduction via regulation of gonadotropin secretion, which is essential for gametogenesis and production of gonadal steroids. GnRH receptors for more than 20 mammalian species have been sequenced, including human, mouse, and dog. This study reports the molecular cloning and sequencing of GnRH receptor (GnRHR) cDNA from the pituitary gland of the domestic cat, an important species in biomedical research. Feline GnRHR cDNA is composed of 981 nucleotides and encodes a 327 amino acid protein. Unlike the majority of mammalian species sequenced so far, but similar to canine GnRHR, feline GnRHR protein lacks asparagine in position three of the extracellular domain of the protein. At the amino acid level, feline GnRHR exhibits 95.1% identity with canine, 93.8% with human, and 88.9% with mouse GnRHR. Comparative sequence analysis of GnRHRs for multiple mammalian species led to resequencing of canine GnRHR, which differed from that previously published by a single base change that translates to a different amino acid in position 193. This single base change was confirmed in dogs of multiple breeds. Reverse transcriptase PCR analysis of GnRHR messenger RNA in different tissues from four normal cats indicated the presence of amplicons of varying lengths, including full-length as well as shortened GnRHR amplicons, pointing to the existence of truncated GnRHR transcripts in the domestic cat. This study is the first insight into molecular composition and expression of feline GnRHR and promotes better understanding of receptor organization, and distribution in various tissues of this species.

  11. Comparative study between uses of GnRH- agonist versus hCG as an ovulation trigger in patients with polycystic ovary syndrome in antagonist protocol

    Directory of Open Access Journals (Sweden)

    Poornima Nadkarni

    2015-08-01

    Full Text Available Background: Polycystic ovary syndrome is one of the major causes of infertility. Almost 75% of ovulatory women have PCOS. Ovarian hyperstimulation syndrome and multiple pregnancies are known complications of PCOS in ART. Many studies are available now, to reduce the incidence and severity of OHSS in these patients, at the same time achieving acceptable pregnancy rate .In our study, we used Antagonist protocol in PCOS patients and compared the results using GnRH-Agonist versus hCG as ovulation trigger. Methods: This is double blinded comparative study between uses of GnRH- Agonist versus hCG as an ovulation trigger in 100 patients with polycystic ovary syndrome in antagonist protocol, done in private ART setting. In the study, 100 patients randomly allotted in two groups (A and B, each 50 patients, given ovulation trigger (When leading three follicles were >18 mm as group A-GnRH-Agonist (Inj. Triptoreline 0.1 mg, 12 hours apart two doses subcutaneously and group B hCG as (Inj. Recombinant hCG, 250 mcg single dose subcutaneously. Results: In our study, In 50 patients of group A, total 31 patients were pregnant. In group B of 50 cases, 29 patients were pregnant. There was no significant difference between two groups (P>0.05. Incidence of ovarian hyperstimulation syndrome is significantly less in PCOS patients, when GnRH agonist is used as ovulation trigger in Antagonist protocol, as compared to hCG (P 0.05. None patient of two groups developed severe OHSS. Conclusions: Incidence of the ovarian hyperstimulation syndrome is significantly less in patients with Polycystic Ovarian Syndrome when GnRH agonist is used as an ovulation trigger, as compared to hCG, in Antagonist protocol. In our study, there was no significant difference in pregnancy rates between two groups. [Int J Reprod Contracept Obstet Gynecol 2015; 4(4.000: 1161-1164

  12. A randomized assessor-blind trial comparing highly purified hMG and recombinant FSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer

    DEFF Research Database (Denmark)

    Devroey, Paul; Pellicer, Antonio; Nyboe Andersen, Anders;

    2012-01-01

    OBJECTIVE: To compare the efficacy and safety of highly purified menotropin (hphMG) and recombinant FSH (rFSH) for controlled ovarian stimulation in a GnRH antagonist cycle with compulsory single-blastocyst transfer. DESIGN: Randomized, open-label, assessor-blind, parallel groups, multicenter......, noninferiority trial. SETTING: Twenty-five infertility centers in seven countries. PATIENT(S): Seven hundred forty-nine women. INTERVENTION(S): Controlled ovarian stimulation with hphMG or rFSH in a GnRH antagonist cycle with compulsory single-blastocyst transfer on day 5 in one fresh or subsequent frozen......% and 38% for women treated with hphMG and rFSH, respectively (both PP and ITT). Significant differences in pharmacodynamic end points were found between the two gonadotropin preparations. CONCLUSION(S): Highly purified hMG is at least as effective as rFSH in GnRH antagonist cycles with compulsory single...

  13. Endometrial gene expression in the early luteal phase is impacted by mode of triggering final oocyte maturation in recFSH stimulated and GnRH antagonist co-treated IVF cycles

    DEFF Research Database (Denmark)

    Humaidan, P; Van Vaerenbergh, I; Bourgain, C

    2012-01-01

    Do differences in endometrial gene expression exist after ovarian stimulation with four different regimens of triggering final oocyte maturation and luteal phase support in the same patient? SUMMARY ANSWER: Significant differences in the expression of genes involved in receptivity and early...... implantation were seen between the four protocols. WHAT IS KNOWN ALREADY: GnRH agonist triggering is an alternative to hCG triggering in GnRH antagonist co-treated cycles, resulting in an elimination of early ovarian hyperstimulation syndrome. Whereas previous studies have revealed a low ongoing clinical...... pregnancy rate after GnRH agonist trigger due to a high early pregnancy loss rate, despite supplementation with the standard luteal phase support, more recent studies, employing a 'modified' luteal phase support including a bolus of 1500 IU hCG on the day of oocyte aspiration, have reported ongoing...

  14. Comportamiento reproductivo de ovejas F1 (Damara x Merino) sincronizadas con CIDR y dos tiempos de aplicación de GnRH

    OpenAIRE

    JJ Martínez-Tinajero; MT Sánchez Torres-Esqueda; G Torres-Hernández; JG Herrera-Haro; L Bucio-Alanís; R. Rojo-Rubio; J. Hernández-Martínez

    2008-01-01

    Este experimento se realizó para evaluar el comportamiento reproductivo en ovejas F1 (Damara x Merino) importadas de Australia, sincronizadas con un dispositivo liberador de la hormona (CIDR) y dos tiempos de aplicación de hormona liberadora de gonadotropinas (GnRH). Cuarenta y cinco ovejas F1 de primer parto con 18.08 ± 0.07 meses de edad y 43.3 ± 5.6 kg de peso corporal, fueron asignadas aleatoriamente a uno de tres tratamientos: T1 (n = 15): CIDR por doce días; T2 (n = 15): CIDR por doce d...

  15. Expression of salmon gonadotropin-releasing hormone (GnRH) and chicken GnRH-II precursor messenger ribonucleic acids in the brain and ovary of goldfish.

    Science.gov (United States)

    Lin, X W; Peter, R E

    1996-03-01

    The complementary DNAs (cDNA) encoding the [Trp7Leu8]gonadotropin-releasing hormone (salmon GnRH; sGnRH) precursor and the [His5Trp7Tyr8]GnRH (chicken GnRH-II; cGnRH-II) precursor of the goldfish brain were isolated and sequenced using reverse transcription and rapid amplification of cDNA ends (RACE). The sGnRH precursor cDNA consists of 540 bp, including an open reading frame of 282 bp, and the cGnRH-II precursor cDNA consists of 682 bp, including an open reading frame of 258 bp. The 94 amino acid-long goldfish sGnRH precursor and 86 amino acid-long goldfish cGnRH-II precursor have the same molecular architecture as GnRH precursors identified to date in other vertebrate species. Using two sets of primers designed to be sense and antisense to the goldfish brain sGnRH precursor cDNA sequence, reverse transcription-polymerase chain reaction (RT-PCR) amplification of total RNA from brain and ovary at gonadal recrudescent, mature ( = prespawning), and postovulatory stages resulted in two predicted sizes of PCR products. The intensities of staining signals of ethidium bromide were similar between brain and ovary samples. The same RT-PCRs were carried out with two sets of primers for cGnRH-II precursor cDNA, resulting in two PCR products of predicted size; however, the ethidium bromide staining signals are much weaker for products amplified from ovarian cDNA than that from brain cDNA. Restriction enzyme analysis verified the expected RT-PCR products. Sequence analysis of ovarian sGnRH precursor cDNA generated by RACE of total RNA from recrudescent ovarian tissue revealed the identical sequence to that of the brain sGnRH cDNA. Northern blot analysis detected a single mRNA transcript of approximately 650 bases for the sGnRH precursor in both the brain and ovary, and 750 bases for the cGnRH-II precursor in the brain. These results demonstrate that two forms of GnRH precursor (sGnRH and cGnRH-II) mRNA are expressed in goldfish brain tissue and that the sGnRH transcript and a

  16. Pharmacokinetic/Pharmacodynamic Modelling of GnRH Antagonist Degarelix: A Comparison of the Non-linear Mixed-Effects Programs NONMEM and NLME

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg

    2004-01-01

    In this paper, the two non-linear mixed-effects programs NONMEM and NLME were compared for their use in population pharmacokinetic/pharmacodynamic (PK/PD) modelling. We have described the first-order conditional estimation (FOCE) method as implemented in NONMEM and the alternating algorithm in NLME...... proposed by Lindstrom and Bates. The two programs were tested using clinical PK/PD data of a new gonadotropin-releasing hormone (GnRH) antagonist degarelix currently being developed for prostate cancer treatment. The pharmacokinetics of intravenous administered degarelix was analysed using a three...

  17. Progesterone (CIDR)-based timed AI protocols using GnRH, porcine LH or estradiol cypionate for dairy heifers: ovarian and endocrine responses and pregnancy rates.

    Science.gov (United States)

    Ambrose, J D; Kastelic, J P; Rajamahendran, R; Aali, M; Dinn, N

    2005-10-15

    The overall objective was to compare the efficacy of GnRH, porcine LH (pLH) and estradiol cypionate (ECP), in a modified Ovsynch/fixed-time AI (FTAI) protocol that included a controlled internal drug [progesterone] release (CIDR) device. In Experiment 1, heifers received a CIDR on Day -10, and PGF (25mg) on Day -3. At CIDR insertion, heifers received 100 microg of GnRH (n=6), 0.5mg of ECP (n=6), 5.0mg of pLH (n=6) or 2 mL of saline (n=7); these treatments were repeated on Day -1, except for ECP, that was repeated on Day -2, concurrent with CIDR-removal. The 5.0 mg pLH was the least effective with a longer interval to ovulation than the other groups combined (102 versus 64 h; PpLH compared to all other groups (4.5 versus 10.3 ng/mL; PpLH (n=6; pLH-low), 25.0 mg pLH (n=6, pLH-high), or 100 microg GnRH (n=5; control). Heifers in the pLH-high group had greater (PpLH treatments did not differ (P>0.10). Area under the curve for LH (ng/32 h) was at least 50% greater (PpLH-treated heifers compared to GnRH-treated heifers (mean, 41.3, 56.3 and 20.3 for pLH-low, pLH-high and GnRH, respectively). Ovulation occurred in 15 of 17 heifers. Progesterone concentrations were higher on Days 9 and 14 in heifers given 25mg of pLH, suggesting enhanced CL function. In Experiment 3, 240 heifers were assigned to CIDR-based Ovsynch/FTAI protocols. The first and second hormonal treatments (with an intervening PGF treatment on Day -3) were GnRH/GnRH (100 microg), ECP/ECP (0.5 mg), pLH/pLH (12.5 mg) or GnRH/ECP, respectively; pregnancy rates were 58.7, 66.1, 45.9 and 48.3%, respectively (ECP/ECP>both pLH/pLH and GnRH/ECP; P

  18. Comparison of three superovulation protocols with or without GnRH treatment at the time of artificial insemination on ovarian response and embryo quality in Thai native heifers.

    Science.gov (United States)

    Chankitisakul, Vibuntita; Pitchayapipatkul, Jakkhaphan; Chuawongboon, Phirawit; Rakwongrit, Dumrongrak; Sakhong, Denpong; Boonkum, Wuttigrai; Vongpralub, Thevin

    2017-03-01

    To optimize the superovulation protocol in Thai native cattle, the present research was designed to (1) compare three different protocols designed to induce superstimulation and (2) study the effect of gonadotropin-releasing hormone (GnRH) administration at insemination time (to induce ovulation) on ovarian follicular activities in terms of the number of large follicles, corpora lutea (CLs) and unovulated follicles, and the number and quality of ova/embryos recovered in Thai native heifers. Initially, the estrous cycles of animals (n = 36) at unknown stages were synchronized by two prostaglandin F2α (PGF2α) injections at an interval of 12 days. Follicular development of heifers was randomly superstimulated with one of three different treatment protocols: treatment A-a total of 100 mg of pituitary-derived FSH (pFSH; Folltropin®-V) administered in eight decreasing doses; treatment B-a single dose of 100 mg pFSH dissolved in 30% (w/v) polyvinylpyrrolidone; or treatment C-ablation of all follicles ≥5 mm with a single dose of pFSH. All heifers received PGF2α 48 h after the initiation of FSH treatment to induce luteolysis from the previous cycle, and they were twice inseminated at 12 and 24 h after the onset of estrus. Heifers in each treatment were assigned to be injected or not with GnRH at the time of first insemination with frozen/thawed semen to induce ovulation. About 7 days after artificial insemination (AI), ova/embryos were collected and classified. The numbers of large follicles at the onset of estrus were not statistically significantly different; meanwhile, the maximum diameters of follicles at the time of first insemination in treatment C were smaller compared with the other treatment groups (p < 0.001). The administration of GnRH at the first insemination time resulted in a greater number of CLs and fewer unovulated follicles at the time of ova/embryo collection (p = 0.001), which subsequently resulted in a higher number of total

  19. Comportamiento reproductivo de ovejas F1 (Damara x Merino) sincronizadas con CIDR y dos tiempos de aplicación de GnRH

    OpenAIRE

    JJ Martínez-Tinajero

    2008-01-01

    Este experimento se realizó para evaluar el comportamiento reproductivo en ovejas F1 (Damara x Merino) importadas de Australia, sincronizadas con un dispositivo liberador de la hormona (CIDR) y dos tiempos de aplicación de hormona liberadora de gonadotropinas (GnRH). Cuarenta y cinco ovejas F1 de primer parto con 18.08 ± 0.07 meses de edad y 43.3 ± 5.6 kg de peso corporal, fueron asignadas aleatoriamente a uno de tres tratamientos: T1 (n = 15): CIDR por doce días; T2 (n = 15): CIDR por doce d...

  20. Effect of estradiol cypionate and GnRH treatment on plasma estradiol-17β concentrations, synchronization of ovulation and on pregnancy rates in suckled beef cows treated with FTAI-based protocols.

    Science.gov (United States)

    Uslenghi, G; Vater, A; Rodríguez Aguilar, S; Cabodevila, J; Callejas, S

    2016-10-01

    Two experiments were conducted to evaluate the effect of different ovulation inducers on E-17β plasma concentrations, synchronized ovulations and pregnancy rates. In Experiment 1, cows received a progesterone intravaginal device (PID) with 1 g of progesterone (P4) plus 2 mg of estradiol benzoate (EB) (day 0). At PID removal (day 8), cows received 0.150 mg of D-cloprostenol and were randomly assigned to four treatment groups (n = 10/treatment): Group ECP: 1 mg of estradiol cypionate at PID removal, Group EB: 1 mg of EB 24 hr after PID removal, Group GnRH: 10 μg of GnRH 48 hr after PID removal, Group ECP-GnRH: 1 mg of ECP at PID removal plus 10 μg of GnRH 48 hr later. Ultrasonographic examinations were performed to detect the dominant follicle and ovulation. GnRH-treated cows ovulated later (p decreased later compared to treatments without ECP. In Experiment 2, cows received (i) ECP: n = 126; (ii) EB: n = 126; (iii) GnRH: n = 136; (iv) ECP+GnRH: n = 139; FTAI was performed 48-50 hr after PID removal. Pregnancy rates did not differ among ovulation inducers (p > .05; ECP: 54.0%, 68/126; EB: 49.2%, 62/126; GnRH: 40.4%, 55/136; ECP+GnRH: 43.9%, 61/139). In conclusion, ECP administration (ECP and ECP+GnRH treatments) affected E-17β concentrations, determining its earlier increase and later decrease compared to treatments without ECP (EB and GnRH treatments). ECP+GnRH-treated cows achieved the best distribution of ovulations without affecting pregnancy rates.

  1. 妊娠与非妊娠大鼠子宫内膜促性腺激素释放激素及其受体的免疫组织化学研究%IMMUNOHISTOCHEMICAL LOCALIZATION OF GnRH AND GnRH RECEPTOR IN THE ENDOMETRIUM OF PREGNANT RATS AND UNPREGNANT RATS

    Institute of Scientific and Technical Information of China (English)

    夏永娟; 黄威权

    2001-01-01

    目的:研究促性腺激素释放激素(GnRH)及其受体在妊娠与非妊娠大鼠子宫内膜中的分布及相对含量,为了解促性腺激素释放激素对子宫内膜的可能功能提供依据。方法:免疫组织化学ABC法及图像分析技术。结果:非妊娠大鼠子宫内促性腺激素释放激素及促性腺激素释放激素受体阳性反应发生在内膜上皮、腺上皮及基质细胞。妊娠大鼠子宫内这二者阳性反应主要发生在内膜上皮及基蜕膜的蜕膜细胞,妊娠大鼠子宫上皮细胞中的促性腺激素释放激素及其受体的相对含量明显高于非妊娠大鼠子宫内膜。结论:妊娠与非妊娠大鼠子宫内膜均能表达促性腺激素释放激素及其受体。%Objective: To study the distribution and relative contents of GnRH and GnRH receptor in the endometrium in pregnant rats and unpregnant rat. Methids: Immunohistochemical ABC method and image analysis were used in the experiment. Results: GnRH and GnRH recepter positive immunoreaction occured in the endometrium epithelium and the glandular epithelium of unpregnant rats, and in the endometrium epithelium and deciduate cells of the basal decidua of rpegnant rat.Conclusion: The GnRH may take partin regulating endometrial function through its receptor, its effect on endometrium may be strong in pregnant uterine than in unpregnant.

  2. Riot Control Agents

    Science.gov (United States)

    ... Submit What's this? Submit Button Facts About Riot Control Agents Interim document Recommend on Facebook Tweet Share Compartir FACT SHEET What riot control agents are Riot control agents (sometimes referred to ...

  3. Interacting agents in finance

    NARCIS (Netherlands)

    C. Hommes

    2008-01-01

    Interacting agents in finance represent a behavioural, agent-based approach in which financial markets are viewed as complex adaptive systems consisting of many boundedly rational agents interacting through simple heterogeneous investment strategies, constantly adapting their behaviour in response t

  4. Interacting agents in finance

    NARCIS (Netherlands)

    Hommes, C.; Durlauf, S.N.; Blume, L.E.

    2008-01-01

    Interacting agents in finance represent a behavioural, agent-based approach in which financial markets are viewed as complex adaptive systems consisting of many boundedly rational agents interacting through simple heterogeneous investment strategies, constantly adapting their behaviour in response

  5. Intermittent treatment with parathyroid hormone (PTH) as well as a non-peptide small molecule agonist of the PTH1 receptor inhibits adipocyte differentiation in human bone marrow stromal cells.

    Science.gov (United States)

    Rickard, David J; Wang, Fei-Lan; Rodriguez-Rojas, Ana-Maria; Wu, Zining; Trice, Wen J; Hoffman, Sandra J; Votta, Bartholomew; Stroup, George B; Kumar, Sanjay; Nuttall, Mark E

    2006-12-01

    Whereas continuous PTH infusion increases bone resorption and bone loss, intermittent PTH treatment stimulates bone formation, in part, via reactivation of quiescent bone surfaces and reducing osteoblast apoptosis. We investigated the possibility that intermittent and continuous PTH treatment also differentially regulates osteogenic and adipocytic lineage commitment of bone marrow stromal progenitor/mesenchymal stem cells (MSC). The MSC were cultured under mildly adipogenic conditions in medium supplemented with dexamethasone, insulin, isobutyl-methylxanthine and troglitazone (DIIT), and treated with 50 nM human PTH(1-34) for either 1 h/day or continuously (PTH replenished every 48 h). After 6 days, cells treated with PTH for 1 h/day retained their normal fibroblastic appearance whereas those treated continuously adopted a polygonal, irregular morphology. After 12-18 days numerous lipid vacuole and oil red O-positive adipocytes had developed in cultures treated with DIIT alone, or with DIIT and continuous PTH. In contrast, adipocyte number was reduced and alkaline phosphatase staining increased in the cultures treated with DIIT and 1 h/day PTH, indicating suppression of adipogenesis and possible promotion of early osteoblastic differentiation. Furthermore, intermittent but not continuous PTH treatment suppressed markers of differentiated adipocytes such as mRNA expression of lipoprotein lipase and PPARgamma as well as glycerol 3-phosphate dehydrogenase activity. All of these effects of intermittent PTH were also produced by a 1 h/day treatment with AH3960 (30 microM), a small molecule, non-peptide agonist of the PTH1 receptor. AH3960, like PTH, activates both the cAMP and calcium signaling pathways. Treatment with the adenylyl cyclase activator forskolin for 1 h/day, mimicked the anti-adipogenic effect of intermittent PTH, whereas pretreatment with the protein kinase-A inhibitor H89 prior to intermittent PTH resulted in almost complete conversion to adipocytes. In

  6. Significantly lower pregnancy rates in the presence of progesterone elevation in patients treated with GnRH antagonists and gonadotrophins: a systematic review and meta-analysis.

    Science.gov (United States)

    Kolibianakis, E M; Venetis, C A; Bontis, J; Tarlatzis, B C

    2012-03-01

    The current meta-analysis aimed to answer the following research question: is progesterone elevation on the day of hCG administration associated with the probability of clinical pregnancy in women undergoing ovarian stimulation for IVF using GnRH antagonists? A literature search in MEDLINE, EMBASE and CENTRAL electronic databases followed by extensive hand-searching from two independent reviewers was performed to identify relevant studies. Eventually five eligible studies (n=585 patients) were identified. No significant differences were present between patients with and those without progesterone elevation regarding female age, duration of stimulation and total dose of gonadotrophins required. However, patients with progesterone elevation were characterized by higher serum estradiol levels on the day of hCG administration (+956 pg/ml, 95% +248 to +1664, random effects model, p=0.008) and more COCs retrieved (+2.9, 95% CI +1.5 to +4.4, fixed effects model, p decreased probability of clinical pregnancy per cycle (-9%, 95% CI -17 to -2, fixed model effects, p). In conclusion, in patients treated with GnRH antagonists and gonadotrophins, progesterone elevation on the day of hCG administration is significantly associated with a lower probability of clinical pregnancy.

  7. The carboxy-terminal tail or the intracellular loop 3 is required for β-arrestin-dependent internalization of a mammalian type II GnRH receptor.

    Science.gov (United States)

    Madziva, Michael T; Mkhize, Nonhlanhla N; Flanagan, Colleen A; Katz, Arieh A

    2015-08-15

    The type II GnRH receptor (GnRH-R2) in contrast to mammalian type I GnRH receptor (GnRH-R1) has a cytosolic carboxy-terminal tail. We investigated the role of β-arrestin 1 in GnRH-R2-mediated signalling and mapped the regions in GnRH-R2 required for recruitment of β-arrestin, employing internalization assays. We show that GnRH-R2 activation of ERK is dependent on β-arrestin and protein kinase C. Appending the tail of GnRH-R2 to GnRH-R1 enabled GRK- and β-arrestin-dependent internalization of the chimaeric receptor. Surprisingly, carboxy-terminally truncated GnRH-R2 retained β-arrestin and GRK-dependent internalization, suggesting that β-arrestin interacts with additional elements of GnRH-R2. Mutating serine and threonine or basic residues of intracellular loop 3 did not abolish β-arrestin 1-dependent internalization but a receptor lacking these basic residues and the carboxy-terminus showed no β-arrestin 1-dependent internalization. Our results suggest that basic residues at the amino-terminal end of intracellular loop 3 or the carboxy-terminal tail are required for β-arrestin dependent internalization.

  8. Distribution Patterns and Developmental Changes of GnRH and GnRHR-Immunopositive Cells in the Pituitary of Ji Ning Gray Goats

    Directory of Open Access Journals (Sweden)

    Liu Xiao, Wang Shu-Ying, Huang Li-Bo, Hou Yan-Meng and Shi Yun-Zhi

    2014-01-01

    Full Text Available Immunohistochemical Strept Avidin Biotin-Peroxidase Complex (SABC three-step method was used to investigate the distribution patterns and developmental changes of GnRH and GnRHR immunopositive (GnRH-ip and GnRHR-ip cells in the pituitary of Ji Ning Gray goats during 0-180 days of age. The results showed that GnRH-ip and GnRHR-ip cells were detected only in the pars distalis of adenohypophysis. There were no positive cells in the pars intermedia and neurohypophysis. GnRH-ip and GnRHR-ip cells were not observed in the anterior pituitary at birth day and 30 days of age. At 60 days, a number of GnRH-ip and GnRHR-ip cells were found in the anterior pituitary. GnRH-ip cells were pale brown which scattered or clustered around the sinusoid capillary; GnRHR-ip cells were brown and the cytomembrane was darker. The size and percentage of GnRH-ip and GnRHR-ip cells increased with the age growth. The numbers of GnRH-ip and GnRHR-ip cells after sexual maturity were significantly bigger than that before sexual maturity. The results above suggested that GnRH and GnRHR in the pituitary of Ji Ning Gray goats play a pivotal role in the sexual development and sexual maturity.

  9. Direct evidence for the co-expression of URP and GnRH in a sub-population of rat hypothalamic neurones: anatomical and functional correlation.

    Directory of Open Access Journals (Sweden)

    Johann-Günther Egginger

    Full Text Available Urotensin-II-related peptide (URP is an eight amino-acid neuropeptide recently isolated from rat brain and considered as the endogenous ligand for the GPR14 receptor. Using single and double immunohistochemical labelling, in situ hybridization and ultrastructural immunocytochemistry, we explored the cellular and subcellular localization of URP in the male rat brain. URP peptide was detected in numerous varicose fibres of the median eminence (ME and organum vasculosum laminae terminalis (OVLT as well as in neuronal cell bodies of the medial septal nucleus and diagonal band of Broca where corresponding mRNA were also detected. Combining in situ hybridization with immunohistochemistry, we showed that cell bodies of the rat anterior hypothalamus contained both URP mRNA and GnRH peptide. In addition, double ultrastructural immunodetection of URP and GnRH peptides clearly revealed, in the median eminence, the co-localization of both peptides in the same neuronal processes in the vicinity of fenestrated portal vessels. This remarkable cellular and subcellular distribution led us to test the effect of URP on the GnRH-induced gonadotrophins release in the anterior pituitary, and to discuss its putative role at the level of the median eminence.

  10. Split-time artificial insemination in beef cattle: II. Comparing pregnancy rates among nonestrous heifers based on administration of GnRH at AI.

    Science.gov (United States)

    Bishop, B E; Thomas, J M; Abel, J M; Poock, S E; Ellersieck, M R; Smith, M F; Patterson, D J

    2017-01-01

    This experiment was designed to evaluate split-time artificial insemination (AI) in beef heifers following administration of the 14-day controlled internal drug release (CIDR)-prostaglandin F2α (PG) protocol and to compare pregnancy rates among nonestrous heifers based on administration of GnRH at AI. Estrus was synchronized for 1138 heifers across six locations. Heifers received a CIDR insert (1.38 g progesterone) on Day 0 with removal on Day 14. Estrus detection aids (Estrotect) were applied at PG (25 mg), 16 days after CIDR removal on Day 30. Heifers were assigned to balanced treatments based on reproductive tract score and weight, and treatments were represented within each location. Split-time AI was performed at 66 and 90 hours after PG, and estrus was recorded at these times. Heifers in both treatments that exhibited estrus by 66 hours were inseminated and did not receive GnRH, whereas AI was delayed 24 hours until 90 hours after PG for heifers that failed to exhibit estrus by 66 hours. For heifers in treatment 1 that were inseminated at 90 hours, GnRH (100 μg) was administered concurrent with AI at 90 hours. Heifers in treatment 2 that were inseminated at 90 hours did not receive GnRH. Estrous response did not differ between treatments at 66 hours after PG (treatment 1 = 70%; treatment 2 = 71%; P = 0.58) or during the 24-hour delay period (treatment 1 = 59%; treatment 2 = 52%; P = 0.21). There was no effect of treatment on pregnancy rates resulting from AI for heifers inseminated at 66 hours (treatment 1 = 58%; treatment 2 = 62%; P = 0.86) or 90 hours (treatment 1 = 44%; treatment 2 = 39%; P = 0.47) after PG; and there was no difference between treatments when considering total AI pregnancy rate (treatment 1 = 54%; treatment 2 = 56%; P = 0.60). Ovulation was confirmed via ultrasonography for a subset of heifers that failed to exhibit estrus prior to 90 hours after PG. For heifers that failed to exhibit estrus by 90

  11. Manipulation of progesterone to increase ovulatory response to the first GnRH treatment of an Ovsynch protocol in lactating dairy cows receiving first timed artificial insemination.

    Science.gov (United States)

    Carvalho, P D; Wiltbank, M C; Fricke, P M

    2015-12-01

    Ovulation to the first GnRH (G1) treatment of the Ovsynch protocol improves synchronization rate and pregnancies per AI (P/AI). Elevated progesterone (P4) concentrations at G1 decrease the ovulatory response by decreasing the magnitude of the GnRH-induced LH surge. Therefore, our objective was to evaluate the effect of temporarily decreasing P4 concentrations before initiation of an Ovsynch protocol on ovulatory response to G1 and P/AI. Lactating Holstein cows (n=800) at 53±3 (herd A) or 51±3 (herd B) d in milk (DIM) were synchronized using a modified Double-Ovsynch protocol [pre-Ovsynch protocol (d 0, GnRH; d 7, PGF2α; d 10, GnRH) followed 7 d later by an Ovsynch-56 protocol (d 0, G1; d 7, PGF2α; d 8, PGF2α; d 9.5, GnRH)] to receive first timed artificial insemination (TAI; 80±3 DIM) 16h after the last GnRH treatment. Cows were randomly assigned to receive 12.5mg of PGF2α (a half-dose of dinoprost tromethamine) 2 d before G1 (low-P4) or serve as untreated controls (high-P4). Overall, high-P4 cows had greater P4 concentrations at G1 compared with low-P4 cows (3.0 vs. 1.3ng/mL, respectively). Ovulatory response to G1 was greater for low-P4 than high-P4 cows [81.1 vs. 60.3%, respectively]. Premature luteal regression during the second Ovsynch protocol did not differ between treatments [15.0% vs. 10.7%; for low-P4 vs. high-P4 cows, respectively]. Overall, P/AI did not differ between treatments 32 d after TAI [56.3 vs. 52.9%, for low-P4 vs. high-P4 cows, respectively] or 67 d after AI [50.5 vs. 47.6%, for low-P4 vs. high-P4 cows, respectively]. Pregnancy loss from 32 to 67 d after TAI did not differ between treatments [9.9 vs. 9.3%, for low-P4 vs. high-P4 cows, respectively]. Overall, cows that ovulated to G1 had more P/AI than cows that did not ovulate [58.2 vs. 41.8%, respectively]. The increase in P/AI for cows that ovulated to G1 (16.4%) combined with the observed increase in ovulation to G1 due to treatment (20.8%; low-P4 - high-P4) resulted in the expected

  12. Synchronization of oestrus and ovulation by short time combined FGA, PGF(2α), GnRH, eCG treatments for natural service or AI fixed-time.

    Science.gov (United States)

    Martemucci, G; D'Alessandro, A G

    2011-01-01

    Two experiments were conducted in ewes in order to develop an oestrus-ovulation short time synchronization protocol based on combined FGA, PGF(2α), GnRH, eCG treatments, for use in dairy sheep before natural service (Experiment 1) or for fixed-time artificial insemination (Experiment 2), during the breeding season. In Experiment 1 seventy-five non-lactating dairy ewes were subdivided into 5 treatment groups (N=15): (1) Group Fe - control, which received FGA vaginal sponges (14 days)+eCG (Day 14); (2) Group FPe, FGA (5 days)+PGF(2α) (Day 5)+eCG (Day 5); (3) Group PFe, PGF(2α) (Day 0)+FGA (5 days)+eCG (Day 5); (4) Group PFG, PGF(2α) (Day 0)+FGA (5 days)+GnRH (30h after sponge removal, s.r.); (5) Group GPe, GnRH (Day 0)+PGF(2α) (Day 5)+eCG (Day 5). Ewes were checked for oestrus and hand-mated. Time of ovulation was recorded by laparoscopy for 10 animals from each treatment. The percentages of female in oestrus and the interval to oestrus (h after treatment), fertility and prolificacy rate were recorded. There were no treatment differences in the percentage of females in oestrus. The interval to oestrus was earlier in Fe Group and delayed in FPe Group (P<0.01). Ovulation time was earlier in GPe Group compared to FPe Group (P<0.05). Fertility rates were significantly different (P<0.05) between the PFe and the FPeG Groups compared with the PFG Group. No significant differences were observed in prolificacy among the treatments. In Experiment 2, sixty dry ewes were subdivided (N=20) into the following three experimental treatment groups: (1) Group FP, FGA (5 days)+PGF(2α) (Day 5); (2) Group FPG, FGA (5 days)+PGF(2α) (Day 5)+GnRH (30hs.r.); (3) Group FPeG, FGA (5 days)+PGF(2α) (Day 5)+eCG (Day 5)+GnRH (30hs.r.). These were further subdivided into two groups (N=10) corresponding to 52 and 60hs.r. fixed-time insemination. Laparoscopic intrauterine insemination was performed with frozen semen (80×10(6)spermatozoa/dose) and ovulation time was recorded in a subgroup (N

  13. The addition of GnRH antagonists in intrauterine insemination cycles with mild ovarian hyperstimulation does not increase live birth rates-a randomized, double-blinded, placebo-controlled trial

    NARCIS (Netherlands)

    Cantineau, A. E. P.; Cohlen, B. J.; Klip, H.; Heineman, M. J.; Hoek, Annemieke

    2011-01-01

    BACKGROUND: This multicenter, double-blinded RCT investigated the efficacy of GnRH antagonists in cycles with mild ovarian hyperstimulation (MOH) followed by IUI in subfertile women. METHODS: Couples diagnosed with unexplained, male factor subfertility or associated with the presence of minimal or m

  14. Randomized GH trial with two different dosages in combination with a GnRH analogue in short small for gestational age children: Effects on metabolic profile and serum GH, IGF1, and IGFBP3 levels

    NARCIS (Netherlands)

    D.C.M. van der Kaay (Danielle); B. Bakker (Boudewijn); F. van der Hulst (Flip); D. Mul (Dick); J.C. Mulder (Jaap); E.J. Schroor (Eelco); D. van Elswijk (Denise); I. Rowaan (Inge); M. Willeboer (Merel); M.A.J. de Ridder (Maria); A.C.S. Hokken-Koelega (Anita)

    2010-01-01

    textabstractBackground: GnRH analogue (GnRHa) combined with GH treatment has been proposed to increase adult height. Effect on metabolic profile and GH, IGF1, and IGFBP3 levels in short small for gestational age (SGA) children is unknown. Objective: To assess fat mass and lean body mass SDS, percent

  15. Biological warfare agents.

    Science.gov (United States)

    Pohanka, Miroslav; Kuca, Kamil

    2010-01-01

    Biological warfare agents are a group of pathogens and toxins of biological origin that can be potentially misused for military or criminal purposes. The present review attempts to summarize necessary knowledge about biological warfare agents. The historical aspects, examples of applications of these agents such as anthrax letters, biological weapons impact, a summary of biological warfare agents and epidemiology of infections are described. The last section tries to estimate future trends in research on biological warfare agents.

  16. Effectivness of the GnRH analogue deslorelin as a reversible contraceptive in a neotropical primate, the Common Marmoset Callithrix Jacchus (Mammalia: Primates: Callitrichidae

    Directory of Open Access Journals (Sweden)

    Derek A. Rosenfield

    2016-04-01

    Full Text Available Deslorelin is a synthetic GnRH analogue, which is being used as a contraceptive in animals by acting as a gonadal suppressant.  The product Suprelorin (Virbac, Australia contains deslorelin as a biocompatible, slow release subcutaneous implant. The continuous release of deslorelin provokes a down-regulation of GnRH receptors, and subsequently, inhibition of the synthesis and release of the gonadotropins FSH and LH, necessary for gonadal activities.  The intention of this study was to investigate the effectiveness of a subcutaneous deslorelin acetate implant (2,35mg in suppressing ovarian cyclic activity and inhibiting ovulation in captive Common Marmoset Callithrix jacchus, and investigate the reversibility of the treatment.  Two experimental groups were formed, group deslorelin (D with three couples and control group (C with two couples.  To monitor the effect of the implants, hormones indicating ovarian cyclic activity were monitored non-invasively by enzyme immunoassay (fecal monoclonal antibody anti-progesterone CL 425.  Fecal samples were collected three times a week from all females during three trial phases (phase I: month 1,2,3 and 4; phase II: month: 5,6 and 7 and phase III: month 8,9 and 10.  In contrast to expectations the results of this trial indicated that there was no suppression of the ovarian cyclic activity, nor inhibition of the ovulation after the application of the implants.  The outcome of our trial can possibly be explained by the fact that the dosage of 2.35mg of deslorelin is not effective in C. jacchus.  We confirmed significant changes (p<0.05 of P4 metabolites from phase I to phase II due to the treatment after the implantation of the GnRH analogue Deslorelin.  The employed non-invasive fecal progesterone monitoring could be biologically validated and proved to be efficient in the detection of ovarian cyclic activity in this neotropical primate species, C. jacchus. 

  17. Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse

    Science.gov (United States)

    Jacquier, Sandrine; Csaba, Zsolt; Genin, Emmanuelle; Meyer, Vincent; Leka, Sofia; Dupont, Joelle; Charles, Perrine; Chevenne, Didier; Carel, Jean-Claude; Léger, Juliane; de Roux, Nicolas

    2014-01-01

    Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological

  18. Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.

    Directory of Open Access Journals (Sweden)

    Brooke Tata

    2014-09-01

    Full Text Available Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH and follicle-stimulating hormone (FSH within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a

  19. Haploinsufficiency of Dmxl2, encoding a synaptic protein, causes infertility associated with a loss of GnRH neurons in mouse.

    Science.gov (United States)

    Tata, Brooke; Huijbregts, Lukas; Jacquier, Sandrine; Csaba, Zsolt; Genin, Emmanuelle; Meyer, Vincent; Leka, Sofia; Dupont, Joelle; Charles, Perrine; Chevenne, Didier; Carel, Jean-Claude; Léger, Juliane; de Roux, Nicolas

    2014-09-01

    Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological

  20. Hindbrain lactate regulates preoptic gonadotropin-releasing hormone (GnRH) neuron GnRH-I protein but not AMPK responses to hypoglycemia in the steroid-primed ovariectomized female rat.

    Science.gov (United States)

    Shrestha, P K; Briski, K P

    2015-07-09

    Steroid positive-feedback activation of the gonadotropin-releasing hormone (GnRH)-pituitary luteinizing hormone (LH) neuroendocrine axis propagates the pre ovulatory LH surge, a crucial component of female reproduction. Our work shows that this key event is restrained by inhibitory metabolic input from hindbrain A2 noradrenergic neurons. GnRH neurons express the ultra-sensitive energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK); here, we investigated the hypothesis that GnRH nerve cell AMPK and peptide neurotransmitter responses to insulin-induced hypoglycemia are controlled by hindbrain lack of the oxidizable glycolytic end-product L-lactate. Data show that hypoglycemic inhibition of LH release in steroid-primed ovariectomized female rats was reversed by coincident caudal hindbrain lactate infusion. Western blot analyses of laser-microdissected A2 neurons demonstrate hypoglycemic augmentation [Fos, estrogen receptor-beta (ER-β), phosphoAMPK (pAMPK)] and inhibition (dopamine-beta-hydroxylase, GLUT3, MCT2) of protein expression in these cells, responses that were normalized by insulin plus lactate treatment. Hypoglycemia diminished rostral preoptic GnRH nerve cell GnRH-I protein and pAMPK content; the former, but not the latter response was reversed by lactate. Results implicate caudal hindbrain lactoprivic signaling in hypoglycemia-induced suppression of the LH surge, demonstrating that lactate repletion of that site reverses decrements in A2 catecholamine biosynthetic enzyme and GnRH neuropeptide precursor protein expression. Lack of effect of lactate on hypoglycemic patterns of GnRH AMPK activity suggests that this sensor is uninvolved in metabolic-inhibition of positive-feedback-stimulated hypophysiotropic signaling to pituitary gonadotropes.

  1. The distribution of substance P and kisspeptin in the mediobasal hypothalamus of the male rhesus monkey and a comparison of intravenous administration of these peptides to release GnRH as reflected by LH secretion

    Science.gov (United States)

    Kalil, Bruna; Ramaswamy, Suresh; Plant, Tony M.

    2016-01-01

    Substance P (SP) was recently reported to be expressed in human KNDy neurons and to enhance KNDy neuron excitability in the mouse hypothalamus. We therefore examined 1) interactions of SP and kisspeptin in the mediobasal hypothalamus of adult male rhesus monkeys using immunofluorescence, and 2) the ability of SP to induce LH release in GnRH primed, agonadal juvenile male monkeys. SP cell bodies were observed only occasionally in the arcuate nucleus (Arc), but more frequently dorsal to the Arc in the region of the pre-mammilary nucleus. Castration resulted in an increase in the number of SP cell bodies in the Arc but not in the other nuclei. SP fibers innervated the Arc where they were found in close apposition with kisspeptin perikarya in the periphery of this nucleus. Beaded SP axons projected to the median eminence where they terminated in the external layer and intermingled with beaded kisspeptin axons. Colocalization of the two peptides, however, was not observed. Although close apposition between SP fibers and kisspeptin neurons suggest a role for SP in modulating GnRH pulse generator activity, iv injections of SP failed to elicit release of GnRH (as reflected by LH) in the juvenile monkey. Although the finding of structural interactions between SP and kisspeptin neurons are consistent with the notion that this tachykinin may be involved in regulating pulsatile GnRH release, the apparent absence of expression of SP in KNDy neurons suggests that this peptide is unlikely to be a fundamental component of the primate GnRH pulse generator. PMID:26580201

  2. Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females.

    Science.gov (United States)

    True, Cadence; Verma, Saurabh; Grove, Kevin L; Smith, M Susan

    2013-08-01

    Cocaine- and amphetamine-regulated transcript (CART) is a hypothalamic neuropeptide implicated in both metabolic and reproductive regulation, raising the possibility that CART plays a role in reproductive inhibition during negative metabolic conditions. The current study characterized CART's regulatory influence on GnRH and kisspeptin (Kiss1) cells and determined the sensitivity of different CART populations to negative energy balance. CART fibers made close appositions to 60% of GnRH cells, with the majority of the fibers (>80%) originating from the arcuate nucleus (ARH) CART/pro-opiomelanocortin population. Electrophysiological recordings in GnRH-green fluorescent protein rats demonstrated that CART postsynaptically depolarizes GnRH cells. CART fibers from the ARH were also observed in close contact with Kiss1 cells in the ARH and anteroventral periventricular nucleus (AVPV). Recordings in Kiss1-GFP mice demonstrated CART also postsynaptically depolarizes ARH Kiss1 cells, suggesting CART may act directly and indirectly, via Kiss1 populations, to stimulate GnRH neurons. CART protein and mRNA levels were analyzed in 2 models of negative energy balance: caloric restriction (CR) and lactation. Both CART mRNA levels and the number of CART-immunoreactive cells were suppressed in the ARH during CR but not during lactation. AVPV CART mRNA was suppressed during CR, but not during lactation when there was a dramatic increase in CART-immunoreactive cells. These data suggest differing regulatory signals of CART between the models. In conclusion, both morphological and electrophysiological methods identify CART as a novel and potent stimulator of Kiss1 and GnRH neurons and suppression of CART expression during negative metabolic conditions could contribute to inhibition of the reproductive axis.

  3. Role of GnRH Neurons and Their Neuronal Afferents as Key Integrators between Food Intake Regulatory Signals and the Control of Reproduction

    Directory of Open Access Journals (Sweden)

    Juan Roa

    2013-01-01

    Full Text Available Reproductive function is regulated by a plethora of signals that integrate physiological and environmental information. Among others, metabolic factors are key components of this circuit since they inform about the propitious timing for reproduction depending on energy availability. This information is processed mainly at the hypothalamus that, in turn, modulates gonadotropin release from the pituitary and, thereby, gonadal activity. Metabolic hormones, such as leptin, insulin, and ghrelin, act as indicators of the energy status and convey this information to the reproductive axis regulating its activity. In this review, we will analyse the central mechanisms involved in the integration of this metabolic information and their contribution to the control of the reproductive function. Particular attention will be paid to summarize the participation of GnRH, Kiss1, NPY, and POMC neurons in this process and their possible interactions to contribute to the metabolic control of reproduction.

  4. Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol.

    Directory of Open Access Journals (Sweden)

    Georg Griesinger

    Full Text Available What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS based on the number of growing follicles ≥ 11 mm and/or estradiol (E2 levels?The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2 levels were less prognostic of OHSS than the number of follicles ≥ 11 mm.In comparison to long gonadotropin-releasing hormone (GnRH agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF, while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years IVF population treated in a GnRH-antagonist protocol.From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses.The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH in a gonadotropin-releasing hormone (GnRH-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG, and a combination of both, were determined.The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at

  5. Uso de antagonistas de la hormona liberadora de gonadotrofinas (GnRH) en la preparación endometrial de las receptoras de ovocitos

    OpenAIRE

    2015-01-01

    INTRODUCCIÓN: La donación de ovocitos está bien establecida como técnica de reproducción asistida y ofrece la oportunidad única de tratar a mujeres con diferentes entidades clínicas, tanto con función ovárica como sin ella. En las pacientes con función ovárica conservada, se utilizan análogos de la GnRH (a-GnRH) para provocar una supresión hipofisaria, lo que permite conseguir una sincronización entre la donante y la receptora, evitando picos ovulatorios espontáneos que abrirían la ventana de...

  6. Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide.

    Science.gov (United States)

    Matsui, Hisanori; Masaki, Tsuneo; Akinaga, Yumiko; Kiba, Atsushi; Takatsu, Yoshihiro; Nakata, Daisuke; Tanaka, Akira; Ban, Junko; Matsumoto, Shin-ichi; Kumano, Satoshi; Suzuki, Atsuko; Ikeda, Yukihiro; Yamaguchi, Masashi; Watanabe, Tatsuya; Ohtaki, Tetsuya; Kusaka, Masami

    2014-07-15

    Kisspeptin/metastin, a hypothalamic peptide, plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons, and we have shown that continuous subcutaneous administration of kisspeptin analogues suppresses plasma testosterone in male rats. This study examined pharmacologic profiles of investigational kisspeptin analogues, TAK-448 and TAK-683, in male rats. Both analogues showed high receptor-binding affinity and potent and full agonistic activity for rat KISS1R, which were comparable to natural peptide Kp-10. A daily subcutaneous injection of TAK-448 and TAK-683 (0.008-8μmol/kg) for consecutive 7 days initially induced an increase in plasma luteinizing hormone and testosterone levels; however, after day 7, plasma hormone levels and genital organ weights were reduced. Continuous subcutaneous administrations of TAK-448 (≥10pmol/h, ca. 0.7nmol/kg/day) and TAK-683 (≥30pmol/h, ca. 2.1nmol/kg/day) induced a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3-7 days. This profound testosterone-lowering effect was sustained throughout 4-week dosing periods. At those dose levels, the weights of the prostate and seminal vesicles were reduced to castrate levels. These suppressive effects of kisspeptin analogues were more rapid and profound than those induced by the GnRH agonist analogue leuprolide treatment. In addition, TAK-683 reduced plasma prostate specific antigen (PSA) in the JDCaP androgen-dependent prostate cancer rat model. Thus, chronic administration of kisspeptin analogues may hold promise as a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases such as prostate cancer. Further studies are warranted to elucidate clinical significance of TAK-448 and TAK-683.

  7. EFFECT OF EXOGENOUS GnRH AND PGF2 ON POSTPARTUM ESTROUS ACTIVITY AND FERTILITY OF BUFFALOES DURING LOW BREEDING SEASON

    Directory of Open Access Journals (Sweden)

    Rafiq H. Usmani

    2001-02-01

    Full Text Available Pluriparous Nili-Ravi buffaloes (n = 18 which calved during the months of November to July were treated with a single injection of 50 g of GnRH on day 30 postpartum followed by an injection of 150 g of PGF2 seven days later. Response of hormonal treatment in terms of induced estrus within 96 hours after the injection of PGF2 was 27.8%. Only 3 buffaloes conceived at the induced estrus giving an overall fertility response of 16.7%. During first three months postpartum, 61.1% of buffaloes resumed observable estrous activity with a mean postpartum interval of 53.71+15.6 days. Ten of eighteen buffaloes (55.5% became pregnant within 90 days postpartum with an average postpartum interval of 63.01+20.0 days. Retrospective grouping of experimental buffaloes that received hormonal treatment during initial stage (n=9 or terminal stage (n=9 of the low breeding season revealed that the estrus response (within 96 hours was higher during initial than the terminal stage (44.4 vs 11.1%; P<0.05. Cumulative estrous activity during first 90 days postpartum was also higher during the initial stage (77.7 vs 44.4%; P<0.05. The mean postpartum intervals to first observed estrus (47 .3 vs 64.5 days and to conception (56.8 vs 72.5 days were significantly shorter during the initial than the terminal stage of low breeding season. It is concluded that during the low breeding season, the early postpartum Nili-Ravi buffaloes show poor response to exogenous GnRH plus PGF2 treatment, in terms of induced estrus and subsequent fertility. The efficiency of hormonal treatment is; however, comparatively better during the initial than the terminal stage of low breeding season.

  8. Infectious Agents and Cancer

    African Journals Online (AJOL)

    these agents on subsequent risk of cancer. There are currently ... tween genetic and environmental factors (that include infectious agents) .... opment of gastric adenocarcinoma and gastric lym- phoma. However .... Lung cancer i. Skin cancers ...

  9. Animal Capture Agents

    Science.gov (United States)

    1990-01-01

    agents and delivery systems reviewed . Questionnaires were sent to 137 Air Force bases to obtain information about the chemical agents and delivery systems...used by animal control personnel. A literature review included chemical agents, delivery methods, toxicity information and emergency procedures from...34-like agent. Users should familiarize themselves with catatonia in general and particularly that its successful use as an immobilizer doesn’t necessarily

  10. Reasoning about emotional agents

    NARCIS (Netherlands)

    Meyer, J.-J.

    2008-01-01

    In this paper we discuss the role of emotions in artificial agent design, and the use of logic in reasoning about the emotional or affective states an agent can reside in. We do so by extending the KARO framework for reasoning about rational agents appropriately. In particular we formalize in this f

  11. Intelligent Agents: A Primer.

    Science.gov (United States)

    Yu, Edmund; Feldman, Susan

    1999-01-01

    Provides an in-depth introduction to the various technologies that are bringing intelligent agents into the forefront of information technology, explaining how such agents work, the standards involved, and how agent-based applications can be developed. (Author/AEF)

  12. Users, Bystanders and Agents

    DEFF Research Database (Denmark)

    Krummheuer, Antonia Lina

    2015-01-01

    Human-agent interaction (HAI), especially in the field of embodied conversational agents (ECA), is mainly construed as dyadic communication between a human user and a virtual agent. This is despite the fact that many application scenarios for future ECAs involve the presence of others. This paper...

  13. Culturally Aware Agent Communication

    DEFF Research Database (Denmark)

    Rehm, Matthias; Nakano, Yukiko; Koda, Tomoko

    2012-01-01

    Agent based interaction in the form of Embodied Conversational Agents (ECAs) has matured over the last decade and agents have become more and more sophisticated in terms of their verbal and nonverbal behavior like facial expressions or gestures. Having such “natural” communication channels...

  14. Repositioning antimicrobial agent pentamidine as a disruptor of the lateral interactions of transmembrane domain 5 of EBV latent membrane protein 1.

    Science.gov (United States)

    Wang, Xiaohui; Fiorini, Zeno; Smith, Christina; Zhang, Yingning; Li, Jing; Watkins, Linda R; Yin, Hang

    2012-01-01

    The lateral transmembrane protein-protein interactions (PPI) have been regarded as "undruggable" despite their importance in many essential biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV). Herein we repurpose the antimicrobial agent pentamidine as a regulator of LMP-1 TMD-5 lateral interactions. The results of ToxR assay, tryptophan fluorescence assay, courmarin fluorescence dequenching assay, and Bis-Tris sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) consistently show pentamidine disrupts LMP-1 TMD-5 lateral interactions. Furthermore, pentamidine inhibits LMP-1 signaling, inducing cellular apoptosis and suppressing cell proliferation in the EBV infected B cells. In contrast, EBV negative cells are less susceptible to pentamidine. This study provides a novel non-peptide small molecule agent for regulating LMP-1 TMD-5 lateral interactions.

  15. Repositioning antimicrobial agent pentamidine as a disruptor of the lateral interactions of transmembrane domain 5 of EBV latent membrane protein 1.

    Directory of Open Access Journals (Sweden)

    Xiaohui Wang

    Full Text Available The lateral transmembrane protein-protein interactions (PPI have been regarded as "undruggable" despite their importance in many essential biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5 of latent membrane protein 1 (LMP-1 is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV. Herein we repurpose the antimicrobial agent pentamidine as a regulator of LMP-1 TMD-5 lateral interactions. The results of ToxR assay, tryptophan fluorescence assay, courmarin fluorescence dequenching assay, and Bis-Tris sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE consistently show pentamidine disrupts LMP-1 TMD-5 lateral interactions. Furthermore, pentamidine inhibits LMP-1 signaling, inducing cellular apoptosis and suppressing cell proliferation in the EBV infected B cells. In contrast, EBV negative cells are less susceptible to pentamidine. This study provides a novel non-peptide small molecule agent for regulating LMP-1 TMD-5 lateral interactions.

  16. Expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in control of GnRH secretion

    Institute of Scientific and Technical Information of China (English)

    Ying YANG; Li-bin ZHOU; Shang-quan LIU; Jing-feng TANG; Feng-yin LI; Rong-ying LI; Huai-dong SONG; Ming-dao CHEN

    2005-01-01

    Aim: To investigate the expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in the control of GnRH secretion.Methods: Receptors of bombesin3, cholecystokinin (CCK)-A, CCK-B, glucagonlike peptide (GLP)1, melanin-concentrating hormone (MCH)1, orexinl, orexin2,neuromedin-B, neuropeptide Y (NPY) 1 and NPY5, neurotensin (NT) 1, NT2, NT3,and leptin receptor long form mRNA in GT1-7 cells were detected by reversed transcriptase-polymerase chain reaction. GT1-7 cells were treated with leptin,orexin A and orexin B at a cohort of concentrations for different lengths of time,and GnRH in medium was determined by radioimmunoassay (RIA). Results:Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexinl, neuromedin-B, NPY1,NPY5, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7cells, of which, receptors of GLP1, neuromedin-B, NPY1, and NT3 were highly expressed. No amplified fragments of orexin2, NT2, and CCK-A receptor cDNA were generated with GT1-7 RNA, indicating that the GT1-7 cells did not express mRNA of them. Leptin induced a significant stimulation of GnRH release, the results being most significant at 0.1 nmol/L for 15 min. In contrast to other studies in hypothalamic explants, neither orexin A nor orexin B affected basal GnRH secretion over a wide range of concentrations ranging from 1 nmol/L to 500 nmol/Lat 15, 30, and 60 min. Conclusion: Feeding and reproductive function are closely linked. Many orexigenic and anorexigenic signals may control feeding behavior as well as alter GnRH secretion through their receptors on GnRH neurons.

  17. Moral actor, selfish agent.

    Science.gov (United States)

    Frimer, Jeremy A; Schaefer, Nicola K; Oakes, Harrison

    2014-05-01

    People are motivated to behave selfishly while appearing moral. This tension gives rise to 2 divergently motivated selves. The actor-the watched self-tends to be moral; the agent-the self as executor-tends to be selfish. Three studies present direct evidence of the actor's and agent's distinct motives. To recruit the self-as-actor, we asked people to rate the importance of various goals. To recruit the self-as-agent, we asked people to describe their goals verbally. In Study 1, actors claimed their goals were equally about helping the self and others (viz., moral); agents claimed their goals were primarily about helping the self (viz., selfish). This disparity was evident in both individualist and collectivist cultures, attesting to the universality of the selfish agent. Study 2 compared actors' and agents' motives to those of people role-playing highly prosocial or selfish exemplars. In content (Study 2a) and in the impressions they made on an outside observer (Study 2b), actors' motives were similar to those of the prosocial role-players, whereas agents' motives were similar to those of the selfish role-players. Study 3 accounted for the difference between the actor and agent: Participants claimed that their agent's motives were the more realistic and that their actor's motives were the more idealistic. The selfish agent/moral actor duality may account for why implicit and explicit measures of the same construct diverge, and why feeling watched brings out the better angels of human nature.

  18. THE INTEGRATED AGENT IN MULTI-AGENT SYSTEMS

    OpenAIRE

    Maleković, Mirko; Čubrilo, Mirko

    2000-01-01

    [n this paper, we characterize the integrated agent in multi-agent systems. The following result is proved: if a multi-agent system is reflexive (symmetric, transitive, Euclidean) then the integrated agent of the multi-agent system is reflexive (symmetric, transitive, Euclidean), respectively. We also prove that the analogous result does not hold for multi-agent system's serial ness. A knowledge relationship between the integrated agent and agents in a multiagent system is presented.

  19. Mobile agent security using proxy-agents and trusted domains

    OpenAIRE

    Mitrovic, Nikola; Arronategui Arribalzaga, Unai

    2009-01-01

    Commercial or wide-network deployment of Mobile Agent Systems is not possible without satisfying security architecture. In this paper we propose architecture for secure Mobile Agent Systems, using Trusted Domains and Proxy agents. Existing approaches are based on security services at the level of an agent system, library or specific objects. Our concept uses proxy agents to enable transparent security services both to security-aware mobile agents and legacy agents. Per-agent and domain-level...

  20. Agent Architectures for Compliance

    Science.gov (United States)

    Burgemeestre, Brigitte; Hulstijn, Joris; Tan, Yao-Hua

    A Normative Multi-Agent System consists of autonomous agents who must comply with social norms. Different kinds of norms make different assumptions about the cognitive architecture of the agents. For example, a principle-based norm assumes that agents can reflect upon the consequences of their actions; a rule-based formulation only assumes that agents can avoid violations. In this paper we present several cognitive agent architectures for self-monitoring and compliance. We show how different assumptions about the cognitive architecture lead to different information needs when assessing compliance. The approach is validated with a case study of horizontal monitoring, an approach to corporate tax auditing recently introduced by the Dutch Customs and Tax Authority.

  1. The IVF Outcome Counseling Based on the Model Combining DHEAS and Age in Patients with Low AMH Prior to the First Cycle of GnRH Antagonist Protocol of Ovarian Stimulation

    Science.gov (United States)

    Alebić, Miro Šimun; Žuvić-Butorac, Marta

    2013-01-01

    Objective. To investigate the endocrine and/or clinical characteristics of women with low anti-Müllerian hormone (AMH) that could improve the accuracy of IVF outcome prediction based on the female age alone prior to the first GnRH antagonist IVF cycle. Methods. Medical records of 129 patients with low AMH level (5.7 pmol/L, 60% (9/15) of all pregnancies were achieved with CPR of 37.5%. Conclusions. DHEAS appears to be predictive for clinical pregnancy in younger women (<37.5 years) with low AMH after the first GnRH antagonist IVF cycle. Therefore, DHEAS-age model could refine the pretreatment counseling on pregnancy prospects following IVF. PMID:23509455

  2. Split-time artificial insemination in beef cattle: I-Using estrous response to determine the optimal time(s) at which to administer GnRH in beef heifers and postpartum cows.

    Science.gov (United States)

    Bishop, B E; Thomas, J M; Abel, J M; Poock, S E; Ellersieck, M R; Smith, M F; Patterson, D J

    2016-09-01

    Two experiments evaluated timing of GnRH administration in beef heifers and cows on the basis of estrous status during split-time artificial insemination (AI) after controlled internal drug release (CIDR) based protocols. In experiment 1, estrus was synchronized for 816 pubertal and prepubertal or peripubertal heifers using the 14-day CIDR-PGF2α (PG) protocol, and in experiment 2, estrus was synchronized for 622 lactating cows using the 7-day CO-Synch + CIDR protocol. For both experiments, estrus detection aids (Estrotect) were applied at PG, with estrus recorded at 66 and 90 hours after PG. Treatments were balanced across locations for heifers using reproductive tract score and weight; whereas for cows, treatments were assigned and balanced to treatment according to age, body condition score, and days postpartum. Timing of AI for heifers and cows was on the basis of estrus expression 66 hours after PG. Females in each treatment that exhibited estrus before 66 hours were inseminated at 66 hours, whereas AI was delayed 24 hours until 90 hours after PG for females failing to exhibit estrus before 66 hours. Females in treatment one received GnRH 66 hours after PG irrespective of estrus expression; however, in treatment 2, GnRH was administered coincident with delayed AI only to females not detected in estrus at 66 hours after PG. Among heifers, there was no effect of treatment on overall estrous response (P = 0.49) or AI pregnancy rate (P = 0.54). Pregnancy rate for heifers inseminated at 66 hours was not influenced by GnRH (P = 0.65), and there were no differences between treatments in estrous response during the 24 hours delay period (P = 0.22). Cows in treatment 2 had a greater (P = 0.04) estrous response during the 24-hour delay period resulting in a greater overall estrous response (P = 0.04), but this did not affect AI pregnancy rate at 90 hours (P = 0.51) or total AI pregnancy rate (P = 0.89). Pregnancy rate resulting from AI for

  3. Adaptive auctioneer agents

    OpenAIRE

    2011-01-01

    M.Sc. This dissertation investigates how auctioneer agents can maximise the revenue of an auction. Auctions are an effective solution to agent negotiation because of their simplicity. They are therefore the most widely used approach to agent negotiation. A review of auction theory proves that auction revenue is influenced by factors such as the auction format and the auction parameters. The optimal auction format and parameters are dependent on the bidders and the auction environment. A st...

  4. Culturally Aware Agent Communication

    DEFF Research Database (Denmark)

    Rehm, Matthias; Nakano, Yukiko; Koda, Tomoko

    2012-01-01

    Agent based interaction in the form of Embodied Conversational Agents (ECAs) has matured over the last decade and agents have become more and more sophisticated in terms of their verbal and nonverbal behavior like facial expressions or gestures. Having such “natural” communication channels...... available for expressing not only task-relevant but also socially and psychologically relevant information makes it necessary to take influences into account that are not readily implemented like emotions or cultural heuristics. These influences have a huge impact on the success of an interaction...... the expression of multimodal behavior in agents....

  5. Decontamination Data - Blister Agents

    Data.gov (United States)

    U.S. Environmental Protection Agency — Decontamination efficacy data for blister agents on various building materials using various decontamination solutions. This dataset is associated with the following...

  6. GnRH在性成熟高白鲑神经系统及性腺中的分布定位%An Immunocytochemical Localization of GnRH in the Nerve System and Gonad of Mature Coregonus peled

    Institute of Scientific and Technical Information of China (English)

    曹玉洁; 贾斌; 柳建新; 李志远; 张莉

    2011-01-01

    摘要:应用免疫组织化学方法,系统观察性成熟期高白鲑(Coregonus peled)神经系统及性腺中的促性腺激素释放激素( GnRH)的分布情况。结果表明,GnRH在大脑、小脑、中脑、脊髓、延髓中免疫阳性反应明显,且主要分布在神经元内。GnRH免疫阳性细胞在卵巢和精巢中均有分布,而且其阳性部位在卵巢主要分布于小生长期卵母细胞;在精巢中主要分布于间质细胞和精原细胞中。本文讨论了GnRH直接或间接参与高白鲑性腺发育成熟调节的可能性。%Immunocytochemical staining technique was used to study the expression of gonadotropin-releasing hormone (GnRH) in the nervous system and gonad of Coregonus peled. The results showed that there were GnRH immunoreactive endocrine cells in the cerebrum,cerebellum,diencephalon,medulla oblongata,and spinal cord. There were GnRH immunoreactive endocrine cells in the ovary and testis. The positive staining was observed mainly in the small growing oocyte, and in the interstitial cells and spermatogonia. The possible physiological function and morphological evidence of GnRH regulation on the development of gonad in C. Peled were discussed.

  7. [Protective effect of GnRH analogues on the reproductive capacity of women with neoplasia or autoimmune disease who require chemotherapy. Final results of a phase ii clinical trial].

    Science.gov (United States)

    Gris-Martínez, José M; Trillo-Urrutia, Lourdes; Gómez-Cabeza, Juan José; Encabo-Duró, Gloria

    2016-02-05

    In order to avoid the toxic effect of chemotherapy, it has been proposed to use GnRH agonist analogues (GnRHa) to inhibit the depletion of ovarian follicles. Nevertheless, there is controversy about its effectiveness. This clinical trial has been conducted with the aim to assess the protective effect of GnRH analogues on the reproductive capacity of women with malignancies or autoimmune diseases, which require chemotherapy. Open phase ii single-center clinical trial. During chemotherapy, a total of 5 doses of GnRH antagonist analogue at a dose interval of 3 days and/or a monthly dose of GnRHa were administered. Hormonal determinations prior to the start of the CT treatment were conducted during treatment and at the end of it. The inclusion of patients was prematurely concluded when incorporating the determination of anti-Müllerian hormone (AMH) as a parameter for assessing the ovarian reserve. Out of 38 patients, 23 (60.5%, 95%CI 43.4-76.0) had AMH values below normal following completion of treatment. An intermediate analysis was carried out observing that while most patients were recovering the menstrual cycle (86.6% 95%CI 71.9-95.6), they had reduced levels of AMH. Although most patients recovered their menstrual cycles, the ovarian reserve, assessed by the concentration of AMH, decreased in many patients. Therefore, we can conclude that the concomitant treatment of chemotherapy and GnRH analogues does not preserve the loss of follicular ovarian reserve. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  8. Gonadotropin-releasing hormone (GnRH) agonist triptorelin inhibits estradiol-induced serum response element (SRE) activation and c-fos expression in human endometrial, ovarian and breast cancer cells.

    Science.gov (United States)

    Gründker, Carsten; Günthert, Andreas R; Hellriegel, Martin; Emons, Günter

    2004-11-01

    The majority of human endometrial (>80%), ovarian (>80%) and breast (>50%) cancers express GnRH receptors. Their spontaneous and epidermal growth-factor-induced proliferation is dose- and time-dependently reduced by treatment with GnRH and its agonists. In this study, we demonstrate that the GnRH agonist triptorelin inhibits estradiol (E2)-induced cancer cell proliferation. The proliferation of quiescent estrogen receptor alpha (ER alpha)-/ER beta-positive, but not of ER alpha-negative/ER beta-positive endometrial, ovarian and breast cancer cell lines, was significantly stimulated (P<0.001) (ANOVA) after treatment with E2 (10(-8) M). This effect was time- and dose-dependently antagonized by simultaneous treatment with triptorelin. The inhibitory effect was maximal at 10(-5) M concentration of triptorelin (P<0.001). In addition, we could show that, in ER alpha-/ER beta-positive cell lines, E2 induces activation of serum response element (SRE) and expression of the immediate early-response gene c-fos. These effects were blocked by triptorelin (P<0.001). E2-induced activation of estrogen-response element (ERE) was not affected by triptorelin. The transcriptional activation of SRE by E2 is due to ER alpha activation of the mitogen-activated protein kinase (MAPK) pathway. This pathway is impeded by GnRH, resulting in a reduction of E2-induced SRE activation and, in consequence, a reduction of E2-induced c-fos expression. This causes downregulation of E2-induced cancer cell proliferation.

  9. Effect of PGF2α and GnRH on the reproductive performance of postpartum dairy cows subjected to synchronization of ovulation and timed artificial insemination during the warm or cold periods of the year.

    Science.gov (United States)

    Akbarabadi, M Afsari; Shabankareh, H Karami; Abdolmohammadi, A; Shahsavari, M H

    2014-08-01

    This study was designed to evaluate the reproductive performance of lactating dairy cows (Holstein Friesian) after the injection of PGF2α analogue on Day 15 postpartum, and GnRH analogue on Day 23 after artificial insemination (AI) with Presynch (two injections of PGF2α, administered 14 days apart starting at 30-35 days postpartum) + Ovsynch-based (GnRH-7 days-PGF2α-2 days-GnRH-16-20 hours-timed artificial insemination) treatments, during the warm and cold periods of the year. All the cows (n = 313) were assigned to one of the four groups including: M1 (n = 72) in which the cows were treated with PGF2α on Day 15 postpartum + Presynch-Ovsynch + GnRH on Day 23 post-AI; M2 (n = 41) in which the cows received PGF2α on Day 15 postpartum + Presynch-Ovsynch; M3 (n = 100) including the cows that got Presynch-Ovsynch; and control group (n = 100) including the cows that were not treated and were inseminated at natural estrus. Pregnancy diagnosis was performed 28 to 35 days post-insemination by means of ultrasound. The results showed that treatment with PGF2α on Day 15 postpartum significantly decreased the days to conception and the number of services per conception (P 0.05). In contrast, administration of GnRH on Day 23 post-AI increased the days to conception and the number of service per conception (P artificial insemination after Presynch-Ovsynch protocol but also reduced that.

  10. 促性腺激素释放激素(GnRH)结构及调控的研究进展%Research Progress on Structure and Regulation of Gonadotropin-releasing Hormone (GnRH)

    Institute of Scientific and Technical Information of China (English)

    徐元青; 王建林; 邵宝平

    2014-01-01

    促性腺激素释放激素(GnRH)最初被认为是一种下丘脑神经肽,但是越来越多的研究发现该激素具有多重功能,如参与类固醇生成、细胞增殖、受精、粘连细胞外基质和细胞迁移等生理功能的调节,并在动物的生长发育、生殖行为、妊娠、分娩等生命活动中起着至关重要的作用。主要对GnRH的结构特点及其调控进行了综述。%Gonadotropin-releasing hormone (GnRH) is firstly taken as a kind of hypothalamic neuropeptide, but more and more researches show that GnRH has multiple functions, such as participating in the regulation of generation of steroids, cell proliferation, fertilization, adhesion of extracellular matrix, cell migration, etc., and also plays a crucial role in the growth, reproductive behavior, pregnancy and delivery of animals. The structure and regulation of GnRH were summarized.

  11. Cloning and expression analysis in mature individuals of two chicken type-II GnRH (cGnRH-II) genes in common carp (Cyprinus carpio).

    Science.gov (United States)

    Li, Shuangfei; Hu, Wei; Wang, Yaping; Zhu, Zuoyan

    2004-08-01

    Gonadotropin-releasing hormone (GnRH) is a conservative neurodecapeptide family, which plays a crucial role in regulating the gonad development and in controlling the final sexual maturation in vertebrate. Two differing cGnRH-II cDNAs of common carp, namely cGnRH-II cDNA1 and cDNA2, were firstly cloned from the brain by rapid amplification of cDNA end (RACE) and reverse transcription- polymerase chain reaction (RT-PCR). The length of cGnRH-II cDNA1 and cDNA2 was 622 and 578 base pairs (bp), respectively. The cGnRH-II precursors encoded by two cDNAs consisted of 86 amino acids, including a signal peptide, cGnRH-II decapeptide and a GnRH-associated peptide (GAP) linked by a Gly-Lys-Arg proteolytic site. The results of intron trapping and Southern blot showed that two differing cGnRH-II genes in common carp genome were further identified, and that two genes might exist as a single copy. The multi-gene coding of common carp cGnRH-II gene offered novel evidence for gene duplication hypothesis. Using semi-quantitative RT-PCR, expression and relative expression levels of cGnRH-II genes were detected in five dissected brain regions, pituitary and gonad of common carp. With the exception of no mRNA2 in ovary, two cGnRH-II genes could be expressed in all the detected tissues. However, expression levels showed an apparent difference in different brain regions, pituitary and gonad. According to the expression characterization of cGnRH-II genes in brain areas, it was presumed that cGnRH-II might mainly work as the neurotransmitter and neuromodulator and also operate in the regulation for the GnRH releasing. Then, the expression of cGnRH-II genes in pituitary and gonad suggested that cGnRH-II might act as the autocrine or paracrine regulator.

  12. Change Agent Survival Guide

    Science.gov (United States)

    Dunbar, Folwell L.

    2011-01-01

    Consulting is a rough racket. Only a tarantula hair above IRS agents, meter maids and used car sales people, the profession is a prickly burr for slings and arrows. Throw in education, focus on dysfunctional schools and call oneself a "change agent," and this bad rap all but disappears. Unfortunately, though, consulting/coaching/mentoring in…

  13. Agents in domestic environments

    NARCIS (Netherlands)

    Moergestel, Leo van; Langerak, Wouter; Meerstra, Glenn; Nieuwenburg, Niels van; Pape, Franc; Telgen, Daniël; Puik, Erik; Meyer, John-Jules

    2013-01-01

    Athor supplied : "This paper describes an agent-based architecture for domotics. This architecture is based on requirements about expandability and hardware independence. The heart of the system is a multi-agent system. This system is distributed over several platforms to open the possibility to ti

  14. Agents in domestic environments

    NARCIS (Netherlands)

    Glenn Meerstra; Wouter Langerak; Leo van Moergestel; Niels van Nieuwenburg; John-Jules Meyer; Ing. Erik Puik; Franc Pape; Daniël Telgen

    2013-01-01

    Athor supplied : "This paper describes an agent-based architecture for domotics. This architecture is based on requirements about expandability and hardware independence. The heart of the system is a multi-agent system. This system is distributed over several platforms to open the possibility to

  15. Asimovian Adaptive Agents

    CERN Document Server

    Gordon, D F

    2011-01-01

    The goal of this research is to develop agents that are adaptive and predictable and timely. At first blush, these three requirements seem contradictory. For example, adaptation risks introducing undesirable side effects, thereby making agents' behavior less predictable. Furthermore, although formal verification can assist in ensuring behavioral predictability, it is known to be time-consuming. Our solution to the challenge of satisfying all three requirements is the following. Agents have finite-state automaton plans, which are adapted online via evolutionary learning (perturbation) operators. To ensure that critical behavioral constraints are always satisfied, agents' plans are first formally verified. They are then reverified after every adaptation. If reverification concludes that constraints are violated, the plans are repaired. The main objective of this paper is to improve the efficiency of reverification after learning, so that agents have a sufficiently rapid response time. We present two solutions: ...

  16. Non-invasive assessment of the reproductive cycle in free-ranging female African elephants (Loxodonta africana treated with a gonadotropin-releasing hormone (GnRH vaccine for inducing anoestrus

    Directory of Open Access Journals (Sweden)

    Benavides Valades Gabriela

    2012-08-01

    Full Text Available Abstract Background In southern Africa, various options to manage elephant populations are being considered. Immunocontraception is considered to be the most ethically acceptable and logistically feasible method for control of smaller and confined populations. In this regard, the use of gonadotropin-releasing hormone (GnRH vaccine has not been investigated in female elephants, although it has been reported to be safe and effective in several domestic and wildlife species. The aims of this study were to monitor the oestrous cycles of free-ranging African elephant cows using faecal progestagen metabolites and to evaluate the efficacy of a GnRH vaccine to induce anoestrus in treated cows. Methods Between May 2009 - June 2010, luteal activity of 12 elephant cows was monitored non-invasively using an enzyme immunoassay detecting faecal 5alpha-reduced pregnanes (faecal progestagen metabolites, FPM on a private game reserve in South Africa. No bulls of breeding age were present on the reserve prior to and for the duration of the study. After a 3-month control period, 8 randomly-selected females were treated twice with 600 micrograms of GnRH vaccine (Improvac®, Pfizer Animal Health, Sandton, South Africa 5-7 weeks apart. Four of these females had been treated previously with the porcine zona pellucida (pZP vaccine for four years (2004-2007. Results All 12 monitored females (8 treated and 4 controls showed signs of luteal activity as evidenced by FPM concentrations exceeding individual baseline values more than once. A total of 16 oestrous cycles could be identified in 8 cows with four of these within the 13 to 17 weeks range previously reported for captive African elephants. According to the FPM concentrations the GnRH vaccine was unable to induce anoestrus in the treated cows. Overall FPM levels in samples collected during the wet season (mean 4.03 micrograms/gram dry faeces were significantly higher (P Conclusions The GnRH vaccination protocol failed

  17. Mathematical Model for the Effect of Ghrelinon basal,GNRH Induced FSH and LH Secretion in Normal Women by using four Variate Weibull Distribution

    Directory of Open Access Journals (Sweden)

    S. Lakshmi

    2016-12-01

    Full Text Available In this paper, we introduce probability density function of four variate Weibull distributions. A multivariate survival function of Weibull Distribution is used for four variables. From the survival function, the probability density function and cumulative probability function are derived. Ghrelin may affect reproductive function in animals and humans.In the application part the experimental conditions of an acute injection of ghrelin (1g/kg to normal women, basal and GnRH-induced LH and FSH secretion were not affected and suggested that ghrelin does not play a major physiological role in gonadotrophin secretion in women.In the mathematical part, we have found that the Survival function of the curveis suddenly decreased in Mid-luteal phase compare with other phases. Pdf of the curve is suppressed in late follicular phase and it will be increased at the time of7min.Pdf for early follicular phase of control cycleis increased from 4 min .Also Pdf curve for early follicular phase with ghrelin administration and mid-luteal phase with ghrelin and GnRH are also increased at the time of 5 and 3 minutes respectively.

  18. Elevated progesterone in GnRH agonist down regulated in vitro fertilisation (IVFICSI) cycles reduces live birth rates but not embryo quality.

    Science.gov (United States)

    Lahoud, Robert; Kwik, Michele; Ryan, John; Al-Jefout, Moamar; Foley, Jane; Illingworth, Peter

    2012-02-01

    To assess the impact of pre-hCG elevated progesterone on live birth outcomes during GnRH agonist long down regulated protocol assisted reproduction cycles. Retrospective cohort study. Single Centre Private IVF Clinic. A total of 582 consecutive cycles of IVF/ICSI in 2003. All patients underwent a long down-regulation protocol, controlled ovarian stimulation and IVF/ICSI. Serum progesterone concentrations were measured just prior to HCG administration. 253 patients were followed to 2009 for outcomes of their frozen embryo cycles. Live birth rate in fresh and frozen cycles. Patients in the upper quartile pre-hCG progesterone concentration (≥ 5.4 pmol/L) had a higher final estradiol level, more oocytes collected and more usable embryos, when compared to those with lower quartiles. They also had lower live birth rates per cycle started (21.9% vs. 15%, P live birth rates from frozen embryo cycles were not significantly different between the groups. Pre-hCG progesterone elevation leads to lower live birth rates in stimulated IVF cycles. Live birth rates achieved with frozen embryos in the high progesterone cycles suggest, that pre-hCG progesterone elevation negatively affects endometrial receptivity without adversely affecting embryo quality.

  19. Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.

    Science.gov (United States)

    Iliodromiti, Stamatina; Lan, Vuong Thi Ngoc; Tuong, Ho Manh; Tuan, Phung Huy; Humaidan, Peter; Nelson, Scott M

    2013-12-26

    Conventional luteal support packages are inadequate to facilitate a fresh transfer after GnRH agonist (GnRHa) trigger in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). By providing intensive luteal-phase support with oestradiol and progesterone satisfactory implantation rates can be sustained. The objective of this study was to assess the live-birth rate and incidence of OHSS after GnRHa trigger and intensive luteal steroid support compared to traditional hCG trigger and conventional luteal support in OHSS high risk Asian patients. We conducted a retrospective cohort study of 363 women exposed to GnRHa triggering with intensive luteal support compared with 257 women exposed to conventional hCG triggering. Women at risk of OHSS were defined by ovarian response ≥15 follicles ≥12 mm on the day of the trigger. Live-birth rates were similar in both groups GnRHa vs hCG; 29.8% vs 29.2% (p = 0.69). One late onset severe OHSS case was observed in the GnRHa trigger group (0.3%) compared to 18 cases (7%) after hCG trigger. GnRHa trigger combined with intensive luteal steroid support in this group of OHSS high risk Asian patients can facilitate fresh embryo transfer, however, in contrast to previous reports the occurrence of late onset OHSS was not completely eliminated.

  20. Biological warfare agents

    Directory of Open Access Journals (Sweden)

    Duraipandian Thavaselvam

    2010-01-01

    Full Text Available The recent bioterrorist attacks using anthrax spores have emphasized the need to detect and decontaminate critical facilities in the shortest possible time. There has been a remarkable progress in the detection, protection and decontamination of biological warfare agents as many instrumentation platforms and detection methodologies are developed and commissioned. Even then the threat of biological warfare agents and their use in bioterrorist attacks still remain a leading cause of global concern. Furthermore in the past decade there have been threats due to the emerging new diseases and also the re-emergence of old diseases and development of antimicrobial resistance and spread to new geographical regions. The preparedness against these agents need complete knowledge about the disease, better research and training facilities, diagnostic facilities and improved public health system. This review on the biological warfare agents will provide information on the biological warfare agents, their mode of transmission and spread and also the detection systems available to detect them. In addition the current information on the availability of commercially available and developing technologies against biological warfare agents has also been discussed. The risk that arise due to the use of these agents in warfare or bioterrorism related scenario can be mitigated with the availability of improved detection technologies.

  1. The value of GnRH - a in treatment of endometrial atypical hyperplasia%GnRH-a 对子宫内膜非典型增生的治疗价值

    Institute of Scientific and Technical Information of China (English)

    宋宁; 程迪; 马晓欣; 张淑兰

    2015-01-01

    Objective:To investigate the value of GnRH - a in the treatment of endometrial atypical hyperplasia (AEH). Methods:All 66 cases of endometrial atypical hyperplasia patients were randomly divided into 2 groups. The patients in group A(32 cases)were treated with GnRH - a for 6 months. Patients in group B(34 cases)were treated with progesterone therapy for 6 months. Hysteroscopy examination and endometrial biopsy were applied every three months. Results:Among the patients with mild to moderate atypical hyperplasia,there was no statistical difference in the therapeutic effect between the two groups(P > 0. 05),while GnRH - a was not as effective as progesterone in the treatment of severe endometrial atypical hyperplasia(P 0. 05). Conclusion:The therapeutic effect of GnRH - a was similar to that of medroxyprogesterone acetate in the treatment of endometrial atypical hyperplasia.%目的:探讨 GnRH - a 在子宫内膜非典型增生(AEH)中的治疗价值。方法:将66例子宫内膜非典型增生患者按照随机的原则分为2组,A 组患者(32例)使用 GnRH - a(诺雷德)治疗,每月一次,连用6个月。B 组患者(34例)使用孕激素(醋酸甲羟孕酮)连续治疗6个月。每3个月行宫腔镜检查,并行内膜活检,记录结果并进行统计学分析。结果:两组轻中度非典型性增生治疗效果,无统计学意义(P >0.05)。重度非典型增生治疗效果 GnRH - a 组低于孕激素组,P <0.05,有统计学意义。两组总的治疗效果比较,无统学意义(P >0.05)。结论:GnRH - a 用于治疗子宫内膜非典型增生效果与醋酸甲羟孕酮相似,具有每月一次的方便性,但价格较贵。

  2. Agent-Based Optimization

    CERN Document Server

    Jędrzejowicz, Piotr; Kacprzyk, Janusz

    2013-01-01

    This volume presents a collection of original research works by leading specialists focusing on novel and promising approaches in which the multi-agent system paradigm is used to support, enhance or replace traditional approaches to solving difficult optimization problems. The editors have invited several well-known specialists to present their solutions, tools, and models falling under the common denominator of the agent-based optimization. The book consists of eight chapters covering examples of application of the multi-agent paradigm and respective customized tools to solve  difficult optimization problems arising in different areas such as machine learning, scheduling, transportation and, more generally, distributed and cooperative problem solving.

  3. Health care agents

    Science.gov (United States)

    ... make decisions during a stressful time. Your agent's duty is to see that your wishes are followed. ... Philadelphia, PA: Elsevier; 2016:chap 5. Zorowitz RA. Ethics. In: Ham RJ Jr, Sloane PD, Warshaw GA, ...

  4. Agent Standards Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The innovation of the work herein proposed is the development of standards for software autonomous agents. These standards are essential to achieve software...

  5. Steroidal neuromuscular blocking agents

    NARCIS (Netherlands)

    Wierda, JMKH; Mori, K; Ohmura, A; Toyooka, H; Hatano, Y; Shingu, K; Fukuda, K

    1998-01-01

    Since 1964 approximately 20 steroidal neuromuscular blocking agents have been evaluated clinically. Pancuronium, a bisquaternary compound designed on the drawingboard, was the first steroidal relaxant introduced into clinical practice worldwide in the 1970's. Although a major improvement, pancuroniu

  6. Biological Warfare Agents

    Directory of Open Access Journals (Sweden)

    Dev Vrat Kamboj

    2006-10-01

    Full Text Available There is a long historic record of use of biological warfare (BW agents by warring countriesagainst their enemies. However, the frequency of their use has increased since the beginningof the twentieth century. World war I witnessed the use of anthrax agent against human beingsand animals by Germans, followed by large-scale field trials by Japanese against war prisonersand Chinese population during world war II. Ironically, research and development in biologicalwarfare agents increased tremendously after the Geneva Protocol, signed in 1925, because ofits drawbacks which were overcome by Biological and Toxin Weapons Convention (BTWC in1972. Biological warfare programme took back seat after the 1972 convention but biologicalagents regained their importance after the bioterrorist attacks of anthrax powder in 2001. In thelight of these attacks, many of which turned out to be hoax, general awareness is required aboutbiological warfare agents that can be used against them. This review has been written highlightingimportant biological warfare agents, diseases caused by them, possible therapies and otherprotection measures.

  7. Oestrus synchronization with short-term and long-term progestagen treatments in goats: the use of GnRH prior to short-term progestagen treatment

    Directory of Open Access Journals (Sweden)

    Cafer Tayyar Ateş

    2010-02-01

    Full Text Available The aim of the present study was to determine the efficacy of the synchronization of oestrus using short- and long-term progestagen treatments in Hair goats at the onset of the breeding season, and to evaluate the effect of the exogenous GnRH administration immediately prior to short-term progestagen treatment on the reproductive performance. A total of 75 Hair goats, aged 2.5-5 years-old were used in this experiment. Goats were divided equally into three groups (n=25 per group. Animals in LT-FGA (long-term progestagen treatment, ST-FGA (short-term progestagen treatment and Gn-ST-FGA (GnRH-short-term progestagen treatment groups received an intravaginal sponge (day 0 containing 30 mg fluorogestone acetate (FGA for 14, 8 and 8 days, respectively, plus 75 μg cloprostenol i.m. 24 h before sponge removal and 400 I.U. equine chorionic gonadotrophin (eCG i.m. at the time of sponge removal. In addition, the goats in the Gn-ST-FGA group received 10.5 μg busereline acetate i.m. at the time of sponge insertion (day 0. Oestrus response for all treatment groups was 100%. The mean interval from sponge removal and the onset of oestrus for the LT-FGA, ST-FGA and Gn-ST-FGA groups was 28.0±1.0 h, 28.83±1.1 h and 33.1±2.0 h, respectively. No significant difference in onset of oestrus among groups was recorded. The pregnancy rate, kidding rate, multiple kidding rates and litter size were 72.0, 61.1, 45.5% and 1.6 in the LT-FGA, 70.8, 76.5, 69.2% and 1.8 in the ST-FGA and 58.3, 78.6, 63.6% and 1.6 in the Gn-ST-FGA groups, respectively. The pregnancy rates were similar in the LT-FGA (72.0% and ST-FGA (70.8%. However, the kidding rate, multiple kidding rates and litter size were numerically higher in the ST-FGA (76.5%, 69.2% and 1.8, respectively group than in the LT-FGA (61.1%, 45.5% and 1.6, respectively group. Although not statistically different, pregnancy rate and litter size was lower in the Gn-ST-FGA group (58.3% and 1.6, respectively compared with the ST

  8. Serum dehydroepiandrosterone sulphate concentration is not a predictive factor in IVF outcomes before the first cycle of GnRH agonist administration in women with normal ovarian reserve.

    Directory of Open Access Journals (Sweden)

    Michał Kunicki

    Full Text Available The aim of our study was to determine whether serum dehydroepiandrosterone sulphate (DHEAS concentration and the models incorporating it could help clinicians to predict IVF outcomes in women with normal ovarian reserve undergoing their first long protocol.We performed a retrospective analysis of 459 women undergoing cycles of intracytoplasmic sperm injection (ICSI for the first time in a long GnRH agonist protocol.Embryo transfer was performed in 407 women (88.7%. The fertilisation rate was 78.6%. The clinical pregnancy rate was 44.8% per started cycle and 50.6% per embryo transfer. Our univariate model revealed that the best predictors of clinical pregnancy were the number of mature oocytes, the number of embryos transferred and the number of good quality embryos, account for the clinical parameters that reflect ovarian reserve the best being AMH level and AFC. DHEAS did not predict clinical pregnancy (OR 1.001, 95% CI, 0.999-1.004. After adjusting for the number of embryos transferred and class of embryos in a multivariate model, the best predictors were age (OR 0.918, 95% CI, 0.867-0.972 and AFC (OR 1.022, 95% CI, 0.992-1.053. Serum DHEAS levels were positively correlated with AFC (r = 0.098, P<0.039 and testosterone levels (r = 0.371, P<0.001, as well as the number of mature oocytes (r = 0.109, P<0.019; serum DHEAS levels were negatively correlated with age (r = -0.220, P<0.001, follicle-stimulating hormone (FSH, (r = -0.116, P<0.015 and sex hormone-binding globulin (SHBG, (r = -0.193, P<0.001.DHEAS concentration (in addition to the known factors of ovarian reserve does not predict clinical pregnancy in women with normal ovarian reserve who are undergoing ICSI.

  9. Role of color Doppler US in the evaluation of uterine leiomyoma treated with gonadotrophin-releasing hormone (GnRH) agonist (Zoladex)

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Sik; Sohn, Cheol Ho; Lee, Tae Sung [Keimyung University Dongsan Medical Center, Taegu (Korea, Republic of)

    1999-03-15

    To access the role of color Doppler US in the evaluation of uterine leiomyoma treated with GnRH agonist (Zoladex). Out of 25 patients with uterine leiomyoma treated with Zoladex, nineteen cases of leiomyoma in 18 women who had US examination before and after medication were included in this study. Zoladex was injected subcutaneously three times within three months. Both gray scale and color Doppler US were obtained before and 1-3 months after the medication. The size, volume, location and internal echoes of the leiomyoma were recorded with gray scale US. Changes in the amount of color signal within leiomyomas were recorded. Pulsatility index (PI), resistive index (RI), peak systolic velocity (PSV) of both uterine artery and arteries within leiomyomas were also recorded. The image findings of good response group and poor response group in which the volume reduction of the leiomyoma was above or below 50% respectively were compared with each other. The reduction of the volume of leiomyoma was compared between a group with decrease in the amount of color signals during follow-up US and a group with increase or no change. Mean reduction of the volume of leiomyomas was 52%. Changes in the amount of color signals of the leiomyoma, PI, RI, PSV obtained from the arteries within leiomyomas were not correlated with the change of the volume of leiomyomas. PSV of uterine artery in one month follow-up and PI of two month follow-up were correlated with the changes of the volume of leiomyomas (p<0.05). RI of uterine artery in two month follow-up was useful in prediction of the good response group and the poor response group (p<0.05). The prediction of the volume reduction of leiomyoma following Zoladex medication might be possible by obtaining RI of uterine artery in two month follow-up. Doppler US of the arteries within the leiomyoma was not useful.

  10. Molecular characterization and transcriptional regulation by GH and GnRH of insulin-like growth factors I and II in white seabream (Diplodus sargus).

    Science.gov (United States)

    Pérez, Laura; Ortiz-Delgado, Juan Bosco; Manchado, Manuel

    2016-03-10

    Insulin-like growth factors (IGF) I and II are key regulators of development, growth and reproduction in fish. In the present study we have cloned and characterized the cDNA and genomic sequences of IGF-I and IGF-II in the white seabream (Diplodus sargus). The igf1 and igf2 genes were encoded putatively by five and four exons, respectively. Moreover, the 5'-flanking upstream region of the igf1 gene contained highly conserved regulatory elements including HNF-1α, HNF-3β, CCAAT/enhancer binding protein (C/EBP) and the TATA box. The full-length cDNAs were 1225 and 1666 nucleotides long for igf1 and igf2, respectively. Sequence analysis identified the A-E domains as well as three spliced forms involving the E domain in exons 3-5. ORF identities were higher than 83% with respect to other fish orthologs. Expression analysis demonstrated that igf1 and its spliced forms were mostly expressed in liver, whereas the igf2 was expressed ubiquitously not detecting significant differences among the ten tissues analyzed. Hormonal treatments using the porcine GH demonstrated a sharply increase of both igf1 and igf2 mRNA levels in liver and gills at 30 min and 1h after injection. In the gonads, igf1 mRNA levels increased steadily with testis and ovary maturation. In contrast, igf2 transcript amounts were higher in immature stages (S1-S2). Hormonal treatments using GH and GnRH demonstrated that igf1 and igf2 expression were upregulated in the gonads. Overall, these data demonstrate that IGF-I and IGF-II are locally expressed in several tissues and regulated by key hormones of the somatotropic and gonadotropic axes.

  11. Reproductive Performance of Rabbit does Artificially Inseminated with Semen Supplemented with GnRH Analogue [des-Gly10, D-Ala6]-LH-RH Ethylamide.

    Science.gov (United States)

    Gogol, P

    2016-09-01

    The aim of the study was to evaluate, the ability of a GnRH synthetic analogue [des-Gly10, D-Ala6]-LH-RH ethylamide to induce ovulation in rabbit does using intravaginal administration. A total of 138 primiparous lactating does were randomly divided into 4 groups that at the time of insemination received following treatments for ovulation induction: 1 μg of buserelin administered intramuscularly (control group); 5 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D5 group); 10 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D10 group); 15 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide added to the semen dose (D15 group). Kindling rates were 68.8% in D10 and 66.7% in D15 groups and were comparable to that obtained in the control group (72.2%). The kindling rate in group D5 (29.4%) was significantly lower than those recorded in the other groups. The number of live born kits was not significantly affected by the ovulation induction treatment. The results of this study show that [des-Gly10, D-Ala6]-LH-RH ethylamide added directly into the semen dose can effectively stimulate ovulation in rabbits. The dose of 10 μg of [des-Gly10, D-Ala6]-LH-RH ethylamide per doe was sufficient to produce results comparable to those obtained by intramuscular administration of buserelin.

  12. Agent Oriented Programming进展%Advances in Agent Oriented Programming

    Institute of Scientific and Technical Information of China (English)

    王一川; 石纯一

    2002-01-01

    Agent-oriented programming (AOP) is a framework to develop agents, and it aims to link the gap betweentheory and practical in agent research. The core of an AOP framework is its language and semantics. In this paper,we propose the necessary properties which agents should have, and then give a summary and analysis about differentAOP languages based on these properties.

  13. Teaching Tourism Change Agents

    DEFF Research Database (Denmark)

    Stilling Blichfeldt, Bodil; Kvistgaard, Hans-Peter; Hird, John

    2017-01-01

    This article discuss es know ledge, competencies and skills Master’s students should obtain during their academic studies and particularly, the differences between teaching about a topic and teaching to do. This is ex emplified by experiential learning theory and the case of a change management...... course that is part of a Tourism Master’s program, where a major challenge is not only to teach students about change and change agents, but to teach them how change feels and ho w to become change agents. The c hange management course contains an experiment inspired by experiential teaching literature...... and methods. The experiment seeks to make students not only hear/learn about change agency and management, but to make them feel cha nge, hereby enabling them to develop the skills and competencies necessary for them to take on the role as change agent s and thus enable them to play key role s in implementing...

  14. Agents unleashed a public domain look at agent technology

    CERN Document Server

    Wayner, Peter

    1995-01-01

    Agents Unleashed: A Public Domain Look at Agent Technology covers details of building a secure agent realm. The book discusses the technology for creating seamlessly integrated networks that allow programs to move from machine to machine without leaving a trail of havoc; as well as the technical details of how an agent will move through the network, prove its identity, and execute its code without endangering the host. The text also describes the organization of the host's work processing an agent; error messages, bad agent expulsion, and errors in XLISP-agents; and the simulators of errors, f

  15. Indução da ovulação em cabras, fora da estação reprodutiva, com LH e GnRH e com estro induzido por progestágenos Induction of the out-of-season ovulation (with LH and GnRH and estrus (with progesterone in goats

    Directory of Open Access Journals (Sweden)

    P.A.G. Leite

    2006-06-01

    Full Text Available Quarenta e cinco cabras foram sincronizadas com o uso de esponjas intravaginais impregnadas com 60mg de acetato de medroxiprogesterona (MAP por nove dias, associadas com 200UI de gonadotrofina coriônica equina (eCG e 37,5µg de cloprostenol no sétimo dia. Os animais foram separados em três grupos e receberam, 24 horas após a retirada das esponjas, solução salina ou hormônios, no seguinte esquema: T1 (controle - 1ml de solução salina; T2 - 5mg de hormônio luteinizante (LH e T3 - 12,5µg do hormônio liberador de gonadotrofina (GnRH. Houve diferença (P0,05 quanto ao intervalo da retirada da esponja ao aparecimento do estro, que foi, em média, 34,8, 29,3 e 31,5 horas, respectivamente. O intervalo médio da retirada da esponja à ovulação foi de 46,6, 52,1 e 41,6 horas, respectivamente, com diferença significativa entre T2 e T3 (P0,05. A aplicação de LH e do GnRH para induzir e sincronizar a ovulação em cabras fora da estação reprodutiva não apresentou resultados satisfatórios.In order to achieve estrous synchronization, intravaginal sponges impregnated with 60mg of medroxyprogesterone acetate (MPA were implanted in 45 goats for nine days. On day 7, 200IU of equine chorionic gonadotropin (eCG and 37.5µg of cloprostenol were administered to each doe. The animals were randomly allocated in three treatments with 15 animals each. Twenty four hours after intravaginal sponge removal, does were administered 1ml saline solution (control T1, 5mg LH (T2 and 2.5µg GnRH (T3 intramuscular injection. Percentages of animals in estrus were 100.0; 73.3 and 66.6 (P<0.05 and average intervals from sponge removal to start of estrus were 34.8, 29.3 and 31.5 hours for T1, T2 and T3, respectively, being those differences not statistically significant. The average intervals from sponge removal to ovulation were 46.6, 52.1 and 41.6 hours for T1, T2 and T3, respectively, with the difference between T2 and T3 being statistically significant (P<0

  16. The IVF Outcome Counseling Based on the Model Combining DHEAS and Age in Patients with Low AMH Prior to the First Cycle of GnRH Antagonist Protocol of Ovarian Stimulation

    Directory of Open Access Journals (Sweden)

    Miro Šimun Alebić

    2013-01-01

    Full Text Available Objective. To investigate the endocrine and/or clinical characteristics of women with low anti-Müllerian hormone (AMH that could improve the accuracy of IVF outcome prediction based on the female age alone prior to the first GnRH antagonist IVF cycle. Methods. Medical records of 129 patients with low AMH level (<6.5 pmol/L who underwent their first GnRH antagonist ovarian stimulation protocol for IVF/ICSI were retrospectively analyzed. The main outcome measure was the area under the ROC curve (AUC-ROC for the models combining age and other potential predictive factors for the clinical pregnancy. Results. Clinical pregnancy rate (CPR per initiated cycles was 11.6%. For the prediction of clinical pregnancy, DHEAS and age showed AUC-ROC of 0.726 (95%CI 0.641–0.801 and 0.662 (95%CI 0.573–0.743, respectively (. The predictive accuracy of the model combining age and DHEAS (AUC-ROC 0.796; 95%CI 0.716–0.862 was significantly higher compared to that of age alone (. In patients <37.5 years with DHEAS  pmol/L, 60% (9/15 of all pregnancies were achieved with CPR of 37.5%. Conclusions. DHEAS appears to be predictive for clinical pregnancy in younger women (<37.5 years with low AMH after the first GnRH antagonist IVF cycle. Therefore, DHEAS-age model could refine the pretreatment counseling on pregnancy prospects following IVF.

  17. The effects of thyroxine or a GnRH analogue on thyroid hormone deiodination in the olfactory epithelium and retina of rainbow trout, Oncorhynchus mykiss, and sockeye salmon, Oncorhynchus nerka.

    Science.gov (United States)

    Plate, E M; Adams, B A; Allison, W T; Martens, G; Hawryshyn, C W; Eales, J G

    2002-06-01

    Using low (0.5nM) substrate levels we determined the activities of thyroxine (T4) outer-ring deiodination (ORD), T4 inner-ring deiodination (T4IRD) and 3,5,3(')-triiodothyronine (T3) IRD activities in the olfactory epithelium (OLF) and retina (RET) of laboratory-held immature 1-year-old rainbow trout and immature 2.5-year-old sockeye salmon. In both species all three deiodination activities were detected in OLF and RET. For OLF, no particular pathway predominated and activities were similar to those of brain. For RET, T3IRD activity was greater than T4ORD activity and in sockeye RET T3IRD activity exceeded that of liver. Trout immersion for 6 weeks in 100ppm T4 increased plasma T4 levels 3-fold and plasma T3 levels by 50% and caused the anticipated autoregulatory responses in brain and liver deiodination ( downward arrow T4ORD, upward arrow T4IRD, and upward arrow T3IRD); OLF deiodination and RET T4ORD activity were unaltered but RET T4IRD and T3IRD activities increased dramatically. Two injections of a GnRH analogue (20 microgkg(-1)) into sockeye increased plasma T3 levels but not T4 levels and decreased RET T4IRD and T3IRD activities without changing liver, brain, or OLF deiodination. We conclude that in salmonids the main TH deiodination pathways occur in OLF but show no regulation by T4 or GnRH. In contrast, T3IRD activity predominates in RET and can be regulated by T4 and GnRH, suggesting that for RET plasma may be the major T3 source. These findings have implications for thyroidal regulation of sensory functions during salmonid diadromous migrations.

  18. Developing Enculturated Agents

    DEFF Research Database (Denmark)

    Rehm, Matthias

    2010-01-01

    Embodied Conversational Agents (ECAs) are complex multimodal systems with rich verbal and nonverbal repertoires. There human-like appearance raises severe expectations regarding natural communicative behaviors on the side of the user. But what is regarded as “natural” is to a large degree dependent...... on our cultural profiles that provide us with heuristics of behavior and interpretation. Thus, integrating cultural aspects of communicative behaviors in virtual agents and thus enculturating such systems seems to be inevitable. But culture is a multi-defined domain and thus a number of pitfalls arise...

  19. A study on the effect of GnRH administration on the ovarian response and laparoscopic intrauterine insemination of Awassi ewes treated with eCG to induce superovulation.

    Science.gov (United States)

    Azawi, Osama Ibrahim; Al-Mola, Muzahim Khider Mahmood Ahmed

    2011-10-01

    The effect of GnRH administration on superovulatory response of ewes treated with equine chorionic gonadotrophin (eCG) in breeding and nonbreeding seasons and the contribution of laparoscopic insemination to the improvement of fertilization and embryo recovery were investigated. Twenty-four nonpregnant Awassi ewes of 3-4 years of age were randomly allocated into two groups (n = 12). Each ewe was treated with a progesterone impregnated intravaginal sponge for 12 days. The following superovulation treatment was used: ewes of group 1 received 1,200 IU of eCG once as an intramuscular injection 48 h prior to sponge withdrawal; ewes of group 2 also received 1,200 IU of eCG once as an intramuscular injection, 48 h prior to sponge withdrawal and after 24 h of sponge removal. Ewes were injected with 80 μg of GnRH. Ewes of groups 1 and 2 were further subdivided into four equal groups (n = 6). Subgroups A and C (superovulated with eCG and eCG plus GnRH, respectively) were mated naturally at least two times with Awassi rams of proven fertility at 8-h intervals. Subgroups B and D (same as A and C) had intrauterine insemination at 44-46 h after sponge removal, under laparoscopic visualization of uterine horns, depositing 1 ml of diluted semen containing 100 × 10(6) motile sperm in the distal portion of each uterine horn. Ovarian response was assessed by determining the number of corpora lutea by laparoscopy at day 6 after mating. Embryo recovery was performed by using a semi-laparoscopic flushing procedure in both uterine horns. Results of the present study showed that ewes treated in breeding season with eCG plus GnRH has a higher number (P superovulation in the nonbreeding season. A higher number of unfertilized ova (P superovulation in the breeding season. The use of eCG to induce superovulation in Awassi ewes combined with laparoscopic intrauterine insemination increases the fertilization rate.

  20. Efeito da aplicação de hCG ou GnRH sobre a concentração sérica de progesterona e eficiência reprodutiva em porcas Effect of injection of hCG or GnRH on progesterone serum concentration and reproductive efficiency of sows

    Directory of Open Access Journals (Sweden)

    L.F.R. Carvalho

    2003-12-01

    Full Text Available Avaliou-se o efeito da aplicação de diferentes hormônios no quinto dia após a primeira inseminação sobre a concentração sérica de progesterona e sobre as características reprodutivas, em 103 porcas entre o terceirro e sexto parto. As matrizes foram divididas em: grupo-controle (n=35, não tratado, grupo GnRH (n=34, animais submetidos à aplicação intramuscular (IM de 50mcg de um análogo-GnRH no quinto dia após a primeira inseminação, e grupo hCG (n=34, animais submetidos à aplicação IM de 500UI de hCG no quinto dia após a primeira inseminação. A aplicação dos hormônios não influenciou as características reprodutivas taxa de parto, número total de nascidos, número de nascidos vivos e peso da leitegada (P>0,05. Cinco animais de cada grupo foram submetidos a coletas de sangue da veia cava nos dias 3, 5, 8, 12, 21 e 28 após a primeira inseminação para avaliação da concentração sérica de progesterona (ng/ml, utilizando a técnica de radioimunoensaio. Não houve diferença significativa quanto à concentração sérica de progesterona entre os grupos.Two different hormones were administered on the fifth day after the first insemination to evaluate their influence on serum progesterone concentrations and on reproductive efficiency, in multiparous sows between the third and the sixth parturition. The reproductive performance was evaluated in 103 sows distributed into three groups: 1-Control (n=35; 2-GnRH, 50m g of GnRH-analogue, administered IM on the fifth day after the first insemination (n=34; and 3-hCG, 500 IU of hCG administered IM in the fifth day after the first insemination (n=34. No effect (P>0.05 of hormone treatments on farrowing rate, litter size, live born and litter weight was observed. Five sows of each group were blood sampled on days 3, 5, 8, 12, 21, 28, after the first insemination, to evaluate serum progesterone concentrations (ng/ml. Serum progesterone concentrations were not affected (P>0.05 by

  1. Software Agent Techniques in Design

    DEFF Research Database (Denmark)

    Hartvig, Susanne C

    1998-01-01

    This paper briefly presents studies of software agent techniques and outline aspects of these which can be applied in design agents in integrated civil engineering design environments.......This paper briefly presents studies of software agent techniques and outline aspects of these which can be applied in design agents in integrated civil engineering design environments....

  2. Agent Persuasion Mechanism of Acquaintance

    Science.gov (United States)

    Jinghua, Wu; Wenguang, Lu; Hailiang, Meng

    Agent persuasion can improve negotiation efficiency in dynamic environment based on its initiative and autonomy, and etc., which is being affected much more by acquaintance. Classification of acquaintance on agent persuasion is illustrated, and the agent persuasion model of acquaintance is also illustrated. Then the concept of agent persuasion degree of acquaintance is given. Finally, relative interactive mechanism is elaborated.

  3. Programming Agents with Emotions

    NARCIS (Netherlands)

    Dastani, Mehdi; Floor, Chr.; Meyer, John-Jules Charles

    2014-01-01

    In this paper we show how a cognitive agent programming language can be endowed with ways to program emotions. In particular we show how the programming language 2APL can be augmented so that it can work together with the computational emotion model ALMA to deal with appraisal, emotion/mood generati

  4. The need for agents

    DEFF Research Database (Denmark)

    Abolfazlian, Ali Reza Kian

    1996-01-01

    I denne artikel arbejder vi med begrebet Intelligent Software Agents (ISAs), som autonomous, social, reactive, proactive og subservient computer systemer. Baseret på socialt psykologiske argumenter viser jeg endvidere, hvordan både den menneskelige natur og det teknologiske stadium, som mennesket...

  5. Socially Intelligent Tutor Agents

    NARCIS (Netherlands)

    Heylen, Dirk K.J.; Nijholt, Antinus; op den Akker, Hendrikus J.A.; Vissers, M.; Aylett, R.; Ballin, D.; Rist, T.

    2003-01-01

    Emotions and personality have received quite a lot of attention the last few years in research on embodied conversational agents. Attention is also increasingly being paid to matters of social psychology and interpersonal aspects, for work of our group). Given the nature of an embodied

  6. SECOND BUYING AGENT

    CERN Multimedia

    SPL - SERVICES ACHATS

    2000-01-01

    Last year the buying agent LOGITRADE started operations on the CERN site, processing purchasing requests for well-defined families of products up to a certain value. It was planned from the outset that a second buying agent would be brought in to handle the remaining product families. So, according to that plan, the company CHARLES KENDALL will be commencing operations at CERN on 8 May 2000 in Building 73, 1st floor, offices 31 and 35 (phone and fax numbers to be announced).Each buying agent will have its own specific list of product families and will handle purchasing requests up to 10'000 CHF.Whenever possible they will provide the requested supplies at a price (including the cost of their own services) which must be equivalent to or lower than the price mentioned on the purchasing request, changing the supplier if necessary. If a lower price cannot be obtained, agents will provide the necessary administrative support free of charge.To ensure that all orders are processed in the best possible conditions, us...

  7. Remote Agent Experiment

    Science.gov (United States)

    Benard, Doug; Dorais, Gregory A.; Gamble, Ed; Kanefsky, Bob; Kurien, James; Millar, William; Muscettola, Nicola; Nayak, Pandu; Rouquette, Nicolas; Rajan, Kanna; Norvig, Peter (Technical Monitor)

    2000-01-01

    Remote Agent (RA) is a model-based, reusable artificial intelligence (At) software system that enables goal-based spacecraft commanding and robust fault recovery. RA was flight validated during an experiment on board of DS1 between May 17th and May 21th, 1999.

  8. Agent-Based Cloud Computing

    OpenAIRE

    Sim, Kwang Mong

    2012-01-01

    Agent-based cloud computing is concerned with the design and development of software agents for bolstering cloud service\\ud discovery, service negotiation, and service composition. The significance of this work is introducing an agent-based paradigm for\\ud constructing software tools and testbeds for cloud resource management. The novel contributions of this work include: 1) developing\\ud Cloudle: an agent-based search engine for cloud service discovery, 2) showing that agent-based negotiatio...

  9. Uso de antagonista de GnRH (cetrorelix em dose única para evitar ovulações prematuras em ciclos de fertilização assistida Single dose of GnRH antagonist (cetrorelix to avoid premature ovulation in assisted fertilization cycles

    Directory of Open Access Journals (Sweden)

    Pedro Luís Rosan

    2003-09-01

    Full Text Available OBJETIVO: verificar a eficácia de uma dose única subcutânea de acetato de cetrorelix em evitar a ovulação prematura em ciclos de fertilização assistida. MÉTODOS: estudo prospectivo, randomizado e controlado, pelo qual foram avaliados 20 ciclos de estimulação ovariana em mulheres submetidas a fertilização assistida, 10 das quais utilizaram o esquema tradicional de bloqueio hipofisário com análogos de GnRH em doses diárias (grupo controle e 10 utilizaram antagonista de GnRH em dose única de 3 mg no 7º dia de estimulação ovariana (grupo cetrorelix. Foram dosados FSH, LH, estradiol e progesterona no soro no primeiro e sétimo dia da estimulação, no dia da injeção de HCG e no dia da captação de oócitos. Os grupos foram comparados entre si quanto a eficácia do bloqueio hipofisário (nível de progesterona no dia da aplicação do HCG e desempenho nos ciclos de fertilização assistida (ampolas de gonadotrofinas utilizadas, folículos maiores que 18 mm, oócitos captados, taxas de fertilização, implantação e gravidez utilizando os testes de Mann-Whitney e exato de Fisher. RESULTADOS: não houve diferença significativa entre os grupos controle e cetrorelix, respectivamente, para a mediana da idade (31,5 e 34 anos, índice de massa corpórea (24 e 22, ampolas de gonadotrofinas utilizadas (34 e 32, folículos recrutados (3,5 e 3,0, oócitos captados (11 e 5, embriões obtidos (4 e 3, taxas de fertilização (93,7 e 60%, p = 0,07 e gravidez (50 e 60%, p = 0,7. Em ambos os grupos observou-se bloqueio hipofisário eficaz durante o período de estimulação ovariana. CONCLUSÕES: estes resultados confirmam a eficácia da dose única de 3 mg de acetato de cetrorelix em prevenir ovulações prematuras em pacientes submetidas a fertilização assistida, mostrando tendência a obtenção de menor número de embriões e menores taxas de fertilização no grupo cetrorelix em relação ao grupo controle. As taxas de implantação e

  10. [Pharmacology of inotropic agents].

    Science.gov (United States)

    Pastelín Hernández, Gustavo

    2002-01-01

    High-risk patients, during anesthesia and after surgery present changes in pharmacokinetics (biotransformation reactions, renal clearance, drug interactions, etc.) modifying the usefulness of most drugs, cardiac inotropics included. This group of substances is formed by adrenergic agents, phospodiesterase inhibitors and digitalis compounds. Adrenergic agents are the catecholamines, adrenaline (A), noradrenaline (NA) and dopamine (D), plus dopaminergic agonists as dobutamine and pirbuterol. Phosphodiesterase inhibitors, as amrinone and milrinone, produce their inotropic action by preserving cyclic adenosine monophosphate (AMPc) from its intracellular catabolism. Recent studies on the utility of digitalis compounds demonstrated the valuable applicability of digoxin in chronic and acute heart failure. Another group of substances whose mechanism of action differs from that of the inotropics, offers future utility in high risk patients, they include: inhibitors of nitric oxide sintases, natriuretic atrial peptide inhibitors, Q-10 coenzyme, endothelin antagonists, and anti-tumoral necrosis factor.

  11. Announcements to Attentive Agents

    DEFF Research Database (Denmark)

    Bolander, Thomas; van Ditmarsch, Hans; Herzig, Andreas;

    2016-01-01

    In public announcement logic it is assumed that all agents pay attention to the announcement. Weaker observational conditions can be modelled in action model logic. In this work, we propose a version of public announcement logic wherein it is encoded in the states of the epistemic model which...... agents pay attention to the announcement. This logic is called attention-based announcement logic. We give an axiomatization of the logic and prove that complexity of satisfiability is the same as that of public announcement logic, and therefore lower than that of action model logic. An attention......-based announcement can also be described as an action model. We extend our logic by integrating attention change. Finally, we add the notion of common belief to the language, we exploit this to formalize the concept of joint attention, that has been widely discussed in the philosophical and cognitive science...

  12. [The antiretroviral agent Fullevir].

    Science.gov (United States)

    Nosik, D N; Lialina, I K; Kalnina, L B; Lobach, O A; Chataeva, M S; Rasnetsov, L D

    2009-01-01

    The antiretroviral properties of Fullevir (sodium salt of fullerenepolyhydropolyaminocaproic acid) manufactured by IntelFarm Co.) were studied in the human cell culture infected with human immunodeficiency virus (HIV). The agent was ascertained to be able to protect the cell from the cytopathic action of HIV. The 90% effective concentration (EF90) was 5 microg/ml. The 50% average toxic concentration was 400 microg/ml. Testing of different (preventive and therapeutic) Fullevir dosage regimens has shown that the drug is effective when used both an hour before and an hour after infection and when administered simultaneously with cell infection. The longer contact time for the agent with the cells increased the degree of antiviral defense. Co-administration of Fullevir and the HIV reverse transcriptase inhibitor Retrovir (azidothymidine) showed a synergistic antiretroviral effect. Thus, Fullevir may be regarded as a new promising antiretroviral drug for the treatment of HIV infection.

  13. Pharmacology of antiplatelet agents.

    Science.gov (United States)

    Kalra, Kiran; Franzese, Christopher J; Gesheff, Martin G; Lev, Eli I; Pandya, Shachi; Bliden, Kevin P; Tantry, Udaya S; Gurbel, Paul A

    2013-12-01

    Pharmacotherapies with agents that inhibit platelet function have proven to be effective in the treatment of acute coronary syndromes, and in the prevention of complications during and after percutaneous coronary intervention. Because of multiple synergetic pathways of platelet activation and their close interplay with coagulation, current treatment strategies are based not only on platelet inhibition, but also on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current strategies can be broadly categorized as anticoagulants, antiplatelet agents, and fibrinolytics. This review focuses on the pharmacology of current antiplatelet therapy primarily targeting the inhibition of the enzyme cyclooxygenase 1, the P2Y12 receptor, the glycoprotein IIb/IIIa receptor, and protease-activated receptor 1.

  14. Sunscreening Agents: A Review

    OpenAIRE

    Latha, M. S.; Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; B R Naveen Kumar

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food an...

  15. Intelligent Agent Integration Technology

    Science.gov (United States)

    1998-04-01

    The DARPA knowledge sharing effort: Progress report. In B. Nebel , C. Rich, and W. Swartout, editors, Principles of Knowledge Representation and...and Automation, pages 2,785-2,788. IEEE CS Press. [18] Carl Hewitt. Offices are open systems. Communications of the ACM, 4(3):271-287, July 1986...19] Carl Hewitt and Jeff Inman. DAI betwixt and be- tween: From "intelligent agents" to open systems sci- ence. IEEE Transactions on Systems, Man

  16. Avoidance of weekend oocyte retrievals during GnRH antagonist treatment by simple advancement or delay of hCG administration does not adversely affect IVF live birth outcomes.

    Science.gov (United States)

    Tremellen, K P; Lane, M

    2010-05-01

    The use of GnRH antagonists in IVF treatment has many advantages over agonist long down-regulation, yet its uptake has been hampered by an inability to program the start date for gonadotrophin stimulation so as to minimize weekend oocyte retrievals (ORs). In this study, we retrospectively analyzed whether conducting a strict Monday to Friday OR program impacts on IVF outcomes. A total of 1642 non-programmed IVF antagonist cycles were analyzed to determine if advancing or delaying the OR by 1 day from 'ideal' to avoid Saturday or Sunday OR, respectively, had any impact on IVF outcomes. The IVF outcomes of Tuesday to Thursday served as a control as no modification in OR timing was required on these days. Advancing the OR by 1 day from the ideal resulted in a small but significant decrease in the number of oocytes collected and embryos created. Delaying the OR by 1 day from ideal resulted in a small increase in the number of oocytes collected and embryos created. However, deviation from the ideal day of OR had no significant effect on live birth rates. It is possible to safely avoid weekend ORs during GnRH antagonist cycles by simply advancing an ideal Saturday OR to Friday, and delaying an ideal Sunday OR to Monday, without adversely impacting on IVF live birth outcomes.

  17. Differential proteome analysis of the cell differentiation regulated by BCC, CRH, CXCR4, GnRH, GPCR, IL1 signaling pathways in Chinese fire-bellied newt limb regeneration.

    Science.gov (United States)

    Geng, Xiaofang; Xu, Tiantian; Niu, Zhipeng; Zhou, Xiaochun; Zhao, Lijun; Xie, Zhaohui; Xue, Deming; Zhang, Fuchun; Xu, Cunshuan

    2014-01-01

    Following amputation, the newt has the remarkable ability to regenerate its limb, and this process involves dedifferentiation, proliferation and differentiation. To investigate the potential proteome during a dynamic network of Chinese fire-bellied newt limb regeneration (CNLR), two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mass spectrum (MS) were applied to examine changes in the proteome that occurred at 11 time points after amputation. Meanwhile, several proteins were selected to validate their expression levels by Western blot. The results revealed that 1476 proteins had significantly changed as compared to the control group. Gene Ontology annotation and protein network analysis by Ingenuity Pathway Analysis 9.0 (IPA) software suggested that the differentially expressed proteins were involved in 33 kinds of physiological activities including signal transduction, cell proliferation, cell differentiation, etc. Among these proteins, 407 proteins participated in cell differentiation with 212 proteins in the differentiation of skin cell, myocyte, neurocyte, chondrocyte and osteocyte, and 37 proteins participated in signaling pathways of BCC, CRH, CXCR4, GnRH, GPCR and IL1 which regulated cell differentiation and redifferentiation. On the other hand, the signal transduction activity and cell differentiation activity were analyzed by IPA based on the changes in the expression of these proteins. The results showed that BCC, CRH, CXCR4, GnRH, GPCR and IL1 signaling pathways played an important role in regulating the differentiation of skin cell, myocyte, neurocyte, chondrocyte and osteocyte during CNLR.

  18. Cloning and expression analysis in mature individuals of two chicken type-Ⅱ GnRH (cGnRH-Ⅱ) genes in common carp (Cyprinus carpio )

    Institute of Scientific and Technical Information of China (English)

    LI; Shuangfei; HU; Wei; WANG; Yaping; ZHU; Zuoyan

    2004-01-01

    Gonadotropin-releasing hormone(GnRH)is a conservative neurodecapeptide family,which plays a crucial role in regulating the gonad development and in controlling the final sexual maturation in vertebrate.Two differing cGnRH-Ⅱ cDNAs of common carp,namely cGnRH-Ⅱ cDNA1 and cDNA2,were firstly cloned from the brain by rapid amplification of cDNA end(RACE)and reverse transcription- polymerase chain reaction(RT-PCR).The length of cGnRH-Ⅱ cDNA1 and cDNA2 was 622 and 578 base pairs(bp),respectively.The cGnRH-Ⅱ precursors encoded by two cDNAs consisted of 86 amino acids,including a signal peptide,cGnRH-Ⅱ decapeptide and a GnRH-associated peptide(GAP)linked by a Gly-Lys-Arg proteolytic site.The results of intron trapping and Southern blot showed that two differing cGnRH-Ⅱ genes in common carp genome were further identified,and that two genes might exist as a single copy.The multi-gene coding of common carp cGnRH-Ⅱ gene offered novel evidence for gene duplication hypothesis.Using semi-quantitative RT-PCR,expression and relative expression levels of cGnRH-Ⅱ genes were detected in five dissected brain regions,pituitary and gonad of common carp.With the exception of no mRNA2 in ovary,two cGnRH-Ⅱ genes could be expressed in all the detected tissues.However,expression levels showed an apparent difference in different brain regions,pituitary and gonad.According to the expression characterization of cGnRH-Ⅱ genes in brain areas,it was presumed that cGnRH-Ⅱ might mainly work as the neurotransmitter and neuromodulator and also operate in the regulation for the GnRH releasing.Then,the expression of cGnRH-Ⅱ genes in pituitary and gonad suggested that cGnRH-Ⅱ might act as the autocrine or paracrine regulator.

  19. Respostas hormonais ao tratamento com GnRH e estradiol e suas correlações com desenvolvimento testicular e número de células sertoli em touros angus x charolês na fase de pré-puberdade

    Directory of Open Access Journals (Sweden)

    Arlindo de Alencar Araripe Moura

    1999-02-01

    Full Text Available O objetivo desta pesquisa foi determinar as correlações entre níveis hormonais aos 2 e 6 meses de idade e diâmetro e histologia testicular em tourinhos Angus x Charolês aos 6 meses de idade (n=15. Aos dois meses, duas amostras basais de sangue foram coletadas a intervalos de 1 hora. Após a última coleta, os animais receberam 5 mg de GnRH e 1,5 e 3,0 horas depois novas amostras foram coletadas. Aos seis meses, os tourinhos foram tratados com 1 mg de estradiol benzoato (E e receberam 10 mg de GnRH doze horas depois. Após cinco dias, os tourinhos receberam 10 mg de GnRH, mas sem pré-tratamento com estradiol. As amostras de sangue foram coletadas 1,5 e 3,0 horas após a injeção de GnRH nas duas ocasiões. Imediatamente antes dos tratamentos com estradiol e GnRH, duas amostras basais foram coletadas. Os animais foram cirurgicamente castrados aos seis meses. Houve correlações entre níveis de FSH estimulados com GnRH aos dois meses e diâmetro testicular e número de células Sertoli e espermatogônias A1 por testículo aos seis meses de idade (r = -0,65 a -0,80. As associações entre FSH aos dois meses e número de seções de túbulos seminíferos sem células germinativas (r = 0,59 e número de túbulos com espermátides circulares (r = -0,55 também foram significativas. As correlações entre níveis de LH e esteróides e parâmetros testiculares não foram significativas. Aos 6 meses, níveis basais de FSH não alteraram 12 horas após estradiol, mas as concentrações de FSH estimuladas com GnRH foram 2,5 vezes mais elevadas, quando se usou estradiol em relação ao uso somente de GnRH. Modelos de regressão com número de células Sertoli, em função dos níveis de FSH após GnRH, mostraram que, quando se utilizaram GnRH + estradiol, obteve-se maior valor de R² (0,43 em comparação à injeção somente de GnRH (0,30. Portanto, concentrações periféricas de FSH são potenciais indicadores do desenvolvimento testicular na fase

  20. NOVEL ATYPICAL ANTIPSYCHOTIC AGENTS

    Directory of Open Access Journals (Sweden)

    Vijay Vinay

    2011-05-01

    Full Text Available Antipsychotics are a group of drugs commonly but not exclusively used to treat psychosis. Antipsychotic agents are grouped in two categories: Typical and Atypical antipsychotics. The first antipsychotic was chlorpromazine, which was developed as a surgical anesthetic. The first atypical anti-psychotic medication, clozapine, was discovered in the 1950s, and introduced in clinical practice in the 1970s. Both typical and atypical antipsychotics are effective in reducing positive and negative symptoms of schizophrenia. Blockade of D2 receptor in mesolimbic pathway is responsible for antipsychotic action. Typical antipsychotics are not particularly selective and also block Dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some of the unwanted side effects. Atypical antipsychotics differ from typical psychotics in their "limbic-specific" dopamine type 2 (D2-receptor binding and high ratio of serotonin type 2 (5-HT2-receptor binding to D2. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, narcoleptic malignant syndrome, and hyperprolactinemia. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs and tardive dyskinesia (TD.

  1. Análogo de GnRH disminuye la secreción de hormona folículo estimulante (FSH en ovejas prepúberes A gonadotropin releasing hormone analogue decreases follicle stimulating hormone (FSH secretion in prepubertal female sheep

    Directory of Open Access Journals (Sweden)

    S E Recabarren

    2006-01-01

    Full Text Available La secreción de LH y FSH depende de la liberación pulsátil de GnRH desde el hipotálamo; sin embargo, el grado de dependencia así como la relación entre los pulsos de GnRH y la secreción de FSH es menos clara. Experimentos en monos han mostrado que altas frecuencias de liberación de pulsos de GnRH estimulan preferentemente la secreción de LH, mientras que bajas frecuencias de pulsos de GnRH favorecen la secreción de FSH. Estudios sobre el control de la secreción de FSH en ovejas prepúberes son escasos. Con el objetivo de reconocer la dependencia de la secreción de FSH por parte de la GnRH, se administró un análogo de GnRH en microcápsulas de liberación lenta (Trp6-GnRH, Decapeptyl® y cuyo efecto bloqueador sobre la secreción de LH ha sido demostrado. El análogo se administró intramuscularmente cada cuatro semanas a partir de las 20 semanas de edad a cinco borregas Suffolk por tres veces. Otro grupo de ovejas prepúberes de las mismas edades recibió el vehículo. Estudios de pulsatilidad de FSH se efectuaron a las, 20, 26 y 30 semanas de edad. Se utilizó el programa Cluster para reconocer las características de la secreción pulsátil de FSH. En las borregas del grupo control no hubo cambios en las características de la secreción pulsátil de FSH entre las 20 y 30 semanas de edad. En el grupo tratado con el análogo de GnRH, las concentraciones plasmáticas de FSH disminuyeron desde 3,4±0,3 ng/mL/5h a las 20 semanas de edad hasta los 0,36±0,1 ng/mL/5h a las 30 semanas de edad (pLH and FSH secretions depend on the pulsatile secretion of GnRH from the hypothalamus. However, the grade of dependency as well as the relationship between pulses of GnRH and pulses of FSH secretion is less clear. Experiments in monkeys have shown that high GnRH pulse frequency favors LH secretion while low frequency of GnRH pulses preferentially stimulates the FSH secretion. The objective of the present work was to recognize the dependence of GnRH

  2. 不同时期阿尔茨海默病小鼠脑中GnRH表达的变化%Changes of expression of GnRH in Alzheimer's disease mice at different periods

    Institute of Scientific and Technical Information of China (English)

    林茂; 王春梅; 万章; 王敏

    2011-01-01

    Objective To study expression changes of gonadotropin releasing hormone (GnRH) in Alzheimer' s disease mice at different periods and analyze their relationship with AD. Methods Mice were randomly divided into 2 groups: control group (n = 70), AD model group (n = 70). Each groups were divided into 7 subgroups (n = 10) according to different days (0, 15, 30, 45, 60, 75 and 90 d).AD model mice were made by D-galactose and aluminum chloride. The ability of learning and memory in mice were observed by step-down test. The level of estrogen in serum was measured by ELISA. And the expression of Tau-pThr231 and GnRH were detected by Western Blot and immunohistochemistry. Results Compared with the control group, AD model mice at the 45th, 60th, 75th, 90th days showed a significant decrease in the learning and memory abilities (P < 0.05), and the expression of Tau-pThr231 increased at the same time. The level of GnRH in brains of AD model mice was significantly decreased compared with control group (P < 0.01) at the 60th, 75th, 90th days. The level of estrogen in serum in AD model mice was obviously lower than that in control group at the 90th day (P < 0.05). Conclusions The results suggested that there was positive correlation of GnRH with severity of AD. The decreased expression of GnRH may be one of the risk factors of AD, happened earlier than estrogen.%目的:观察不同时期阿尔茨海默病(AD)小鼠脑中促性腺激素释放激素(GnRH)表达的变化,探讨其与AD的内在关系.方法:140只昆明鼠随机分为对照组和AD模型组,每组又按取样时间不同分为0、15、30、45、60、75和90 d七个亚组,每亚组10只.采用D-半乳糖联合氯化铝构建AD小鼠模型,跳台实验观察各组小鼠认知功能;Western blot法测定海马苏氨酸231位点磷酸化tau蛋白(Tau-pThr231)水平;ELISA法测定血清中雌二醇(E2)水平;免疫组化观察脑组织中GnRH的表达.结果:AD模型组45、60、75、90 d小鼠

  3. Agents Play Mix-game

    CERN Document Server

    Gou, C

    2005-01-01

    In mix-game which is an extension of minority game, there are two groups of agents; group1 plays the majority game, but the group2 plays the minority game. This paper studies the change of the average winnings of agents and volatilities vs. the change of mixture of agents in mix-game model. It finds that the correlations between the average winnings of agents and the mean of local volatilities are different with different combinations of agent memory length when the proportion of agents in group 1 increases. This study result suggests that memory length of agents in group1 be smaller than that of agent in group2 when mix-game model is used to simulate the financial markets.

  4. Product and Agent

    DEFF Research Database (Denmark)

    Montecino, Alex; Valero, Paola

    2015-01-01

    In this paper we will explore how the “mathematics teacher” becomes a subject and, at the same time, is subjected as part of diverse dispositive of power. We argue that the mathematics teacher becomes both a product and a social agent, which has been set, within current societies, from the ideas...... of globalization, social progress, and competitive logic. For our approximation, we use the concepts societies of control, dispositive, and discourses from a Foucault–Deleuze toolbox. Our purpose is to cast light on the social and cultural constitution of the ways of thinking about the mathematics teacher. Hence...

  5. Agentes selladores en endodoncia

    OpenAIRE

    2003-01-01

    Recibido: Noviembre 2002 Aceptado: Enero 2003 La gutapercha sigue siendo uno de los materiales predilectos, pero debido a su falta de adhesión a las paredes dentinarias, debe estar siempre combinada con un sellador que actúe como interfase entre la masa de gutapercha y la estructura dentaria. El uso de un agente sellador para obturar los conductos radiculares es esencial para el éxito del proceso de obturación. Un buen sellador debe ser biocompatible y bien tolerado por los tejid...

  6. Secure Mobile Trade Agent

    Directory of Open Access Journals (Sweden)

    Musbah M. Aqe

    2007-01-01

    Full Text Available E-commerce on the internet has the ability to produce millions of transactions and a great number of merchants whose supply merchandise over the internet. As a result, it is difficult for entities to roam over every site on the internet and choose the best merchandise to trade. So, in this paper we introduced a mobile trade agent that visit the sites to gather and evaluate the information from merchant servers and decide to trade goods on behalf of the user. We observed that the combination of public key cryptosystem with distributed object technology make this proposed scheme more secure and efficient than the already existed schemes.

  7. Product and Agent

    DEFF Research Database (Denmark)

    Montecino, Alex; Valero, Paola

    2015-01-01

    In this paper we will explore how the “mathematics teacher” becomes a subject and, at the same time, is subjected as part of diverse dispositive of power. We argue that the mathematics teacher becomes both a product and a social agent, which has been set, within current societies, from the ideas...... of globalization, social progress, and competitive logic. For our approximation, we use the concepts societies of control, dispositive, and discourses from a Foucault–Deleuze toolbox. Our purpose is to cast light on the social and cultural constitution of the ways of thinking about the mathematics teacher. Hence...

  8. Antineoplastic agents and thrombotic microangiopathy.

    Science.gov (United States)

    Garcia, Gwenalyn; Atallah, Jean Paul

    2017-03-01

    Thrombotic microangiopathy is an uncommon but reported adverse effect of a variety of antineoplastic drugs, including chemotherapy agents such as mitomycin C and gemcitabine, and newer targeted agents such as the vascular endothelial growth factor inhibitors. We present a review of thrombotic microangiopathy associated with antineoplastic agents and its implications in current cancer therapy.

  9. Cultural Differentiation of Negotiating Agents

    NARCIS (Netherlands)

    Hofstede, G.J.; Jonker, C.M.; Verwaart, D.

    2012-01-01

    Negotiations proceed differently across cultures. For realistic modeling of agents in multicultural negotiations, the agents must display culturally differentiated behavior. This paper presents an agent-based simulation model that tackles these challenges, based on Hofstede’s model of national cultu

  10. Cultural differentiation of negotiating agents

    NARCIS (Netherlands)

    Hofstede, G.J.; Jonker, C.M.; Verwaart, T.

    2010-01-01

    Negotiations proceed differently across cultures. For realistic modeling of agents in multicultural negotiations, the agents must display culturally differentiated behavior. This paper presents an agent-based simulation model that tackles these challenges, based on Hofstede’s model of national cultu

  11. Implementing an Agent Trade Server

    OpenAIRE

    Boman, Magnus; Sandin, Anna

    2003-01-01

    An experimental server for stock trading autonomous agents is presented and made available, together with an agent shell for swift development. The server, written in Java, was implemented as proof-of-concept for an agent trade server for a real financial exchange.

  12. Assigning agents to a line

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Moreno-Ternero, Juan D.; Østerdal, Lars Peter Raahave

    2014-01-01

    We consider the problem of assigning agents to slots on a line, where only one agent can be served at a slot and each agent prefers to be served as close as possible to his target. Our focus is on aggregate gap minimizing methods, i.e., those that minimize the total gap between targets and assigned...

  13. Agentes de información Information Agents

    Directory of Open Access Journals (Sweden)

    Alfonso López Yepes

    2005-12-01

    Full Text Available Este artículo realiza un repaso sobre las tipologías de agentes de información y describe aspectos como movilidad, racionalidad y adaptatividad, y el ajuste final de estos conceptos a entornos distribuidos como Internet, donde este tipo de agentes tienen un amplio grado de aplicación. Asimismo, se propone una arquitectura de agentes para un sistema multiagente de recuperación de información donde se aplica un paradigma documental basado en el concepto de ciclo documental.This article summarizes the main information agent types reflecting on issues such as mobility, rationality, adaptability and the final adjustment of this concepts to distributed environments such as the Internet, where this kind of agents has wide range application. Likewise, an information agent architecture is proposed to create a multi-agent information retrieval system in which a documentary paradigm based on the documentary cycle is developed.

  14. [New agents for hypercholesterolemia].

    Science.gov (United States)

    Pintó, Xavier; García Gómez, María Carmen

    2016-02-19

    An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  15. Holograms as Teaching Agents

    Science.gov (United States)

    Walker, Robin A.

    2013-02-01

    Hungarian physicist Dennis Gabor won the Pulitzer Prize for his 1947 introduction of basic holographic principles, but it was not until the invention of the laser in 1960 that research scientists, physicians, technologists and the general public began to seriously consider the interdisciplinary potentiality of holography. Questions around whether and when Three-Dimensional (3-D) images and systems would impact American entertainment and the arts would be answered before educators, instructional designers and students would discover how much Three-Dimensional Hologram Technology (3DHT) would affect teaching practices and learning environments. In the following International Symposium on Display Holograms (ISDH) poster presentation, the author features a traditional board game as well as a reflection hologram to illustrate conventional and evolving Three-Dimensional representations and technology for education. Using elements from the American children's toy Operation® (Hasbro, 2005) as well as a reflection hologram of a human brain (Ko, 1998), this poster design highlights the pedagogical effects of 3-D images, games and systems on learning science. As teaching agents, holograms can be considered substitutes for real objects, (human beings, organs, and animated characters) as well as agents (pedagogical, avatars, reflective) in various learning environments using many systems (direct, emergent, augmented reality) and electronic tools (cellphones, computers, tablets, television). In order to understand the particular importance of utilizing holography in school, clinical and public settings, the author identifies advantages and benefits of using 3-D images and technology as instructional tools.

  16. Amphoteric surface active agents

    Directory of Open Access Journals (Sweden)

    Eissa, A.M. F.

    1995-10-01

    Full Text Available 2-[trimethyl ammonium, triethyl ammonium, pyridinium and 2-amino pyridinium] alkanoates, four series of surface active agents containing carbon chain C12, C14, C16 and C18carbon atoms, were prepared. Their structures were characterized by microanalysis, infrared (IR and nuclear magnetic resonance (NMR. Surface and interfacial tension, Krafft point, wetting time, emulsification power, foaming height and critical micelle concentration (cmc were determined and a comparative study was made between their chemical structure and surface active properties. Antimicrobial activity of these surfactants was also determined.

    Se prepararon cuatro series de agentes tensioactivos del tipo 2-[trimetil amonio, trietil amonio, piridinio y 2-amino piridinio] alcanoatos, que contienen cadenas carbonadas con C12, C14, C16 y C18 átomos de carbono.
    Se determinaron la tensión superficial e interfacial, el punto de Krafft, el tiempo humectante, el poder de emulsionamiento, la altura espumante y la concentración critica de miscela (cmc y se hizo un estudio comparativo entre la estructura química y sus propiedades tensioactivas. Se determinó también la actividad antimicrobiana de estos tensioactivos. Estas estructuras se caracterizaron por microanálisis, infrarrojo (IR y resonancia magnética nuclear (RMN.

  17. Glucagon-like peptide-1 excites firing and increases GABAergic miniature postsynaptic currents (mPSCs in gonadotropin-releasing hormone (GnRH neurons of the male mice via activation of nitric oxide (NO and suppression of endocannabinoid signaling pathways

    Directory of Open Access Journals (Sweden)

    Imre Farkas

    2016-09-01

    Full Text Available Glucagon-like peptide-1 (GLP-1, a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9-39 (1 μM. Intracellular application of the G-protein inhibitor GDP-beta-S (2 mM impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO synthesis by L-NAME (100 μM or NPLA (1 μM or intracellular scavenging of NO by CPTIO (1 mM partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using CB1 inverse-agonist AM251 (1 μM. Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the TRPV1-antagonist AMG9810 (10 μM or the FAAH-inhibitor PF3845 (5 μM impeded the GLP-1-triggered endocannabinoid pathway indicating an anandamide-TRPV1-sensitive control of 2-AG production. Furthermore, GLP-1 immunoreactive axons innervated GnRH neurons in the hypothalamus suggesting that GLP-1 of both peripheral and neuronal sources can modulate GnRH neurons. RT-qPCR study confirmed the expression of GLP-1R and nNOS mRNAs in GnRH-GFP neurons. Immuno-electron microscopic analysis revealed the presence of neuronal nitric oxide synthase (nNOS protein in GnRH

  18. Agent-oriented Software Engineering

    Institute of Scientific and Technical Information of China (English)

    GUAN Xu; CHENG Ming; LIU Bao

    2001-01-01

    An increasing number of computer systems are being viewed in terms of autonomous agents.Most people believe that agent-oriented approach is well suited to design and build complex systems. Yet. todate, little effort had been devoted to discuss the advantages of agent-oriented approach as a mainstreamsoftware engineering paradigm. Here both of this issues and the relation between object-oriented and agent-oriented will be argued. we describe an agent-oriented methodology and provide a quote for designing anauction system.

  19. GnRH激动剂主动免疫母羊对生殖激素分泌的作用%Effects of GnRH agonist active immunization on reproductive hormone secretion of Ewes (Ovis aries)

    Institute of Scientific and Technical Information of China (English)

    魏锁成; 巩转娣; 欧阳霞辉; 董江陵; 李琼毅; 韦敏; 谢坤; 张锋; 孙建龙

    2012-01-01

    Objective; To explore the characteristics of reproductive hormones synthesis and secretion in ewes actively immunized with GnRH agonist,further to study the mechanisms of GnRH agonists regulating reproductive functions in animals. Methods:Forty-two ewes were randomly assigned into six groups ( each of 7 eves ). Ewes in experiment group ( EG)-I ,EG-Ⅱ and EG-Ⅲ were injected subcutaneously twice ( at days 0 and 7 ) with 200,300 and 400 μg GnRH agonist ( Alarelin ) antigen respectively. Animals in EG-IV and EG-Vwere injected subcutaneously with 200 μg and 300 μg Alarelin antigen for four times ( at days 0,7,14 and 21 ) respectively. The control group ( CG ) was injected with 2. 0 ml solvent subcutaneously twice ( at days 0 and 7 ). Blood samples were collected from jugular vein. Serum concentrations of anti-GnRH antibody,GnRH,FSH,LH and estradiol( E2 ) were detected using ELISA. ResultS:( 1 ) Anti-GnRH antibody was detected at days 7 after the first injection of alarelin antigen,antibody concentrations in EG- I , EG-Ⅱ and EG-Ⅲ reached peak levels at days 28,28 and 35 respectively. Both EG-IV and EG-V reached the peak values at days 45.Serum concentrations of GnRH antibody in five experiment groups were higher than that CG ( P <0. 05 ) from days 14 to 70. ( 2 ) When compared to CG, serum GnRH concentrations in EG- I , EG- Ⅱ, EG- Ⅲ , EG- IV and EG- V reached the bottom values at days 21,28 ( P <0. 05 ),45,45 and 45 ( P <0.01 ). GnRH concentrations in EG-V was the lowest. ( 3 ) Serum FSH concentrations in experiment groups began to increase gradually from days 14. FSH concentrations in experiment groups were higher than that in CG during whole experiment. ( 4 )Serum LH concentrations in experiment groups declined compared to CG. At days 35, EG-IV and EG-Vwere lower than EG- I ,EG-II and EG-!. ( 5 ) Serum estradiol levels had no significant differences among all groups. Conclusion: GnRH agonist ( alarelin )antigen active immunization could stimulate

  20. Flexible, secure agent development framework

    Science.gov (United States)

    Goldsmith,; Steven, Y [Rochester, MN

    2009-04-07

    While an agent generator is generating an intelligent agent, it can also evaluate the data processing platform on which it is executing, in order to assess a risk factor associated with operation of the agent generator on the data processing platform. The agent generator can retrieve from a location external to the data processing platform an open site that is configurable by the user, and load the open site into an agent substrate, thereby creating a development agent with code development capabilities. While an intelligent agent is executing a functional program on a data processing platform, it can also evaluate the data processing platform to assess a risk factor associated with performing the data processing function on the data processing platform.

  1. GnRH受体在山羊颈中神经节的分布特点%Distribution characteristics of GnRH receptor in the middle cervical ganglion of goat

    Institute of Scientific and Technical Information of China (English)

    范洁; 明佳; 陈文东; 王志豪; 任妮; 吴卫妮; 徐永平

    2012-01-01

    This experiment was conducted to detect the existence of GnRH receptor(GnRHR) in the middle cervical ganglion(MCG) of goat. Five pairs of MCG were taken from mature female and male goats, respectively. The distribution characteristics of GnRHR were observed after immunohistochemical SP stai- ning. The results showed that: for neurons, strong GnRHR immunoreactivity(GnRHR-ir) and weak Gn- RHR-ir products distributed on the membrane and the whole cytoplasm,respectively;the vascular endothe- lial cells were moderate positive ~ while the nerve fibers, the satellite cells and the Schwan cells were weak positive. The wide distribution of GnRHR in MCG implied that GnRH may regulate MCG,which provided morphologic basis for studies on non-reproductive regulating function of GnRH and neuroendocrine regula- tion of MCG.%为了证实GnRH受体在山羊颈中神经节是否存在,取雄性和雌性成年山羊的颈中神经节各5对,经免疫组织化学SP法染色后,观察GnRH受体在颈中神经节的分布特点。结果表明,山羊颈中神经节的神经元、血管内皮细胞、神经纤维及卫星细胞均有不同程度的阳性染色。神经元中GnRH受体强阳性产物分布于胞膜上,中等阳性产物分布于整个胞质中;血管内皮细胞有中等阳性产物;神经纤维、卫星细胞和施万细胞有弱阳性产物分布。证实,GnRH受体在山羊颈中神经节中分布广泛,提示颈中神经节可能受GnRH调节,这为研究GnRH非生殖调节功能及颈中神经节的神经内分泌调节机制提供了形态学依据。

  2. Combined use of progesterone inserts, ultrasongraphy, and GnRH to identify and resynchronize nonpregnant cows and heifers 21 days after timed artificial insemination.

    Science.gov (United States)

    Kelley, D E; Ibarbia, L; Daetz, R; Bittar, J H; Risco, C A; Santos, J E P; Ribeiro, E S; Galvão, K N

    2016-01-15

    The objective was to decrease the reinsemination interval (RI) when dairy cows and heifers are inseminated using all timed artificial insemination (TAI) programs. Holstein cows (n = 211) and heifers (n = 153) were randomly assigned to a control or 21-day Resynch (21dRES) at 13 days after TAI. Animals in 21dRES (n = 109 cows and 77 heifers) had a progesterone device inserted on Day 13 and removed on Day 20 after TAI and ovaries scanned by ultrasonography. Animals found not to have an active CL (<15 mm) or a CL that decreased 10 mm or greater from Days 13 to 20, and to have a follicle of 12 mm or greater received GnRH and TAI on Day 21. Pregnancy diagnosis was performed on Day 32. Nonpregnant control cows (n = 102) were resynchronized immediately using Ovsynch-56, and control heifers (n = 76) were resynchronized using 5-day Cosynch starting on Day 34; therefore, cows and heifers were reinseminated on Day 42. Nonpregnant 21dRES animals that had not been reinseminated on Day 21 were resynchronized concurrently with the control animals. Pregnancy per AI (PAI) for the initial TAI was similar (P = 0.80) for 21dRES and control cows (30.3% vs. 29.4%) and heifers (49.4% vs. 51.3%). Of the nonpregnant 21dRES animals, 33 of 76 cows (43.4%) and 22 of 39 heifers (56.4%) had been reinseminated on Day 21. Therefore, the RI was decreased by 9.9 days (33.3 ± 1.0 vs. 43.2 ± 1.0 days; P < 0.001) in 21dRES cows and by 12.2 days in 21dRES heifers (30.1 ± 1.3 vs. 42.3 ± 1.3 days; P < 0.001) compared with controls. The overall resynchronized PAI was similar for 21dRES cows compared with controls (31.6% vs. 25.0%; P = 0.23). The PAI was 24.2% for 21dRES cows reinseminated on Day 21 and 37.2% for 21dRES cows reinseminated on Day 42. The overall resynchronized PAI was increased for 21dRES heifers compared with controls (57.5% vs. 32.4%; P = 0.03) because 21dRES heifers reinseminated on Day 21 had similar PAI compared with controls (43.5% vs. 32

  3. MORBIDITY AGENTS: A REVIEW

    Directory of Open Access Journals (Sweden)

    Shrivastava Neelesh

    2011-09-01

    Full Text Available This paper discuss on clinical representation of morbid jealousy which often termed delusional jealousy or ‘Othello Syndrome’ is a psychiatric condition where a lover believes against all reason and their beloved is being sexually unfaithful. Patients will be preoccupied with their partner’s perceived lack of sexual fidelity and will often behave in an unacceptable or extreme way as they endeavor to prove their ideas. Misuse of any psychomotor is an important association cause morbidity jealousy agents, like CNS stimulants that release the catecholamine, particularly dopamine, from pre synaptic terminals substance should be treated as a priority. Where higher levels of violence are reported Sildenafil may be useful as a diagnostic as well as therapeutic test in such cases .Many studies have shown an association between high alcohol consumption and developing morbid jealousy. Amphetamine-induced psychosis has been extensively studied because of its close resemblance to schizophrenia.

  4. UTBot: A Virtual Agent Platform for Teaching Agent System Design

    Directory of Open Access Journals (Sweden)

    In-Cheol Kim

    2007-02-01

    Full Text Available We introduce UTBot, a virtual agent platform for teaching agent system design. UTBot implements a client for the Unreal Tournament game server and Gamebots system. It provides students with the basic functionality required to start developing their own intelligent virtual agents to play autonomously UT games. UTBot includes a generic agent architecture, CAA (Context-sensitive Agent Architecture, a domain-specific world model, a visualization tool, several basic strategies (represented by internal modes and internal behaviors, and skills (represented by external behaviors. The CAA architecture can support complex long-term behaviors as well as reactive short-term behaviors. It also realizes high context-sensitivity of behaviors. We also discuss our experience using UTBot as a pedagogical tool for teaching agent system design in undergraduate Artificial Intelligence course.

  5. Avaliação psicológica de meninas com puberdade precoce central idiopática antes e durante o bloqueio puberal com análogos de GnRH

    OpenAIRE

    Tais Alencar Santos Menk

    2015-01-01

    Introdução: A puberdade é considerada precoce quando ocorre antes dos 8 anos nas meninas. É classificada como puberdade precoce central (PPC) quando decorre da ativação prematura do eixo gonadotrófico e é considerada idiopática quando não há alteração no sistema nervoso central. O bloqueio puberal com análogos de GnRH é o tratamento de escolha da PPC e visa a regressão ou estabilização dos caracteres sexuais secundários, desaceleração da velocidade de crescimento e da maturação óssea com melh...

  6. Effect of a low dose combined oral contraceptive pill on the hormonal profile and cycle outcome following COS with a GnRH antagonist protocol in women over 35 years old.

    Science.gov (United States)

    Bakas, Panagiotis; Hassiakos, Dimitrios; Grigoriadis, Charalampos; Vlahos, Nikolaos F; Liapis, Angelos; Creatsas, George

    2014-11-01

    This prospective study examines if pre-treatment with two different doses of an oral contraceptive pill (OCP) modifies significantly the hormonal profile and/or the IVF/ICSI outcome following COS with a GnRH antagonist protocol. Infertile patients were allocated to receive either OCP containing 0.03 mg of ethinylestradiol and 3 mg of drospirenone, or OCP containing 0.02 mg of ethinylestradiol and 3 mg of drospirenone prior to initiation of controlled ovarian stimulation (COS) with recombinant gonadotropins on a variable multi-dose antagonist protocol (Ganirelix), while the control group underwent COS without OCP pretreatment. Lower dose OCP was associated with recovery of FSH on day 3 instead of day 5, but the synchronization of the follicular cohort, the number of retrieved oocytes and the clinical pregnancy rate were similar to higher dose OCP.

  7. Odor Classification using Agent Technology

    Directory of Open Access Journals (Sweden)

    Sigeru OMATU

    2014-03-01

    Full Text Available In order to measure and classify odors, Quartz Crystal Microbalance (QCM can be used. In the present study, seven QCM sensors and three different odors are used. The system has been developed as a virtual organization of agents using an agent platform called PANGEA (Platform for Automatic coNstruction of orGanizations of intElligent Agents. This is a platform for developing open multi-agent systems, specifically those including organizational aspects. The main reason for the use of agents is the scalability of the platform, i.e. the way in which it models the services. The system models functionalities as services inside the agents, or as Service Oriented Approach (SOA architecture compliant services using Web Services. This way the adaptation of the odor classification systems with new algorithms, tools and classification techniques is allowed.

  8. Agent-based enterprise integration

    Energy Technology Data Exchange (ETDEWEB)

    N. M. Berry; C. M. Pancerella

    1998-12-01

    The authors are developing and deploying software agents in an enterprise information architecture such that the agents manage enterprise resources and facilitate user interaction with these resources. The enterprise agents are built on top of a robust software architecture for data exchange and tool integration across heterogeneous hardware and software. The resulting distributed multi-agent system serves as a method of enhancing enterprises in the following ways: providing users with knowledge about enterprise resources and applications; accessing the dynamically changing enterprise; locating enterprise applications and services; and improving search capabilities for applications and data. Furthermore, agents can access non-agents (i.e., databases and tools) through the enterprise framework. The ultimate target of the effort is the user; they are attempting to increase user productivity in the enterprise. This paper describes their design and early implementation and discusses the planned future work.

  9. Agent-based enterprise integration

    Energy Technology Data Exchange (ETDEWEB)

    N. M. Berry; C. M. Pancerella

    1998-12-01

    The authors are developing and deploying software agents in an enterprise information architecture such that the agents manage enterprise resources and facilitate user interaction with these resources. The enterprise agents are built on top of a robust software architecture for data exchange and tool integration across heterogeneous hardware and software. The resulting distributed multi-agent system serves as a method of enhancing enterprises in the following ways: providing users with knowledge about enterprise resources and applications; accessing the dynamically changing enterprise; locating enterprise applications and services; and improving search capabilities for applications and data. Furthermore, agents can access non-agents (i.e., databases and tools) through the enterprise framework. The ultimate target of the effort is the user; they are attempting to increase user productivity in the enterprise. This paper describes their design and early implementation and discusses the planned future work.

  10. Timing of human chorionic gonadotropin (hCG) hormone administration in IVF/ICSI protocols using GnRH agonist or antagonists: a systematic review and meta-analysis.

    Science.gov (United States)

    Chen, Ying; Zhang, Yi; Hu, Min; Liu, Xiru; Qi, Hongbo

    2014-06-01

    To evaluate the effect of altering the timing of human chorionic gonadotropin (hCG) administration on the clinical outcome of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) using gonadotropic hormone releasing hormone (GnRH) agonist or antagonist. We systematically searched six databases. Randomized controlled trials (RCTs) of the effects of altering the timing of hCG administration on the clinical outcome of IVF and ICSI using GnRH agonist or antagonist were included. A meta-analysis was conducted following a quality evaluation performed with Cochrane Collaboration's Review Manager (RevMan) 5.0.2. Seven RCTs and a total of 1295 participants were included. Significant difference was observed regarding estradiol and progesterone levels on the day of hCG administration and oocyte retrieval between early hCG and late hCG administration group and in favor of the latter. The fertilization rate was not statistically different between early and 24-h late hCG groups, but it is significantly higher in the 48-h late hCG group. The pooled results showed no significant differences in the ongoing pregnancy rate per oocyte pick-up, the miscarriage rate and the live birth rate. The prolongation of follicular phase by delaying hCG administration could increase estradiol, progesterone levels and oocyte retrieval, which will not influence ongoing pregnancy rate per oocyte pick-up, miscarriage rate and live birth rate. Postponing hCG may enable increased flexibility of cycle scheduling to avoid weekend procedures.

  11. A Reevaluation of the Question: Is the Pubertal Resurgence in Pulsatile GnRH Release in the Male Rhesus Monkey (Macaca mulatta) Associated With a Gonad-Independent Augmentation of GH Secretion?

    Science.gov (United States)

    Shahab, M; Trujillo, M Vargas; Plant, T M

    2015-10-01

    A somatic signal has been posited to trigger the pubertal resurgence in pulsatile GnRH secretion that initiates puberty in highly evolved primates. That GH might provide such a signal emerged in 2000 as a result of a study reporting that circulating nocturnal GH concentrations in castrated juvenile male monkeys increased in a 3-week period immediately preceding the pubertal resurgence of LH secretion. The present study was conducted to reexamine this intriguing relationship, again in an agonadal model. Four castrated juvenile male monkeys were implanted with indwelling jugular catheters, housed in remote sampling cages, and subjected to 24 hours of sequential blood sampling (every 30 min) every 2 weeks from 19.5 to 22 months of age. Twenty-four-hour profiles of circulating GH concentrations were analyzed using the pulse detection algorithm, PULSAR, and developmental changes in pulsatile GH release with respect to the initiation of the pubertal rise of LH secretion (week 0; observed between 22.5 and 32 mo of age) were examined for significance by a repeated-measures ANOVA. Changes in the parameters of pulsatile GH secretion, including mean 24-hour GH concentration and GH pulse frequency and pulse amplitude for 3 (n = 4) and 6 (n = 3) months before week 0 were unremarkable and nonsignificant. These findings fail to confirm those of the earlier study and lead us to conclude that the timing of the pubertal resurgence of GnRH release in the male monkey is not dictated by GH. Reasons for the discrepancy between the two studies are unclear.

  12. Anticancer agents from medicinal plants

    Directory of Open Access Journals (Sweden)

    Mohammad Shoeb

    2006-12-01

    Full Text Available Cancer is a major public health burden in both developed and developing countries. Plant derived agents are being used for the treatment of cancer. Several anticancer agents including taxol, vinblas-tine, vincristine, the camptothecin derivatives, topotecan and irinotecan, and etoposide derived from epipodophyllotoxin are in clinical use all over the world. A number of promising agents such as flavopiridol, roscovitine, combretastatin A-4, betulinic acid and silvestrol are in clinical or preclinical development.

  13. Anticancer agents from medicinal plants

    Directory of Open Access Journals (Sweden)

    Mohammad Shoeb

    2006-06-01

    Full Text Available Cancer is a major public health burden in both developed and developing countries. Plant derived agents are being used for the treatment of cancer. Several anticancer agents including taxol, vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, and etoposide derived from epipodophyllotoxin are in clinical use all over the world. A number of promising agents such as flavopiridol, roscovitine, combretastatin A-4, betulinic acid and silvestrol are in clinical or preclinical development.

  14. Research on Negotiating Agent Development

    Institute of Scientific and Technical Information of China (English)

    WEI Ding-guo; PENG Hong

    2004-01-01

    The paper presents a flexible and effective method of development of negotiating agents.A strategy specification, which is specified by a state chart and defeasible rules, can be dynamically inserted into an agent shell incorporating a state chart interpreter and a defeasible logic inference engine, in order to yield a desirable agent.The set of desirable criteria and rules is required to be justified with different context of the application.

  15. Agent 与Multi-Agent System 技术研究%The Research on Agent and Multi-Agent System

    Institute of Scientific and Technical Information of China (English)

    党建武; 韩泉叶; 崔文华

    2002-01-01

    分析了Multi-Agent System 涉及的相关问题,在普通的Multi-Agent System的组织结构的基础上提出了管理服务机构,中介服务机构和主控流动服务机构的Multi-Agent System,并对不同组织结构的Agent之间的协同进行了讨论.

  16. Broad-spectrum antiviral agents

    Directory of Open Access Journals (Sweden)

    Jun-Da eZhu

    2015-05-01

    Full Text Available Development of highly effective, broad-spectrum antiviral agents is the major objective shared by the fields of virology and pharmaceutics. Antiviral drug development has focused on targeting viral entry and replication, as well as modulating cellular defense system. High throughput screening of molecules, genetic engineering of peptides, and functional screening of agents have identified promising candidates for development of optimal broad-spectrum antiviral agents to intervene in viral infection and control viral epidemics. This review discusses current knowledge, prospective applications, opportunities, and challenges in the development of broad-spectrum antiviral agents.

  17. Business Intelligence using Software Agents

    Directory of Open Access Journals (Sweden)

    Ana-Ramona BOLOGA

    2011-12-01

    Full Text Available This paper presents some ideas about business intelligence today and the importance of developing real time business solutions. The authors make an exploration of links between business intelligence and artificial intelligence and focuses specifically on the implementation of software agents-based systems in business intelligence. There are briefly presented some of the few solutions proposed so far that use software agents properties for the benefit of business intelligence. The authors then propose some basic ideas for developing real-time agent-based software system for business intelligence in supply chain management, using Case Base Reasoning Agents.

  18. GnRH在青年摩杂一代水牛下丘脑-垂体-卵巢轴的免疫组化定位%Distribution of Gonadotropin (GnRH) Releasing Hormone in Hypothalamus-pituitary-ovary Axis of Youth Murrah Hybrid Water Buffalo

    Institute of Scientific and Technical Information of China (English)

    凌泽继; 李瑞明; 谢莹雪; 周辰瑜; 黎金秀; 秦津; 潘堂峰; 宋小白; 杨柄壮; 许典新; 韩涛; 潘琼

    2009-01-01

    [Objective] The research aimed to study the distribution of gonadotropin (GnRH) releasing hormone in hypothalamus-pituitary-ovary axis of youth murrah hybrid water buffalo.[Method] The immunohistochemistry SuperPicTureTM two step method was used to detect the distribution of GnRH in hypothalamus-pituitary-ovary axis of five femal murrah hybrid water buffalos.The association of GnRH 's distribution in hypothalamus, pituitary and ovary, and understand how the GnRH secrete releasing in hypothalamus, pituitary and ovary.[Result] The GnRH was first discovered in singulorum link of hypothalamus-pituitary-ovary axis of murrah hybrid water bufflo.The GnRH immunoreactive neurons were first discovered in every main nucleus of murrah hybrid water bufflo hypothalamus, especially distributed in supraoptic nucleus, preoptic nucleus, paraventricular nucleus most.The GnRH immunoactive productions were first discovered only in murrah hybrid water bufflo adenohypophysis for pituitary.The GnRH immunoactive productions were first discovered in the germinal epithelium cells, granulosa cells and lutein cells of murrah hybrid water bufflo.[Conclusion] The test results could provide morphological basis for the study of the GnRH's synthesis and mechanism of action, and could play reference and directions part in breeding murrah hybrid water bufflo.%[目的]研究促性腺激素释放激素(GnRH)在青年摩杂一代水牛下丘脑-垂体-卵巢轴的免疫组化定位.[方法]采用免疫组织化学SuperPicTureTM二步法检测5头青年摩杂一代水牛下丘脑、垂体和卵巢中GnRH的分布情况,研究GnRH在下丘脑、垂体及卵巢的分布上的联系,进而了解GnRH在下丘脑、垂体及卵巢三者之间分泌释放的途径.[结果]GnRH存在于青年摩杂一代水牛下丘脑-垂体-卵巢轴的各个环节.青年摩杂一代水牛下丘脑中各主要核团都有GnRH免疫阳性神经元的分布,尤其以视上核、视前核、室旁核分布较多.对于垂体,Gn

  19. Incorporating BDI Agents into Human-Agent Decision Making Research

    Science.gov (United States)

    Kamphorst, Bart; van Wissen, Arlette; Dignum, Virginia

    Artificial agents, people, institutes and societies all have the ability to make decisions. Decision making as a research area therefore involves a broad spectrum of sciences, ranging from Artificial Intelligence to economics to psychology. The Colored Trails (CT) framework is designed to aid researchers in all fields in examining decision making processes. It is developed both to study interaction between multiple actors (humans or software agents) in a dynamic environment, and to study and model the decision making of these actors. However, agents in the current implementation of CT lack the explanatory power to help understand the reasoning processes involved in decision making. The BDI paradigm that has been proposed in the agent research area to describe rational agents, enables the specification of agents that reason in abstract concepts such as beliefs, goals, plans and events. In this paper, we present CTAPL: an extension to CT that allows BDI software agents that are written in the practical agent programming language 2APL to reason about and interact with a CT environment.

  20. TACtic- A Multi Behavioral Agent for Trading Agent Competition

    Science.gov (United States)

    Khosravi, Hassan; Shiri, Mohammad E.; Khosravi, Hamid; Iranmanesh, Ehsan; Davoodi, Alireza

    Software agents are increasingly being used to represent humans in online auctions. Such agents have the advantages of being able to systematically monitor a wide variety of auctions and then make rapid decisions about what bids to place in what auctions. They can do this continuously and repetitively without losing concentration. To provide a means of evaluating and comparing (benchmarking) research methods in this area the trading agent competition (TAC) was established. This paper describes the design, of TACtic. Our agent uses multi behavioral techniques at the heart of its decision making to make bidding decisions in the face of uncertainty, to make predictions about the likely outcomes of auctions, and to alter the agent's bidding strategy in response to the prevailing market conditions.

  1. Deliberate evolution in multi-agent systems

    NARCIS (Netherlands)

    Brazier, F.M.T.; Jonker, C.M.; Treur, J.; Wijngaards, N.J.E.

    1998-01-01

    This paper presents an architecture for an agent capable of deliberation about the creation of new agents, and of actually creating a new agent in the multi-agent system, on the basis of this deliberation. After its creation the new agent participates fully in the running multi-agent system. The age

  2. Utilização da contagem de folículos antrais para predição do padrão de resposta em ciclos de hiperestimulação controlada com antagonista de GnRH Use of antral follicle count to predict the response pattern in controlled ovarian hyperstimulation cycles with GnRH antagonist

    Directory of Open Access Journals (Sweden)

    Maria do Carmo Borges de Souza

    2008-01-01

    Full Text Available OBJETIVO: verificar se existe relação preditiva entre a contagem de folículos antrais (CFA no segundo dia do ciclo com o padrão de resposta em ciclos de hiperestimulação ovariana controlada para injeção intracitoplasmática de espermatozóide (ICSI. MÉTODOS: estudo prospectivo, desenvolvido de maio de 2004 a maio de 2005, no qual 51 pacientes com idade 15 mm no dia do desencadeamento da ovulação, número total e em metáfase II de oócitos captados, número de embriões de boa qualidade transferidos e taxa de gestação. A análise estatística foi realizada pelos testes t de Student e de Mann-Whitney, com significância estatística de 5% (pPURPOSE: to establish whether there is a predictive relationship between the antral follicle count (AFC on the second day of the cycle and the response pattern in controlled ovarian hyperstimulation cycles for intracytoplasmic sperm injection (ICSI. METHODS: a prospective study developed from May 2004 to May 2005, in which 51 patients aged 15 mm on the day of ovulation triggering, the total number of oocytes retrieved and in metaphases II, the number of good quality embryos transferred and pregnancy rate. The statistical analysis was performed by the t-Student test and the Mann-Whitney test, with statistical significance of 5% (p15 mm on the day of ovulation triggering (p=0.0001, the total number of oocytes retrieved (p=0.0001 and those in metaphases II (p=0.0001. Such correlation between AFC and pregnancy was not observed (p=0.43. There was no significant correlation between AFC and the number of good quality embryos transferred (p=0.081. CONCLUSIONS: AFC on the second day of the stimulated cycle can be used to predict the quality of ovarian stimulation, the number of oocytes retrieved and the number of mature oocytes in in vitro fertilization cycles using GnRH antagonist.

  3. Regulative Effect of Artificial Northern Chinese Caterpillar Fungus on mRNA Expression of GnRH Cell in Hypothalamus%人工栽培北冬虫夏草子实体对大鼠下丘脑GnRH细胞mRNA表达的调节作用

    Institute of Scientific and Technical Information of China (English)

    徐维蓉; 王奕; 雍丽; 叶其明

    2009-01-01

    目的 观察人工栽培北冬虫夏草子实体细粉和复合粉对下丘脑促性腺激素释放激素细胞(GnRH细胞)作用的影响.方法 用腺嘌呤加入饲料喂饲大鼠,造成大鼠肾阳虚模型,用人工栽培的北冬虫夏草子实体细粉和复合粉进行治疗,通过分子原位杂交的方法 显示下丘脑GnRH细胞的mRNA表达以观察北冬虫夏草子实体细粉对其的影响.结果 与正常组相比,模型组的Gn-RH细胞杂交信号减弱,阳性细胞数减少,而中药组GnRH杂交信号及阳性细胞数较模型组有提高趋势.结论 人工栽培的北冬虫夏草子实体细粉和复合粉可促进大鼠下丘脑GnRH细胞的mRNA表达,增加GnRH分泌,从而调节大鼠的生殖功能.%Objective To observe the effects of artificial cultivated northern Chinese caterpillar fungus' fruiting body powder and compound powder on ganadotropin- re-leasing hormone(GnRH) cells in hypothalamus. Methods Establish the model of kidney-yang asthenia by feeding male rats with forage mixed with adenine, then treat the rats with northern Chinese caterpillar fungus' fruiting body powder and compound powder. In situ hybridization was used to study the expression of the mRNA of GnRH cells in hypothalamus aod the effect of northern Chinese caterpillar fungus' fruiting body on the GnRH cells. Results Compared with the normal group, hybridization signal of GnRH mRNA in the model group weakened, and the positive cell count decreased, while hybridization signal of GnRH mRNA and the positive cell count in the Chinese medicine group had the tendency to increase,. Conclusion Artificial cultivated northern Chinese, caterpillar thngus' fruiting body powder and compound powder can promote the expression of the mRNA of GnRH cell in hypothalamus, and inerems the secre, tion of GnRH, thus to regulate the reproduction function of the rats.

  4. An Introduction to Software Agents

    Science.gov (United States)

    2008-02-01

    Tropos .......................................................................................................................... 34 8.3 Gaia...32 DRDC Atlantic TM 2007-221 Each of these methodologies (Prometheus, Tropos and Gaia) guide the user to develop a specification for agents...specific agents required. While Prometheus and Tropos cover similar portions of the overall design process (from requirements to implementation

  5. Agent Based Individual Traffic Guidance

    DEFF Research Database (Denmark)

    Wanscher, Jørgen

    This thesis investigates the possibilities in applying Operations Research (OR) to autonomous vehicular traffic. The explicit difference to most other research today is that we presume that an agent is present in every vehicle - hence Agent Based Individual Traffic guidance (ABIT). The next...

  6. Topical agents in burn care

    Directory of Open Access Journals (Sweden)

    Momčilović Dragan

    2002-01-01

    Full Text Available Introduction Understanding of fluid shifts and recognition of the importance of early and appropriate fluid replacement therapy have significantly reduced mortality in the early post burn period. After the bum patient successfully passes the resuscitation period, the burn wound represents the greatest threat to survival. History Since the dawn of civilization, man has been trying to find an agent which would help burn wounds heal, and at the same time, not harm general condition of the injured. It was not until the XX century, after the discovery of antibiotics, when this condition was fulfilled. In 1968, combining silver and sulfadiazine, fox made silver-sulfadiazine, which is a 1% hydro-soluble cream and a superior agent in topical treatment of burns today. Current topical agents None of the topical antimicrobial agents available today, alone or combined, have the characteristics of ideal prophylactic agents, but they eliminate colonization of burn wound, and invasive infections are infrequent. With an excellent spectrum of activity, low toxicity, and ease of application with minimal pain, silver-sulfadiazine is still the most frequently used topical agent. Conclusion The incidence of invasive infections and overall mortality have been significantly reduced after introduction of topical burn wound antimicrobial agents into practice. In most burn patients the drug of choice for prophylaxis is silver sulfadiazine. Other agents may be useful in certain clinical situations.

  7. Multimodal nanoparticulate bioimaging contrast agents.

    Science.gov (United States)

    Sharma, Parvesh; Singh, Amit; Brown, Scott C; Bengtsson, Niclas; Walter, Glenn A; Grobmyer, Stephen R; Iwakuma, Nobutaka; Santra, Swadeshmukul; Scott, Edward W; Moudgil, Brij M

    2010-01-01

    A wide variety of bioimaging techniques (e.g., ultrasound, computed X-ray tomography, magnetic resonance imaging (MRI), and positron emission tomography) are commonly employed for clinical diagnostics and scientific research. While all of these methods use a characteristic "energy-matter" interaction to provide specific details about biological processes, each modality differs from another in terms of spatial and temporal resolution, anatomical and molecular details, imaging depth, as well as the desirable material properties of contrast agents needed for augmented imaging. On many occasions, it is advantageous to apply multiple complimentary imaging modalities for faster and more accurate prognosis. Since most imaging modalities employ exogenous contrast agents to improve the signal-to-noise ratio, the development and use of multimodal contrast agents is considered to be highly advantageous for obtaining improved imagery from sought-after imaging modalities. Multimodal contrast agents offer improvements in patient care, and at the same time can reduce costs and enhance safety by limiting the number of contrast agent administrations required for imaging purposes. Herein, we describe the synthesis and characterization of nanoparticulate-based multimodal contrast agent for noninvasive bioimaging using MRI, optical, and photoacoustic tomography (PAT)-imaging modalities. The synthesis of these agents is described using microemulsions, which enable facile integration of the desired diversity of contrast agents and material components into a single entity.

  8. Implementing Lego Agents Using Jason

    CERN Document Server

    Jensen, Andreas Schmidt

    2010-01-01

    Since many of the currently available multi-agent frameworks are generally mostly intended for research, it can be difficult to built multi-agent systems using physical robots. In this report I describe a way to combine the multi-agent framework Jason, an extended version of the agent-oriented programming language AgentSpeak, with Lego robots to address this problem. By extending parts of the Jason reasoning cycle I show how Lego robots are able to complete tasks such as following lines on a floor and communicating to be able to avoid obstacles with minimal amount of coding. The final implementation is a functional extension that is able to built multi-agent systems using Lego agents, however there are some issues that have not been addressed. If the agents are highly dependent on percepts from their sensors, they are required to move quite slowly, because there currently is a high delay in the reasoning cycle, when it is combined with a robot. Overall the system is quite robust and can be used to make simple...

  9. Activity Recognition for Agent Teams

    Science.gov (United States)

    2007-07-01

    seek to use in the upcoming confrontation. There is not a simple mapping between a character capabilities and this policy; an effective team role must...additional research challenges, specific to the team role assumed by the agent. Agents that support individual human team members face the following chal

  10. Pharmacologic Agents for Chronic Diarrhea

    OpenAIRE

    Lee, Kwang Jae

    2015-01-01

    Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reductio...

  11. Fatores determinantes do ganho na altura em meninas com puberdade precoce central idiopática tratadas com análogo de GnRH Predictive factors for height gain in idiopathic central precocious puberty treated with GnRH analogues

    Directory of Open Access Journals (Sweden)

    Cristina Laguna Benetti-Pinto

    2008-12-01

    Full Text Available OBJETIVO: avaliar fatores determinantes de maior ganho na estatura como resultado do tratamento com GnRHa. MÉTODOS: estudo retrospectivo de 33 meninas com puberdade precoce central idiopática tratadas com GnRHa. Foram avaliadas: idade no início dos sintomas e no início do tratamento, tempo decorrido entre o início de aparecimento dos caracteres puberais e o início do tratamento, idade óssea, avanço da idade óssea, duração do tratamento com GnRHa, altura real e escore Z, altura predita e escore Z e dosagens hormonais de FSH e LH após estímulo com GnRH, que foram correlacionadas com o ganho de altura no final do tratamento, calculada pela diferença entre altura predita no final e início do tratamento. Para análise estatística foi utilizada a correlação linear de Pearson, além da regressão linear múltipla. RESULTADOS: a média de idade no início do tratamento foi 7,8±1,3 anos, com idade óssea média de 10,1±1,6 anos. O avanço da idade óssea era de 2,3±1,1 anos e foi controlado com o tratamento. O ganho em altura predita foi de 2,5±1,3 cm e foi correlacionado positivamente com o tempo decorrido entre o início dos sintomas e o início do tratamento e com o avanço da idade óssea, além de se correlacionar negativamente com o escore Z da altura no início do tratamento e com a altura predita no início do tratamento, sendo este último o principal fator determinante do ganho obtido com o tratamento. CONCLUSÕES: meninas com maior comprometimento da altura predita para a idade adulta, visualizado pelo maior desvio em relação à população (escore Z e pelo maior avanço na idade óssea foram as que obtiveram maior benefício com o tratamento com GnRHa, não devendo ser excluídas do grupo a ser tratado.PURPOSE: to evaluate predictive factors of response to GnRHa treatment in girls with idiopathic central precocious puberty. METHODS: a retrospective cohort study was conducted involving 33 girls diagnosed with idiopathic

  12. Mobile agent driven by aspect

    Directory of Open Access Journals (Sweden)

    Youssef Hannad

    2010-11-01

    Full Text Available Domain application of mobile agents is quite large. They are used for network management and the monitoring of complex architecture. Mobile agent is also essential into specific software architecture such that adaptable grid architecture. Even if the concept of mobile agent seems to be obvious, the development is always complex because it needs to understand network features but also security features and negotiation algorithms. We present a work about an application of aspects dedicated to mobile agent development over a local network. At this level, the underlying protocol is called jini and allows managing several essential concepts such that short transaction and permission management. Three subsets of aspects are defined in this work. A part is for the description of agent host and its security level, accessible resource, etc. A second part is about mobile agent and their collaboration. This means how they can operate on an agent host with the respect of the execution context. All the results are illustrated through a distributed monitoring application called DMA. Its main objective is the observation of component servers.

  13. Antibacterial agents in the cinema.

    Science.gov (United States)

    García Sánchez, J E; García Sánchez, E; Merino Marcos, M L

    2006-12-01

    Numerous procedures used as antibacterial therapy are present in many films and include strategies ranging from different antimicrobial drugs to surgery and supporting measures. Films also explore the correct use and misuse of antimicrobial agents. Side effects and other aspects related to antibacterial therapy have also been reflected in some films. This article refers to the presence of antibacterial agents in different popular movies. There are movies in which antibacterial agents form part of the central plot, while in others it is merely an important part of the plot. In still others, its presence is isolated, and in these it plays an ambient or anecdotal role.

  14. Agent Based Multiviews Requirements Model

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Based on the current researches of viewpoints oriented requirements engineering and intelligent agent, we present the concept of viewpoint agent and its abstract model based on a meta-language for multiviews requirements engineering. It provided a basis for consistency checking and integration of different viewpoint requirements, at the same time, these checking and integration works can automatically realized in virtue of intelligent agent's autonomy, proactiveness and social ability. Finally, we introduce the practical application of the model by the case study of data flow diagram.

  15. GnRH脉冲对体外原代培养大鼠GTH细胞中LHβmRNA表达水平的影响%The Influence of GnRH Impulse on the Expression of LHβ mRNA in Rats' GTH Cells Primarily Cultured in vitro

    Institute of Scientific and Technical Information of China (English)

    王新; 谭建华; 赖小平; 万忠海; 韦旭斌

    2011-01-01

    To explain at molecular level the influence of GnRH at different impulse frequencies on the secretion of LH by GTH. Research the change of LHβ mRNA in cells when the pituicytes of original generation of rats cultured in vitro were stimulated by GnRH at different impulse frequencies, by applying the technique of culture in vitro of cells in combination with the fluorescent quantitation of PCR. The result showed that in the condition of the same vibration amplitude, when the cells were stimulated by impulse at high frequency (at the interval of 30 min), the level of LHβ mRNA reached the top. This supports the hypothesis that GnRH impulse frequency itself is a regulation signal,and GnRH impulse at high frequency brings about mainly the response of LHβ.%研究不同脉冲频率GnRH对GTH细胞分泌LH的影响.利用细胞体外培养技术结合荧光定量PCR技术,对体外培养的大鼠原代垂体细胞在不同脉冲频率GnRH刺激下,细胞LHβ mRNA的变化进行了研究.在相同振幅条件下,高频刺激(30 min间隔)时,LHβ mRNA表达水平达到高峰.结果表明,高频脉冲主要引起LH的表达.支持了GnRH脉冲频率本身就是一个调控信号的假说.

  16. Deliberate Evolution in Multi-Agent Systems

    NARCIS (Netherlands)

    Brazier, F.M.T.; Jonker, C.M.; Treur, J.; Wijngaards, N.J.E.

    2000-01-01

    This paper presents an architecture for an agent capable of deliberation about the creation of new agents, and of actually creating a new agent in the multi-agent system, on the basis of this deliberation. The agent architecture is based on an existing

  17. Computational Environment of Software Agents

    Directory of Open Access Journals (Sweden)

    Martin Tomášek

    2008-05-01

    Full Text Available Presented process calculus for software agent communication and mobility canbe used to express distributed computational environment and mobile code applications ingeneral. Agents are abstraction of the functional part of the system architecture and theyare modeled as process terms. Agent actions model interactions within the distributedenvironment: local/remote communication and mobility. Places are abstraction of thesingle computational environment where the agents are evaluated and where interactionstake place. Distributed environment is modeled as a parallel composition of places whereeach place is evolving asynchronously. Operational semantics defines rules to describebehavior within the distributed environment and provides a guideline for implementations.Via a series of examples we show that mobile code applications can be naturally modeled.

  18. Infectious Agents Trigger Trophic Cascades.

    Science.gov (United States)

    Buck, Julia C; Ripple, William J

    2017-09-01

    Most demonstrated trophic cascades originate with predators, but infectious agents can also cause top-down indirect effects in ecosystems. Here we synthesize the literature on trophic cascades initiated by infectious agents including parasitoids, pathogens, parasitic castrators, macroparasites, and trophically transmitted parasites. Like predators, infectious agents can cause density-mediated and trait-mediated indirect effects through their direct consumptive and nonconsumptive effects respectively. Unlike most predators, however, infectious agents are not fully and immediately lethal to their victims, so their consumptive effects can also trigger trait-mediated indirect effects. We find that the frequency of trophic cascades reported for different consumer types scales with consumer lethality. Furthermore, we emphasize the value of uniting predator-prey and parasite-host theory under a general consumer-resource framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Bacteriocins as Potential Anticancer Agents

    National Research Council Canada - National Science Library

    Kaur, Sumanpreet; Kaur, Sukhraj

    2015-01-01

    .... Thus, the demand for novel anti-cancer agents is increasing day by day. Some of the experimental studies have reported the therapeutic potential of bacteriocins against various types of cancer cell lines...

  20. Distribution of GnRH Receptor in Celiac-superior Mesenteric Ganglia of Goat and Its Implications%GnRH受体在山羊腹腔肠系膜前神经节的分布及其意义

    Institute of Scientific and Technical Information of China (English)

    范洁; 陈文东; 郭晓; 王志豪; 明佳; 郭瑜龙; 徐永平

    2013-01-01

    本研究旨在观察促性腺激素释放激素受体(Gonadotropin-releasing hormone receptor,GnRHR)在山羊腹腔肠系膜前神经节的分布特点,以探讨GnRH是否可以影响腹腔肠系膜前神经节(Celiac-superior mesenteric ganglia,CSMG)的活动.取雄性和雌性成年山羊的腹腔肠系膜前神经节各5个,经免疫组织化学SP法染色后,观察GnRHR在肠系膜前神经节的分布特点,并用Image-Pro Plus 6.0 (IPP 6.0)软件图像半定量分析技术,分析腹腔肠系膜前神经节中的神经元和非神经元的GnRHR分布差异.结果表明:GnRHR强阳性产物主要分布神经元的胞膜和胞质中;血管内皮细胞、神经纤维和卫星细胞中只有GnRHR弱阳性产物;GnRHR在神经细胞和非神经细胞中的表达量呈极显著性差异(P<0.01).上述结果表明,腹腔肠系膜前神经节对GnRH具有反应性,且神经元为其作用的靶细胞,提示GnRH可能通过影响腹腔肠系膜前神经节神经元的活动,进而影响其发出的交感节后神经纤维所支配的靶器官功能这一途径来调节胃肠的生理活动.%This experiment was conducted to detect existence of Gonadotropin-releasing hormone receptor (GnRHR) in the celiac-superior mesenteric ganglia (CSMG) of goats, and determine the possible influence of GnRH on CSMG. Five CSMG were taken from mature female and male goats, respectively. The distribution characteristics of GnRHR were observed after immunohisto-chemical SP staining. Image-Pro Plus 6. 0 (IPP 6. 0) was used as the method of semi-quantitative image analysis to evaluate expression difference of GnRHR between neurons and non-neuron cells. The results showed that strong GnRHR immunoreactivity (GnRHR-ir) products mainly distributed on the membrane and whole cytoplasm of neurons and weak GnRHR-ir products on non-neuron cells. Expression difference of GnRHR between these two sorts of cells was highly significant (P<0. 01). The wide distribution of GnRHR in CSMG suggests

  1. Business Intelligence using Software Agents

    OpenAIRE

    Ana-Ramona BOLOGA; Razvan BOLOGA

    2011-01-01

    This paper presents some ideas about business intelligence today and the importance of developing real time business solutions. The authors make an exploration of links between business intelligence and artificial intelligence and focuses specifically on the implementation of software agents-based systems in business intelligence. There are briefly presented some of the few solutions proposed so far that use software agents properties for the benefit of business intelligence. The authors then...

  2. Humor and embodied conversational agents

    OpenAIRE

    Nijholt, A.

    2003-01-01

    This report surveys the role of humor in human-to-human interaction and the possible role of humor in human-computer interaction. The aim is to see whether it is useful for embodied conversational agents to integrate humor capabilities in their internal model of intelligence, emotions and interaction (verbal and nonverbal) capabilities. A current state of the art of research in embodied conversational agents, affective computing and verbal and nonverbal interaction is presented. The report ad...

  3. Antimicrobials for bacterial bioterrorism agents.

    Science.gov (United States)

    Sarkar-Tyson, Mitali; Atkins, Helen S

    2011-06-01

    The limitations of current antimicrobials for highly virulent pathogens considered as potential bioterrorism agents drives the requirement for new antimicrobials that are suitable for use in populations in the event of a deliberate release. Strategies targeting bacterial virulence offer the potential for new countermeasures to combat bacterial bioterrorism agents, including those active against a broad spectrum of pathogens. Although early in the development of antivirulence approaches, inhibitors of bacterial type III secretion systems and cell division mechanisms show promise for the future.

  4. Business Intelligence using Software Agents

    OpenAIRE

    Ana-Ramona BOLOGA; Razvan BOLOGA

    2011-01-01

    This paper presents some ideas about business intelligence today and the importance of developing real time business solutions. The authors make an exploration of links between business intelligence and artificial intelligence and focuses specifically on the implementation of software agents-based systems in business intelligence. There are briefly presented some of the few solutions proposed so far that use software agents properties for the benefit of business intelligence. The authors then...

  5. Natural products as antimitotic agents.

    Science.gov (United States)

    Dall'Acqua, Stefano

    2014-01-01

    Natural products still play an important role in the medicinal chemistry, especially in some therapeutic areas. As example more than 60% of currently-used anticancer agents are derives from natural sources including plants, marine organisms or micro-organism. Thus natural products (NP) are an high-impact source of new "lead compounds" or new potential therapeutic agents despite the large development of biotechnology and combinatorial chemistry in the drug discovery and development. Many examples of anticancer drugs as paclitaxel, combretastatin, bryostatin and discodermolide have shown the importance of NP in the anticancer chemotherapy through many years. Many organisms have been studied as sources of drugs namely plants, micro-organisms and marine organisms and the obtained NP can be considered a group of "privileged chemical structures" evolved in nature to interact with other organisms. For this reason NP are a good starting points for pharmaceutical research and also for library design. Tubulin and microtubules are one of the most studied targets for the search of anticancer compounds. Microtubule targeting agents (MTA) also named antimitotic agents are compounds that are able to perturb mitosis but are also able to arrest cell growing during interphase. The anticancer drugs, taxanes and vinca alkaloids have established tubulin as important target in cancer therapy. More recently the vascular disrupting agents (VDA) combretastatin analogues were studied for their antimitotics properties. This review will consider the anti mitotic NP and their potential impact in the development of new therapeutic agents.

  6. What makes virtual agents believable?

    Science.gov (United States)

    Bogdanovych, Anton; Trescak, Tomas; Simoff, Simeon

    2016-01-01

    In this paper we investigate the concept of believability and make an attempt to isolate individual characteristics (features) that contribute to making virtual characters believable. As the result of this investigation we have produced a formalisation of believability and based on this formalisation built a computational framework focused on simulation of believable virtual agents that possess the identified features. In order to test whether the identified features are, in fact, responsible for agents being perceived as more believable, we have conducted a user study. In this study we tested user reactions towards the virtual characters that were created for a simulation of aboriginal inhabitants of a particular area of Sydney, Australia in 1770 A.D. The participants of our user study were exposed to short simulated scenes, in which virtual agents performed some behaviour in two different ways (while possessing a certain aspect of believability vs. not possessing it). The results of the study indicate that virtual agents that appear resource bounded, are aware of their environment, own interaction capabilities and their state in the world, agents that can adapt to changes in the environment and exist in correct social context are those that are being perceived as more believable. Further in the paper we discuss these and other believability features and provide a quantitative analysis of the level of contribution for each such feature to the overall perceived believability of a virtual agent.

  7. Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial.

    Science.gov (United States)

    Stormlund, Sacha; Løssl, Kristine; Zedeler, Anne; Bogstad, Jeanette; Prætorius, Lisbeth; Nielsen, Henriette Svarre; Bungum, Mona; Skouby, Sven O; Mikkelsen, Anne Lis; Andersen, Anders Nyboe; Bergh, Christina; Humaidan, Peter; Pinborg, Anja

    2017-07-31

    Pregnancy rates after frozen embryo transfer (FET) have improved in recent years and are now approaching or even exceeding those obtained after fresh embryo transfer. This is partly due to improved laboratory techniques, but may also be caused by a more physiological hormonal and endometrial environment in FET cycles. Furthermore, the risk of ovarian hyperstimulation syndrome is practically eliminated in segmentation cycles followed by FET and the use of natural cycles in FETs may be beneficial for the postimplantational conditions of fetal development. However, a freeze-all strategy is not yet implemented as standard care due to limitations of large randomised trials showing a benefit of such a strategy. Thus, there is a need to test the concept against standard care in a randomised controlled design. This study aims to compare ongoing pregnancy and live birth rates between a freeze-all strategy with gonadotropin-releasing hormone (GnRH) agonist triggering versus human chorionic gonadotropin (hCG) trigger and fresh embryo transfer in a multicentre randomised controlled trial. Multicentre randomised, controlled, double-blinded trial of women undergoing assisted reproductive technology treatment including 424 normo-ovulatory women aged 18-39 years from Denmark and Sweden. Participants will be randomised (1:1) to either (1) GnRH agonist trigger and single vitrified-warmed blastocyst transfer in a subsequent hCG triggered natural menstrual cycle or (2) hCG trigger and single blastocyst transfer in the fresh (stimulated) cycle. The primary endpoint is to compare ongoing pregnancy rates per randomised patient in the two treatment groups after the first single blastocyst transfer. The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committees in Denmark and Sweden. The results of the study will be publically disseminated. NCT02746562; Pre-results. © Article author(s) (or their

  8. GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles-A Systematic PRISMA Review and Meta-analysis.

    Science.gov (United States)

    Haahr, Thor; Roque, Matheus; Esteves, Sandro C; Humaidan, Peter

    2017-01-01

    The use of GnRH agonist (GnRHa) for final oocyte maturation trigger in oocyte donation and elective frozen embryo transfer cycles is well established due to lower ovarian hyperstimulation syndrome (OHSS) rates as compared to hCG trigger. A recent Cochrane meta-analysis concluded that GnRHa trigger was associated with reduced live birth rates (LBRs) in fresh autologous IVF cycles compared to hCG trigger. However, the evidence is not unequivocal, and recent trials have found encouraging reproductive outcomes among couples undergoing GnRHa trigger and individualized luteal LH activity support. Thus, the aim was to compare GnRHa trigger followed by luteal LH activity support with hCG trigger in IVF patients undergoing fresh embryo transfer. We conducted a systematic review and meta-analysis of randomized trials published until December 14, 2016. The population was infertile patients submitted to IVF/ICSI cycles with GnRH antagonist cotreatment who underwent fresh embryo transfer. The intervention was GnRHa trigger followed by LH activity luteal phase support (LPS). The comparator was hCG trigger followed by a standard LPS. The critical outcome measures were LBR and OHSS rate. The secondary outcome measures were number of oocytes retrieved, clinical and ongoing pregnancy rates, and miscarriage rates. A total of five studies met the selection criteria comprising a total of 859 patients. The LBR was not significantly different between the GnRHa and hCG trigger groups (OR 0.84, 95% CI 0.62, 1.14). OHSS was reported in a total of 4/413 cases in the GnRHa group compared to 7/413 in the hCG group (OR 0.48, 95% CI 0.15, 1.60). We observed a slight, but non-significant increase in miscarriage rate in the GnRHa triggered group compared to the hCG group (OR 1.85; 95% CI 0.97, 3.54). GnRHa trigger with LH activity LPS resulted in comparable LBRs compared to hCG trigger. The most recent trials reported LBRs close to unity indicating that individualization of the LH activity LPS

  9. GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles—A Systematic PRISMA Review and Meta-analysis

    Directory of Open Access Journals (Sweden)

    Thor Haahr

    2017-06-01

    Full Text Available IntroductionThe use of GnRH agonist (GnRHa for final oocyte maturation trigger in oocyte donation and elective frozen embryo transfer cycles is well established due to lower ovarian hyperstimulation syndrome (OHSS rates as compared to hCG trigger. A recent Cochrane meta-analysis concluded that GnRHa trigger was associated with reduced live birth rates (LBRs in fresh autologous IVF cycles compared to hCG trigger. However, the evidence is not unequivocal, and recent trials have found encouraging reproductive outcomes among couples undergoing GnRHa trigger and individualized luteal LH activity support. Thus, the aim was to compare GnRHa trigger followed by luteal LH activity support with hCG trigger in IVF patients undergoing fresh embryo transfer.Material and methodsWe conducted a systematic review and meta-analysis of randomized trials published until December 14, 2016. The population was infertile patients submitted to IVF/ICSI cycles with GnRH antagonist cotreatment who underwent fresh embryo transfer. The intervention was GnRHa trigger followed by LH activity luteal phase support (LPS. The comparator was hCG trigger followed by a standard LPS. The critical outcome measures were LBR and OHSS rate. The secondary outcome measures were number of oocytes retrieved, clinical and ongoing pregnancy rates, and miscarriage rates.ResultsA total of five studies met the selection criteria comprising a total of 859 patients. The LBR was not significantly different between the GnRHa and hCG trigger groups (OR 0.84, 95% CI 0.62, 1.14. OHSS was reported in a total of 4/413 cases in the GnRHa group compared to 7/413 in the hCG group (OR 0.48, 95% CI 0.15, 1.60. We observed a slight, but non-significant increase in miscarriage rate in the GnRHa triggered group compared to the hCG group (OR 1.85; 95% CI 0.97, 3.54.ConclusionGnRHa trigger with LH activity LPS resulted in comparable LBRs compared to hCG trigger. The most recent trials reported LBRs close to unity

  10. The decision for GnRH antagonist protocol in PCOS patients:with or without oral contraceptive pill ;pretreatment Y%多囊卵巢综合征患者 GnRH 拮抗剂促排卵方案的选择:用或不用口服避孕药预治疗?

    Institute of Scientific and Technical Information of China (English)

    杨硕; 陈新娜; 李蓉; 王海燕; 王颖; 李红真

    2014-01-01

    Objective To assess the impact of oral contraceptive pill (OCP) pretreatment in controlled ovarian stimulation for in vitro fertilization (IVF) using gonadotropin releasing hormone (GnRH) antagonist among polycystic ovarian syndrome (PCOS) patients. Methods This is a predictive cohort study. There were 239 infertile patients with PCOS accepted IVF/ICSI treatment with GnRH antagonist fixed protocol. The patients were divided into two groups depending on using OCP pretreatment or not (without OCP pretreatment, NOCP group, n=116; OCP pretreatment, OCP group, n=123). To compare the general characteristics and clinical outcomes of the two groups. Results There were no significantly difference between the two groups refer to age, infertility time, and basal FSH, E2, T(P>0.05). The BMI and basal LH were significantly lower in NOCP group[BMI (22.7±3.5)kg/m2 vs. (23.7±3.7)kg/m2;LH (5.9±4.3)IU/L vs. (8.4±5.5)IU/L, P0.05). The duration and dose of gonadotropin were no significantly difference, duration of Gn (11±1.6)d vs. (10±1.6)d;Gn dose (1 474±423)IU vs. (1 517±462)IU, P>0.05. The number of oocyte retrieved and good quality embryo were significantly higher in NOCP group (oocyte retrieved 20±10 vs. 16±8;good quality embryo 9±6 vs. 7±5, P<0.05). The clinical pregnancy rate, embryo implantation rate and ongoing pregnancy rate were significantly higher in NOCP group, clinical pregnancy rate 50.5%(46/91) vs. 33.3%(36/108); embryo implantation rate 29.6% (59/199) vs. 19.6%(44/225); ongoing pregnancy rate 49.5%(45/91) vs. 27.8% (30/108), P<0.05. The Regression analysis showed that accepted OCP pretreatment and the patients’ age could affect the clinical outcome. The incidence of moderate/severe OHSS was no significant difference between the two groups, the incidence of cancelled embryo transfer (for preventing OHSS) was significantly lower in OCP group [11.4%(14/123) vs. 21.6%(25/116), P<0.05]. Conclusion Pretreatment with OCP in PCOS patients might have negative

  11. Glutamic acid as anticancer agent: An overview

    National Research Council Canada - National Science Library

    Dutta, Satyajit; Ray, Supratim; Nagarajan, K

    2013-01-01

    The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents...

  12. Geo-Agents: Design and Implement

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Geo-Agents, a multi-agent system that processes distr ib utedgeospatial information and geospatial service was presented. Firstly, the requirement for distributed geographical information process was discussed, and the architecture of Geo-Agents was introduced. Then in-depth discussions were r aised on agent system implementation, such as the basic agent, agent advertising , message passing, and collaborating. An example was also given to explain the p roblem solving process.

  13. Colitis associated with biological agents

    Institute of Scientific and Technical Information of China (English)

    Hugh James Freeman

    2012-01-01

    In the past,there has been considerable focus on a host of drugs and chemicals that may produce colonic toxicity.Now,a variety of new biological monoclonal antibody agents,usually administered by infusion,have appeared in the clinical realm over the last decade or so to treat different chronic inflammatory or malignant disorders.For some of these agents,adverse effects have been documented,including apparently new forms of immune-mediated inflammatory bowel disease.In some,only limited symptoms have been recorded,but in others,severe colitis with serious complications,such as bowel perforation has been recorded.In others,adverse effects may have a direct vascular or ischemic basis,while other intestinal effects may be related to a superimposed infection.Some new onset cases of ulcerative colitis or Crohn's disease may also be attributed to the same agents used to treat these diseases,or be responsible for disease exacerbation.Dramatic and well documented side effects have been observed with ipilimumab,a humanized monoclonal antibody developed to reduce and overcome cytotoxic T-lymphocyte antigen 4,a key negative feedback regulator of the T-cell anti-tumor response.This agent has frequently been used in the treatment of different malignancies,notably,malignant melanoma.Side effects with this agent occur in up to 40% and these are believed to be largely immune-mediated.One of these is a form of enterocolitis that may be severe,and occasionally,fatal.Other agents include rituximab (an antiCD20 monoclonal antibody),bevacizumab (a monoclonal antibody against the vascular endothelial growth factor) and anti-tumor necrosis factor agents,including infliximab,adalimumab and etanercept.

  14. A multi-agent architecture for geosimulation of moving agents

    Science.gov (United States)

    Vahidnia, Mohammad H.; Alesheikh, Ali A.; Alavipanah, Seyed Kazem

    2015-10-01

    In this paper, a novel architecture is proposed in which an axiomatic derivation system in the form of first-order logic facilitates declarative explanation and spatial reasoning. Simulation of environmental perception and interaction between autonomous agents is designed with a geographic belief-desire-intention and a request-inform-query model. The architecture has a complementary quantitative component that supports collaborative planning based on the concept of equilibrium and game theory. This new architecture presents a departure from current best practices geographic agent-based modelling. Implementation tasks are discussed in some detail, as well as scenarios for fleet management and disaster management.

  15. Rapid and specific high-performance liquid chromatography for the in vitro quantification of D-Lys6-GnRH in a microemulsion-type formulation in the presence of peptide oxidation products.

    Science.gov (United States)

    Kafka, Alexandra P; Rades, Thomas; McDowell, Arlene

    2010-02-01

    A high-performance liquid chromatography (HPLC) method for assay of d-Lys(6)-GnRH contained in a microemulsion-type formulation is described. The peptide is extracted from the microemulsion matrix and quantified using a two-step gradient method. Separation from microemulsion compounds and potential peptide oxidation products was achieved on a Jupiter C(18) column at 40 degrees C, using a gradient of 10-35% CH(3)CN for peptide elution. The correlation of peak intensity measured at 220 nm and peptide concentration was linear over the range 2.5-60 microg/mL with a correlation coefficient of 0.9997 and a y-intercept not significantly different from zero (p > 0.05). Intraday and interday variability of the assay was less than 5% for multiple injections of samples containing 7.5, 30 and 60 microg/mL. The lower limit of quantitation was calculated to be 0.38 microg/mL, and the lower limit of detection was 0.13 microg/mL. The assay was applied to samples that were stressed under physiological conditions (37 degrees C, pH 7.4) over 4 days. Three degradation peaks were well resolved from the parent peptide, demonstrating the selectivity of the assay. Off-line MALDI TOF mass spectrometry was applied to identify these degradation species as oxidation products of the peptide.

  16. Agent review phase one report.

    Energy Technology Data Exchange (ETDEWEB)

    Zubelewicz, Alex Tadeusz; Davis, Christopher Edward; Bauer, Travis LaDell

    2009-12-01

    This report summarizes the findings for phase one of the agent review and discusses the review methods and results. The phase one review identified a short list of agent systems that would prove most useful in the service architecture of an information management, analysis, and retrieval system. Reviewers evaluated open-source and commercial multi-agent systems and scored them based upon viability, uniqueness, ease of development, ease of deployment, and ease of integration with other products. Based on these criteria, reviewers identified the ten most appropriate systems. The report also mentions several systems that reviewers deemed noteworthy for the ideas they implement, even if those systems are not the best choices for information management purposes.

  17. Dopamine agents for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Junker, Anders Ellekær; Als-Nielsen, Bodil; Gluud, Christian

    2014-01-01

    BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...... therefore been assessed as a potential treatment for patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy. SEARCH METHODS: Trials were identified through the Cochrane...... of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy...

  18. [Anti-influenza virus agent].

    Science.gov (United States)

    Nakamura, Shigeki; Kohno, Shigeru

    2012-04-01

    The necessity of newly anti-influenza agents is increasing rapidly after the prevalence of pandemic influenza A (H1N1) 2009. In addition to the existing anti-influenza drugs, novel neuraminidase inhibitors such as peramivir (a first intravenous anti-influenza agent) and laninamivir (long acting inhaled anti-influenza agent) can be available. Moreover favipiravir, which shows a novel anti-influenza mechanism acting as RNA polymerase inhibitor, has been developing. These drugs are expected to improve the prognosis of severe cases caused by not only seasonal influenza but pandemic influenza A (H1N1) 2009 virus and H5N1 avian influenza, and also treat oseltamivir-resistant influenza effectively.

  19. Dual Rationality and Deliberative Agents

    Science.gov (United States)

    Debenham, John; Sierra, Carles

    Human agents deliberate using models based on reason for only a minute proportion of the decisions that they make. In stark contrast, the deliberation of artificial agents is heavily dominated by formal models based on reason such as game theory, decision theory and logic—despite that fact that formal reasoning will not necessarily lead to superior real-world decisions. Further the Nobel Laureate Friedrich Hayek warns us of the ‘fatal conceit’ in controlling deliberative systems using models based on reason as the particular model chosen will then shape the system’s future and either impede, or eventually destroy, the subtle evolutionary processes that are an integral part of human systems and institutions, and are crucial to their evolution and long-term survival. We describe an architecture for artificial agents that is founded on Hayek’s two rationalities and supports the two forms of deliberation used by mankind.

  20. Relational agents in clinical psychiatry.

    Science.gov (United States)

    Bickmore, Timothy; Gruber, Amanda

    2010-01-01

    Relational agents are computational artifacts, such as animated, screen-based characters or social robots, that are designed to establish a sense of rapport, trust, and even therapeutic alliance with patients, using ideal therapeutic relationships between human counselors and patients as role models. We describe the development and evaluation of several such agents designed for health counseling and behavioral-change interventions, in which a therapeutic alliance is established with patients in order to enhance the efficacy of the intervention. We also discuss the promise of using such agents as adjuncts to clinical psychiatry, a range of possible applications, and some of the challenges and ethical issues in developing and fielding them in psychiatric interventions.

  1. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

    Science.gov (United States)

    Farkas, Imre; Vastagh, Csaba; Farkas, Erzsébet; Bálint, Flóra; Skrapits, Katalin; Hrabovszky, Erik; Fekete, Csaba; Liposits, Zsolt

    2016-01-01

    Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM–5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9–39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N5-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid

  2. Thyroid Dysfunction from Antineoplastic Agents

    Science.gov (United States)

    Larsen, P. Reed; Marqusee, Ellen

    2011-01-01

    Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%–50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient’s quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. PMID:22010182

  3. Thyroid dysfunction from antineoplastic agents.

    Science.gov (United States)

    Hamnvik, Ole-Petter Riksfjord; Larsen, P Reed; Marqusee, Ellen

    2011-11-02

    Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.

  4. Autonomous sensor manager agents (ASMA)

    Science.gov (United States)

    Osadciw, Lisa A.

    2004-04-01

    Autonomous sensor manager agents are presented as an algorithm to perform sensor management within a multisensor fusion network. The design of the hybrid ant system/particle swarm agents is described in detail with some insight into their performance. Although the algorithm is designed for the general sensor management problem, a simulation example involving 2 radar systems is presented. Algorithmic parameters are determined by the size of the region covered by the sensor network, the number of sensors, and the number of parameters to be selected. With straight forward modifications, this algorithm can be adapted for most sensor management problems.

  5. Agentes infecciosos y enfermedades autoinmunes

    OpenAIRE

    Carlos Riebeling; Vicente Madrid; Beatriz Elena Camarena; Oscar Peralta; Raúl Barrera

    1992-01-01

    En este trabajo se describen los aspectos molecidares de la relación entre agentes infecciosos y enfermedades autoinrnitnes; los mecanismos de respuesta inmune a los agentes infecciosos, y las Iiiyótesis más recientes de la causa de las enfermedades autoinmunes. Los antígenos son procesados y seleccionados por su inmitnogenicidad, ypresentadospor lasmolécitlasde HLA a los receptores de antígeno de los linfocitos T. Aunque existen rnuclias hipótesk sobre el origen de las enfermedades arrtoinmu...

  6. 13 CFR 120.952 - Fiscal agent.

    Science.gov (United States)

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Fiscal agent. 120.952 Section 120... Loan Program (504) Debenture Sales and Service Agents § 120.952 Fiscal agent. SBA shall appoint a Fiscal Agent to assess the financial markets, minimize the cost of sales, arrange for the production...

  7. SEM: A Cultural Change Agent

    Science.gov (United States)

    Barnes, Bradley; Bourke, Brian

    2015-01-01

    The authors advance the concept that institutional culture is a purposeful framework by which to view SEM's utility, particularly as a cultural change agent. Through the connection of seemingly independent functions of performance and behavior, implications emerge that deepen the understanding of the influence of culture on performance outcomes…

  8. Raspberry Pi for secret agents

    CERN Document Server

    Sjogelid, Stefan

    2015-01-01

    This book is an easy-to-follow guide with practical examples in each chapter. Suitable for the novice and expert alike, each topic provides a fast and easy way to get started with exciting applications and also guides you through setting up the Raspberry Pi as a secret agent toolbox.

  9. Multi-Agent Transport Planning

    NARCIS (Netherlands)

    Zutt, J.; Witteveen, C.

    2005-01-01

    We discuss a distributed transport planning problem with competitive autonomous actors that carry out time-constrained pick-up delivery orders from customers. The agents have to find conflict-free routes to execute a series of orders they have accepted. Hatzack and Nebel [2] were the first to sugges

  10. The Power Trading Agent Competition

    NARCIS (Netherlands)

    W. Ketter (Wolfgang); J. Collins (John); P. Reddy (Prashant); C. Flath (Christoph); M.M. de Weerdt (Mathijs)

    2011-01-01

    textabstractThis is the specification for the Power Trading Agent Competition for 2012 (Power TAC 2012). Power TAC is a competitive simulation that models a “liberalized” retail electrical energy market, where competing business entities or “brokers” offer energy services to customers through tariff

  11. The Power Trading Agent Competition

    NARCIS (Netherlands)

    Ketter, W.; Collins, J.; Reddy, P.; Flath, C.; De Weerdt, M.M.

    2011-01-01

    This is the specification for the Power Trading Agent Competition for 2012 (Power TAC 2012). Power TAC is a competitive simulation that models a “liberalized” retail electrical energy market, where competing business entities or “brokers” offer energy services to customers through tariff contracts,

  12. Humor and embodied conversational agents

    NARCIS (Netherlands)

    Nijholt, A.

    2003-01-01

    This report surveys the role of humor in human-to-human interaction and the possible role of humor in human-computer interaction. The aim is to see whether it is useful for embodied conversational agents to integrate humor capabilities in their internal model of intelligence, emotions and interactio

  13. Kriitikute lemmikfilm on "Agent Sinikael"

    Index Scriptorium Estoniae

    2003-01-01

    Eesti Filmiajakirjanike Ühing andis kümnendat korda välja auhinda Aasta film 2002. Parimaks filmiks tunnistati mängufilm "Agent Sinikael" : režissöör Marko Raat. Viimane sai preemiaks Neitsi Maali kuju ja 12 000 krooni

  14. Biotech drugs : biological therapeutic agents

    OpenAIRE

    Grech, Godfrey; Fenech, Anthony

    2009-01-01

    The recent years has seen significant growth in a new therapeutic approach to the management of disease. Biological therapeutic agents, constitute a broad category of drugs, usually generated by recombinant techniques from living organisms. These therapies revolutionise the traditional approaches to drug design and development, and regulatory agencies have been swift in developing the necessary structures to ensure their optimal use.

  15. Relational agents: A critical review

    DEFF Research Database (Denmark)

    Campbell, Robert H.; Grimshaw, Mark Nicholas; Green, Gill

    2009-01-01

    Relationships between people who meet in virtual worlds are common and these relationships can be long term, in some cases lasting a life-time. Although relationships formed in virtual worlds have invited a lot of recent interest, surprisingly little work has been done on developing computer agents...

  16. Biocontrol agents in signalling resistance

    NARCIS (Netherlands)

    Loon, L.C. van; Pieterse, C.M.J.

    2002-01-01

    The mechanisms by which biological control agents suppress disease comprise competition for nutrients, notably iron, production of antibiotics, and secretion of lytic enzymes, as well as inducing resistance in the plant. The former three mechanisms act primarily on the pathogen by decreasing its

  17. Identity Management in Agent Systems

    NARCIS (Netherlands)

    Brazier, F.M.T.; Groot, de D.R.A.

    2006-01-01

    If agent-based applications are to be used in large scale, open environments, security is a main issue; digital identity management (DIDM) an essential element. DIDM is needed to be able to determine the rights and obligations of the four main

  18. Kriitikute lemmikfilm on "Agent Sinikael"

    Index Scriptorium Estoniae

    2003-01-01

    Eesti Filmiajakirjanike Ühing andis kümnendat korda välja auhinda Aasta film 2002. Parimaks filmiks tunnistati mängufilm "Agent Sinikael" : režissöör Marko Raat. Viimane sai preemiaks Neitsi Maali kuju ja 12 000 krooni

  19. Halide test agent replacement study

    Energy Technology Data Exchange (ETDEWEB)

    Banks, E.M.; Freeman, W.P.; Kovach, B.J. [and others

    1995-02-01

    The intended phaseout of the chlorofluorocarbons (CFCs) from commercial use required the evaluation of substitute materials for the testing for leak paths through both individual adsorbers and installed adsorbent banks. The American Society of Mechanical Engineers (ASME) Committee on Nuclear Air and Gas Treatment (CONAGT) is in charge of maintaining the standards and codes specifying adsorbent leak test methods for the nuclear safety related air cleaning systems. The currently published standards and codes cite the use of R-11, R-12 and R-112 for leak path test agents. All of these compounds are CFCs. There are other agencies and organizations (USDOE, USDOD and USNRC) also specifying testing for leak paths or in some cases for special life tests using the above compounds. The CONAGT has recently developed criteria for the suitability evaluation of substitute test agents. On the basis of these criteria, several compounds were evaluated for their acceptability as adsorbent bed leak and life test agents. The ASME CONAGT Test Agent Qualification Criteria. The test agent qualification is based on the following parameters: (1) Similar retention times on activated carbons at the same concentration levels as one of the following: R-11, R-12, R-112 or R-112a. (2) Similar lower detection limit sensitivity and precision in the concentration range of use as R-11, R-12, R-112 and R-112a. (3) Gives the same in-place leak test results as R-11, R-12, R-112, or R-112a. (4) Chemical and radiological stability under the use conditions. (5) Causes no degradation of the carbon and its impregnant or of the other NATS components under the use conditions. (6) Is listed in the USEPA Toxic Substances Control Act (TSCA) inventory for commercial use.

  20. Persuasive Teachable Agent for Intergenerational Learning

    OpenAIRE

    Lim, Su Fang

    2016-01-01

    Teachable agents are computer agents based on the pedagogical concept of learning-by-teaching. During the tutoring process, where students take on the role of the tutor to teach a computer agent tutee, learners have been observed to gain deeper understanding of the subject matter. Teachable agents are commonly used in the areas of science and mathematics learning where learners are able to learn complex concepts and deep reasoning by teaching the teachable agent through graphic representation...