Comparison of long GnRH agonist versus GnRH antagonist protocol in poor responders

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Sadık Şahin

2014-12-01

Full Text Available Objective: To compare long GnRH agonist with GnRH antagonist protocol in poor responders. Materials and Methods: Medical charts of 531 poor responder women undergoing in-vitro fertilization (IVF cycle at Zeynep Kamil Maternity and Children’s Hospital, IVF Center were retrospectively analysed. Those who received at least 300 IU/daily gonadotropin and had ≤3 oocytes retrieved were enrolled in the study. Poor responders were categorized into two groups as those who received long GnRH agonist or GnRH antagonist regimen. Results: Treatment duration and total gonadotropin dosage were significantly higher in women undergoing the long GnRH agonist regimen compared with the GnRH antagonist regimen (p<0.001 for both. Although the number of total and mature oocytes retrieved was similar between the groups, good quality embryos were found to be higher in the GnRH antagonist regimen. The day of embryo transfer and number of transferred embryos were similar in the groups. No statistically significant differences were detected in pregnancy (10.5% vs 14.1%, clinical pregnancy (7.7% vs 10.6% and early pregnancy loss rates (27.2% vs 35% between the groups. Conclusion: GnRH antagonist regimen may be preferable to long GnRH regimen as it could decrease the cost and treatment duration in poor responders.

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

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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

Return to fertility after extended chemical castration with a GnRH antagonist

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Kostanski, Janusz W; Jiang, Ge; Dani, Bhas A; Murty, Santos B; Qiu, Wei; Schrier, Bruce; Thanoo, B C; DeLuca, Patrick P

2001-01-01

Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days) or vehicle alone (control group). Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter) and control (10.6 offspring per litter) were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist

Return to fertility after extended chemical castration with a GnRH antagonist

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Schrier Bruce

2001-10-01

Full Text Available Abstract Background Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. Methods Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days or vehicle alone (control group. Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. Results All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter and control (10.6 offspring per litter were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. Conclusions These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist.

Hedgehog-PKA signaling and gnrh3 regulate the development of zebrafish gnrh3 neurons.

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Ming-Wei Kuo

Full Text Available GnRH neurons secrete GnRH that controls the development of the reproduction system. Despite many studies, the signals controlling the development of GnRH neurons from its progenitors have not been fully established. To understand the development of GnRH neurons, we examined the development of gnrh3-expressing cells using a transgenic zebrafish line that expresses green fluorescent protein (GFP and LacZ driven by the gnrh3 promoter. GFP and LacZ expression recapitulated that of gnrh3 in the olfactory region, olfactory bulb and telencephalon. Depletion of gnrh3 by morpholinos led to a reduction of GFP- and gnrh3-expressing cells, while over-expression of gnrh3 mRNA increased the number of these cells. This result indicates a positive feed-forward regulation of gnrh3 cells by gnrh3. The gnrh3 cells were absent in embryos that lack Hedgehog signaling, but their numbers were increased in embryos overexpressing shhb. We manipulated the amounts of kinase that antagonizes the Hedgehog signaling pathway, protein kinase A (PKA, by treating embryos with PKA activator forskolin or by injecting mRNAs encoding its constitutively active catalytic subunit (PKA* and dominant negative regulatory subunit (PKI into zebrafish embryos. PKA* misexpression or forskolin treatment decreased GFP cell numbers, while PKI misexpression led to ectopic production of GFP cells. Our data indicate that the Hedgehog-PKA pathway participates in the development of gnrh3-expressing neurons during embryogenesis.

GnRH and prostaglandin-based synchronization protocols as alternatives to progestogen-based treatments in sheep.

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Rekik, M; Haile, A; Abebe, A; Muluneh, D; Goshme, S; Ben Salem, I; Hilali, M El-Dine; Lassoued, N; Chanyalew, Y; Rischkowsky, B

2016-12-01

The study investigated, for cycling sheep, synchronizing protocols simultaneously to the standard "P" protocol using progestogens priming with intravaginal devices and gonadotropin. In November 2014, 90 adult Menz ewes were assigned to either the "P" protocol, "PGF" treatment where oestrus and ovulation were synchronized using two injections of prostaglandin 11 days apart or a "GnRH" treatment where the ewes had their oestrus and ovulation synchronized with GnRH (day 0)-prostaglandin (day 6)-GnRH (day 9) sequence. The ewes were naturally mated at the induced oestrus and the following 36 days. Plasma progesterone revealed that 92% of the ewes were ovulating before synchronization and all, except one, ovulated in response to the applied treatments. All "P" ewes exhibited oestrus during the 96-hr period after the end of the treatments in comparison with only 79.3% and 73.3% for "PGF" and "GnRH" ewes, respectively (p sheep after the rainy season when most animals are spontaneously cycling. © 2016 Blackwell Verlag GmbH.

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

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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. Copyright © 2015 Elsevier B.V. All rights reserved.

Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology

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Stenbæk, D. S.; Toftager, M.; Hjordt, L. V.

2015-01-01

STUDY QUESTION: Do mental distress and mood fluctuations in women undergoing GnRH agonist and GnRH antagonist protocols for assisted reproductive technology (ART) differ depending on protocol and the personality trait, neuroticism? SUMMARY ANSWER: ART treatment did not induce elevated levels...... of mental distress in either GnRH antagonist or agonist protocols but neuroticism was positively associated with increased mental distress, independent of protocols. WHAT IS KNOWN ALREADY: ART treatment may increase mental distress by mechanisms linked to sex hormone fluctuations. General psychological...... characteristics, such as personality traits indexing negative emotionality, e.g. neuroticism, are likely to affect mental distress during ART treatment. STUDY DESIGN, SIZE, DURATION: A total of 83 women undergoing their first ART cycle were consecutively randomized 1:1 to GnRH antagonist (n = 42) or GnRH agonist...

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

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

1988-01-01

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 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)] 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)] 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)] 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)] 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 6 , [Orn(2,4-NAPS)] 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

Hormonal changes during GnRH analogue therapy in children with central precocious puberty

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Müller, J; Juul, A; Andersson, A M

2000-01-01

Gonadotropin releasing hormone analogues (GnRHa) have been used for treatment of central precocious puberty (CPP) for more than 15 years. They are generally considered safe although data on potential long-term side effects are scarce. However, GnRHa therapy has profound effects on both the hypoth......Gonadotropin releasing hormone analogues (GnRHa) have been used for treatment of central precocious puberty (CPP) for more than 15 years. They are generally considered safe although data on potential long-term side effects are scarce. However, GnRHa therapy has profound effects on both...

Does polycystic ovarian morphology influence the response to treatment with pulsatile GnRH in functional hypothalamic amenorrhea?

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Dumont, Agathe; Dewailly, Didier; Plouvier, Pauline; Catteau-Jonard, Sophie; Robin, Geoffroy

2016-04-29

Pulsatile GnRH therapy is the gold standard treatment for ovulation induction in women having functional hypothalamic amenorrhea (FHA). The use of pulsatile GnRH therapy in FHA patients with polycystic ovarian morphology (PCOM), called "FHA-PCOM", has been little studied in the literature and results remain contradictory. The aim of this study was to compare the outcomes of pulsatile GnRH therapy for ovulation induction between FHA and "FHA-PCOM" patients in order to search for an eventual impact of PCOM. Retrospective study from August 2002 to June 2015, including 27 patients with FHA and 40 "FHA-PCOM" patients (85 and 104 initiated cycles, respectively) treated by pulsatile GnRH therapy for induction ovulation. The two groups were similar except for markers of PCOM (follicle number per ovary, serum Anti-Müllerian Hormone level and ovarian area), which were significantly higher in patients with "FHA-PCOM". There was no significant difference between the groups concerning the ovarian response: with equivalent doses of GnRH, both groups had similar ovulation (80.8 vs 77.7 %, NS) and excessive response rates (12.5 vs 10.6 %, NS). There was no significant difference in on-going pregnancy rates (26.9 vs 20 % per initiated cycle, NS), as well as in miscarriage, multiple pregnancy or biochemical pregnancy rates. Pulsatile GnRH seems to be a successful and safe method for ovulation induction in "FHA-PCOM" patients. If results were confirmed by prospective studies, GnRH therapy could therefore become a first-line treatment for this specific population, just as it is for women with FHA without PCOM.

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.

GnRHR-II knockdown swine have constitutively lower serum testosterone concentrations, impaired senstitivity to GnRH analogues and reduced semen quality

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The second mammalian GnRH isoform (GnRH-II) and its specific receptor (GnRHR-II) are abundantly produced within swine testes. GnRHR-II localizes to porcine Leydig cells and exogenous GnRH-II treatment robustly stimulates testosterone production in vivo, despite minimal secretion of luteinizing hormo...

Fertility of Angus cross beef heifers after GnRH treatment on day 23 and timing of insemination in 14-day CIDR protocol.

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Kasimanickam, R K; Hall, J B; Whittier, W D

2017-02-01

This study compared artificial insemination pregnancy rate (AI-PR) between 14-day CIDR-GnRH-PGF2α-GnRH and CIDR-PGF2α-GnRH synchronization protocol with two fixed AI times (56 or 72 hr after PGF2α). On day 0, heifers (n = 1311) from nine locations assigned body condition score (BCS: 1, emaciated; 9, obese), reproductive tract score (RTS: 1, immature, acyclic; 5, mature, cyclic) and temperament score (0, calm; and 1, excited) and fitted with a controlled internal drug release (CIDR, 1.38 g of progesterone) insert for 14 days. Within herd, heifers were randomly assigned either to no-GnRH group (n = 635) or to GnRH group (n = 676), and heifers in GnRH group received 100 μg of GnRH (gonadorelin hydrochloride, IM) on day 23. All heifers received 25 mg of PGF2α (dinoprost, IM) on day 30 and oestrous detection aids at the same time. Heifers were observed for oestrus thrice daily until AI. Within GnRH groups, heifers were randomly assigned to either AI-56 or AI-72 groups. Heifers in AI-56 group (n = 667) were inseminated at 56 hr (day 32 PM), and heifers in AI-72 group (n = 644) were inseminated at 72 hr (day 33 AM) after PGF2α administration. All heifers were given 100 μg of GnRH concurrently at the time AI. Controlling for BCS (p < .05), RTS (p < .05), oestrous expression (p < .001), temperament (p < .001) and GnRH treatment by time of insemination (p < .001), the AI-PR differed between GnRH treatment [GnRH (Yes - 60.9% (412/676) vs. No - 55.1% (350/635); p < .05)] and insemination time [AI-56 - 54.6% (364/667) vs. AI-72 - 61.8% (398/644); (p < .01)] groups. The GnRH treatment by AI time interaction influenced AI-PR (GnRH56 - 61.0% (208/341); GnRH72 - 60.9% (204/335); No-GnRH56 - 47.9% (156/326); No-GnRH72 - 62.8% (194/309); p < .001). In conclusion, 14-day CIDR synchronization protocol for FTAI required inclusion of GnRH on day 23 if inseminations were to be performed at 56 hr after PGF2α in order to achieve greater AI-PR. �

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

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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.

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

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

2016-01-01

interval (CI): 0.33-0.57) compared with the traditional GnRH agonist protocol. Previous trials comparing the two protocols mainly included selected patient populations, a limited number of patients and the applied OHSS criteria differed, making direct comparisons difficult. In two recent large meta...... IV, dual-centre, open-label, RCT including 1050 women allocated to either short GnRH antagonist or long GnRH agonist protocol in a 1:1 ratio and enrolled over a 5-year period using a web-based concealed randomization code. This is a superiority study designed to detect a difference in severe OHSS...... 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...

Microdose Flare-up Gonadotropin-releasing Hormone (GnRH) Agonist Versus GnRH Antagonist Protocols in Poor Ovarian Responders Undergoing Intracytoplasmic Sperm Injection.

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Boza, Aysen; Cakar, Erbil; Boza, Barıs; Api, Murat; Kayatas, Semra; Sofuoglu, Kenan

2016-01-01

Microdose flare-up GnRH agonist and GnRH antagonist have become more popular in the management of poor ovarian responders (POR) in recent years; however, the optimal protocol for POR patients undergoing in vitro fertilization has still been a challenge. In this observational study design, two hundred forty four poor ovarian responders were retrospectively evaluated for their response to GnRH agonist protocol (group-1, n=135) or GnRH antagonist protocol (group-2, n=109). Clinical pregnancy rate was the primary end point and was compared between the groups. Student t-test, Mann Whitney U test and χ (2)-test were used to compare the groups. The pmicrodose flare-up protocol has favorable outcomes with respect to the number of oocytes retrieved and implantation rate; nevertheless, the clinical pregnancy rate was found to be similar in comparison to GnRH antagonist protocol in poor ovarian responders. GnRH antagonist protocol appears to be promising with significantly lower gonadotropin requirement and lower treatment cost in poor ovarian responders.

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

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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.

Pregnancy outcome of “delayed start” GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: A clinical trial study

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Abbas Aflatoonian

2017-08-01

Full Text Available Background: Management of poor-responding patients is still major challenge in assisted reproductive techniques (ART. Delayed-start GnRH antagonist protocol is recommended to these patients, but little is known in this regards. Objective: The goal of this study was assessment of delayed-start GnRH antagonist protocol in poor responders, and in vitro fertilization (IVF outcomes. Materials and Methods: This randomized clinical trial included sixty infertile women with Bologna criteria for ovarian poor responders who were candidate for IVF. In case group (n=30, delayed-start GnRH antagonist protocol administered estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin. Control group (n=30 treated with estrogen priming antagonist protocol. Finally, endometrial thickness, the rates of oocytes maturation, , embryo formation, and pregnancy were compared between two groups. Results: Rates of implantation, chemical, clinical, and ongoing pregnancy in delayed-start cycles were higher although was not statistically significant. Endometrial thickness was significantly higher in case group. There were no statistically significant differences in the rates of oocyte maturation, embryo formation, and IVF outcomes between two groups. Conclusion: There is no significant difference between delayed-start GnRH antagonist protocol versus GnRH antagonist protocol.

Prenatal testosterone treatment alters LH and testosterone responsiveness to GnRH agonist in male sheep

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SERGIO E RECABARREN

2007-01-01

Full Text Available Although evidence is accumulating that prenatal testosterone (T compromises reproductive function in the female, the effects of excess T in utero on the postnatal development of male reproductive function has not been studied. The aim of this study was to assess the influence of prenatal T excess on age-related changes in pituitary and gonadal responsiveness to GnRH in the male sheep. We used the GnRH agonist, leuprolide (10 µg/kg, as a pharmacologic challenge at 5, 10, 20 and 30 weeks of age. These time points correspond to early and late juvenile periods and the prepubertal and postpubertal periods of sexual development, respectively. LH and T were measured in blood samples collected before and after GnRH agonist administration. The area under the response curve (AUC of LH increased progressively in both controls and prenatal T-treated males from 5 to 20 weeks of age (P<0.01. The LH responses in prenatal T-treated males were lower at 20 and 30 weeks of age compared to controls (P<0.05. AUC-T increased progressively in control males from 5 through 30 weeks of age and prenatal T-treated males from 5 to 20 weeks of age. The T response in prenatal T-treated males was higher at 20 weeks compared to controls of same age but similar to controls and prenatal T-treated males at 30 weeks of age (P <0.05. Our findings suggest that prenatal T treatment advances the developmental trajectory of gonadal responsiveness to GnRH in male offspring

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.

Differentially expressed miRNAs after GnRH treatment and their potential roles in FSH regulation in porcine anterior pituitary cell.

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Rui-Song Ye

Full Text Available Hypothalamic gonadotropin-releasing hormone (GnRH is a major regulator of follicle-stimulating hormone (FSH secretion in gonadotrope cell in the anterior pituitary gland. microRNAs (miRNAs are small RNA molecules that control gene expression by imperfect binding to the 3'-untranslated region (3'-UTR of mRNA at the post-transcriptional level. It has been proven that miRNAs play an important role in hormone response and/or regulation. However, little is known about miRNAs in the regulation of FSH secretion. In this study, primary anterior pituitary cells were treated with 100 nM GnRH. The supernatant of pituitary cell was collected for FSH determination by enzyme-linked immunosorbent assay (ELISA at 3 hours and 6 hours post GnRH treatment respectively. Results revealed that GnRH significantly promoted FSH secretion at 3 h and 6 h post-treatment by 1.40-fold and 1.80-fold, respectively. FSHβ mRNA at 6 h post GnRH treatment significantly increased by 1.60-fold. At 6 hours, cells were collected for miRNA expression profile analysis using MiRCURY LNA Array and quantitative PCR (qPCR. Consequently, 21 up-regulated and 10 down-regulated miRNAs were identified, and qPCR verification of 10 randomly selected miRNAs showed a strong correlation with microarray results. Chromosome location analysis indicated that 8 miRNAs were mapped to chromosome 12 and 4 miRNAs to chromosome X. Target and pathway analysis showed that some miRNAs may be associated with GnRH regulation pathways. In addition, In-depth analysis indicated that 10 up-regulated and 3 down-regulated miRNAs probably target FSHβ mRNA 3'-UTR directly, including miR-361-3p, a highly conserved X-linked miRNA. Most importantly, functional experimental results showed that miR-361-3p was involved in FSH secretion regulation, and up-regulated miR-361-3p expression inhibited FSH secretion, while down-regulated miR-361-3p expression promoted FSH secretion in pig pituitary cell model. These differentially

Prenatal androgenization of female mice programs an increase in firing activity of gonadotropin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood.

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Roland, Alison V; Moenter, Suzanne M

2011-02-01

Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

A Randomized, Parallel, Comparative Study of the Efficacy and Safety of Nafarelin Versus Danazol in the Treatment of Endometriosis in Taiwan

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Ming-Huei Cheng

2005-07-01

Conclusion: Nafarelin and danazol demonstrated similar clinical efficacy, but nafarelin was associated with fewer laboratory changes and a stable lipid profile, relative to danazol. Moreover, intranasally administered nafarelin is noninvasive, and may be a more comfortable and safer alternative to slow-release injectable GnRH agonists. Based on this study, we suggest that nafarelin, like other GnRH analogues, may be a treatment of choice for Taiwanese women with endometriosis. However, direct comparative studies of nafarelin with slow-release injectable GnRH agonists are now required.

Fertility status of Hodgkin lymphoma patients treated with chemotherapy and adjuvant gonadotropin-releasing hormone analogues.

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Huser, M; Smardova, L; Janku, P; Crha, I; Zakova, J; Stourac, P; Jarkovsky, J; Mayer, J; Ventruba, P

2015-08-01

Aim of this prospective observational study was to analyze fertility status of Hodgkin lymphoma (HL) patients treated with different types of chemotherapy while receiving GnRH analogues to preserve ovarian function. Fertility status was assessed among 108 females in reproductive age treated by curative chemotherapy for freshly diagnosed HL between 2005 and 2010 in university-based tertiary fertility and oncology center. All patients received GnRH analogues during chemotherapy to preserve their ovarian function. Their reproductive functions were assessed by follicle-stimulating hormone (FSH) measurement and pregnancy achievement. Ovarian function was determined separately in three groups with increasing gonadotoxicity of chemotherapy. One year following the treatment, normal ovarian function was found in 89 (82.4%) of patients. Two years after chemotherapy, 98 (90.7%) of patients retained their ovarian function, and 23 (21.3%) achieved clinical pregnancy during the follow-up period. Average FSH after chemotherapy was 11.6 ± 17.9 IU/l 1 year after the treatment resp. 9.0 ± 13.8 at the 2 years interval. There were significantly more patients with chemotherapy induced diminished ovarian reserve (chDOR) among the group receiving escalated BEACOPP chemotherapy in comparison with the other types of treatment (58.1% vs. 87.9% resp. 95.5%). The rate of chDOR is significantly higher after EB poly-chemotherapy and there is no tendency for improvement in time. The 2 + 2 chemotherapy with GnRH-a required for more advanced HL retained ovarian function significantly better after 2 years. Another important advantage of GnRH-a co-treatment is the excellent control of patient's menstrual cycle.

Ontogenic and sexual differences in pituitary GnRH receptors and intracellular Ca2+ mobilization induced by GnRH.

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Lacau-Mengido, I M; González Iglesias, A; Lux-Lantos, V; Libertun, C; Becú-Villalobos, D

1998-04-01

The present experiments were designed in order to elucidate the participation of the developing hypophysis in determining the changing sensitivity of gonadotrophins to gonadotropin-releasing hormone (GnRH) during ontogeny in the rat. To that end, we chose two well defined developmental ages that differ markedly in sexual and ontogenic characteristics of hypophyseal sensitivity to GnRH, 15 and 30 d. In order to study sex differences and the role of early sexual organization of the hypothalamus, experiments were carried out in males, females, and neonatally androgenized females (TP females). We evaluated (1) the characteristics of pituitary GnRH receptors, and (2) associated changes in GnRH-induced mobilization of intracellular Ca2+ (a second messenger involved in gonadotropins exocytosis). We measured binding characteristics of the GnRH analog D-Ser(TBu)6-des-Gly10-GnRH ethylamide in pituitary homogenates. We found that Kds did not vary among the different sex groups. Total number and concentration of receptors decreased in the female rat from 15-30 d of age, whereas in the male and TP female, receptors/pituitary increased, and the concentration/mg tissue did not change. Also, at 30 days of age, males presented higher content and concentration of receptors than females, and higher content than TP females. In order to evaluate if developmental and sexual differences in pituitary sensitivity to GnRH might be expressed through variations in the intracellular Ca2+ signal, we studied the mobilization of intracellular Ca2+ induced by GnRH (1 x 10(-8) to 1 x 10(-11) M) in a suspension of dispersed pituitary cells in the six groups. In cells from 15-d-old females, Ca2+ response was greater than in 30-d-old females at the doses of 10(-8) to 10(-10) M, indicating that in the infantile female rat activation of highly concentrated GnRH receptors is reflected in an increase in signal transduction mediated by Ca2+. In males and in female rats androgenized at birth, there was also

Adult height after spontaneous pubertal growth or GnRH analog treatment in girls with early puberty: a meta-analysis.

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Bertelloni, Silvano; Massart, Francesco; Miccoli, Mario; Baroncelli, Giampiero I

2017-06-01

Early puberty (EP) has been defined as the onset of puberty in the low-normal range; it may be a cause for concern regarding a possible impairment of adult height (AH). This paper meta-analysed data on AH after spontaneous growth or after gonadotropin-releasing hormone (GnRH) analog treatment in girls with EP. A computerized literature search was conducted from 1980 to June 30, 2016. Only published studies in English were considered. Eight papers were selected (483 cases). In untreated girls (n = 300), predicted adult height (PAH) at start of follow-up (-0.559 SDS (95%CI -1.110 to 0.001); P = 0.050) was close to mid-parental height (MPH) (-0.557 SDS (95%CI -0.736 to -0.419); P adult height. What is New: • Untreated and GnRH analog treated girls with early puberty reached similar adult height. • Adult height was consistent with mid-parental height in both untreated and GnRH analog treated girls with early puberty.

A Flexible Multidose GnRH Antagonist versus a Microdose Flare-Up GnRH Agonist Combined with a Flexible Multidose GnRH Antagonist Protocol in Poor Responders to IVF

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Gayem İnayet Turgay Çelik

2015-01-01

Full Text Available Objective. To compare the effectiveness of a flexible multidose gonadotropin-releasing hormone (GnRH antagonist against the effectiveness of a microdose flare-up GnRH agonist combined with a flexible multidose GnRH antagonist protocol in poor responders to in vitro fertilization (IVF. Study Design. A retrospective study in Akdeniz University, Faculty of Medicine, Department of Obstetrics and Gynecology, IVF Center, for 131 poor responders in the intracytoplasmic sperm injection-embryo transfer (ICSI-ET program between January 2006 and November 2012. The groups were compared to the patients’ characteristics, controlled ovarian stimulation (COH results, and laboratory results. Results. Combination protocol was applied to 46 patients (group 1, and a single protocol was applied to 85 patients (group 2. In group 1, the duration of the treatment was longer and the dose of FSH was higher. The cycle cancellation rate was significantly higher in group 2 (26.1% versus 38.8%. A significant difference was not observed with respect to the number and quality of oocytes and embryos or to the number of embryos transferred. There were no statistically significant differences in the hCG positivity (9.5% versus 9.4% or the clinical pregnancy rates (7.1% versus 10.6%. Conclusion. The combination protocol does not provide additional efficacy.

A Flexible Multidose GnRH Antagonist versus a Microdose Flare-Up GnRH Agonist Combined with a Flexible Multidose GnRH Antagonist Protocol in Poor Responders to IVF.

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Çelik, Gayem İnayet Turgay; Sütçü, Havva Kömür; Akpak, Yaşam Kemal; Akar, Münire Erman

2015-01-01

To compare the effectiveness of a flexible multidose gonadotropin-releasing hormone (GnRH) antagonist against the effectiveness of a microdose flare-up GnRH agonist combined with a flexible multidose GnRH antagonist protocol in poor responders to in vitro fertilization (IVF). A retrospective study in Akdeniz University, Faculty of Medicine, Department of Obstetrics and Gynecology, IVF Center, for 131 poor responders in the intracytoplasmic sperm injection-embryo transfer (ICSI-ET) program between January 2006 and November 2012. The groups were compared to the patients' characteristics, controlled ovarian stimulation (COH) results, and laboratory results. Combination protocol was applied to 46 patients (group 1), and a single protocol was applied to 85 patients (group 2). In group 1, the duration of the treatment was longer and the dose of FSH was higher. The cycle cancellation rate was significantly higher in group 2 (26.1% versus 38.8%). A significant difference was not observed with respect to the number and quality of oocytes and embryos or to the number of embryos transferred. There were no statistically significant differences in the hCG positivity (9.5% versus 9.4%) or the clinical pregnancy rates (7.1% versus 10.6%). The combination protocol does not provide additional efficacy.

Regulation versus modulation in GnRH receptor function

International Nuclear Information System (INIS)

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

1985-01-01

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 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 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

Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty

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Beek, J.T. van; Sharafuddin, M.J.A.; Kao, S.C.S. [Department of Radiology-JPP 3889, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52246 (United States); Luisiri, A. [Cardinal Glennon Children' s Hospital, St. Louis, Missouri (United States); Garibaldi, L.R. [Children' s Hospital of New Jersey, Newark Beth Israel Medical Center, Newark, New Jersey (United States); St. Barnabas Medical Center, Livingston, New Jersey (United States)

2000-07-01

Objective. The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. Materials and methods. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. Results. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. Conclusion. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape. (orig.)

Prospective assessment of pituitary size and shape on MR imaging after suppressive hormonal therapy in central precocious puberty

International Nuclear Information System (INIS)

Beek, J.T. van; Sharafuddin, M.J.A.; Kao, S.C.S.; Luisiri, A.; Garibaldi, L.R.

2000-01-01

Objective. The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue. Materials and methods. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume. Results. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy. Conclusion. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape. (orig.)

[Effectiveness and safety of pulsatile GnRH pump therapy on female patients with IHH].

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Liu, Zhaoxiang; Mao, Jiangfeng; Wu, Xueyan; Nie, Min; Huang, Bingkun; Xu, Hongli; Wang, Xi; Zheng, Junjie

2015-11-10

To investigate the therapeutic effect of pulsatile GnRH (gonadorelin) pump on female patients with idiopathic hypogonadotropic hypogonadism (IHH). In this retrospective study, five female IHH patients were recruited. Patients were treated with pulsatile gonadorelin (10 µg per 90 min) via a pump for at least 12 weeks. Serum gonadotropins and sex steroid levels were measured, and menses were recorded. After one-week treatment, luteinizing hormone (LH) level increased from (2.2 ± 2.0) U/L to (5.4 ± 2.5) U/L (P=0.028), follicle-stimulating hormone(FSH) level increased from (3.7 ± 2.7) U/L to(6.3 ± 1.0) U/L (P=0.162), and estradiol (E2) level increased from (58 ± 13) pmol/L to (260 ± 97) pmol/L (P=0.011). Menstrual bleeding was observed in 4 patients after starting treatment for 35-55 days and two natural pregnancies were reported. No menstrual bleeding was reported in another patient. The frequency of pulsatile GnRH had to be adjusted according to endogenous GnRH secretion during the follicular phase of normal women and regular menses were induced. Pulsatile GnRH is effective in treating female IHH. A constant frequency of pulsatile GnRH is suitable for most of IHH patients. However, for those who failed to produce regular menses, adjusting pulsatile frequency to imitate the physiological rhythm of GnRH may be an alternative option.

A conserved non-reproductive GnRH system in chordates.

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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.

Endocrine dynamics during pulsatile GnRH administration in patients with hypothalamic amenorrhea and polycystic ovarian disease.

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Rossmanith, W G; Wirth, U; Benz, R; Wolf, A S

1989-01-01

The LH secretory patterns and ovarian endocrine responses have been determined during pulsatile gonadotropin-releasing hormone (GnRH) administration for induction of ovulation in patients with hypothalamic amenorrhea (HA). However, until now these endocrine dynamics during GnRH therapy have not been thoroughly investigated in patients with polycystic ovarian disease (PCOD). Seven patients with HA and 4 patients with PCOD have therefore been studied to determine changes in LH pulsatile activity and in serum sex steroid levels in response to chronic intermittent GnRH stimulation. GnRH was administered intravenously (5-10 micrograms/90 minutes) by means of a portable infusion pump. Blood samples were obtained at 15-minute intervals for 4 hours on the day before the start of GnRH stimulation (control day) and on treatment days 5, 10 and 15. LH was determined in all samples and FSH, serum androgens and estrogens were measured in baseline samples by RIA. While 8 (62%) ovulations and 5 conceptions were observed in 13 treatment cycles in patients with HA, no ovulations were achieved during 9 treatment cycles in patients with PCOD. On the control day significantly (p less than 0.05) higher basal LH and testosterone (T) levels and significantly (p less than 0.05) lower FSH levels were found in the PCOD patients. The LH pulsatile profiles of the PCOD patients showed significantly (p less than 0.05) higher pulse amplitudes and areas under the curve (integrated responses). Pulsatile GnRH administration induced a significant (p less than 0.05) increase in LH pulse amplitudes in both HA and PCOD patients, and also increased (p less than 0.05) the integrated responses in patients with HA. During the GnRH stimulation, the LH interpulse intervals of both HA and PCOD patients were found to be similar to the frequency in which exogenous GnRH was administered. FSH levels rose continuously (p less than 0.001) during stimulation in patients with HA, but remained unchanged in patients

Effects of GnRH, a progesterone-releasing device, and energy balance on an oestrus synchronisation program in anoestrous dairy cows.

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Sahu, S K; Cockrem, J F; Parkinson, T J; Laven, R A

2017-08-01

The aim of this research was to study the roles of the day 0 energy balance and gonadotrophin-releasing hormone (GnRH) and progesterone levels on dominant follicle (DF) and corpus luteum (CL) development during the first 7 days of a gonadotrophin-prostaglandin-gonadotrophin (GPG) + progesterone (P4) program in anoestrous dairy cows. Cows (n = 81) were allocated to one of the three treatments: (1) GPG + P4 (days 0 and 9, 100 µg GnRH; day 0-7, intravaginal P4 device; day 7, 500 µg PGF 2α ); (2) GPG (as for treatment 1 but excluding the P4 device) and (3) prostaglandin + GnRH + P4 (as for treatment 1, but excluding day 0 GnRH). DF and CL size, plasma concentrations of insulin, insulin-like growth factor-I (IGF-I) and non-esterified fatty acid (NEFA) were measured on days 0 and 7. The proportion of cows with a CL on day 7 was significantly different between groups (GPG: 78%, GPG+P4: 69%, PGF 2α + GnRH + P4: 42%, P = 0.02). The CL volume on day 7 was significantly associated with treatment, treatment by time postpartum and plasma concentrations of insulin, IGF-I and NEFA. In cows without a CL present on day 0 of an oestrus synchronisation program, removal of the day 0 GnRH treatment led to reduced CL development; however, no effect of adding progesterone was found. In contrast, in cows with a CL present on day 0 inclusion of a progesterone device led to a higher CL volume, but removal of the first GnRH injection had no effect. Response to the treatment was affected by plasma concentrations of insulin, IGF-I and NEFA. © 2017 Australian Veterinary Association.

GnRH signalling pathways and GnRH-induced homologous desensitization in a gonadotrope cell line (alphaT3-1).

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Poulin, B; Rich, N; Mas, J L; Kordon, C; Enjalbert, A; Drouva, S V

1998-07-25

Exposure of the gonadotrope cells to gonadotropin-releasing hormone (GnRH) reduces their responsiveness to a new GnRH stimulation (homologous desensitization). The time frame as well as the mechanisms underlying this phenomenon are yet unclear. We studied in a gonadotrope cell line (alphaT3-1) the effects of short as well as long term GnRH pretreatments on the GnRH-induced phospholipases-C (PLC), -A2 (PLA2) and -D (PLD) activities, by measuring the production of IP3, total inositol phosphates (IPs), arachidonic acid (AA) and phosphatidylethanol (PEt) respectively. We demonstrated that although rapid desensitization of GnRH-induced IP3 formation did not occur in these cells, persistent stimulation of cells with GnRH or its analogue resulted in a time-dependent attenuation of GnRH-elicited IPs formation. GnRH-induced IPs desensitization was potentiated after direct activation of PKC by the phorbol ester TPA, suggesting the involvement of distinct mechanisms in the uncoupling exerted by either GnRH or TPA on GnRH-stimulated PI hydrolysis. The levels of individual phosphoinositides remained unchanged under any desensitization condition applied. Interestingly, while the GnRH-induced PLA2 activity was rapidly desensitized (2.5 min) after GnRH pretreatments, the neuropeptide-evoked PLD activation was affected at later times, indicating an important time-dependent contribution of these enzymatic activities in the sequential events underlying the GnRH-induced homologous desensitization processes in the gonadotropes. Under GnRH desensitization conditions, TPA was still able to induce PLD activation and to further potentiate the GnRH-evoked PLD activity. AlphaT3-1 cells possess several PKC isoforms which, except PKCzeta, were differentially down-regulated by TPA (PKCalpha, betaII, delta, epsilon, eta) or GnRH (PKCbetaII, delta, epsilon, eta). In spite of the presence of PKC inhibitors or down-regulation of PKC isoforms by TPA, the desensitizing effect of the neuropeptide on

Identification of Genes Enriched in GnRH Neurons by Translating Ribosome Affinity Purification and RNAseq in Mice.

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Burger, Laura L; Vanacker, Charlotte; Phumsatitpong, Chayarndorn; Wagenmaker, Elizabeth R; Wang, Luhong; Olson, David P; Moenter, Suzanne M

2018-04-01

Gonadotropin-releasing hormone (GnRH) neurons are a nexus of fertility regulation. We used translating ribosome affinity purification coupled with RNA sequencing to examine messenger RNAs of GnRH neurons in adult intact and gonadectomized (GDX) male and female mice. GnRH neuron ribosomes were tagged with green fluorescent protein (GFP) and GFP-labeled polysomes isolated by immunoprecipitation, producing one RNA fraction enhanced for GnRH neuron transcripts and one RNA fraction depleted. Complementary DNA libraries were created from each fraction and 50-base, paired-end sequencing done and differential expression (enhanced fraction/depleted fraction) determined with a threshold of >1.5- or <0.66-fold (false discovery rate P ≤ 0.05). A core of ∼840 genes was differentially expressed in GnRH neurons in all treatments, including enrichment for Gnrh1 (∼40-fold), and genes critical for GnRH neuron and/or gonadotrope development. In contrast, non-neuronal transcripts were not enriched or were de-enriched. Several epithelial markers were also enriched, consistent with the olfactory epithelial origins of GnRH neurons. Interestingly, many synaptic transmission pathways were de-enriched, in accordance with relatively low innervation of GnRH neurons. The most striking difference between intact and GDX mice of both sexes was a marked downregulation of genes associated with oxidative phosphorylation and upregulation of glucose transporters in GnRH neurons from GDX mice. This may suggest that GnRH neurons switch to an alternate fuel to increase adenosine triphosphate production in the absence of negative feedback when GnRH release is elevated. Knowledge of the GnRH neuron translatome and its regulation can guide functional studies and can be extended to disease states, such as polycystic ovary syndrome.

The comparision of effect of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients.

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Ozcan Cenksoy, Pinar; Ficicioglu, Cem; Kizilkale, Ozge; Suhha Bostanci, Mehmet; Bakacak, Murat; Yesiladali, Mert; Kaspar, Cigdem

2014-07-01

To compare the effects of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients. Of 225 patients, 83 patients were in microdose flare-up group (Group 1), 70 patients were in GnRH antagonist/letrozole group (Group 2) and 72 patients were in GnRH antagonist/clomiphene citrate group (Group 3). Demographic and endocrine characteristics, the total number of oocytes retrieved, cancellation rate and clinical pregnancy rate were collected Results: Total dosage of gonadotropins (p=0.002) and serum E2 levels on the day of hCG administration (p=0.010) were significantly higher and duration of stimulations (p=0.03) was significantly longer in group 1. The number of oocytes retrieved was significantly greater in group 1 and 2 when compare to those of group 3 (p=0,000). There was a trend towards increasing cycle cancellation rates with GnRH antagonist/clomiphene citrate and GnRH antagonist/letrozole. Our finding suggest that the results of microdose flare-up protocol are better than other two used treatment protocols, in terms of maximum estradiol levels, number of mature oocytes retrieved, and cancellation rate and it still seems to be superior the ovarian stimulation regime for the poor responder patients.

Quality of life and psychosocial and physical well-being among 1,023 women during their first assisted reproductive technology treatment

DEFF Research Database (Denmark)

Toftager, Mette; Sylvest, Randi; Schmidt, Lone

2018-01-01

at university hospitals. PATIENT(S): Women referred for their first ART treatment were randomized in a 1:1 ratio and started standardized ART protocols. INTERVENTION(S): Gonadotropin-releasing hormone analogue; 528 women allocated to a short GnRH antagonist protocol and 495 women allocated to a long Gn...

Polycystic ovarian disease unmasked by pulsatile GnRH therapy in a subgroup of women with hypothalamic amenorrhea.

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Mattle, Verena; Bilgyicildirim, Aysen; Hadziomerovic, Dijana; Ott, Helmut W; Zervomanolakis, Ioannis; Leyendecker, Gerhard; Wildt, Ludwig

2008-02-01

To present the observation in six out of 120 women treated with pulsatile GnRH for ovulation induction, who developed hyperandrogenemia and polycystic ovaries during treatment. Clinical observation. Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Innsbruck, Austria. A total of 120 women initially diagnosed as suffering from primary or secondary hypothalamic amenorrhea were treated for ovulation induction with pulsatile administration of GnRH for up to 140 days. There was no indication of the presence of polycystic ovaries or hyperandrogenemia before therapy. Pulsatile GnRH therapy using the Zyklomat pump. Ovulatory menstrual cycles. Initially, all patients responded to pulsatile GnRH administration with ovulation and corpus luteum formation. During continuation of treatment, 6 patients developed an increase in LH and LH/FSH ratio as well as a progressive rise in serum T levels resulting in hyperandrogenemia. This was accompanied by the development of polycystic ovaries and cessation of follicular maturation. We conclude from these observations that restoration of normal GnRH stimulation of the pituitary gland can result in the development of hyperandrogenemia and polycystic ovaries, suggesting a pituitary or ovarian defect underlying the pathogenesis of this disorder.

Microdose GnRH Agonist Flare-Up versus Ultrashort GnRH Agonist Combined with Fixed GnRH Antagonist in Poor Responders of Assisted Reproductive Techniques Cycles

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Parisa Khani

2013-01-01

Full Text Available Background: This study compares the microdose flare-up protocol to the ultrashort gonadotropinreleasinghormone (GnRH agonist flare combined with the fixed multidose GnRH antagonistprotocol in poor responders undergoing ovarian stimulation.Materials and Methods: In this randomized clinical trial, 120 women who were candidates forassisted reproductive techniques (ART and had histories of one or more failed in vitro fertilization(IVF cycles with three or fewer retrieved oocytes were prospectively randomized into two groups.Group I (60 patients received the microdose flare-up regimen and group II (60 patients receivedthe ultrashort GnRH agonist combined with fixed GnRH antagonist.Results: There were no significant differences between the groups in the number of used gonadotropinampoules (p=0.591, duration of stimulation (p=0.610, number of retrieved oocytes (p=0.802,fertilization rate (p=0.456, and the number of transferred embryos (p=0.954. The clinical pregnancyrates were statistically similar in group I (10% compared with group II (13.3%, p=0.389.Conclusion: According to our results, there is no significant difference between these protocolsfor improving the ART outcome in poor responders. Additional prospective, randomizedstudies with more patients is necessary to determine the best protocol (Registration Number:IRCT201105096420N1.

Microdose GnRH Agonist Flare-Up versus Ultrashort GnRH Agonist Combined with Fixed GnRH Antagonist in Poor Responders of Assisted Reproductive Techniques Cycles.

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Eftekhar, Maryam; Mohammadian, Farnaz; Yousefnejad, Fariba; Khani, Parisa

2013-01-01

This study compares the microdose flare-up protocol to the ultrashort gonadotropinreleasing hormone (GnRH) agonist flare combined with the fixed multidose GnRH antagonist protocol in poor responders undergoing ovarian stimulation. In this randomized clinical trial, 120 women who were candidates for assisted reproductive techniques (ART) and had histories of one or more failed in vitro fertilization (IVF) cycles with three or fewer retrieved oocytes were prospectively randomized into two groups. Group I (60 patients) received the microdose flare-up regimen and group II (60 patients) received the ultrashort GnRH agonist combined with fixed GnRH antagonist. There were no significant differences between the groups in the number of used gonadotropin ampoules (p=0.591), duration of stimulation (p=0.610), number of retrieved oocytes (p=0.802), fertilization rate (p=0.456), and the number of transferred embryos (p=0.954). The clinical pregnancy rates were statistically similar in group I (10%) compared with group II (13.3%, p=0.389). According to our results, there is no significant difference between these protocols for improving the ART outcome in poor responders. Additional prospective, randomized studies with more patients is necessary to determine the best protocol (Registration Number: IRCT201105096420N1).

ADHD-like behavior in a patient with hypothalamic hamartoma.

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Katayama, Koujyu; Yamashita, Yushiro; Yatsuga, Shuichi; Koga, Yasutoshi; Matsuishi, Toyojiro

2016-01-01

We report a male patient with hypothalamic hamartoma (HH) who manifested central precocious puberty (CPP) at 4 years of age. Gonadotropin-releasing hormone (GnRH) analogue treatment was started at 6 years of age and his pubertal signs were suppressed. At 9 years of age, the patient was emotionally unstable, aggressive, and antisocial. He had severe attention deficit hyperactivity disorder (ADHD)-like behavior and conduct disorder. No seizure activity was observed. GnRH analogue treatment was discontinued for 8 months from 9 years and 4 months of age due to his mother's illness. During this period sexual urges were observed. Treatment with daily methylphenidate markedly improved his behavioral problems. However, his sexual urges were not suppressed until 3 months after the GnRH analogue treatment was restarted. The present case is unique because the patient's behavioral problems were observed despite the parahypothalamic type of HH and absence of seizures. This case is also rare because behavioral problems were observed without seizures, and no ADHD cases with hamartoma have been reported previously. Recently, clinical studies have described an association between psychiatric morbidity, including ADHD, and hyperandrogenism disorders. Our patient's ADHD-like symptoms might be due to hyperandrogenism. In such cases, GnRH analogue with methylphenidate could be effective for improving ADHD-like symptoms. Copyright © 2015. Published by Elsevier B.V.

Effect of reproductive methods and GnRH administration on long-term protocol in Santa Ines ewes.

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Biehl, Marcos V; Ferraz Junior, Marcos V C; Ferreira, Evandro M; Polizel, Daniel M; Miszura, Alexandre A; Barroso, José P R; Oliveira, Gabriela B; Bertoloni, Analisa V; Pires, Alexandre V

2017-08-01

This study aimed to determine whether reproductive performance of ewes submitted to laparoscopic timed artificial insemination (TAI) would be similar to ante meridiem (AM)/post meridiem (PM) rule and assisted natural mating (NM), and whether GnRH may enhance the pregnancy rate in TAI. In experiment I, 191 non-lactating ewes were synchronized, then TAI was performed either 48 h after progesterone (P4) removal (TAI-48 h) or 12 h after estrus detection (AM/PM); moreover, some ewes were submitted to NM (NM) as control treatment. In experiment II, 247 non-lactating ewes were allocated in five treatments, a control (no-GnRH on protocol) and four treatments arranged in a factorial design 2 × 2. The factors were time and dose of GnRH: ewes that received either 10 μg (TAI-10 μg-36 h) or 25 μg of GnRH (TAI-25 μg-36 h) 36 h after P4 removal and ewes that received either 10 μg (TAI-10 μg-48 h) or 25 μg of GnRH (TAI-25 μg-48 h) at time of insemination, 48 h after P4 removal. In experiment I, pregnancy rate in TAI-48 h was lower (P = 0.03) than AM/PM and NM. Moreover, the probability of pregnancy in TAI-48 h was higher (P = 0.06) in ewes detected in estrus early. In experiment II, the use of GnRH in TAI protocols increased (P < 0.01) pregnancy rate at synchronization, and TAI-25 μ-48 h and TAI-10 μg-36 h treatments increased (P = 0.02) pregnancy rate compered to TAI-10 μg-48 h. We conclude that TAI decreased pregnancy rate compered to NM and AM/PM, which may be improved by GnRH use in TAI to synchronize ovulation.

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.

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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.

Cloning and functional analysis of promoters of three GnRH genes in a cichlid

International Nuclear Information System (INIS)

Kitahashi, Takashi; Sato, Hideki; Sakuma, Yasuo; Parhar, Ishwar S.

2005-01-01

Mechanisms regulating gonadotropin-releasing hormone (GnRH) types, a key molecule for reproductive physiology, remain unclear. In the present study, we cloned the promoters of GnRH1, GnRH2, and GnRH3 genes in the tilapia, Oreochromis niloticus; and found putative binding sites for glucocorticoid receptors, Sp1, C/EBP, GATA, and Oct-1, but not for androgen receptors in all three GnRH promoters using computer analysis. The presence of binding sites for progesterone receptors in GnRH1, estrogen receptors in GnRH1 and GnRH2, and thyroid hormone receptors in GnRH1 and GnRH3 suggests direct action of steroid hormones on GnRH types. Our observation of SOX and LINE-like sequences exclusively in GnRH1, COUP in GnRH2, and retinoid X receptors in GnRH3 suggests their role in sexual differentiation, midbrain segmentation, and visual cue integration, respectively. Thus, the characteristic binding sites for nuclear receptors and transcription factors support the notion that each GnRH type is regulated differently and has distinct physiological roles

GnRH neurons of young and aged female rhesus monkeys co-express GPER but are unaffected by long-term hormone replacement.

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Naugle, Michelle M; Gore, Andrea C

2014-01-01

Menopause is caused by changes in the function of the hypothalamic-pituitary-gonadal axis that controls reproduction. Hypophysiotropic gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus orchestrate the activity of this axis and are regulated by hormonal feedback loops. The mechanisms by which GnRH responds to the primary regulatory sex steroid hormone, estradiol (E2), are still poorly understood in the context of menopause. Our goal was to determine whether the G protein-coupled estrogen receptor (GPER) is co-expressed in adult primate GnRH neurons and whether this changes with aging and/or E2 treatment. We used immunofluorescence double-labeling to characterize the co-expression of GPER in GnRH perikarya and terminals in the hypothalamus. Young and aged rhesus macaques were ovariectomized and given long-term (~2-year) hormone treatments (E2, E2 + progesterone, or vehicle) selected to mimic currently prescribed hormone replacement therapies used for the alleviation of menopausal symptoms in women. We found that about half of GnRH perikarya co-expressed GPER, while only about 12% of GnRH processes and terminals in the median eminence (ME) were double-labeled. Additionally, many GPER-labeled processes were in direct contact with GnRH neurons, often wrapped around the perikarya and processes and in close proximity in the ME. These results extend prior work by showing robust co-localization of GPER in GnRH in a clinically relevant model, and they support the possibility that GPER-mediated E2 regulation of GnRH occurs both in the soma and terminals in nonhuman primates.

Sexual dimorphism of gonadotropin-releasing hormone type-III (GnRH3) neurons and hormonal sex reversal of male reproductive behavior in Mozambique tilapia.

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Kuramochi, Asami; Tsutiya, Atsuhiro; Kaneko, Toyoji; Ohtani-Kaneko, Ritsuko

2011-10-01

In tilapia, hormone treatment during the period of sexual differentiation can alter the phenotype of the gonads, indicating that endocrine factors can cause gonadal sex reversal. However, the endocrine mechanism underlying sex reversal of reproductive behaviors remains unsolved. In the present study, we detected sexual dimorphism of gonadotropin-releasing hormone type III (GnRH3) neurons in Mozambique tilapia Oreochromis mossambicus. Our immunohistochemical observations showed sex differences in the number of GnRH3 immunoreactive neurons in mature tilapia; males had a greater number of GnRH3 neurons in the terminal ganglion than females. Treatment with androgen (11-ketotestosterone (11-KT) or methyltestosterone), but not that with 17β-estradiol, increased the number of GnRH3 neurons in females to a level similar to that in males. Furthermore, male-specific nest-building behavior was induced in 70% of females treated with 11-KT within two weeks after the onset of the treatment. These results indicate androgen-dependent regulation of GnRH3 neurons and nest-building behavior, suggesting that GnRH3 is importantly involved in sex reversal of male-specific reproductive behavior.

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

Fanconi Anemia a Is a Nucleocytoplasmic Shuttling Molecule Required for Gonadotropin-Releasing Hormone (GnRH) Transduction of the GnRH Receptor

OpenAIRE

Larder, Rachel; Karali, Dimitra; Nelson, Nancy; Brown, Pamela

2006-01-01

GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common α- and hormone-specific β-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LβT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60%...

The role of GABA in the regulation of GnRH neurons

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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.

Six-month gonadotropin releasing hormone (GnRH agonist depots provide efficacy, safety, convenience, and comfort

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Phillips JM

2011-07-01

Full Text Available E David Crawford, Jason M PhillipsUniversity of Colorado Health Sciences Center, Aurora, CO, USAAbstract: Two different 6-month GnRH agonist depot formulations approved for palliative treatment of advanced and metastatic prostate cancer in the United States – leuprolide acetate 45 mg and triptorelinpalmoate 22.5 mg – provide patients with efficacy and safety comparable to those of existing 1-, 3-, and 4-month GnRH agonist depots. However, the 6-month formulations can increase patient convenience, comfort, and compliance by reducing the number of physician visits and injections required. At the conclusion of their pivotal trials, the 6-month formulations demonstrated efficacy rates in achieving chemical castration (serum testosterone #50 ng/dL that ranged between 93% and 99%. As with existing GnRH agonist depot formulations, hot flashes represented the most common adverse event reported in trials of 6-month leuprolide acetate or triptorelin. As such, these products may prove useful not only for their labeled indication, but also as adjuncts to other treatments such as radical prostatectomy, radiotherapy, and chemotherapy. We recommend further research, including head-to-head trials between the 6-month GnRH depots, to refine our understanding of these products.Keywords: prostate cancer, leuprorelin, leuprolide, triptorelin, 6-month depot, testosterone

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

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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.

Biosynthesis of gonadotropin-releasing hormone (GnRH) and GnRH receptor (GnRHR) in hypothalamic-pituitary unit of anoestrous and cyclic ewes.

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Ciechanowska, M O; Łapot, M; Mateusiak, K; Paruszewska, E; Malewski, T; Przekop, F

2017-02-01

This study was performed to explain how the molecular processes governing the biosynthesis of gonadotropin-releasing hormone (GnRH) and GnRH receptor (GnRHR) in the hypothalamic-pituitary unit are reflected by luteinizing hormone (LH) secretion in sheep during anoestrous period and during luteal and follicular phases of the oestrous cycle. Using an enzyme-linked immunosorbent assay (ELISA), we analyzed the levels of GnRH and GnRHR in preoptic area (POA), anterior (AH) and ventromedial hypothalamus (VM), stalk-median eminence (SME), and GnRHR in the anterior pituitary gland (AP). Radioimmunoassay has also been used to define changes in plasma LH concentrations. The study provides evidence that the levels of GnRH in the whole hypothalamus of anoestrous ewes were lower than that in sheep during the follicular phase of the oestrous cycle (POA: p pituitary unit, as well as LH level, in the blood in anoestrous ewes were significantly lower than those detected in animals of both cyclic groups. Our data suggest that decrease in LH secretion during the long photoperiod in sheep may be due to low translational activity of genes encoding both GnRH and GnRHR.

Gonadotropin Releasing Hormone Agonists or Antagonists for Preimplantation Genetic Diagnosis (PGD)? A Prospective Randomised Trial.

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Verpoest, Willem; De Vos, Anick; De Rycke, Martine; Parikh, Shruti; Staessen, Catherine; Tournaye, Herman; De Vos, Michel; Vloeberghs, Veerle; Blockeel, Christophe

2017-11-10

The use of GnRH analogue medication is essential in reproductive medicine to avoid premature ovulation by pituitary suppression for the duration of ovarian stimulation by gonadotrophins. The type of pituitary suppression by either GnRH agonist analogues versus GnRH antagonist analogues may result in different embryological hence clinical results. Preimplantation genetic diagnosis is a subtype of IVF in which embryos are created for genetic diagnosis of hereditary disorders in order to avoid genetically affected children. Embryological quality hence ovarian stimulation in preimplantation genetic diagnosis is crucial as genetic selection will reduce the number of available embryos to a fraction of the total. The aim of this study was to assess the efficiency of GnRH antagonist versus GnRH agonist treatment for pituitary suppression in ovarian stimulation for PGD, by proxy of number and quality of embryos at cleavage stage available for biopsy. We conducted a prospective randomised controlled trial comparing pituitary suppression by GnRH antagonist versus GnRH agonist in ovarian stimulation for PGD. The primary outcome measure was the number of embryos of sufficient quality for biopsy at cleavage stage. Secondary outcome parameters were the number of blastocysts available of top quality, and clinical pregnancy rate. There was no difference in number of oocytes retrieved, embryos at cleavage stage available for biopsy or embryo quality. The clinical pregnancy rate was higher in the GnRH agonist group; however the sample size was insufficient to allow conclusions. The use of GnRH agonist versus antagonist treatment does not result in differences in a number of oocytes, embryos or embryo quality in ovarian stimulation for preimplantation genetic diagnosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Circulating Estradiol Regulates Brain-Derived Estradiol via Actions at GnRH Receptors to Impact Memory in Ovariectomized Rats.

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Nelson, Britta S; Black, Katelyn L; Daniel, Jill M

2016-01-01

Systemic estradiol treatment enhances hippocampus-dependent memory in ovariectomized rats. Although these enhancements are traditionally thought to be due to circulating estradiol, recent data suggest these changes are brought on by hippocampus-derived estradiol, the synthesis of which depends on gonadotropin-releasing hormone (GnRH) activity. The goal of the current work is to test the hypothesis that peripheral estradiol affects hippocampus-dependent memory through brain-derived estradiol regulated via hippocampal GnRH receptor activity. In the first experiment, intracerebroventricular infusion of letrozole, which prevents the synthesis of estradiol, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory in a radial-maze task. In the second experiment, hippocampal infusion of antide, a long-lasting GnRH receptor antagonist, blocked the ability of peripheral estradiol administration in ovariectomized rats to enhance hippocampus-dependent memory. In the third experiment, hippocampal infusion of GnRH enhanced hippocampus-dependent memory, the effects of which were blocked by letrozole infusion. Results indicate that peripheral estradiol-induced enhancement of cognition is mediated by brain-derived estradiol via hippocampal GnRH receptor activity.

[Ovulation induction by pulsatile GnRH therapy in 2014: literature review and synthesis of current practice].

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Gronier, H; Peigné, M; Catteau-Jonard, S; Dewailly, D; Robin, G

2014-10-01

The hypogonadotropic hypogonadism is an easily treatable form of female infertility. The most common cause of hypogonadotropic hypogonadism is functional hypothalamic amenorrhea. The GnRH pump is a simple and effective treatment to restore fertility of patients with hypothalamic amenorrhea: cumulative pregnancy rate is estimated between 70 and 100% after 6 cycles, compared to a low rate of complications and multiple pregnancies. While only 2.8 cycles are on average required to achieve a pregnancy with a pump, this induction of ovulation stays underused in France. The objective of this paper is to propose a practical manual of pulsatile GnRH, in order to improve the accessibility of pulsatile GnRH for patients with hypogonadotropic hypogonadism. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Fanconi anemia A is a nucleocytoplasmic shuttling molecule required for gonadotropin-releasing hormone (GnRH) transduction of the GnRH receptor.

Science.gov (United States)

Larder, Rachel; Karali, Dimitra; Nelson, Nancy; Brown, Pamela

2006-12-01

GnRH binds its cognate G protein-coupled GnRH receptor (GnRHR) located on pituitary gonadotropes and drives expression of gonadotropin hormones. There are two gonadotropin hormones, comprised of a common alpha- and hormone-specific beta-subunit, which are required for gonadal function. Recently we identified that Fanconi anemia a (Fanca), a DNA damage repair gene, is differentially expressed within the LbetaT2 gonadotrope cell line in response to stimulation with GnRH. FANCA is mutated in more than 60% of cases of Fanconi anemia (FA), a rare genetically heterogeneous autosomal recessive disorder characterized by bone marrow failure, endocrine tissue cancer susceptibility, and infertility. Here we show that induction of FANCA protein is mediated by the GnRHR and that the protein constitutively adopts a nucleocytoplasmic intracellular distribution pattern. Using inhibitors to block nuclear import and export and a GnRHR antagonist, we demonstrated that GnRH induces nuclear accumulation of FANCA and green fluorescent protein (GFP)-FANCA before exporting back to the cytoplasm using the nuclear export receptor CRM1. Using FANCA point mutations that locate GFP-FANCA to the cytoplasm (H1110P) or functionally uncouple GFP-FANCA (Q1128E) from the wild-type nucleocytoplasmic distribution pattern, we demonstrated that wild-type FANCA was required for GnRH-induced activation of gonadotrope cell markers. Cotransfection of H1110P and Q1128E blocked GnRH activation of the alphaGsu and GnRHR but not the beta-subunit gene promoters. We conclude that nucleocytoplasmic shuttling of FANCA is required for GnRH transduction of the alphaGSU and GnRHR gene promoters and propose that FANCA functions as a GnRH-induced signal transducer.

GnRH injection before artificial insemination (AI) alters follicle ...

African Journals Online (AJOL)

STORAGESEVER

2009-08-04

Aug 4, 2009 ... releasing hormone (GnRH) injection on day 6 of the estrous cycle. The estrous cycles ... follicle at the time of GnRH injection (Silcox et al., 1993;. Twagiramungu .... Waves and their Effect on pregnancy rate in the Cow. Reprod.

Induction of spermatogenesis and fertility in hypogonadotropic azoospermic men by intravenous pulsatile gonadotropin-releasing hormone (GnRH).

Science.gov (United States)

Blumenfeld, Z; Makler, A; Frisch, L; Brandes, J M

1988-06-01

Gonadotropin-releasing hormone (GnRH) has only recently become a helpful tool in the medication of hypogonadotropic hypogonadism (HH). Two azoospermic patients with HH who had previously been treated with hCG/hMG because of delayed puberty and each of whom had fathered a child after previous gonadotropin therapy were referred due to secondary failure of hCG/hMG treatment to induce spermatogenesis and fertility. A pulse study where blood was drawn every 15 minutes for LH, FSH and PRL RIAs was performed in each patient, and afterwards a bolus of i.v. GnRH was injected to assess gonadotropin responsiveness. A portable GnRH pump was connected to each patient so that it administered 5-20 micrograms of GnRH i.v. every 89 minutes. Spermatogenesis was first detected after 42 and 78 days respectively in the 2 treated HH men and 4 1/2 months from the start of treatment their wives became pregnant. No thrombophlebitis or other complications of the i.v. therapy occurred. In the case of the first patient, the semen was washed and concentrated and intra-uterine inseminations were carried out in an attempt to shorten the time needed to achieve fertility. The first pregnancy was successfully terminated at 38 weeks with the delivery of 2 heterozygotic normal male babies. The second pregnancy ended in spontaneous delivery of a healthy female. We conclude that i.v. pulsatile, intermittent GnRH administration is a safe, efficient and highly successful means of treating azoospermic men with HH.

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.

GnRH mRNA levels in male three-spined sticklebacks, Gasterosteus aculeatus, under different reproductive conditions.

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Shao, Yi Ta; Tseng, Yung Che; Chang, Chia-Hao; Yan, Hong Young; Hwang, Pung Pung; Borg, Bertil

2015-02-01

In vertebrates, reproduction is regulated by the brain-pituitary-gonad (BPG) axis, where the gonadotropin-releasing hormone (GnRH) is one of the key components. However, very little is known about the possible role of GnRH in the environmental and feedback control of fish reproduction. To investigate this, full-length gnrh2 (chicken GnRH II) and gnrh3 (salmon GnRH) sequences of male three-spined sticklebacks (Gasterosteus aculeatus), which are clustered with the taxa of the same GnRH type as other Euteleostei, were cloned and annotated. gnrh1 is absent in this species. The mRNA levels of gnrh2 and gnrh3 in the sticklebacks' brain were measured under breeding and post-breeding conditions as well as in castrated and sham-operated breeding fish and castrated/sham-operated fish kept under long-day (LD 16:8) and short-day (LD 8:16) conditions. Fully breeding males had considerably higher mRNA levels of gnrh2 and gnrh3 in the thalamus (Th) and in the telencephalon and preoptic area (T+POA), respectively, than post-breeding males. Sham-operated breeding males have higher gnrh3 mRNA levels than the corresponding castrated males. Moreover, higher gnrh2 mRNA levels in the Th and higher gnrh3 mRNA levels in the T+POA and hypothalamus (HypTh) were also found in long-day sham-operated males than in sham-operated fish kept under an inhibitory short day photoperiod. Nevertheless, gnrh2 and gnrh3 mRNA levels were not up-regulated in castrated males kept under long-day photoperiod, which suggests that positive feedbacks on the brain-pituitary-gonad axis are necessary for this response. Copyright © 2014 Elsevier Inc. All rights reserved.

Inducción del desove y espermiación de anchoveta peruana Engraulis ringens (Jennyns, 1842 en cautiverio mediante la inyección de un análogo de GnRH Induction of spawning and spermiation in captive Peruvian anchovy Engraulis ringens (Jennyns using GnRH analogue injection

Directory of Open Access Journals (Sweden)

Carlos Espinoza

2010-01-01

Full Text Available Con la finalidad de obtener desoves de ejemplares de Engraulis ringens en cautiverio para realizar pruebas experimentales con huevos y larvas; el presente trabajo evaluó el efecto de inyecciones de acetato de buserelina (un análogo de GnRH; GnRHa sobre desove y espermiación. Además, se utilizó domperidona (DOM para eliminar un posible control dopaminérgico en la liberación de gonadotropinas endógenas en esta especie. Se inyectaron intraperitonealmente ejemplares maduros con 0,005 ug GnRHa g-1 pez (GnRHa; 0,005 ug GnRHa g-1 pez + 0,01 mg DOM g-1 pez (GnRHa+DOM o solución salina a 0,9% (SS. Hubo un efecto inductor de los tratamientos con GnRHa y GnRHa+DOM sobre el desove. Los desoves ocurrieron entre 24 y 48 h post-inyección (p.i. y los porcentajes totales fueron 57,3% y 20,9% con GnRHa y GnRHa+DOM respectivamente, los cuales fueron significativamente diferentes (P , siendo el porcentaje de machos expulsantes a 0 horas p.i. significativamente diferente al control (0 %> (P con GnRHa y 75,0%> con GnRHa+DOM, entre los cuales no se encontró diferencias significativas (P > 0,05. De acuerdo a los resultados obtenidos no existiría un control dopaminérgico en esta especie, ya que hubo expulsión de gametos con o sin la aplicación de domperidona. Por el contrario, se observó significativa reducción de los porcentajes de peces expulsantes al inyectar DOM.In order to achieve spawning in captive Engraulis ringens that would result in eggs and larvae for experimental assays, the present work evaluated the effect of buserelin acétate (an analogue of GnRH; GnRHa injections on spawning and spermiation. Domperidone (DOM was also used in order to reject a possible dopaminergic control in the reléase of endogenous gonadotropins for this species. Ripe fish were mjected mtraperitoneally with 0.005 ug GnRHa g-1 fish (H, 0.005 ug GnRHa g-1 fish + 0.01 mg DOM g-1 fish (HD or saline solution at 0.9%> (SS. The GnRHa and GnRHa+DOM treatments showed an

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

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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

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.

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

International Nuclear Information System (INIS)

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 α-modified Eagles medium followed by 24h in fresh medium +/- estradiol (E 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 2 (10 -11 to 10 -8 M) on 3 H-glucosamine ( 3 H-Gln) and 35 S-methionine ( 35 S-Met) incorporation into LH +/- 1 nM GnRH (4h) were investigated. GnRH (10 -9 M) and E 2 (all doses) significantly increased total 3 H-Gln LH. Moreover, E 2 at 10 -9 M and 10 -8 M significantly enhanced GnRH stimulated LH glycosylation. In contrast, addition of GnRH and/or E 2 did not significantly increase 35 S-Met incorporation into LH over a 4h period. The effects of various GnRH concentrations (10 -11 to 10 -9 M; 8h) +/- E 2 (0.05 nM) on 3 H-Gln LH and 35 S-Met LH production were also investigated. In the absence of E 2 , only 10 -9 M GnRH was effective in increasing total 3 H-Gln LH and 35 S-Met LH synthesis. However, in the presence of E 2 , all concentrations of GnRH stimulated LH synthesis with 3 H-Gln LH production responding in a dose related manner whereas 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 3 H-Gln or 35 S-Met +/- GnRH. Removal of extracellular calcium completely inhibited GnRH stimulated 3 H-Gln LH and 35 S-Met LH production

Kisspeptin Activates Ankrd 26 Gene Expression in Migrating Embryonic GnRH Neurons

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Tomoko eSoga

2016-03-01

Full Text Available Kisspeptin, a newly discovered neuropeptide regulates gonadotropin-releasing hormone (GnRH. Kisspeptins are a large RF-amide family of peptides. The kisspeptin coded by kiss1 gene is a 145-amino acid- protein that is cleaved to C-terminal peptide kisspeptin-10. G-protein coupled receptor 54 (GPR54 has been identified as a kisspeptin receptor, and it is expressed in GnRH neurons and in a variety of cancer cells. In this study, enhanced green fluorescent protein (EGFP labelled GnRH cells with migratory properties, which express GPR54, served as a model to study the effects of kisspeptin on cell migration. We monitored EGFP–GnRH neuronal migration in brain slide culture of embryonic day 14 transgenic rat by live cell imaging system and studied the effects of kisspeptin-10 (1nM treatment for 36h on GnRH migration. Furthermore to determine kisspeptin-induced molecular pathways related with apoptosis, and cytoskeletal changes during neuronal migration, we studied the expression levels of candidate genes in laser captured EGFP–GnRH neurons by real time PCR. We found that there was no change in the expression level of genes related to cell proliferation and apoptosis. The expression of ankyrin repeat domain-containing protein (ankrd 26 in EGFP–GnRH neurons was up-regulated by the exposure to kisspeptin. These studies suggest that ankrd26 gene plays an unidentified role in regulating neuronal movement mediated by kisspeptin-GPR54 signaling, which could be a potential pathway to suppress cell migration.

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

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...

Insulin analogues: have they changed insulin treatment and improved glycaemic control?

DEFF Research Database (Denmark)

Madsbad, Sten

2002-01-01

To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time-action profile most studies....... This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin...... administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting...

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

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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.

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

NARCIS (Netherlands)

Schuiling, GA; Valkhof, N; Koiter, TR

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

Responsiveness to a Physiological Regimen of GnRH Therapy and Relation to Genotype in Women With Isolated Hypogonadotropic Hypogonadism

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Abel, Brent S.; Shaw, Natalie D.; Brown, Jenifer M.; Adams, Judith M.; Alati, Teresa; Martin, Kathryn A.; Pitteloud, Nelly; Seminara, Stephanie B.; Plummer, Lacey; Pignatelli, Duarte; Crowley, William F.; Welt, Corrine K.

2013-01-01

Context: Isolated hypogonadotropic hypogonadism (IHH) is caused by defective GnRH secretion or action resulting in absent or incomplete pubertal development and infertility. Most women with IHH ovulate with physiological GnRH replacement, implicating GnRH deficiency as the etiology. However, a subset does not respond normally, suggesting the presence of defects at the pituitary or ovary. Objectives: The objective of the study was to unmask pituitary or ovarian defects in IHH women using a physiological regimen of GnRH replacement, relating these responses to genes known to cause IHH. Design, Setting, and Subjects: This study is a retrospective analysis of 37 IHH women treated with iv pulsatile GnRH (75 ng/kg per bolus). Main Outcome Measures: Serum gonadotropin and sex steroid levels were measured, and 14 genes implicated in IHH were sequenced. Results: During their first cycle of GnRH replacement, normal cycles were recreated in 60% (22 of 37) of IHH women. Thirty percent of women (12 of 37) demonstrated an attenuated gonadotropin response, indicating pituitary resistance, and 10% (3 of 37) exhibited an exaggerated FSH response, consistent with ovarian resistance. Mutations in CHD7, FGFR1, KAL1, TAC3, and TACR3 were documented in IHH women with normal cycles, whereas mutations were identified in GNRHR, PROKR2, and FGFR1 in those with pituitary resistance. Women with ovarian resistance were mutation negative. Conclusions: Although physiological replacement with GnRH recreates normal menstrual cycle dynamics in most IHH women, hypogonadotropic responses in the first week of treatment identify a subset of women with pituitary dysfunction, only some of whom have mutations in GNRHR. IHH women with hypergonadotropic responses to GnRH replacement, consistent with an additional ovarian defect, did not have mutations in genes known to cause IHH, similar to our findings in a subset of IHH men with evidence of an additional testicular defect. PMID:23341491

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

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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.

Studies on the relationship between thyroid hormones, ovarian hormones, GnRH and reproductive performance of egyptian buffaloes

International Nuclear Information System (INIS)

Farghaly, H.A.M.

1992-01-01

this study was carried out in the experimental farm of animal production department, faculty of agriculture, cairo university. hormonal analysis were performed in the laboratories of animal physiology unit, radiobiology department, nuclear research center, atomic energy authority (radiobiol. Dept., NRC, AEA). The aim of the study was to investigate the following : 1- post-partum reproductive activity of egyptian buffaloes and the factors affecting the resumption of ovarian activity after calving , with particular reference to the patterns of thyroid hormones (T 4 and T 3 ) and progesterone hormone.2- the effectiveness of using GnRH treatment on inducing ovarian activity after calving. 3- the effect of goitrogen administration (thiouracil) on ovarian activity during post-partum and on the response of buffaloes to GnRH treatment and their reproductive patterns

Knockout of the Gnrh genes in zebrafish: effects on reproduction and potential compensation by reproductive and feeding-related neuropeptides.

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Marvel, Miranda; Spicer, Olivia Smith; Wong, Ten-Tsao; Zmora, Nilli; Zohar, Yonathan

2018-04-04

Gonadotropin-releasing hormone (GnRH) is known as a pivotal upstream regulator of reproduction in vertebrates. However, reproduction is not compromised in the hypophysiotropic Gnrh3 knockout line in zebrafish (gnrh3-/-). In order to determine if Gnrh2, the only other Gnrh isoform in zebrafish brains, is compensating for the loss of Gnrh3, we generated a double Gnrh knockout zebrafish line. Surprisingly, the loss of both Gnrh isoforms resulted in no major impact on reproduction, indicating that a compensatory response, outside of the Gnrh system, was evoked. A plethora of factors acting along the reproductive hypothalamus-pituitary axis were evaluated as possible compensators based on neuroanatomical and differential gene expression studies. In addition, we also examined the involvement of feeding factors in the brain as potential compensators for Gnrh2, which has known anorexigenic effects. We found that the double knockout fish exhibited upregulation of several genes in the brain, specifically gonadotropin-inhibitory hormone (gnih), secretogranin 2 (scg2), tachykinin 3a (tac3a), and pituitary adenylate cyclase-activating peptide 1 (pacap1), and downregulation of agouti-related peptide 1 (agrp1), indicating the compensation occurs outside of Gnrh cells and therefore is a non-cell autonomous response to the loss of Gnrh. While the differential expression of gnih and agrp1 in the double knockout line was confined to the periventricular nucleus and hypothalamus, respectively, the upregulation of scg2 corresponded with a broader neuronal redistribution in the lateral hypothalamus and hindbrain. In conclusion, our results demonstrate the existence of a redundant reproductive regulatory system that comes into play when Gnrh2 and Gnrh3 are lost.

Expression of the GnRH and GnRH receptor (GnRH-R) genes in the hypothalamus and of the GnRH-R gene in the anterior pituitary gland of anestrous and luteal phase ewes.

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Ciechanowska, Magdalena; Lapot, Magdalena; Malewski, Tadeusz; Mateusiak, Krystyna; Misztal, Tomasz; Przekop, Franciszek

2008-11-01

Data exists showing that seasonal changes in the innervations of GnRH cells in the hypothalamus and functions of some neural systems affecting GnRH neurons are associated with GnRH release in ewes. Consequently, we put the question as to how the expression of GnRH gene and GnRH-R gene in the hypothalamus and GnRH-R gene in the anterior pituitary gland is reflected with LH secretion in anestrous and luteal phase ewes. Analysis of GnRH gene expression by RT-PCR in anestrous ewes indicated comparable levels of GnRH mRNA in the preoptic area, anterior and ventromedial hypothalamus. GnRH-R mRNA at different concentrations was found throughout the preoptic area, anterior and ventromedial hypothalamus, stalk/median eminence and in the anterior pituitary gland. The highest GnRH-R mRNA levels were detected in the stalk/median eminence and in the anterior pituitary gland. During the luteal phase of the estrous cycle in ewes, the levels of GnRH mRNA and GnRH-R mRNA in all structures were significantly higher than in anestrous ewes. Also LH concentrations in blood plasma of luteal phase ewes were significantly higher than those of anestrous ewes. In conclusion, results from this study suggest that low expression of the GnRH and GnRH-R genes in the hypothalamus and of the GnRH-R gene in the anterior pituitary gland, amongst others, may be responsible for a decrease in LH secretion and the anovulatory state in ewes during the long photoperiod.

GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type.

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Lambalk, C B; Banga, F R; Huirne, J A; Toftager, M; Pinborg, A; Homburg, R; van der Veen, F; van Wely, M

2017-09-01

Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist was not the only variable between the compared study arms. The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF population, women with PCOS and women with poor ovarian response. Pre-planned subgroup analyses were performed for various antagonist treatment schedules. We included 50 studies. Of these, 34 studies reported on general IVF patients, 10 studies reported on PCOS patients and 6 studies reported on poor responders. In general IVF patients, ongoing pregnancy rate was significantly lower in the antagonist group compared with the agonist group (RR 0.89, 95% CI 0.82-0.96). In women with PCOS and in women with poor ovarian response, there was no evidence of a difference in ongoing pregnancy between the antagonist and agonist groups (RR 0.97, 95% CI 0.84-1.11 and RR 0.87, 95% CI 0.65-1.17, respectively). Subgroup analyses for various antagonist treatment schedules compared to the long protocol GnRH agonist showed a significantly lower ongoing

GnRH Antagonist/Letrozole Versus Microdose GnRH Agonist Flare Protocol in Poor Responders Undergoing In Vitro Fertilization

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Robab Davar

2010-09-01

Conclusion: The addition of letrozole to the GnRH antagonist for poor responders does not improve the outcome of assisted reproductive technology cycles. The MF protocol remains the most appropriate protocol in poor responders.

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

both gonadotropins and estradiol levels become suppressed. We therefore investigated serum levels of inhibin A and inhibin B in girls with CPP at diagnosis and during treatment in order to test the hypothesis that inhibin secretion would increase and decrease in parallel with the activation......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...... and suppression of the hypothalamic-pituitary-gonadal axis. Serum levels of inhibin A and inhibin B were significantly (p 0.0005) elevated in 42 girls at diagnosis of CPP (inhibin A: 7 pg/ml (...

Medical Treatments for Endometriosis-Associated Pelvic Pain

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Gabriella Zito

2014-01-01

Full Text Available The main sequelae of endometriosis are represented by infertility and chronic pelvic pain. Chronic pelvic pain causes disability and distress with a very high economic impact. In the last decades, an impressive amount of pharmacological agents have been tested for the treatment of endometriosis-associated pelvic pain. However, only a few of these have been introduced into clinical practice. Following the results of the controlled studies available, to date, the first-line treatment for endometriosis associated pain is still represented by oral contraceptives used continuously. Progestins represent an acceptable alternative. In women with rectovaginal lesions or colorectal endometriosis, norethisterone acetate at low dosage should be preferred. GnRH analogues may be used as second-line treatment, but significant side effects should be taken into account. Nonsteroidal anti-inflammatory drugs are widely used, but there is inconclusive evidence for their efficacy in relieving endometriosis-associated pelvic pain. Other agents such as GnRH antagonist, aromatase inhibitors, immunomodulators, selective progesterone receptor modulators, and histone deacetylase inhibitors seem to be very promising, but there is not enough evidence to support their introduction into routine clinical practice. Some other agents, such as peroxisome proliferator activated receptors-γ ligands, antiangiogenic agents, and melatonin have been proven to be efficacious in animal studies, but they have not yet been tested in clinical studies.

Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice.

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Nakata, Daisuke; Masaki, Tsuneo; Tanaka, Akira; Yoshimatsu, Mie; Akinaga, Yumiko; Asada, Mari; Sasada, Reiko; Takeyama, Michiyasu; Miwa, Kazuhiro; Watanabe, Tatsuya; Kusaka, Masami

2014-01-15

TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor. The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic-pituitary-gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

Selective enhancement of main olfactory input to the medial amygdala by GnRH.

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Blake, Camille Bond; Meredith, Michael

2010-03-04

In male hamsters mating behavior is dependent on chemosensory input from the main olfactory and vomeronasal systems, whose central pathways contain cell bodies and fibers of gonadotropin-releasing hormone (GnRH) neurons. In sexually naive males, vomeronasal organ removal (VNX), but not main olfactory lesions, impairs mating behavior. Intracerebroventricular (i.c.v.)-GnRH restores mating in sexually naive VNX males and enhances medial amygdala (Me) immediate-early gene activation by chemosensory stimulation. In sexually experienced males, VNX does not impair mating and i.c.v.-GnRH suppresses Me activation. Thus, the main olfactory system is sufficient for mating in experienced-VNX males, but not in naive-VNX males. We investigated the possibility that GnRH enhances main olfactory input to the amygdala in naive-VNX males using i.c.v.-GnRH and pharmacological stimulation (bicuculline/D,L-homocysteic acid mixture) of the main olfactory bulb (MOB). In sexually naive intact males there was a robust increase of Fos protein expression in the anteroventral medial amygdala (MeAv) with MOB stimulation, but no effect of GnRH. There was no effect of stimulation or GnRH in posterodorsal medial amygdala (MePd). In naive-VNX animals, GnRH increased Fos in MeAv and MePv. Only combined MOB stimulation and i.c.v.-GnRH produced a significant increase in Fos in the dorsal (reproduction-related) portion of MeP (MePd). When the animals were sexually experienced before VNX, a condition in which GnRH does not enhance mating, i.c.v.-GnRH combined with MOB stimulation suppressed Fos expression in MePd. This suggests a more selective effect of GnRH on olfactory input in MePd than elsewhere in medial amygdala of VNX males. 2009 Elsevier B.V. All rights reserved.

A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance.

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Hoffmann, Hanne M; Mellon, Pamela L

2016-01-01

Fertility depends on the correct maturation and function of approximately 800 gonadotropin-releasing hormone (GnRH) neurons in the brain. GnRH neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates fertility. In adulthood, GnRH neurons are scattered throughout the anterior hypothalamic area and project to the median eminence, where GnRH is released into the portal vasculature to stimulate release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH then regulate gonadal steroidogenesis and gametogenesis. Absence of GnRH neurons or inappropriate GnRH release leads to infertility. Despite the critical role of GnRH neurons in fertility, we still have a limited understanding of the genes responsible for proper GnRH neuron development and function in adulthood. GnRH neurons originate in the olfactory placode then migrate into the brain. Homeodomain transcription factors expressed within GnRH neurons or along their migratory path are candidate genes for inherited infertility. Using a combined in vitro and in vivo approach, we have identified Ventral Anterior Homeobox 1 ( Vax1 ) as a novel homeodomain transcription factor responsible for GnRH neuron maturation and fertility. GnRH neuron counts in Vax1 knock-out embryos revealed Vax1 to be required for the presence of GnRH-expressing cells at embryonic day 17.5 (E17.5), but not at E13.5. To localize the effects of Vax1 on fertility, we generated Vax1 flox mice and crossed them with Gnrh cre mice to specifically delete Vax1 within GnRH neurons. GnRH staining in Vax1 flox/flox :GnRH cre mice show a total absence of GnRH expression in the adult. We performed lineage tracing in Vax1 flox/flox :GnRH cre :RosaLacZ mice which proved GnRH neurons to be alive, but incapable of expressing GnRH. The absence of GnRH leads to delayed puberty, hypogonadism and complete infertility in both sexes. Finally, using the immortalized model GnRH neuron cell lines, GN11 and

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, Barto; 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

Comparison between pulsatile GnRH therapy and gonadotropins for ovulation induction in women with both functional hypothalamic amenorrhea and polycystic ovarian morphology.

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Dumont, Agathe; Dewailly, Didier; Plouvier, Pauline; Catteau-Jonard, Sophie; Robin, Geoffroy

2016-12-01

Ovulation induction in patients having both functional hypothalamic amenorrhea (FHA) and polycystic ovarian morphology (PCOM) has been less studied in the literature. As results remain contradictory, no recommendations have yet been established. To compare pulsatile GnRH therapy versus gonadotropins for ovulation induction in "FHA-PCOM" patients and to determine if one treatment strikes as superior to the other. A 12-year retrospective study, comparing 55 "FHA-PCOM" patients, treated either with GnRH therapy (38 patients, 93 cycles) or with gonadotropins (17 patients, 53 cycles). Both groups were similar, defined by low serum LH and E2 levels, low BMI, excessive follicle number per ovary and/or high serum AMH level. Ovulation rates were significantly lower with gonadotropins (56.6% versus 78.6%, p = 0.005), with more cancellation and ovarian hyper-responses (14% versus 34% per initiated cycle, p < 0.005). Pregnancy rates were significantly higher with GnRH therapy, whether per initiated cycle (26.9% versus 7.6%, p = 0.005) or per patient (65.8% versus 23.5%, p = 0.007). In our study, GnRH therapy was more successful and safer than gonadotropins, for ovulation induction in "FHA-PCOM" patients. If results were confirmed by prospective studies, it could become a first-line treatment for this population, just as it is for FHA women without PCOM.

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

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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.

Effects of corticotropin-releasing hormone and its antagonist on the gene expression of gonadotrophin-releasing hormone (GnRH) and GnRH receptor in the hypothalamus and anterior pituitary gland of follicular phase ewes.

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Ciechanowska, Magdalena; Łapot, Magdalena; Malewski, Tadeusz; Mateusiak, Krystyna; Misztal, Tomasz; Przekop, Franciszek

2011-01-01

There is no information in the literature regarding the effect of corticotropin-releasing hormone (CRH) on genes encoding gonadotrophin-releasing hormone (GnRH) and the GnRH receptor (GnRHR) in the hypothalamus or on GnRHR gene expression in the pituitary gland in vivo. Thus, the aim of the present study was to investigate, in follicular phase ewes, the effects of prolonged, intermittent infusion of small doses of CRH or its antagonist (α-helical CRH 9-41; CRH-A) into the third cerebral ventricle on GnRH mRNA and GnRHR mRNA levels in the hypothalamo-pituitary unit and on LH secretion. Stimulation or inhibition of CRH receptors significantly decreased or increased GnRH gene expression in the hypothalamus, respectively, and led to different responses in GnRHR gene expression in discrete hypothalamic areas. For example, CRH increased GnRHR gene expression in the preoptic area, but decreased it in the hypothalamus/stalk median eminence and in the anterior pituitary gland. In addition, CRH decreased LH secretion. Blockade of CRH receptors had the opposite effect on GnRHR gene expression. The results suggest that activation of CRH receptors in the hypothalamus of follicular phase ewes can modulate the biosynthesis and release of GnRH through complex changes in the expression of GnRH and GnRHR genes in the hypothalamo-anterior pituitary unit. © CSIRO 2011 Open Access

Prospective, randomized comparison between pulsatile GnRH therapy and combined gonadotropin (FSH+LH) treatment for ovulation induction in women with hypothalamic amenorrhea and underlying polycystic ovary syndrome.

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Dubourdieu, Sophie; Fréour, Thomas; Dessolle, Lionel; Barrière, Paul

2013-05-01

To compare the efficacy of pulsatile GnRH therapy versus combined gonadotropins for ovulation induction in women with both hypothalamic amenorrhoea and polycystic ovarian syndrome (HA/PCOS) according to their current hypothalamic status. This single-centre, prospective, randomized study was conducted in the Nantes University Hospital, France. Thirty consecutive patients were treated for ovulation induction with either pulsatile GnRH therapy or combined gonadotropins (rFSH+rLH). Frequency of adequate ovarian response (mono- or bi-follicular) and clinical pregnancy rate were then compared between both groups. Ovarian response was similar in both groups with comparable frequency of adequate ovarian response (73% vs 60%), but the clinical pregnancy rate was significantly higher in the pulsatile GnRH therapy group than in the combined gonadotropin group (46% vs 0%). HA/PCOS is a specific subgroup of infertile women. Pulsatile GnRH therapy is an effective and safe method of ovulation induction that can be used successfully in these patients. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Biphasic action of cyclic adenosine 3',5'- monophosphate in gonadotropin-releasing hormone (GnRH) analog-stimulated hormone release from GH3 cells stably transfected with GnRH receptor complementary deoxyribonucleic acid.

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Stanislaus, D; Arora, V; Awara, W M; Conn, P M

1996-03-01

GH3 cells are a PRL-secreting adenoma cell line derived from pituitary lactotropes. These cells have been stably transfected with rat GnRH receptor complementary DNA to produce four cell lines: GGH(3)1', GGH(3)2', GGH(3)6', and GGH(3)12'. In response to either GnRH or Buserelin (a metabolically stable GnRH agonist), these cell lines synthesize PRL in a cAMP-dependent manner. Only GGH(3)6' cells desensitize in response to persistent treatment with 10(-7) g/ml Buserelin. GGH(3)1', GGH(3)2', and GGH(3)12' cells, however, can be made refractory to Buserelin stimulation by raising cAMP levels either by the addition of (Bu)2cAMP to the medium or by treatment with cholera toxin. In GGH(3) cells, low levels of cAMP fulfill the requirements for a second messenger, whereas higher levels appear to mediate the development of desensitization. The observation that in GGH(3)6' cells, cAMP production persists after the onset of desensitization is consistent with the view that the mechanism responsible for desensitization is distal to the production of cAMP. Moreover, the absence of any significant difference in the amount of cAMP produced per cell in GGH(3)2', GGH(3)6', or GGH(3)12' cells suggests that elevated cAMP production per cell does not explain the development of desensitization in GGH(3)6' cells. We suggest that Buserelin-stimulated PRL synthesis in GGH(3)6' cells is mediated by a different cAMP-dependent protein kinase pool(s) than that in nondesensitizing GGH(3) cells. Such a protein kinase A pool(s) may be more susceptible to degradation via cAMP-mediated mechanisms than the protein kinase pools mediating the Buserelin response in nondesensitizing GGH(3) cells. A similar mechanism has been reported in other systems.

Inhibition of RM-1 prostate carcinoma and eliciting robust immune responses in the mouse model by using VEGF-M2-GnRH3-hinge-MVP vaccine.

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Wang, Yiqin; Alahdal, Murad; Ye, Jia; Jing, Liangliang; Liu, Xiaoxin; Chen, Huan; Jin, Liang; Cao, Rongyue

2018-01-23

GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.

Comparison of GnRh Agonist Microdose Flare Up and GnRh Antagonist/Letrozole in Treatment of Poor Responder Patients in Intra Cytoplaspic Sperm Injection: Randomized Clinical Trial.

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Nabati, Azar; Peivandi, Sepideh; Khalilian, Alireza; Mirzaeirad, Sina; Hashemi, Seyyed Abbas

2015-08-06

the prevalence of infertility is up to 10 to 15 % which 9 to 24 % of them are Poor Ovarian Responders (POR). This study was designed to compare two methods of GnRH Agonist Microdose Flareup (MF) and GnRH Antagonist/Letrozole (AL) in treatment of these patients. this randomized clinical trial study consisted of 123 patients. In the first step of treatment in both methods FSH, LH, estradiol, anderostandion, testestron in third day of menstruation period and the thickness of endometrium by Transvaginal sonography were evaluated. At the time of HCG injection the thickness of endometrium and follicles which were more than 14mm ware established and hormones were evaluated. Two weeks later serum βhCG and after 6 to 8 weeks Transvaginal sonography were applied to prove the pregnancy. there were 61 patients with mean age of 38.7±4.58 in MF group and 62 patients with mean age of 38.5±4.6 in AL group (P=0.80). At the time of hCG injection there were significant increase in the level of LH,estradiol, thickness of endometrium and follicles more than 14mm in MF patients (P<0.0001). The mean time of ovary stimulation in MF group was 10.72±1.5 and in AL was 8.45±1.2 (P<0.0001). The mean level of gonadotropin which were used was 80.6±20.1 in MF patients and 64.7±16.4 in AL group (P<0.0001). 18 % of MF group and 38.7% in AL group had no normal cycle of ovulation (OR: 2.87, 95% CI: 1.25-6.57, P=0.011). The mean numbers of oocyte and normal fetus in MF was 5.83±3.5 and 3.7±2.5 and in AL was 3±1.69 and 1.4±1.33 (P<0.0001). The number of chemical pregnancy in MF group was 10 (16.4%) and in AL was 3 (4.8%) (OR:3.85, 95%CI:1.06-14.77, P=0.037). Clinical pregnancy in 10 patients (16.4%) of MF group and 3 (4.8%)in AL was reported. OR: 3.85, 95%CI: 1.06-14.77, P=0.037). this study showed that MF method of pregnancy leads to more positive results in pregnancy based on chemical and clinical evaluation in comparison with AL and is advised for poor responder patients.

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats.

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Yan, Xiaonan; Yuan, Chun; Zhao, Nannan; Cui, Yugui; Liu, Jiayin

2014-07-01

In adolescent girls with polycystic ovary syndrome (PCOS), neuroendocrine derangements manifest after the onset of puberty, characterized by rapid LH pulse frequency. The early mechanism underlying the pubertal regulation of the GNRH/LH pulsatile release in adolescents with PCOS remains uncertain. To determine the effects of prenatal androgen exposure on the activation of GNRH neurons and generation of LH pulse at puberty, we administrated 5α-dihydrotestosterone to pregnant rats and observed serum LH levels and expression of hypothalamic genes in female offspring from postnatal 4 to 8 weeks. The 6-week-old prenatally androgenized (PNA) female rats exhibited an increase in LH pulse frequency. The hypothalamic expression of neurokinin B (Nkb (Tac2)) and Lepr mRNA levels in PNA rats increased remarkably before puberty and remained high during puberty, whereas elevated Kiss1 mRNA levels were detected only after the onset of puberty. Exogenous kisspeptin, NK3R agonist, and leptin triggered tonic stimulation of GNRH neurons and increased LH secretion in 6-week-old PNA rats. Leptin upregulated Kiss1 mRNA levels in the hypothalamus of pubertal PNA rats; however, pretreatment with a kisspeptin antagonist failed to suppress the elevated serum LH stimulated by leptin, indicating that the stimulatory effects of leptin may be conveyed indirectly to GNRH neurons via other neural components within the GNRH neuronal network, rather than through the kisspeptin-GPR54 pathway. These findings validate the hypotheses that NKB and leptin play an essential role in the activation of GNRH neurons and initiation of increased LH pulse frequency in PNA female rats at puberty and that kisspeptin may coordinate their stimulatory effects on LH release. © 2014 Society for Endocrinology.

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

Microdose flare-up vs. flexible-multidose GnRH antagonist protocols for poor responder patients who underwent ICSI.

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Esinler, I

2014-01-01

To compare the performance of microdose flare-up (MF) and flexible-multidose gonadotropin-releasing hormone (GnRH) antagonist protocols in poor responder patients who underwent intracytoplasmic sperm injection (ICSI). One hundred and 12 consecutive patients (217 cycles) suspected to have poor ovarian response were enrolled. Group 1 (MF GnRH agonist group) constituted 64 patients (135 cycles) who underwent MF GnRH agonist protocol. Group 2 (flexible-multidose GnRH antagonist group) constituted 48 patients (82 cycles) who underwent flexible-multidose GnRH antagonist protocol. The duration of stimulation (d) (11.5 +/- 2.1 vs. 10.4 +/- 2.7, p or = seven blastomeres and < 10% fragmentation at day 3 (35.9% vs. 65.1%, p < 0.05) were significantly lower in Group 1 when compared to Group 2. The number of embryos transferred (2.2 +/- 1.3 vs. 2.4 +/- 0.9), the clinical pregnancy per embryo transfer (16.3% vs. 25.8%), and the implantation rate (8.6% vs. 12.2%) were comparable between groups. Although the flexible-multidose GnRH antagonist protocol produced better oocyte and embryo parameters, the clinical pregnancy rate and the implantation rates were comparable between the flexible-multidose GnRH antagonist and MF protocols in poor responder patients.

Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist

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Al Humaidan, Peter Samir Heskjær; Bungum, L; Bungum, M

2006-01-01

Previous studies found a poor clinical outcome when a GnRH agonist (GnRHa) was used to trigger ovulation in GnRH antagonist IVF/ICSI cycles. This study aimed to determine the clinical and endocrine effects as well the optimal timing of HCG supplementation. Forty-five normogonadotrophic IVF/ICSI p......RHa supplemented with 1500 IU HCG 35 h later (group 3) seems to secure a normal luteal phase and a normal clinical pregnancy outcome....

GnRH Neuron Activity and Pituitary Response in Estradiol-Induced vs Proestrous Luteinizing Hormone Surges in Female Mice.

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Silveira, Marina A; Burger, Laura L; DeFazio, R Anthony; Wagenmaker, Elizabeth R; Moenter, Suzanne M

2017-02-01

During the female reproductive cycle, estradiol exerts negative and positive feedback at both the central level to alter gonadotropin-releasing hormone (GnRH) release and at the pituitary to affect response to GnRH. Many studies of the neurobiologic mechanisms underlying estradiol feedback have been done on ovariectomized, estradiol-replaced (OVX+E) mice. In this model, GnRH neuron activity depends on estradiol and time of day, increasing in estradiol-treated mice in the late afternoon, coincident with a daily luteinizing hormone (LH) surge. Amplitude of this surge appears lower than in proestrous mice, perhaps because other ovarian factors are not replaced. We hypothesized GnRH neuron activity is greater during the proestrous-preovulatory surge than the estradiol-induced surge. GnRH neuron activity was monitored by extracellular recordings from fluorescently tagged GnRH neurons in brain slices in the late afternoon from diestrous, proestrous, and OVX+E mice. Mean GnRH neuron firing rate was low on diestrus; firing rate was similarly increased in proestrous and OVX+E mice. Bursts of action potentials have been associated with hormone release in neuroendocrine systems. Examination of the patterning of action potentials revealed a shift toward longer burst duration in proestrous mice, whereas intervals between spikes were shorter in OVX+E mice. LH response to an early afternoon injection of GnRH was greater in proestrous than diestrous or OVX+E mice. These observations suggest the lower LH surge amplitude observed in the OVX+E model is likely not attributable to altered mean GnRH neuron activity, but because of reduced pituitary sensitivity, subtle shifts in action potential pattern, and/or excitation-secretion coupling in GnRH neurons. Copyright © 2017 by the Endocrine Society.

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

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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.

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.

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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

THE USE OF GnRH ANTAGONISTS IN OVARIAN STIMULATION FOR INTRAUTERINE INSEMINATION

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Mete Işıkoğlu

2013-12-01

Full Text Available The first paper entitled intrauterine insemination (IUI was published in 1962. By time, several methods involving the technique and the ovulation induction schedules have evolved in order to improve the success rates. Although gonadotrophin releasing hormone antagonists (GnRHa is a crucial part of assisted reproductive treatments now, concerns also arouse regarding the need for the use of it in IUI cycles. These drugs may be considered in IUI programs basically in order to prevent premature LH surges and related cycle cancellations. Although administration of a GnRH antagonist almost completely abolishes premature luteinization, it does not substantially improve the pregnancy rate. The decision of using GnRH antagonists in IUI cycles should be based primarily on the local cost/benefit analysis of individual centers. It will be prudent to limit the involvement of the antagonists in ovulation induction protocols to: patients who frequently exhibit premature LH discharges and therefore either fail to complete treatment or result in unsuccessful outcome; initiated cycles intented for IUI but converted to ART; if it is not possible for logistic reasons (weekend to perform the insemination or for medical centers in which a gynecologist on call is not available and in order to decrease clinical task burden resulting from strict cycle monitoring such as serial transvaginal sonography and/or frequent urine tests.

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

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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.

Glucosensing by GnRH Neurons: Inhibition by Androgens and Involvement of AMP-Activated Protein Kinase

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Roland, Alison V.

2011-01-01

GnRH neurons integrate steroidal and metabolic cues to regulate fertility centrally. Central glucoprivation reduces LH secretion, which is governed by GnRH release, suggesting GnRH neuron activity is modulated by glucose availability. Here we tested whether GnRH neurons can sense changes in extracellular glucose, and whether glucosensing is altered by the steroids dihydrotestosterone (DHT) and/or estradiol (E). Extracellular recordings were made from GnRH neurons in brain slices from ovariectomized (OVX) mice ± DHT and/or E implants. Firing rate was reduced by a switch from 4.5 to 0.2 mm glucose in cells from OVX, OVX+E, and OVX+DHT+E mice, but not OVX+DHT mice. This suggests that androgens reduce the sensitivity of GnRH neurons to changes in extracellular glucose, but E mitigates this effect. Next we investigated potential mechanisms. In the presence of the ATP-sensitive potassium channel antagonist tolbutamide, glucosensing persisted. In contrast, glucosensing was attenuated in the presence of compound C, an antagonist of AMP-activated protein kinase (AMPK), suggesting a role for AMPK in glucosensing. The AMPK activator N1-(b-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide (AICAR) mimicked the effect of low glucose and was less effective in cells from DHT-treated mice. The effect of DHT to diminish responses to low glucose and AICAR was abolished by blockade of fast synaptic transmission. Both AICAR and low glucose activated a current with a reversal potential near −50 mV, suggesting a nonspecific cation current. These studies indicate that glucosensing is one mechanism by which GnRH neurons sense fuel availability and point to a novel role for AMPK in the central regulation of fertility. PMID:21393446

Dynamic GnRH and hCG testing

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

2017-01-01

OBJECTIVE: Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) stimulation tests may be used to evaluate the pituitary and testicular capacity. Our aim was to evaluate changes in follicular-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone after Gn...... influence of the tests was illustrated by results from 45 patients suspected of disordered hypothalamic-pituitary-gonadal axis. 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. RESULTS......: For the reference group, LH and FSH increased almost 400% and 40% during GnRH testing, stimulated levels varied from 4.4 to 58.8 U/L and 0.2 to 11.8 U/L and FSH decreased in nine men. Testosterone increased approximately 110% (range: 18.7-67.6 nmol/L) during hCG testing. None of the polymorphisms had any major...

Morphological and Physiological Interactions Between GnRH3 and Hypocretin/Orexin Neuronal Systems in Zebrafish (Danio rerio).

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Zhao, Yali; Singh, Chanpreet; Prober, David A; Wayne, Nancy L

2016-10-01

GnRH neurons integrate internal and external cues to control sexual maturation and fertility. Homeostasis of energy balance and food intake correlates strongly with the status of reproduction. Neuropeptides secreted by the hypothalamus involved in modulating energy balance and feeding may play additional roles in the regulation of reproduction. Hypocretin (Hcrt) (also known as orexin) is one such peptide, primarily controlling sleep/wakefulness, food intake, and reward processing. There is a growing body of evidence indicating that Hcrt/orexin (Hcrt) modulates reproduction through interacting with the hypothalamo-pituitary-gonadal axis in mammals. To explore potential morphological and functional interactions between the GnRH and Hcrt neuronal systems, we employed a variety of experimental approaches including confocal imaging, immunohistochemistry, and electrophysiology in transgenic zebrafish, in which fluorescent proteins are genetically expressed in GnRH3 and Hcrt neurons. Our imaging data revealed close apposition and direct connection between GnRH3 and Hcrt neuronal systems in the hypothalamus during larval development through adulthood. Furthermore, the Hcrt receptor (HcrtR) is expressed in GnRH3 neurons. Electrophysiological data revealed a reversible inhibitory effect of Hcrt on GnRH3 neuron electrical activity, which was blocked by the HcrtR antagonist almorexant. In addition, Hcrt had no effect on the electrical activity of GnRH3 neurons in the HcrtR null mutant zebrafish (HcrtR -/- ). Our findings demonstrate a close anatomical and functional relationship between Hcrt and GnRH neuronal systems in zebrafish. It is the first demonstration of a link between neuronal circuits controlling sleeping/arousal/feeding and reproduction in zebrafish, an important animal model for investigating the molecular genetics of development.

Social Crowding during Development Causes Changes in GnRH1 DNA Methylation.

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Alvarado, Sebastian G; Lenkov, Kapa; Williams, Blake; Fernald, Russell D

2015-01-01

Gestational and developmental cues have important consequences for long-term health, behavior and adaptation to the environment. In addition, social stressors cause plastic molecular changes in the brain that underlie unique behavioral phenotypes that also modulate fitness. In the adult African cichlid, Astatotilapia burtoni, growth and social status of males are both directly regulated by social interactions in a dynamic social environment, which causes a suite of plastic changes in circuits, cells and gene transcription in the brain. We hypothesized that a possible mechanism underlying some molecular changes might be DNA methylation, a reversible modification made to cytosine nucleotides that is known to regulate gene function. Here we asked whether changes in DNA methylation of the GnRH1 gene, the central regulator of the reproductive axis, were altered during development of A. burtoni. We measured changes in methylation state of the GnRH1 gene during normal development and following the gestational and developmental stress of social crowding. We found differential DNA methylation within developing juveniles between 14-, 28- and 42-day-old. Following gestational crowding of mouth brooding mothers, we saw differential methylation and transcription of GnRH1 in their offspring. Taken together, our data provides evidence for social control of GnRH1 developmental responses to gestational cues through DNA methylation.

Effects of GnRH vaccination in wild and captive African Elephant bulls (Loxodonta africana on reproductive organs and semen quality.

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Imke Lueders

Full Text Available Although the African elephant (Loxodonta africana is classified as endangered by the International Union for Conservation of Nature (IUCN, in some isolated habitats in southern Africa, contraception is of major interest due to local overpopulation. GnRH vaccination has been promoted as a non-invasive contraceptive measure for population management of overabundant wildlife. We tested the efficacy of this treatment for fertility control in elephant bulls.In total, 17 male African elephants that were treated with a GnRH vaccine were examined in two groups. In the prospective study group 1 (n = 11 bulls, ages: 8-36 years, semen quality, the testes, seminal vesicles, ampullae and prostate, which were all measured by means of transrectal ultrasound, and faecal androgen metabolite concentrations were monitored over a three-year period. Each bull in the prospective study received 5 ml of Improvac® (1000 μg GnRH conjugate intramuscularly after the first examination, followed by a booster six weeks later and thereafter every 5-7 months. In a retrospective study group (group 2, n = 6, ages: 19-33 years, one examination was performed on bulls which had been treated with GnRH vaccine for 5-11 years.In all bulls of group 1, testicular and accessory sex gland sizes decreased significantly after the third vaccination. In six males examined prior to vaccination and again after more than five vaccinations, the testis size was reduced by 57.5%. Mean testicular height and length decreased from 13.3 ± 2.6 cm x 15.2 ± 2.8 cm at the beginning to 7.6 ± 2.1 cm x 10.2 ± 1.8 cm at the end of the study. Post pubertal bulls (>9 years, n = 6 examined prior to vaccination produced ejaculates with viable spermatozoa (volume: 8-175 ml, sperm concentration: 410-4000x106/ml, total motility: 0-90%, while after 5-8 injections, only 50% of these bulls produced ejaculates with a small number of immotile spermatozoa. The ejaculates of group 2 bulls (vaccinated >8 times were

GnRH dysregulation in polycystic ovarian syndrome (PCOS) is a manifestation of an altered neurotransmitter profile.

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Chaudhari, Nirja; Dawalbhakta, Mitali; Nampoothiri, Laxmipriya

2018-04-11

GnRH is the master molecule of reproduction that is influenced by several intrinsic and extrinsic factors such as neurotransmitters and neuropeptides. Any alteration in these regulatory loops may result in reproductive-endocrine dysfunction such as the polycystic ovarian syndrome (PCOS). Although low dopaminergic tone has been associated with PCOS, the role of neurotransmitters in PCOS remains unknown. The present study was therefore aimed at understanding the status of GnRH regulatory neurotransmitters to decipher the neuroendocrine pathology in PCOS. PCOS was induced in rats by oral administration of letrozole (aromatase inhibitor). Following PCOS validation, animals were assessed for gonadotropin levels and their mRNA expression. Neurotrasnmitter status was evaluated by estimating their levels, their metabolism and their receptor expression in hypothalamus, pituitary, hippocampus and frontal cortex of PCOS rat model. We demonstrate that GnRH and LH inhibitory neurotransmitters - serotonin, dopamine, GABA and acetylcholine - are reduced while glutamate, a major stimulator of GnRH and LH release, is increased in the PCOS condition. Concomitant changes were observed for neurotransmitter metabolising enzymes and their receptors as well. Our results reveal that increased GnRH and LH pulsatility in PCOS condition likely result from the cumulative effect of altered GnRH stimulatory and inhibitory neurotransmitters in hypothalamic-pituitary centre. This, we hypothesise, is responsible for the depression and anxiety-like mood disorders commonly seen in PCOS women.

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

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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.

Effects of metformin on body weight in patients with type 2 diabetes mellitus,receiving insulin analogue treatment

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T I Romantsova

2013-03-01

Full Text Available Aims. To study the dynamics of body weight, waist circumference, blood lipid and insulin demand in patients with type 2 diabetes mellitus (T2DM during first year of combined treatment with metformin and insulin analogues, compared with insulin analogue monotherapy.Materials and Methods. We examined 78 patients with T2DM on newly initiated insulin therapy, including 54 females and 24 males. Median age was 56 [51.0; 64.0] years, median disease duration – 9 [6.8;14.0] years. Participants were subdivided in two groups. First group was comprised of 48 subjects (33 females and 15 males, who received monotherapy with insulin analogues (glargine, de- temir, biphasic Aspart 30 and Humalog Mix 25 or rapid-acting lispro and aspart. Second group included 30 patients (18 females and12 males, who were treated with combined therapy (insulin analogues plus metformin. We measured HbA1c, plasma lipid composition, BMI, waist circumference and insulin demand initially and after one year of follow-up.Results. We showed that combined therapy vs. insulin monotherapy allows better glycemic compensation while reducing insulin demand and lowering risks for weight gain.Conclusions. Combined insulin analogue plus metformin treatment delivers better metabolic control in patients with T2DM and is as- sociated with lower risks for body weight gain and increase in insulin demand against monotherapy with insulin analogues.

Effects of metformin on body weight in patients with type 2 diabetes mellitus,receiving insulin analogue treatment

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Tatiana Ivanovna Romantsova

2013-03-01

Full Text Available Aims. To study the dynamics of body weight, waist circumference, blood lipid and insulin demand in patients with type 2 diabetes mellitus (T2DM during first year of combined treatment with metformin and insulin analogues, compared with insulin analogue monotherapy. Materials and Methods. We examined 78 patients with T2DM on newly initiated insulin therapy, including 54 females and 24 males. Median age was 56 [51.0; 64.0] years, median disease duration ? 9 [6.8;14.0] years. Participants were subdivided in two groups. First group was comprised of 48 subjects (33 females and 15 males, who received monotherapy with insulin analogues (glargine, de- temir, biphasic Aspart 30 and Humalog Mix 25 or rapid-acting lispro and aspart. Second group included 30 patients (18 females and12 males, who were treated with combined therapy (insulin analogues plus metformin. We measured HbA1c, plasma lipid composition, BMI, waist circumference and insulin demand initially and after one year of follow-up. Results. We showed that combined therapy vs. insulin monotherapy allows better glycemic compensation while reducing insulin demand and lowering risks for weight gain. Conclusions. Combined insulin analogue plus metformin treatment delivers better metabolic control in patients with T2DM and is as- sociated with lower risks for body weight gain and increase in insulin demand against monotherapy with insulin analogues.

Neuroregulatory and neuroendocrine GnRH pathways in the hypothalamus and forebrain of the baboon.

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Marshall, P E; Goldsmith, P C

1980-07-14

The distribution of neurons containing gonadotropin-releasing hormone (GnRH) in the baboon hypothalamus and forebrain was studied immunocytochemically by light and electron microscopy. GnRH was present in the perikarya, axonal and dendritic processes of immunoreactive neurons. Three populations of GnRH neurons could be distinguished. Most of the GnRH neurons which are assumed to directly influence the anterior pituitary were in the medial basal hypothalamus. Other cells that projected to the median eminence were found scattered throughout the hypothalamus. A second, larger population of neurons apparently was not involved with control of the anterior pituitary. These neurons were generally found within afferent and efferent pathways of the hypothalamus and forebrain, and may receive external information affecting reproduction. A few neurons projecting to the median eminence were also observed sending collaterals to other brain areas. Thus, in addition to their neuroendocrine role, these cells possibly have neuroregulatory functions. The inference is made that these bifunctional neurons, together with the widely observed GnRH-GnRH cellular interactions may help to synchronize ovulation and sexual behavior.

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.

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.

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

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

2004-01-01

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...

In vitro evidence of glucose-induced toxicity in GnRH secreting neurons: high glucose concentrations influence GnRH secretion, impair cell viability, and induce apoptosis in the GT1-1 neuronal cell line.

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Pal, Lubna; Chu, Hsiao-Pai; Shu, Jun; Topalli, Ilir; Santoro, Nanette; Karkanias, George

2007-10-01

To evaluate for direct toxic effects of high glucose concentrations on cellular physiology in GnRH secreting immortalized GT1-1 neurons. Prospective experimental design. In vitro experimental model using a cell culture system. GT1-1 cells were cultured in replicates in media with two different glucose concentrations (450 mg/dL and 100 mg/dL, respectively) for varying time intervals (24, 48, and 72 hours). Effects of glucose concentrations on GnRH secretion by the GT1-1 neurons were evaluated using a static culture model. Cell viability, cellular apoptosis, and cell cycle events in GT1-1 neurons maintained in two different glucose concentrations were assessed by flow cytometry (fluorescence-activated cell sorter) using Annexin V-PI staining. Adverse influences of high glucose concentrations on GnRH secretion and cell viability were noted in cultures maintained in high glucose concentration (450 mg/dL) culture medium for varying time intervals. A significantly higher percentage of cells maintained in high glucose concentration medium demonstrated evidence of apoptosis by a fluorescence-activated cell sorter. We provide in vitro evidence of glucose-induced cellular toxicity in GnRH secreting GT1-1 neurons. Significant alterations in GnRH secretion, reduced cell viability, and a higher percentage of apoptotic cells were observed in GT1-1 cells maintained in high (450 mg/dL) compared with low (100 mg/dL) glucose concentration culture medium.

A single sample GnRHa stimulation test in the diagnosis of precocious puberty

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Gonadotropin-releasing hormone (GnRH) has been the standard test for diagnosing central precocious puberty. Because GnRH is no longer available, GnRH analogues (GnRHa) are now used. Random LH concentration, measured by the third-generation immunochemiluminometric assay, is a useful screening tool ...

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

Effect of three methods of estrus synchronization: Osynch, Co-Synch and Prostaglandin on the fertility of subfertile dairy cows

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habib cheraghi

2015-02-01

Full Text Available This study was performed to compare the effect of using 3 different estrus synchronization methods (Ovsynch, Co-Synch and Prostaglandin on the conception rate of subfertile dairy cows. Fifty one subfertile Holstein dairy cows with parity ranging from 1 to 7 were enrolled in this study. Cows were allocated to three groups Ovsynch (n=10, Co-Synch (n=27 and Prostaglandin (n=14. Cows in the Ovsynch group underwent a standard Ovsynch protocol (GnRH analogue on Day 0, PGF2α analogue on Day 7 and GnRH analogue on Day 9, then they were artificially inseminated approximately 16 hours after the second GnRH treatment. The same procedure was done for cows in Co-Synch group, but artificial insemination took place immediately after the last injection. Cows in prostaglandin group underwent a PG protocol (PGF2α, on Day 0 and 12, and artificial insemination was done about 72 hours after the second PGF2α injection. Pregnancy diagnosis was performed 60 days after insemination via rectal examination. By using logistic procedure of SAS 9.1 software, the effects of treatment, season, parity, animal, age and open days were analyzed. The analysis of variables related to animal and the measured effects on pregnancy proved that none of the evaluated parameters were significant. Hence, we cannot declare which of the estrus synchronization methods is suitable to increase pregnancy rate. Further studies with more replicates are required to choose the best method.

The effect of intracerebroventricular injection of L-glutamate on the hypothalamic GnRH content in rat

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Fu Qiang; He Haoming

2001-01-01

Objective: To investigate the effect of intracerebroventricular injection of L-Glutamate (L-Glu) on hypothalamic gonadotrophin-releasing hormone (GnRH) content in male rats. Methods: The GnRH content in the supernatant of hypothalamic homogenates was measured by RIA. Results: The mean values of hypothalamic GnRH content in rat were 1.59 +- 0.41, 0.88 +- 0.34, 0.70 +- 0.42 ng/10mg wet tissue 40 min after intracerebroventricular injection of 0.01176, 0.1176, 1.176 μg/20 μl L-Glu respectively, which were significantly lower than those in controls with saline injections (P 3 H-Glu in rat at 40 min the author found that the intake of 3 H-glu by MBH was 1069.82 +- 490.33 cpm/10 mg wet tissues, the highest value among those taken by cerebrum, cerebellum, pituitary, POA and MBH itself. Conclusion: L-Glu probably participates in the regulation of functional activity of GnRH neurons in the hypothalamus

GnRH-agonist versus GnRH-antagonist IVF cycles

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Papanikolaou, E G; Pados, G; Grimbizis, G

2012-01-01

In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist...

GnRH antagonist versus long agonist protocols in IVF

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Lambalk, C B; Banga, F R; Huirne, J A

2017-01-01

BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH...... in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF...

Identification and characterization of a reptilian GnRH receptor from the leopard gecko.

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Ikemoto, T; Enomoto, M; Park, M K

2004-02-12

Gonadotropin-releasing hormone (GnRH) plays a pivotal role in the regulation of reproductive functions through interactions with its specific receptor. We describe the first molecular cloning and characterization of a full-length GnRH receptor (GnRHR) from the leopard gecko Eublepharis macularius. It has a distinct genomic structure consisting of five exons and four introns, compared with all the other reported GnRHR genes. A native GnRH form, cGnRH-II, stimulated inositol phosphate (IP) production in COS-7 cells transiently transfected with the GnRHR, in a dose dependent manner. The mRNA was expressed in all the tissues and organs examined. Molecular phylogenetic analysis revealed that the cloned GnRHR belongs to the type 2/nonmammalian I GnRHR. Low-expression levels were observed from the pituitary glands of reproductively active leopard geckos, indicating the possibility that there is at least one more type of GnRHR highly expressed in the pituitary gland for the gonadotropin secretion in this reptile.

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

NARCIS (Netherlands)

Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein; Vestergaard, Peter; Starup-Linde, Jakob; Bazelier, Marloes T; De Bruin, Marie L; de Boer, Anthonius; Siezen, Christine L E; van de Water, Bob; van der Laan, Jan Willem; Schmidt, Marjanka K

2015-01-01

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A

The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea.

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Christou, Fotini; Pitteloud, Nelly; Gomez, Fulgencio

2017-08-01

The induction of ovulation by the means of a pump which assures the pulsatile administration of GnRH is a well-known method that applies to women suffering from amenorrhea of hypothalamic origin. Although a simple and efficient method to establish fertility, it is underused. Twelve patients suffering from this condition, 1 Kallmann syndrome, 4 normosmic isolated hypogonadotropic hypogonadism, and 7 functional hypothalamic amenorrhea desiring pregnancy were treated. They underwent one or more cycles of pulsatile GnRH, at a frequency of 90 minutes, either by the intravenous or the subcutaneous route. An initial dose of 5 μg per pulse in the intravenous route was administered and of 15 μg per pulse in the subcutaneous route. The treatment was monitored by regular dosing of gonadotropins, estradiol and progesterone, and the development of follicles and ovulation was monitored by intra-vaginal ultrasonography. All the patients had documented ovulation, after a mean of 17 days on pump stimulation. Single ovulation occurred in 30 of 33 treatment cycles, irrespective of the route of administration. Ovulation resulted in 10 pregnancies over 7 patients (2 pregnancies in 3 of them), distributed in the 3 diagnostic categories. For comparison, a patient with PCOS treated similarly, disclosed premature LH surge without ovulation.

GnRH Neurons on LSD: A Year of Rejecting Hypotheses That May Have Made Karl Popper Proud.

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Moenter, Suzanne M

2018-01-01

Gonadotropin-releasing hormone (GnRH) neurons are critical to many aspects of fertility regulation, from producing episodic release critical to both sexes, to providing a central signal to induce the ovulatory cascade in females. This year saw progress through the rejection, and occasional support, of hypotheses in understanding how GnRH neurons contribute to these processes. This brief review provides one laboratory's view of new insights into possible roles for these cells in development, adult reproductive function, and what may go wrong with GnRH neurons in some cases of infertility. Copyright © 2018 Endocrine Society.

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

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Juul, A; Müller, J; Skakkebaek, N E

1997-01-01

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....

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

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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.

Pregnancy outcome in delayed start antagonist versus microdose flare GnRH agonist protocol in poor responders undergoing IVF/ICSI: An RCT

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Robab Davar

2018-04-01

Full Text Available Background: Over the years, many article on different aspects of pathogenesis and management of poor ovarian responders have been published but there is no clear guideline for treating themyet. Objective: This study was designated to compare the effectiveness of a delayed start protocol with gonadotropin-releasing hormone (GnRH antagonist and microdose flare-up GnRH agonist protocol in poor ovarian responders. Materials and Methods: This randomized clinical trial consisted of 100 poor ovarian responder women in assisted reproductive technologies cycles. They were divided randomly in delayed-start antagonist protocol (with estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation and microdose flare-up GnRH agonist protocol. The main outcome was clinical pregnancy rate and second outcome was the number of retrieved oocytes, mature oocytes, 2PN number, fertilization rate, and implantation rate. Results: Fertilization rate, clinical pregnancy rate, and ongoing pregnancy rates were not significantly different between the two studied protocols. Number of retrieved oocytes (5.10±3.41 vs. 3.08±2.51 with p=0.002, mature oocytes (4.32±2.69 vs. 2.34±1.80 with p=0.003, number of 2PN (3.94±1.80 vs. 2.20±1.01 with p=0.001 and implantation rate (19.40% vs. 10.30% with p=0.022 were significantly higher in delayed antagonist group. Conclusion: The delayed-start protocol can improve ovarian response in poor responders by stimulating and synchronizing follicle development

Differential roles of PKC isoforms (PKCs) in GnRH stimulation of MAPK phosphorylation in gonadotrope derived cells.

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Mugami, Shany; Dobkin-Bekman, Masha; Rahamim-Ben Navi, Liat; Naor, Zvi

2018-03-05

The role of protein kinase C (PKC) isoforms (PKCs) in GnRH-stimulated MAPK [ERK1/2, JNK1/2 and p38) phosphorylation was examined in gonadotrope derived cells. GnRH induced a protracted activation of ERK1/2 and a slower and more transient activation of JNK1/2 and p38MAPK. Gonadotropes express conventional PKCα and PKCβII, novel PKCδ, PKCε and PKCθ, and atypical PKC-ι/λ. The use of green fluorescent protein (GFP)-PKCs constructs revealed that GnRH induced rapid translocation of PKCα and PKCβII to the plasma membrane, followed by their redistribution to the cytosol. PKCδ and PKCε localized to the cytoplasm and Golgi, followed by the rapid redistribution by GnRH of PKCδ to the perinuclear zone and of PKCε to the plasma membrane. The use of dominant negatives for PKCs and peptide inhibitors for the receptors for activated C kinase (RACKs) has revealed differential role for PKCα, PKCβII, PKCδ and PKCε in ERK1/2, JNK1/2 and p38MAPK phosphorylation in a ligand-and cell context-dependent manner. The paradoxical findings that PKCs activated by GnRH and PMA play a differential role in MAPKs phosphorylation may be explained by persistent vs. transient redistribution of selected PKCs or redistribution of a given PKC to the perinuclear zone vs. the plasma membrane. Thus, we have identified the PKCs involved in GnRH stimulated MAPKs phosphorylation in gonadotrope derived cells. Once activated, the MAPKs will mediate the transcription of the gonadotropin subunits and GnRH receptor genes. Copyright © 2017. Published by Elsevier B.V.

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

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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

Developmental expression of the G protein-coupled receptor 54 and three GnRH mRNAs in the teleost fish cobia.

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Mohamed, J Shaik; Benninghoff, Abby D; Holt, G Joan; Khan, Izhar A

2007-02-01

The cDNAs of the G protein-coupled receptor 54 (GPR54) and three prepro-gonadotropin-releasing hormones, GnRH-I (seabream GnRH), GnRH-II (chicken GnRH-II), and GnRH-III (salmon GnRH) were isolated and cloned from the brain of the teleost fish cobia, Rachycentron canadum. The cobia GPR54 cDNA was 95 and 51-56% identical to those of tilapia and mammalian models respectively. The GnRH cDNA sequences of cobia showed strong identities to those of tilapia, Atlantic croaker, red drum, and the seabass and seabream species. The real-time quantitative RT-PCR methods allowed detection of all three GnRH mRNAs on the first day after hatching (DAH). The GnRH-I mRNA levels, which were the lowest among the three GnRHs, increased gradually with two distinct peaks in larvae at 3 and 4 DAH. On the other hand, GnRH-II and GnRH-III mRNAs were significantly higher in larvae at 2 and 6 DAH compared with those on the preceding days. In addition, significant peaks of all the three GnRH mRNAs were observed in the brains of 26-day-old fish. The finding of higher GnRH-I and GnRH-II mRNAs in males than females at 153 DAH may be related to early puberty observed during the first year in laboratory-reared male cobia. Moreover, this study demonstrates for the first time the expression of GPR54 mRNA during larval development in a vertebrate species. The concomitant expression patterns of GPR54 and GnRH mRNAs during different stages of larval and juvenile developments, and during early puberty in male cobia suggest a potential relationship between GPR54 and multiple GnRHs during these stages of development consistent with the role of GPR54 in controlling GnRH release in mammals. The increase in GPR54 and GnRH mRNAs observed during early puberty in cobia is consistent with a similar change reported in pubertal rats. This finding together with the localization of GPR54 mRNAs on GnRH neurons in fish and mammals suggests that the GPR54-GnRH interactions may be conserved in different vertebrate groups.

Genetic variation in total number and locations of GnRH neurons identified using in situ hybridization in a wild-source population.

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Kaugars, Katherine E; Rivers, Charlotte I; Saha, Margaret S; Heideman, Paul D

2016-02-01

The evolution of brain function in the regulation of physiology may depend in part upon the numbers and locations of neurons. Wild populations of rodents contain natural genetic variation in the inhibition of reproduction by winter-like short photoperiod, and it has been hypothesized that this functional variation might be due in part to heritable variation in the numbers or location of gonadotropin releasing hormone (GnRH) neurons. A naturally variable wild-source population of white-footed mice was used to develop lines artificially selected for or against mature gonads in short, winter-like photoperiods. We compared a selection line that is reproductively inhibited in short photoperiod (Responsive) to a line that is weakly inhibited by short photoperiod (Nonresponsive) for differences in counts of neurons identified using in situ hybridization for GnRH mRNA. There was no effect of photoperiod, but there were 60% more GnRH neurons in total in the Nonresponsive selection line than the Responsive selection line. The lines differed specifically in numbers of GnRH neurons in more anterior regions, whereas numbers of GnRH neurons in posterior areas were not statistically different between lines. We compare these results to those of an earlier study that used immunohistochemical labeling for GnRH neurons. The results are consistent with the hypothesis that the selection lines and natural source population contain significant genetic variation in the number and location of GnRH neurons. The variation in GnRH neurons may contribute to functional variation in fertility that occurs in short photoperiods in the laboratory and in the wild source population in winter. © 2015 Wiley Periodicals, Inc.

Long-term effects of GnRH agonists on fertility and behaviour

DEFF Research Database (Denmark)

Goericke-Pesch, Sandra Kathrin

2017-01-01

; a significant positive effect in reducing sexual behaviour and libido, hypersexuality, intermale dominance and excessive territorial urine marking has been described. Rates of improvement of the respective behaviour are comparable to those after surgical castration, making GnRH A-SRI a valuable option...... and behaviour have by now been shown to be fully reversible. Knowledge in females is more limited, and particularly, the initial induction of a possibly fertile oestrus and individual variation in duration of efficacy remain problems in bitches and queens treated for suppression of fertility. However, long......-term suppression of oestrous cycle and fertility seems to be possible with induced effects shown to be reversible including restoration of normal fertility after the end of efficacy/GNRH A-SRI removal....

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

DEFF Research Database (Denmark)

Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein

2015-01-01

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD......: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due...

Differential co-localization with choline acetyltransferase in nervus terminalis suggests functional differences for GnRH isoforms in bonnethead sharks (Sphyrna tiburo).

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Moeller, John F; Meredith, Michael

2010-12-17

The nervus terminalis (NT) is a vertebrate cranial nerve whose function in adults is unknown. In bonnethead sharks, the nerve is anatomically independent of the olfactory system, with two major cell populations within one or more ganglia along its exposed length. Most cells are immunoreactive for either gonadotropin-releasing hormone (GnRH) or RF-amide-like peptides. To define further the cell populations and connectivity, we used double-label immunocytochemistry with antisera to different isoforms of GnRH and to choline acetyltransferase (ChAT). The labeling patterns of two GnRH antisera revealed different populations of GnRH-immunoreactive (ir) cell profiles in the NT ganglion. One antiserum labeled a large group of cells and fibers, which likely contain mammalian GnRH (GnRH-I) as described in previous studies and which were ChAT immunoreactive. The other antiserum labeled large club-like structures, which were anuclear, and a sparse number of fibers, but with no clear labeling of cell bodies in the ganglion. These club structures were choline acetyltrasferase (ChAT)-negative, and preabsorption control tests suggest they may contain chicken-GnRH-II (GnRH-II) or dogfish GnRH. The second major NT ganglion cell-type was immunoreactive for RF-amides, which regulate GnRH release in other vertebrates, and may provide an intraganglionic influence on GnRH release. The immunocytochemical and anatomical differences between the two GnRH-immunoreactive profile types indicate possible functional differences for these isoforms in the NT. The club-like structures may be sites of GnRH release into the general circulation since these structures were observed near blood vessels and resembled structures seen in the median eminence of rats. Copyright © 2010 Elsevier B.V. All rights reserved.

Effect of endotoxin on the expression of GnRH and GnRHR genes in the hypothalamus and anterior pituitary gland of anestrous ewes.

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Herman, Andrzej Przemysław; Tomaszewska-Zaremba, Dorota

2010-07-01

An immune/inflammatory challenge can affect reproduction at the level of the hypothalamus, pituitary gland, or gonads. Nonetheless, the major impact is thought to occur within the brain or the pituitary gland. The present study was designed to examine the effect of intravenous (i.v.) lipopolysaccharide (LPS) injection on the expression of gonadotropin-releasing hormone (GnRH) and the gonadotropin-releasing hormone receptor (GnRHR) genes in the hypothalamic structures where GnRH neurons are located as well as in the anterior pituitary gland (AP) of anestrous ewes. We also determined the effect of LPS on luteinizing hormone (LH) release. It was found that i.v. LPS injection significantly decreased GnRH and GnRHR mRNAs levels in the preoptic area (40%, ppituitary cells to GnRH stimulation. The presence of GnRH mRNA in the median eminence, the hypothalamic structure where GnRH-ergic neurons' terminals are located, suggests that the axonal transport of GnRH mRNA may occur in these neurons. This phenomenon could play an important role in the physiology of GnRH neurons. Our data demonstrate that immune stress could be important inhibitor of this process. Copyright 2010 Elsevier B.V. All rights reserved.

Extracellular signal-regulated kinase 1 and 2 are not required for GnRH neuron development and normal female reproductive axis function in mice.

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Wierman, Margaret E; Xu, Mei; Pierce, A; Bliesner, B; Bliss, S P; Roberson, M S

2012-01-01

Selective deletion of extracellular signal-regulated kinase (ERK) 1 and ERK2 in the pituitary gonadotrope and ovarian granulosa cells disrupts female reproductive axis function. Thus, we asked if ERK1 and ERK2 are critical for GnRH neuron ontogeny or the central control of female reproductive function. GnRH-Cre-recombinase (Cre+) expressing mice were crossed with mice with a global deletion of ERK1 and a floxed ERK2 allele (Erk1-/Erk2fl/fl) to selectively delete ERK2 in GnRH neurons. Cre-recombinase mRNA was selectively expressed in the brain of Cre+ mice. GnRH neuron number and location were determined during embryogenesis and in the adult. GnRH neuron counts at E15 did not differ between experimental and control groups (1,198 ± 65 and 1,160 ± 80 respectively, p = NS). In adults, numbers of GnRH neurons in the GnRHCre+Erk1-/Erk2- mice (741 ± 157) were similar to those in controls (756 ± 7), without alteration in their distribution across the forebrain. ERK1 and 2 deficiency did not alter the timing of vaginal opening, age at first estrus, or estrous cyclicity. Although ERK1 and 2 are components of a dominant signaling pathway in GnRH neuronal cells that modulates survival and control of GnRH gene expression, other signaling pathways compensate for their deletion in vivo to allow GnRH neuron survival and targeting and normal onset of female sexual maturation and reproductive function. In contrast to effects at the pituitary and the ovary, ERK1 and ERK2 are dispensable at the level of the GnRH neuron. Copyright © 2011 S. Karger AG, Basel.

Single and repeated GnRH agonist stimulation tests compared with basal markers of ovarian reserve in the prediction of outcome in IVF

NARCIS (Netherlands)

Hendriks, D.J.; Broekmans, F.J.M.; Bancsi, L.F.J.M.M.; Looman, C.W.N.; Jong, F.H. de; Velde, E.R. te

Purpose: To study the value of a single or repeated GnRH agonist stimulation test (GAST) in predicting outcome in IVF compared to basal ovarian reserve tests. Methods: A total of 57 women was included. In a cycle prior to the IVF treatment, on day 3, an antral follicle count (AFC) was performed

Application of autoclaving-cooling cycling treatment to improve resistant starch content of corn-based rice analogues

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Hidayat, B.; Muslihudin, M.; Akmal, S.

2018-01-01

Resistant starch is one important component determining the characteristics of a functional food. The aim of the research was to determine the cooling time optimum in the autoclaving-cooling treatment to increase the resistance starch content corn-based rice analogues, with 6 level of cooling time (0 hours/control, 12 hours, 24 hours, 36 hours, 48 hours and 60 hours). The results showed that cooling at 4°C for 60 hours would increase the resistant starch content (6.27% to 15.38%), dietary fiber content (14.53% to 20.17%); and decrease the digestible starch content (61.81% to 52.70%). Cooling time level at 4°C for 24 hours, would increase the sensory score of corn-based rice analogues then back down until cooling time level of 60 hours. Microscopic analysis of granular structure using SEM indicated that cooling time had a linear correlation with cracks intensity on the granule surface of the corn-based rice analogues. The high content of resistant starch showed that the application of cooling time level at 4°C for 24 hours would improve the functional properties of corn-based rice analogues with sensory characteristics remain favorable to panelists.

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

Emerging treatment of endometriosis

Directory of Open Access Journals (Sweden)

Aboubakr Elnashar

2015-06-01

Full Text Available Current treatment of endometriosis is mainly based on surgery and ovarian suppressive agents (oral contraceptives, progestins, GnRh agonist and androgenic agents. Hormonal treatments are often associated with unwanted effects, delayed conception and recurrence of disease and symptoms when stopped. For these reasons, new drugs that aim new targets are required to cause regression of the disease & symptoms without adverse hypo-estrogenic effects. This review aims to provide an update on the new drugs used for treatment of endometriosis. These include the levonorgestrel-releasing intrauterine device, GnRH antagonists, aromatase inhibitors, selective estrogen-receptor modulators, progesterone antagonist, selective progesterone receptor modulators, angiogenesis inhibitors, and immunomodulatory drugs.

[EFECTOS NEUROENDOCRINOS DE INSULINA, IGF-I Y LEPTINA SOBRE LA SECRECIÓN DE HORMONA LIBERADORA DE GONADOTROPINAS (GnRH

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Ana Maria Rosales-Torres

2011-10-01

Full Text Available El balance energético del individuo determina en gran medida su eficiencia reproductiva. Bajo condiciones de balance negativo de energía, en la mayoría de los mamíferos, hay una reducción en la síntesis de hormona liberadora de gonadotropinas (GnRH, lo cual disminuye la actividad del eje hipotálamo-hipófisis-gónadas. Cuando el balance energético es revertido, el hipotálamo puede monitorear este cambio y restablecer la secreción de GnRH. La Insulina, el Factor de Crecimiento similar a la Insulina I (IGF-I y Leptina parecen ser los principales mensajeros que informan al hipotálamo sobre el estado energético del animal puesto que las concentraciones periféricas de estas hormonas en situaciones energéticas negativas o positivas, se han asociado con los cambios en la secreción de GnRH. En la presente revisión se muestra como IGF-I actúa directamente sobre neuronas secretoras de GnRH, afectando su síntesis, en tanto que insulina y leptina actúan sobre neuronas en el núcleo arcuato, las cuales hacen sinapsis con neuronas GnRH en el área preóptica medial. Sobre neuronas productoras de neuropéptido Y (NPY insulina y leptina reducen su expresión y por lo tanto el efecto negativo del NPY sobre neuronas GnRH. En cambio insulina y leptina estimulan la síntesis de péptido similar a la galanina (GLAP y propiomelanocortina (POMC. Tanto GALP como los metabolitos de POMC (hormona estimulante de melanocitos principalmente incrementan la síntesis de GnRH. Finalmente, la leptina, incrementa la expresión de kispeptina en neuronas del núcleo ARC. Kispeptina por su parte también tiene un efecto positivo sobre la síntesis y secreción de GnRH.

Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.

Science.gov (United States)

Praseetha, Sugathan; Bandaru, Srinivas; Nayarisseri, Anuraj; Sureshkumar, Sivanpillai

2016-01-01

Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy.

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

Genomic structure and promoter functional analysis of GnRH3 gene in large yellow croaker (Larimichthys crocea).

Science.gov (United States)

Huang, Wei; Zhang, Jianshe; Liao, Zhi; Lv, Zhenming; Wu, Huifei; Zhu, Aiyi; Wu, Changwen

2016-01-15

Gonadotropin-releasing hormone III (GnRH3) is considered to be a key neurohormone in fish reproduction control. In the present study, the cDNA and genomic sequences of GnRH3 were cloned and characterized from large yellow croaker Larimichthys crocea. The cDNA encoded a protein of 99 amino acids with four functional motifs. The full-length genome sequence was composed of 3797 nucleotides, including four exons and three introns. Higher identities of amino acid sequences and conserved exon-intron organizations were found between LcGnRH3 and other GnRH3 genes. In addition, some special features of the sequences were detected in partial species. For example, two specific residues (V and A) were found in the family Sciaenidae, and the unique 75-72 bp type of the open reading frame 2 and 3 existed in the family Cyprinidae. Analysis of the 2576 bp promoter fragment of LcGnRH3 showed a number of transcription factor binding sites, such as AP1, CREB, GATA-1, HSF, FOXA2, and FOXL1. Promoter functional analysis using an EGFP reporter fusion in zebrafish larvae presented positive signals in the brain, including the olfactory region, the terminal nerve ganglion, the telencephalon, and the hypothalamus. The expression pattern was generally consistent with the endogenous GnRH3 GFP-expressing transgenic zebrafish lines, but the details were different. These results indicate that the structure and function of LcGnRH3 are generally similar to the other teleost GnRH3 genes, but there exist some distinctions among them. Copyright © 2015 Elsevier B.V. All rights reserved.

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

Science.gov (United States)

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.

The use of Goserelin in the management of endometriosis | Moodley ...

African Journals Online (AJOL)

Zoladex (Goserelin acetate implant) contains a synthetic decapeptide analogue of luteinising hormone releasing (GnRH) agonist analogue. Zoladex is designed for subcutaneous injection (sterile biodegradable product equivalent to 3.6mg Goserelin) ...

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.

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction.

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Wu, Min; Dumalska, Iryna; Morozova, Elena; van den Pol, Anthony; Alreja, Meenakshi

2009-10-06

A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba(2+)-sensitive K(+) channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.

Reproductive physiology of a humanized GnRH receptor mouse model: application in evaluation of human-specific analogs.

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Tello, Javier A; Kohout, Trudy; Pineda, Rafael; Maki, Richard A; Scott Struthers, R; Millar, Robert P

2013-07-01

The human GnRH receptor (GNRHR1) has a specific set of properties with physiological and pharmacological influences not appropriately modeled in laboratory animals or cell-based systems. To address this deficiency, we have generated human GNRHR1 knock-in mice and described their reproductive phenotype. Measurement of pituitary GNRHR1 transcripts from homozygous human GNRHR1 knock-in (ki/ki) mice revealed a severe reduction (7- to 8-fold) compared with the mouse Gnrhr1 in wild-type mice. ¹²⁵I-GnRH binding assays on pituitary membrane fractions corroborated reduced human GNRHR1 protein expression in ki/ki mice, as occurs with transfection of human GNRHR1 in cell lines. Female homozygous knock-in mice displayed normal pubertal onset, indicating that a large reduction in GNRHR1 expression is sufficient for this process. However, ki/ki females exhibited periods of prolonged estrous and/or metestrous and reduced fertility. No impairment was found in reproductive maturity or adult fertility in male ki/ki mice. Interestingly, the serum LH response to GnRH challenge was reduced in both knock-in males and females, indicating a reduced GNRHR1 signaling capacity. Small molecules targeting human GPCRs usually have poor activities at homologous rodent receptors, thus limiting their use in preclinical development. Therefore, we tested a human-specific GnRH1 antagonist, NBI-42902, in our mouse model and demonstrated abrogation of a GnRH1-induced serum LH rise in ki/ki mice and an absence of effect in littermates expressing the wild-type murine receptor. This novel model provides the opportunity to study the human receptor in vivo and for screening the activity of human-specific GnRH analogs.

A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomised placebo-controlled trial.

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Jacob, S L; Brewer, C; Tang, T; Picton, H M; Barth, J H; Balen, A H

2016-12-01

Does 'metformin' reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for women with polycystic ovary syndrome (PCOS) undergoing a GnRH antagonist assisted conception treatment cycle? A short course of metformin does not reduce the incidence of OHSS for women with PCOS undergoing a GnRH antagonist treatment cycle. Metformin does reduce the incidence of OHSS in a GnRH-agonist treatment cycle. A randomised placebo-controlled trial (RCT) using metformin or placebo. Randomisation was blinded to both patient and investigator, using a random permuted blocks method with a 50:50 allocation ratio. The study was completed over 5 years (2009-2014) with 153 randomised patients. A sample size calculation based on the incidence of OHSS was completed prospectively suggesting a minimum of 146 recruits was required for the trial with a power of 80% and a type 1 error of 0.05. All patients met the Rotterdam criteria for PCOS and were treated with a standard GnRH antagonist IVF/ICSI treatment cycle in a tertiary infertility clinic. The study medication was started prior to stimulation and continued to oocyte retrieval. Of the 153 patients, 77 received metformin and 76 placebo. There was no reduction in the incidence of moderate-severe OHSS (Placebo (PLA) 12.2%, metformin (MET) = 16%, 95% CI -0.08-0.16, P = 0.66). There was no difference in total gonadotrophin dose (PLA = 1200, MET = 1200, 95% CI -118.67-118.67, P = 0.75), oocytes retrieved (PLA = 15, MET = 14, 95% CI -2.37-4.37, P = 0.66) or fertilisation rate (PLA = 60.7%, MET = 53.3%, 95% CI -0.96-14.94, P = 0.07). However, using metformin resulted in a reduced clinical pregnancy rate (CPR) per cycle started (PLA = 48.7%, MET = 28.6%, 95% CI 0.04-0.35, P = 0.02) and live birth rate (PLA = 51.6%, MET = 27.6%, 95% CI 0.05-0.40, P = 0.02). Furthermore, when ethnicity was taken into account there was a significant reduction in pregnancy outcome for the South Asian population irrespective of metformin or

[Revelation of a polymicrocystic ovary syndrome after one month's treatment by pulsatile GnRH in a patient presenting with functional hypothalamic amenorrhea].

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Reyss, A C; Merlen, E; Demerle, C; Dewailly, D

2003-12-01

Polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA) are the most frequent causes of endocrine infertility, but their association is an uncommon occurrence. We report the case of a 28-year old woman suffering from infertility and amenorrhea. Her weight was normal (BMI = 19) and she had no hirsutism. She self-reported food restriction and a 10 kg weight loss 5 years ago, concomitant with the onset of amenorrhea. At the initial evaluation, the patient was considered as having HA due to food restriction. At ultrasonography, ovaries were small and multifollicular (right and left area: 2.2 and 2.5 cm(2), respectively; number of cysts 2-9 mm in diameter: 15 and 12, respectively), and no stromal hypertrophy was noted. She has been treated for 1 month by intravenous pulsatile GnRH administration. Although the doses were increased from 5 to 15 microg/pulse every 90 min, no E2 response and no follicular development were observed. Hormonal re-evaluation revealed normal levels of serum LH, FSH and androgens, and a normal LH/FSH ratio. However, a typical aspect of PCO was found at ultrasound (right and left area: 6.5 and 5.5 cm(2), respectively, and more than 15 small cysts arranged peripherally around an increased central stroma in each ovary). The treatment has been then switched to hMG, using the low dose step-up regimen and starting with 75 U/day. In the absence of response after 2 weeks, the dose was increased to 112.5 U/day and a multifollicular reaction occurred, leading to cancellation. In conclusion, we hypothesize that this patient had a "hidden" PCOS when she was hypogonadotrophic and that it developed very rapidly after restitution of a normal gonadotropin level under exogenous GnRH. This occurred despite a low insulin level, showing that hyperinsulinism is not a prerequisite for the development of PCOS in every case.

Use of a GnRH antagonist in controlled ovarian hyperstimulation for assisted conception in women with polycystic ovary disease: a randomized, prospective, pilot study.

Science.gov (United States)

Bahçeci, Mustafa; Ulug, Ulun; Ben-Shlomo, Izhar; Erden, Halit Firat; Akman, Mehmet Ali

2005-02-01

To compare the outcome of using gonadotropin-releasing hormone (GnRH) antagonists versus agonists in women with polycystic ovary disease (PCOD) who underwent controlled ovarian hyperstimulation (COH) for assisted reproductive techniques (ART). A total of 129 patients with PCOD were randomly allocated to undergo COH with a GnRH antagonist (59 patients) and GnRH agonist (leuprolide acetate) (70 patients) to prevent a premature luteinizing hormone (LH) surge. Assisted fertilization following oocyte retrieval and embryo transfer was performed. None of the cycles were cancelled due to a premature LH surge. There was no significant difference between the antagonist and agonist arms in the number of gonadotropin ampules consumed per cycle. However, in the antagonist arm a shorter duration of ovarian stimulation was recorded as compared to the agonist arm. Although similar numbers of oocytes was retrieved from both groups of patients, the quality of the oocytes, as measured by metaphase 2/total oocyte ratio, was lower in the antagonist arm as compared to the agonist arm. Pregnancy rates were 57.6% and 58.5% in the antagonist and agonist arms, respectively (p > 0.05). Implantation rates were not different (34.0% and 34.6%, respectively). The frequency of ovarian hyperstimulation syndrome also did not differ between the treatment groups (5% and 7.1%, respectively). The size of our study, on a specific subgroup of patients, does not allow a reliable conclusion regarding ART outcomefollowing the use of a GnRH antagonist versus agonist. Nevertheless, the protocol with the antagonist gave results that were as good as those of the protocol with the agonist in this PCOD patient population.

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

Science.gov (United States)

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

Analogue Gravity

Directory of Open Access Journals (Sweden)

Carlos Barceló

2011-05-01

Full Text Available Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity.

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.

Degarelix 240/80 mg: a new treatment option for patients with advanced prostate cancer

DEFF Research Database (Denmark)

Boccon-Gibod, L.; Iversen, P.; Persson, B.E.

2009-01-01

Gonadotrophin-releasing hormone (GnRH) receptor blockers (antagonists) are the latest addition to the hormonal therapy armamentarium for patients with prostate cancer. In contrast to the GnRH agonists, GnRH blockers have an immediate onset of action and do not cause an initial surge in testosterone...... levels that can lead to clinical flare in patients with advanced disease. Degarelix (Firmagon is a new GnRH blocker that has recently been approved by the EMEA and US FDA for the treatment of men with hormone-sensitive advanced prostate cancer. In this article, we briefly review the Phase III trial data...

Gonadotropin releasing hormone agonists: Expanding vistas

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Navneet Magon

2011-01-01

Full Text Available Gonadotropin-releasing hormone (GnRH agonists are derived from native GnRH by amino acid substitution which yields the agonist resistant to degradation and increases its half-life. The hypogonadotropic hypogonadal state produced by GnRH agonists has been often dubbed as "pseudomenopause" or "medical oophorectomy," which are both misnomers. GnRH analogues (GnRH-a work by temporarily "switching off" the ovaries. Ovaries can be "switched off" for the therapy and therapeutic trial of many conditions which include but are not limited to subfertility, endometriosis, adenomyosis, uterine leiomyomas, precocious puberty, premenstrual dysphoric disorder, chronic pelvic pain, or the prevention of menstrual bleeding in special clinical situations. Rapidly expanding vistas of usage of GnRH agonists encompass use in sex reassignment of male to female transsexuals, management of final height in cases of congenital adrenal hyperplasia, and preserving ovarian function in women undergoing cytotoxic chemotherapy. Hypogonadic side effects caused by the use of GnRH agonists can be tackled with use of "add-back" therapy. Goserelin, leuprolide, and nafarelin are commonly used in clinical practice. GnRH-a have provided us a powerful therapeutic approach to the treatment of numerous conditions in reproductive medicine. Recent synthesis of GnRH antagonists with a better tolerability profile may open new avenues for both research and clinical applications. All stakeholders who are partners in women′s healthcare need to join hands to spread awareness so that these drugs can be used to realize their full potential.

The Effect of a GnRH Agonist Injection or Progesterone Implant at Diestrus in Cryopreserved Embryo Transferred Cows

OpenAIRE

KIRBAŞ, Mesut; BÜLBÜL, Bülent; KÖSE, Mehmet; DURSUN, Şükrü; ÇOLAK, Mehmet

2014-01-01

In this study, the effect of a single dose of GnRH on d 13 or progesterone implant for 7 days between d 13 and 20 on plasma progesterone levels and pregnancy rates on cryopreserved embryo transferred cows were investigated. Synchronized 48 Brown Swiss recipient cows were used as animal material. Seven days after estrus detection, cryopreserved cattle embryos were transferred into recipients and cows were assigned randomly into three groups. In GnRH group (n=16), cows were intramuscularly inje...

Hormonal responses to GnRH injection given at different stages of ...

African Journals Online (AJOL)

USER

2010-04-05

Apr 5, 2010 ... In conclusion, the results presented here indicate that. GnRH given at the beginning (days 5 to 7) or at the end. (days 15 to 17) of the estrous cycle did not alter the profile of progesterone and estradiol concentration in water buffaloes as previously described in cattle (Kohram et al., 1998a, b). REFERENCES.

COMPARISON BETWEEN ESTRADIOL CYPIONATE AND GONADOTROPIN RELEASING HORMONE AS OVULATION SYNCHRONIZATION TREATMENTS FOR FIXED-TIME ARTIFICIAL INSEMINATION PROGRAMS IN BRAHMAN-CROSS HEIFERS IN A SUBTROPICAL REGION OF NORTHEASTERN MEXICO

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Miguel Angel Dominguez

2012-12-01

Full Text Available Synchronization protocols with intravaginal progesterone releasing devices (CIDR and PGF2α were evaluated, with GnRH or estradiol cypionate (ECP added for fixed-time artificial insemination (FTAI in five counties in Tamaulipas, Mexico. Brahman-cross heifers (≥15 months old were selected based on body condition (≥3 on a 5-point scale and confirmed ovarian activity. The six treatments (n = 320 each were: T1 (9-d CIDR, ECP on insertion, PGF2α on day 9, ECP on day 10, FTAI 54 h after removal; T2 (7-d CIDR, ECP on insertion, PGF2α on day 7, ECP on day 8, FTAI 54 h after removal; T3 (7-d CIDR, GnRH on insertion, PGF2α on day 7, FTAI and GnRH 48 h after removal; T4 (7-d CIDR, GnRH on insertion, PGF2α on day 6, FTAI and GnRH 48 h after removal; T5 (7-d CIDR, GnRH on insertion, PGF2α on day 7, FTAI and GnRH 60 h after removal; and T6 (7-d CIDR, GnRH on insertion, PGF2α on day 7, FTAI alone 48 h after removal. Pregnancy was diagnosed ultrasonically 45 days after FTAI. Analyses included pregnancy rates and treatment costs (hormones and handling. Pregnancy rates ranged from 31.6 ± 3.9 to 48.0 ± 10.6%; neither treatment nor county affected these rates (p > 0.05. In conclusion, the inclusion of treatment costs showed two more economical treatments (T2 using estradiol or T3 using GnRH under the nutritional, weather and handling conditions present in the tropical region of southeastern Tamaulipas.

Analogue Gravity

Directory of Open Access Journals (Sweden)

Barceló Carlos

2005-12-01

Full Text Available Analogue models of (and for gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity.

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

In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestrus by a timed, stimulatory signal originating from the circadian clock in the suprachiasmatic nucleus (SCN). The present studies explored whether kisspeptin is part of the essential neural circuit...... 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...... of ovulatory control with interactions among the circadian system, kisspeptin signaling, and a GnRH gating mechanism of control....

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

Hormone treatment of gender identity disorder in a cohort of children and adolescents.

Science.gov (United States)

Hewitt, Jacqueline K; Paul, Campbell; Kasiannan, Porpavai; Grover, Sonia R; Newman, Louise K; Warne, Garry L

2012-05-21

To describe the experience of hormone treatment of gender identity disorder (GID) in children and adolescents within a specialist clinic. Cohort study by medical record review of children aged 0-17 years referred during 2003-2011 for management at the GID clinic in a tertiary paediatric referral centre - the Royal Children's Hospital, Melbourne, Victoria. Clinical characteristics of the patient population, hormone treatment provided, frequency of referrals with time. Thirty-nine children and adolescents were referred for gender dysphoria. Seventeen individuals were pubertal with persistent GID, and were considered eligible for hormone treatment. Seven patients, comprising three biological males and four biological females, had legally endorsed hormone treatment. In this group, gender dysphoria was first noted at 3-6 years of age. Hormone treatment with GnRH analogue to suppress pubertal progression (phase 1) was given at 10-16 years of age. Treatment with cross-sex hormones (phase 2) was given at 15.6-16 years. One patient purchased cross-sex hormone treatment overseas. One patient received oestrogen and progesterone for menstrual suppression before phase 1. The annual frequency of new referrals increased continuously over the study period. Hormone treatment for pubertal suppression and subsequent gender transition needs to be individualised within stringent protocols in multidisciplinary specialist units.

The utility of the gonadotrophin releasing hormone (GnRH) test in the diagnosis of polycystic ovary syndrome (PCOS).

Science.gov (United States)

Lewandowski, Krzysztof C; Cajdler-Łuba, Agata; Salata, Ireneusz; Bieńkiewicz, Małgorzata; Lewiński, Andrzej

2011-01-01

Polycystic ovary syndrome (PCOS) is characterised by increased frequency of hypothalamic GnRH pulses leading to a relative increase in LH synthesis by the pituitary. As GnRH stimulation can reveal a relative LH excess, we have endeavoured to assess whether GnRH test might be useful in the diagnosis of PCOS. The study involved 185 subjects: a PCOS group, n = 151, all with oligo- or amenorrhoea, aged (mean ± SD) 24.8 ± ± 5.4 years, BMI 24.5 ± 6.0 kg/m²; and regularly menstruating controls, n = 34, aged 26.6 ± 5.0 years, BMI 24.6 ± 5.5 kg/m². In 121 subjects with PCOS and in 32 controls, serum LH and FSH were measured before (0 minutes) and 30 and 60 minutes after GnRH stimulation (100 μg i.v.). Insulin resistance was assessed by HOMA and Insulin Resistance Index derived from glucose and insulin concentrations during 75 gram oral glucose tolerance test. Women with PCOS had higher testosterone (p = 0.0002), androstendione (p = 0.0021), 17OH-progesterone (p PCOS. Baseline and stimulated LH concentrations were higher in PCOS (9.09 ± 5.56 vs 4.83 ± 1.71 IU/L, 35.48 ± 31.4 vs 16.30 ± 6.68 IU/L, 33.86 ± 31.8 vs 13.45 ± 5.2 IU/L, at 0, 30 and 60 mins post GnRH, respectively, p PCOS in comparison to controls (LH0 min/FSH(₀ min) 1.59 ± 0.95 vs 0.76 ± 0.2, LH(₃₀ min) /FSH(₃₀ min) 4.07 ± 3.0 vs 1.89 ± 0.79, LH(₆₀ min)/FSH(₆₀ min) 3.56 ± 2.58 vs 1.55 ± 0.63, p 2.11 or LH(₆₀ min)/FSH(₆₀ min) > 1.72 had 78.3% and 87.5% sensitivity and 81.7% and 81.3% specificity for the diagnosis of PCOS, respectively. Women with PCOS have higher baseline and GnRH-stimulated LH concentrations. GnRH stimulation results in an increase in LH/FSH ratio in women with PCOS. Therefore we postulate that this phenomenon might be potentially useful as an additional tool in the diagnosis of PCOS.

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

To use peptides as synthetic vaccines, they have to be coupled to a carrier protein to make them more immunogenic. Coupling efficiency between a carrier protein and a peptide, however, is difficult to control with respect to loading density of the peptide, This makes these carrier proteins poorly...... for the induction of antibodies against GnRH and immunocastration of pigs....

Long-term follow-up after cervical cancer treatment and subsequent successful surrogate pregnancy.

Science.gov (United States)

Agorastos, T; Zafrakas, M; Mastrominas, M

2009-08-01

Preservation of fertility is a major concern for premenopausal women after diagnosis of cervical cancer. Successful surrogate pregnancy after treatment for cervical cancer has very rarely been reported. In the present report, a case of successful surrogate pregnancy after radical hysterectomy, lymphadenectomy and ovarian transposition for cervical cancer, followed by radiation therapy, is presented. After stimulation of the transposed ovaries using the short gonadotrophin-releasing hormone (GnRH) analogue protocol, four oocytes were retrieved transabdominally from the genetic mother. IVF followed and two embryos were transferred to the surrogate mother, leading to an uneventful singleton pregnancy, and ultimately normal vaginal delivery of a healthy female infant at term. The unique aspect in this case is the long-lasting favourable outcome for both genetic mother and child, observed during 8.5 years of follow-up, the longest follow-up period reported to date in such cases.

Evaluation of the pituitary-gonadal response to GnRH, and adrenal status, in the leopard (Panthera pardus japonensis) and tiger (Panthera tigris).

Science.gov (United States)

Brown, J L; Goodrowe, K L; Simmons, L G; Armstrong, D L; Wildt, D E

1988-01-01

Frequent blood samples were collected to study hormonal responses to GnRH in male and female leopards and tigers. Animals were anaesthetized with ketamine-HCl and blood samples were collected every 5 min for 15 min before and 160 min after i.v. administration of GnRH (1 micrograms/kg body weight) or saline. No differences in serum cortisol concentrations were observed between sexes within species, but mean cortisol was 2-fold greater in leopards than tigers. GnRH induced a rapid rise in LH in all animals (18.3 +/- 0.9 min to peak). Net LH peak height above pretreatment levels was 3-fold greater in males than conspecific females and was also greater in tigers than leopards. Serum FSH increased after GnRH, although the magnitude of response was less than that observed for LH. Basal LH and FSH and GnRH-stimulated FSH concentrations were not influenced by sex or species. Serum testosterone increased within 30-40 min after GnRH in 3/3 leopard and 1/3 tiger males. Basal testosterone was 3-fold greater in tiger than leopard males. LH pulses (1-2 pulses/3 h) were detected in 60% of saline-treated animals, suggesting pulsatile gonadotrophin secretion; however, in males concomitant testosterone pulses were not observed. These results indicate that there are marked sex and species differences in basal and GnRH-stimulated hormonal responses between felids of the genus Panthera which may be related to differences in adrenal activity.

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 < 0.001), harem-tending behavior (P < 0.001), and agonistic behavior (P = 0.02). There was no difference between the mean body condition of control females (4

Degarelix: A Novel Gonadotropin-Releasing Hormone (GnRH) Receptor Blocker-Results from a 1-yr, Multicentre, Randomised, Phase 2 Dosage-Finding Study in the Treatment of Prostate Cancer

NARCIS (Netherlands)

van Poppel, Hendrik; Tombal, Bertrand; de la Rosette, Jean J.; Persson, Bo-Eric; Jensen, Jens-Kristian; Kold Olesen, Tine

2008-01-01

Background: Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. Objective: To determine the efficacy and safety of initial doses of 200 mg or

The potential for castration of domestic animals by active immunization against GnRH

International Nuclear Information System (INIS)

Gonzalez, A.; Allen, A.F.; Murphy, B.D.; Mapletoft, R.J.; Cohen, R.

1990-01-01

Trials have been carried out in sheep and beef cattle in attempts to induce immunity against gonadotropin releasing hormone (GnRH), with the objective of using immunocastration as a replacement for surgical castration. Of the protein carriers used, ovalbumin and horse albumin yielded highest responses, with keyhole limpet haemocyanin (KLH) being a potent substitute for both. Different adjuvants were also used. In these trials, highest titre responses were obtained using Freund's complete (FCA) or Freund's incomplete (FIA) adjuvant in cattle and sheep. Although no adjuvant was found to yield as high a response as FCA and Alhydrogel, an aluminium hydroxide adjuvant generally yielded a high response in cattle and sheep. The results from the trials in beef calves indicate that active immunization against GnRH does not affect average daily gains, total body weight gain or carcass dressing percentage. The results suggest the potential of immunocastration as a substitute for surgical castration in cattle and sheep. (author). 30 refs, 8 figs, 2 tabs

Solid-phase synthesis of new saphenamycin analogues with antimicrobial activity

DEFF Research Database (Denmark)

Laursen, Jane B.; de Visser, P.C.; Nielsen, H.K.

2002-01-01

in parallel with a series of differently substituted benzoic acid derivatives. Treatment with TFA-CH2Cl2 (5:995) released the expected saphenamycin analogues into solution. These new analogues were purified, characterized and screened for antimicrobial activity against Bacillus subtilis and Proteus mirabilis...

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.

Vitamin E analogues and immune response in cancer treatment

Czech Academy of Sciences Publication Activity Database

Tomasetti, M.; Neužil, Jiří

2007-01-01

Roč. 76, - (2007), s. 463-491 ISSN 0083-6729 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : vitamin E analogues * inducers of apoptosis * immune surveillance Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.889, year: 2007

Incidence of premature estrus in lactating dairy cows and conception rates to standing estrus or fixed-time inseminations after synchronization using GnRH and PGF(2alpha).

Science.gov (United States)

DeJarnette, J M; Salverson, R R; Marshall, C E

2001-07-03

Fixed-time AI (TAI) after GnRH-PGF(2alpha)-GnRH treatment is a method to achieve pregnancies in dairy herds without estrous detection. However, cows that fail to respond to the initial GnRH may have compromised TAI conception rates due to asynchronous ovarian response. This study documented the percentage of GnRH-treated Holstein cows (n=345) in two herds that displayed estrus at an inopportune time for optimum TAI conception rate (conception rates of two TAI protocols in cows that did not display PE. At biweekly herd health exams, cows diagnosed as not pregnant to a previous AI and cows >80 days postpartum with no AI were treated with 100 microg GnRH (day -7) and 25mg PGF(2alpha) (day 0). Cows detected in PE by twice-daily visual observation from day -7 to day 2 were bred by AI 8-12h later. Cows not detected in PE were randomly assigned by parity, body condition score, and postpartum interval to receive either: (1) 100microg GnRH at 48h after PGF(2alpha) and TAI 16 to 18h later (Ovsynch); or (2) TAI at 72h post-PGF(2alpha) and a concurrent 100 microg GnRH injection to those cows not detected in estrus between 48 and 72h post-PGF(2alpha) (modified Ovsynch (MOV)). All hormone injections were im. Twenty percent (68/345) of the cows were detected in estrus before 48 after PGF(2alpha), of which 5% (17/345) were detected in estrus before PGF(2alpha) (Conception rates were not affected by treatment (PE versus Ovsynch versus MOV; 32% (21/65) versus 30% (37/125) versus 32% (47/145); P>0.10). However, within MOV-treated cows, conception rates were greater (Prates are to be achieved. Although additional estrous detection is required compared to Ovsynch, reduced cow handling and hormone usage, efficient use of expensive semen through greater conception rates in cows detected in estrus, and comparable TAI conception rates, suggests the MOV protocol may be a cost effective alternative to Ovsynch in many dairy herd reproductive management programs.

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

Directory of Open Access Journals (Sweden)

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.

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)

International Nuclear Information System (INIS)

Canzian, Federico; Calle, Eugenia E; Chanock, Stephen; Clavel-Chapelon, Francoise; Dossus, Laure; Feigelson, Heather Spencer; Haiman, Christopher A; Hankinson, Susan E; Hoover, Robert; Hunter, David J; Isaacs, Claudine; Kaaks, Rudolf; Lenner, Per; Lund, Eiliv; Overvad, Kim; Palli, Domenico; Pearce, Celeste Leigh; Quiros, Jose R; Riboli, Elio; Stram, Daniel O; Thomas, Gilles; Thun, Michael J; Cox, David G; Trichopoulos, Dimitrios; Gils, Carla H van; Ziegler, Regina G; Henderson, Katherine D; Henderson, Brian E; Berg, Christine; Bingham, Sheila; Boeing, Heiner; Buring, Julie

2009-01-01

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). 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. 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. Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians

Antibodies against gonadotropin-releasing hormone (GnRH) in patients with diabetes mellitus is associated with lower body weight and autonomic neuropathy.

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Berntorp, Kerstin; Frid, Anders; Alm, Ragnar; Fredrikson, Gunilla Nordin; Sjöberg, Klas; Ohlsson, Bodil

2013-08-17

Esophageal dysmotility and gastroparesis are common secondary complications in patients with diabetes mellitus. Patients with dysmotility express antibodies against gonadotropin-releasing hormone (GnRH) in serum. The aim of the present study was to scrutinize patients with diabetes mellitus with regard to the presence of GnRH antibodies, and to examine associations between antibodies and clinical findings. Thirty-nine consecutive patients with diabetes mellitus were included in the study after clinical examination and examination by esophageal manometry and gastric emptying scintigraphy. Serum was analyzed for the presence of antibodies against GnRH using an ELISA, and values are expressed as relative units (RU). Two age- and gender-matched healthy subjects per each patient served as controls. The prevalence of IgM GnRH antibodies in patients was 33% compared to 14% in controls (p = 0.027), with a higher antibody titer; 1.2 (0.6-5.0) and 0.2 (0.1-0.3) RU, respectively (p = 0.000). The expression of IgG antibodies was 15% in patients and none in controls (p = 0.000). Lower body mass index was associated with the presence of IgM antibodies (OR = 0.835, 95% CI = 0.699-0.998), and autonomic neuropathy with the presence IgG antibodies (OR = 9.000, 95% CI = 1.327-61.025). Esophageal dysmotility (69%) or gastroparesis (18%) were not associated with the presence of IgM antibodies (OR = 0.589, 95% CI = 0.143-2.424 and OR = 3.407, 95% CI = 0.633-18.350, respectively). Neither was esophageal dysmotility associated with IgG antibodies (OR = 2.500, 95% CI = 0.259-24.096). Antibodies against GnRH are more common in patients with diabetes mellitus compared with healthy controls. IgM antibodies are associated with lower body mass index and IgG antibodies are associated with autonomic neuropathy.

Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height.

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Tanaka, Toshiaki; Naiki, Yasuhiro; Horikawa, Reiko

2012-04-01

Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin(®)) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean duration of 4.1 yr. The anabolic steroid hormone was started approximately 1 yr after initiation of treatment with the GnRH analog. The mean pubertal height gain from onset of puberty till adult height was significantly greater in the combination treatment group (33.9 cm) than in the untreated group (26.4 cm) (ppenis and pubic hair is promoted by the anabolic steroid hormone, no psychosocial problems arose because of delayed puberty. No clinically significant adverse events appeared. Combined treatment with GnRH analog and anabolic steroid hormone significantly increased height gain during puberty and adult height in boys who entered puberty with a short stature, since the period until epiphyseal closure was extended due to deceleration of the bone age maturation by administration of the GnRH analog and the growth rate at this time was maintained by the anabolic steroid hormone.

Analogue MIMO Detection

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McNamara Darren

2006-01-01

Full Text Available In this contribution we propose an analogue receiver that can perform turbo detection in MIMO systems. We present the case for a receiver that is built from nonlinear analogue devices, which perform detection in a "free-flow" network (no notion of iterations. This contribution can be viewed as an extension of analogue turbo decoder concepts to include MIMO detection. These first analogue implementations report reductions of few orders of magnitude in the number of required transistors and in consumed energy, and the same order of improvement in processing speed. It is anticipated that such analogue MIMO decoder could bring about the same advantages, when compared to traditional digital implementations.

Meglitinide analogues in the treatment of type 2 diabetes mellitus.

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Landgraf, R

2000-11-01

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e

Valuing Treatments for Parkinson Disease Incorporating Process Utility: Performance of Best-Worst Scaling, Time Trade-Off, and Visual Analogue Scales

NARCIS (Netherlands)

Weernink, Marieke Geertruida Maria; Groothuis-Oudshoorn, Catharina Gerarda Maria; IJzerman, Maarten Joost; van Til, Janine Astrid

2016-01-01

Objective The objective of this study was to compare treatment profiles including both health outcomes and process characteristics in Parkinson disease using best-worst scaling (BWS), time trade-off (TTO), and visual analogue scales (VAS). Methods From the model comprising of seven attributes with

Induction of fertile estrus in bitches using a sustained-release formulation of a GnRH agonist (leuprolide acetate).

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Inaba, T; Tani, H; Gonda, M; Nakagawa, A; Ohmura, M; Mori, J; Torii, R; Tamada, H; Sawada, T

1998-04-01

A single subcutaneous injection of a sustained-release formulation of a potent GnRH agonist, leuprolide acetate (LA; [D-Leu6, Pro9NEt]-GnRH), was evaluated as a method of inducing fertile estrus in 12 mature anestrous and 6 prepubertal beagle bitches. The bitches were treated with microencapsulated LA (100 micrograms/kg, s.c.) at 120 or 150 d post partum, or at 1 yr of age, followed by a GnRH-analogue (fertirelin; [Pro9NEt]-GnRH, 3 micrograms/kg, i.m.) on the first day of induced estrus. Signs of estrus were seen within 10.3 +/- 0.9 d after LA administration in all bitches. The interestrous interval in 120- and 150-d post-partum bitches was shortened (P bitches. All LA treated dogs demonstrated behavioral estrus and mated. Three of 6 (50%) at 120 d post partum, 6 of 6 (100%) at 150 d post partum and 5 of 6 (83%) of prepubertal (1-yr old) bitches then became pregnant and produced a mean litter size of 4.1 +/- 0.8 pups. A normal circulating estrogen and progesterone response pattern was observed in mature anestrous bitches. A prepubertal bitch that failed to become pregnant had a similar estrogen response pattern but an insufficient progesterone profile. The results suggest that microencapsulated LA can be useful in inducing fertile estrus in the domestic dogs.

Comparison of microdose GnRH agonist protocol with GnRH antagonist / letrazole protocol in patients with poor ovarian response

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Yiğit Çakıroğlu

2013-09-01

Full Text Available Objective: To compare microdose GnRH agonist (MDL protocol with GnRH antagonist/letrazole (AL protocol in patients with poor ovarian response. Design: Randomised clinical trial. Setting: Kocaeli University Assisted Reproductive Centre Interventions: POR was diagnosed according to ESHRE Bologna criteria in case of presence of 2 out of 3 criteria. In the MDL group (n=27, 40µg/0.2 cc subcutaneous leuprolid acetate was given two times a day starting on the first day of menstrual cycle. On the second day of the cycle, gonadotrophin stimulation was started at 450-600 IU and/or 150 IU human menopausal gonadotrophin (hMG along with leuprolid. In the AL group (n=28, 5 mg letrazole was given for 5 days starting on the second day of the spontaneous cycle and after the 5th day of the cycle, 450-600 IU and/or 150 IU hMG was given. Main Outcome Measures: To compare the outcomes of MDL protocol with AL protocol in patients with poor ovarian response. Results: Stimulation days, total gonadotrophin dose (IU, peak E2 (pg/ml levels, and endometrial thickness were found to be statistically significantly lower in the AL group. While no cases of cycle cancellation was detected in the MDL group, statistically significantly higher rates of cycle cancellation (%35.7, p<0.001 was detected in the AL group. No statistically significant differences were detected in total oocyte numbers (3.7±2.9 vs 2.7±2.2, number of transferred embryos (1.4±0.5 vs 1.4±1.9, pregnancy rates (3/27 (%11.1 vs 2/28 (%7.1 and implantation rates (3/36 (%8.3 vs 2/22 (%9.1 in between the groups. Comment: Although AL protocol is not superior to MDL protocol in poor ovarian response patients, it may be used as an alternative protocol.

Etude du rôle de l’expression du récepteur Neuropiline-1 et de l’exocytose Calcium-dépendante dans le neurone à GnRH sur le développement et la maturation du système à GnRH et la physiologie de la reproduction

OpenAIRE

Vanacker , Charlotte

2015-01-01

Fertility in mammals is the result of a long development and maturation process of the hypothalamic-pituitary-gonadal axis. The reproductive function is orchestrated by a small population of neurons, located in preoptic area of hypothalamus in rodents, and releasing in a pulsatile manner Gonadotropin-releasing hormon (GnRH) in the portal blood vessels, where it is transported to the anterior pituitary gland. GnRH neuropeptide triggers synthesis and release of the gonadotropins LH and FSH, whi...

The terminal nerve plays a prominent role in GnRH-1 neuronal migration independent from proper olfactory and vomeronasal connections to the olfactory bulbs

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Ed Zandro M. Taroc

2017-10-01

Yoshihara et al., 2005. Our data prove that correct development of the OBs and axonal connection of the olfactory/vomeronasal sensory neurons to the forebrain are not required for GnRH-1 ns migration, and suggest that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in gene expression from olfactory/vomeronasal sensory neurons.

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.

Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'

DEFF Research Database (Denmark)

Nilsson, Lena; Andersen, A.N.; Lindenberg, Svend

2010-01-01

To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot...... study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5...... oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles. Novel GnRH antagonists more specifically targeting FSH release...

Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles.

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Ikemoto, Tadahiro; Park, Min Kyun

2007-02-01

GnRH regulates reproductive functions through interaction with its pituitary receptor in vertebrates. The present study demonstrated that the leopard gecko possessed two and three genes for GnRH ligands and receptors, respectively, though one of the three receptor subtypes had long been thought not to exist in reptiles. Each receptor subtype showed a distinct pharmacology. All types of ligands and receptors showed different expression patterns, and were widely expressed both inside and outside the brain. This report also shows a comparison of the pituitary and ovarian GnRH systems in the leopard gecko during and after the egg-laying season. All three receptor subtypes were expressed in both the whole pituitary and ovary; however, only one receptor subtype could be detected in the anterior pituitary gland. In situ hybridization showed spatial expression patterns of ovarian receptors, and suggested co-expression of multiple receptor subtypes in granulosa cells of larger follicles. Co-transfection of receptor subtypes showed a distinct pharmacology in COS-7 cells compared with those of single transfections. These results suggest that distinct signaling mechanisms are involved in the pituitary and ovarian GnRH systems. Seasonal and developmental variations in receptor expression in the anterior pituitary gland and ovarian follicles may contribute to the seasonal breeding of this animal.

Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support

DEFF Research Database (Denmark)

Iliodromiti, Stamatina; Blockeel, Christophe; Tremellen, Kelton P

2013-01-01

Are clinical pregnancy rates satisfactory and the incidence of OHSS low after GnRH agonist trigger and modified intensive luteal support in patients with a high risk of ovarian hyperstimulation syndrome (OHSS)?......Are clinical pregnancy rates satisfactory and the incidence of OHSS low after GnRH agonist trigger and modified intensive luteal support in patients with a high risk of ovarian hyperstimulation syndrome (OHSS)?...

Expression of feeding-related peptide receptors mRNA in GT1-7 cell line and roles of leptin and orexins in control of GnRH secretion.

Science.gov (United States)

Yang, Ying; Zhou, Li-bin; Liu, Shang-quan; Tang, Jing-feng; Li, Feng-yin; Li, Rong-ying; Song, Huai-dong; Chen, Ming-dao

2005-08-01

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. Receptors of bombesin3, cholecystokinin (CCK)-A, CCK-B, glucagon-like peptide (GLP)1, melanin-concentrating hormone (MCH)1, orexin1, 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). Receptors of bombesin 3, CCK-B, GLP1, MCH1, orexin1, neuromedin-B, NPY1, NPY5, NT1, NT3, and leptin receptor long form mRNA were expressed in GT1-7 cells, 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. 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.

Characterization and differential expression of three GnRH forms during reproductive development in cultured turbot Schophthalmus maximus

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Zhao, Chunyan; Xu, Shihong; Feng, Chengcheng; Liu, Yifan; Yang, Yang; Wang, Yanfeng; Xiao, Yongshuang; Song, Zongcheng; Liu, Qinghua; Li, Jun

2017-10-01

Turbots (Schophthalmus maximus), one of the most important economic marine flatfish species, fail to undergo final spawning and spermiation naturally under artificial farming conditions. In vertebrates, reproduction is regulated by the brain-pituitary-gonadal axis (BPG-axis), and gonadotropin releasing hormone (GnRH) is one of its key components. Therefore, to better understand the physiology of reproduction in the turbot, three of the genes encoding GnRH subtypes—sbGnRH, cGnRH-II and sGnRH—were cloned and sequenced by isolating the cDNA sequences. The localizations and patterns of expression of their mRNAs were also evaluated during seasonal gonadal development. All three mRNAs were expressed abundantly in the brain; sbGnRH and sGnRH mRNAs were also detected in the gonads and pituitary gland, and sbGnRH expression was much higher than that of sGnRH, indicating the critical role of sbGnRH in regulating the BPG-axis. Moreover, the brain expression patterns of sbGnRH and sGnRH mRNAs showed an increased trend during gonadal development, peaking in mature stages. This indicated the direct regulation of gonadal development by the GnRH system. In addition, cGnRH-II mRNA expression showed no significant variations, suggesting that cGnRH-II is not critically involved in the control of reproduction. Further, the mRNA abundances of the three GnRH forms in the breeding season were significantly higher than those in immature and post-breeding stages in all analyzed brain areas. Therefore, we propose that sbGnRH is the most important hormone for the regulation of reproduction in turbot via the BPG-axis. These results will help in better understanding the reproductive endocrine mechanisms of turbots and lay the groundwork for additional studies aimed at comparing the reproductive physiology of wild individuals with those raised under artificial conditions.

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

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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.

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.

Fertility in Women of Reproductive Age After Breast Cancer Treatment: Practice Patterns and Outcomes.

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McCray, Devina K S; Simpson, Ashley B; Flyckt, Rebecca; Liu, Yitian; O'Rourke, Colin; Crowe, Joseph P; Grobmyer, Stephen R; Moore, Halle C; Valente, Stephanie A

2016-10-01

Breast cancer is the most frequently occurring cancer in women of reproductive age, and systemic treatments may adversely affect childbearing plans. Use of assisted reproductive technologies and therapies for ovarian protection improve fertility prospects. We evaluated whether patients had a documented fertility discussion (FD) with their oncology physician prior to therapy, what options were chosen, and if pregnancy was achieved. A retrospective chart review from 2006 to 2014 was performed to evaluate women aged 40 years and younger who were diagnosed with breast cancer and treated with chemotherapy and/or antihormonal therapy. Patient demographics, treatment regimens, presence or absence of FD, in vitro fertilization (IVF) consultation, gonadotropin-releasing hormone (GnRH) agonist use, and subsequent successful pregnancy were analyzed. Among 303 patients meeting the inclusion criteria, 80 (26 %) had an FD with their physician documented; 71 of these 80 women (89 %) sought further fertility consultation and options. Sixteen (20 %) women were prescribed a GnRH agonist only for ovarian protection during chemotherapy, 50 (63 %) underwent IVF consultation only, and 5 (6 %) had both a GnRH agonist prescribed and an IVF consultation. The overall pregnancy rate was 7 % at a mean of 3 years post breast cancer treatment. Pregnancy after treatment was more common among those pursuing IVF consultation or prescribed a GnRH agonist. In treating young breast cancer patients, it is important to assess fertility desire, discuss treatment risks relating to fertility, and discuss preservation options. Although not every woman in this group desired pregnancy, 71/80 (89 %) women having a documented FD sought further fertility consultation and options.

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...... 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....

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.

Synthetic Strigolactone Analogues Reveal Anti-Cancer Activities on Hepatocellular Carcinoma Cells

KAUST Repository

Hasan, Mohammed Nihal

2018-02-09

Hepatocellular carcinoma (HCC) remains one of the leading causes of death worldwide. The complex etiology is attributed to many factors like heredity, cirrhosis, hepatitis infections or the dysregulation of the different molecular pathways. Nevertheless, the current treatment regimens have either severe side effects or tumors gradually acquire resistance upon prolonged use. Thus, developing a new selective treatment for HCC is the need of the hour. Many anticancer agents derived from plants have been evaluated for their cytotoxicity towards many human cancer cell lines. Strigolactones (SLs)-a newly discovered class of phytohormones, play a crucial role in the development of plant-root and shoot. Recently, many synthetic analogues of SLs have demonstrated pro-apoptotic effects on different cancer cell lines like prostate, breast, colon and lung. In this study, we tested synthetic SLs analogues on HCC cell line-HepG2 and evaluated their capability to induce cell proliferation inhibition and apoptosis. Primary WST-1 assays, followed by annexin-V/7AAD staining, demonstrated the anti-proliferative effects. The SLs analogues TIT3 and TIT7 were found to significantly reduce HepG2 cell viability in a dose- and time-dependent manner and induce apoptosis. Interestingly, though TIT3 and TIT7 strongly affected cancer cell proliferation, both compounds showed moderate anti-proliferative effect on normal cells. Further, migration of cancer cells was suppressed upon treatment with TIT3 and TIT7 in a wound healing assay. In summary, these findings suggest that two SLs analogues TIT3 and TIT7 exert selective inhibitory effects on cancer cells most likely through targeting microtubules. SLs analogues could be used in future as potential anti-cancer candidates in chemotherapy.

Synthetic Strigolactone Analogues Reveal Anti-Cancer Activities on Hepatocellular Carcinoma Cells

KAUST Repository

Hasan, Mohammed Nihal; Choudhry, Hani; Razvi, Syed Shoeb; Moselhy, Said Salama; Kumosani, Taha Abduallah; Zamzami, Mazin A.; Omran, Ziad; Halwani, Majed A.; Al-Babili, Salim; Abualnaja, Khalid Omer; Al-Malki, Abdulrahman Labeed; Alhosin, Mahmoud; Asami, Tadao

2018-01-01

Hepatocellular carcinoma (HCC) remains one of the leading causes of death worldwide. The complex etiology is attributed to many factors like heredity, cirrhosis, hepatitis infections or the dysregulation of the different molecular pathways. Nevertheless, the current treatment regimens have either severe side effects or tumors gradually acquire resistance upon prolonged use. Thus, developing a new selective treatment for HCC is the need of the hour. Many anticancer agents derived from plants have been evaluated for their cytotoxicity towards many human cancer cell lines. Strigolactones (SLs)-a newly discovered class of phytohormones, play a crucial role in the development of plant-root and shoot. Recently, many synthetic analogues of SLs have demonstrated pro-apoptotic effects on different cancer cell lines like prostate, breast, colon and lung. In this study, we tested synthetic SLs analogues on HCC cell line-HepG2 and evaluated their capability to induce cell proliferation inhibition and apoptosis. Primary WST-1 assays, followed by annexin-V/7AAD staining, demonstrated the anti-proliferative effects. The SLs analogues TIT3 and TIT7 were found to significantly reduce HepG2 cell viability in a dose- and time-dependent manner and induce apoptosis. Interestingly, though TIT3 and TIT7 strongly affected cancer cell proliferation, both compounds showed moderate anti-proliferative effect on normal cells. Further, migration of cancer cells was suppressed upon treatment with TIT3 and TIT7 in a wound healing assay. In summary, these findings suggest that two SLs analogues TIT3 and TIT7 exert selective inhibitory effects on cancer cells most likely through targeting microtubules. SLs analogues could be used in future as potential anti-cancer candidates in chemotherapy.

Insulin analogues and cancer: a note of caution

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Joseph A.M.J.L. eJanssen

2014-05-01

Full Text Available Abstract In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogues are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogues, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR. However, the classical model of the IGF-IR signaling may be insufficient to explain (all mitogenic effects of insulin analogues since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase (MAPK pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some insulin analogues than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A in (pre cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogues. Further

Eel Kisspeptins: Identification, Functional Activity, and Inhibition on both Pituitary LH and GnRH Receptor Expression

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Jérémy Pasquier

2018-01-01

Full Text Available The European eel (Anguilla anguilla presents a blockade of sexual maturation at a prepubertal stage due to a deficient production of gonadotropins. We previously initiated, in the eel, the investigation of the kisspeptin system, one of the major gatekeepers of puberty in mammals, and we predicted the sequence of two Kiss genes. In the present study, we cloned and sequenced Kiss1 and Kiss2 cDNAs from the eel brain. The tissue distributions of Kiss1 and Kiss2 transcripts, as investigated by quantitative real-time PCR, showed that both genes are primarily expressed in the eel brain and pituitary. The two 10-residue long sequences characteristic of kisspeptin, eel Kp1(10 and Kp2(10, as well as two longer sequences, predicted as mature peptides, eel Kp1(15 and Kp2(12, were synthesized and functionally analyzed. Using rat Kiss1 receptor-transfected Chinese hamster ovary cells, we found that the four synthesized eel peptides were able to induce [Ca2+]i responses, indicating their ability to bind mammalian KissR-1 and to activate second messenger pathways. In primary culture of eel pituitary cells, all four peptides were able to specifically and dose-dependently inhibit lhβ expression, without any effect on fshβ, confirming our previous data with heterologous kisspeptins. Furthermore, in this eel in vitro system, all four peptides inhibited the expression of the type 2 GnRH receptor (gnrh-r2. Our data revealed a dual inhibitory effect of homologous kisspeptins on both pituitary lhβ and gnrh-r2 expression in the European eel.

Female-Specific Glucose Sensitivity of GnRH1 Neurons Leads to Sexually Dimorphic Inhibition of Reproduction in Medaka.

Science.gov (United States)

Hasebe, Masaharu; Kanda, Shinji; Oka, Yoshitaka

2016-11-01

Close interaction exists between energy-consuming reproduction and nutritional status. However, there are differences in costs and priority for reproduction among species and even between sexes, which leads to diversification of interactions between reproduction and nutritional status. Despite such diversified interactions among species and sexes, most of the analysis of the nutritional status-dependent regulation of reproduction has been limited to an endothermic vertebrate, mammalian species of either sex. Therefore, the mechanisms underlying the diversified interactions remain elusive. In the present study, we demonstrated the effects of malnutritional status on reproduction at both organismal and cellular levels in an ectothermic vertebrate, a teleost medaka of both sexes. First, we analyzed the effects of malnutrition by fasting on gonadosomatic index, number of spawned/fertilized eggs, and courtship behavior. Fasting strongly suppressed reproduction in females but, surprisingly, not in males. Next, we analyzed the effects of fasting on firing activity of hypothalamic GnRH1 neurons, which form the final common pathway for the control of reproduction. An electrophysiological analysis showed that low glucose, which is induced by fasting, directly suppresses the firing activity of GnRH1 neurons specifically in females through intracellular ATP-sensitive potassium channels and AMP-activated protein kinase pathways. Based on the fact that such suppressions occurred only in females, we conclude that nutritional status-dependent, glucose-sensing in GnRH1 neurons may contribute to the most fitted reproductive regulation for each sex.

Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study

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Lainas George T

2012-08-01

Full Text Available Abstract Background Management of established severe OHSS requires prolonged hospitalization, occasionally in intensive care units, accompanied by multiple ascites punctures, correction of intravascular fluid volume and electrolyte imbalance. The aim of the present study was to evaluate whether it is feasible to manage women with severe OHSS as outpatients by treating them with GnRH antagonists in the luteal phase. Methods This is a single-centre, prospective, observational, cohort study. Forty patients diagnosed with severe OHSS, five days post oocyte retrieval, were managed as outpatients after administration of GnRH antagonist (0.25 mg daily from days 5 to 8 post oocyte retrieval, combined with cryopreservation of all embryos. The primary outcome measure was the proportion of patients with severe OHSS, in whom outpatient management was not feasible. Results 11.3% (95% CI 8.3%-15.0% of patients (40/353 developed severe early OHSS. None of the 40 patients required hospitalization following luteal antagonist administration and embryo cryopreservation. Ovarian volume, ascites, hematocrit, WBC, serum oestradiol and progesterone decreased significantly (P  Conclusions The current study suggests, for the first time, that successful outpatient management of severe OHSS with antagonist treatment in the luteal phase is feasible and is associated with rapid regression of the syndrome, challenging the dogma of inpatient management. The proposed management is a flexible approach that minimizes unnecessary embryo transfer cancellations in the majority (88.7% of high risk for OHSS patients.

Rethinking of the criteria for natural analogue study. A case of Tono natural analogue study

International Nuclear Information System (INIS)

Yoshida, Hidekazu

1996-01-01

Natural analogue regarding long-term performance of the geological disposal system for radioactive waste isolation is essentially the study of geochemical process which has been evolved in geological environment. All geochemical studies, however, will not be nominated as natural analogue studies. It is, therefore, important to be clear the criteria for natural analogue study with the view of analogy by following three categories, (1) Conceptual model development, (2) Data provision and (3) Model testing, for the concept of geological disposal and safety assessment model. Rethinking of the criteria for natural analogue study through the case of Tono Natural Analogue Study, and the usefulness of natural analogue study for the safety assessment of geological disposal system in Japan have been presented in this paper. (author)

Effect of different hormonal combinations on follicular wave emergence and superovulatory response in sheep.

Science.gov (United States)

Souza-Fabjan, Joanna Maria Gonçalves; da Rosa, Rômulo Mendonça; Balaro, Mário Felipe Alvarez; Pinto, Pedro Henrique Nicolau; Dos Santos, Gustavo Bervian; Arashiro, Eduardo Kenji Nunes; da Fonseca, Jeferson Ferreira; Ungerfeld, Rodolfo; Brandão, Felipe Zandonadi

2017-11-01

The aim of the present study was to compare hormonal treatments to induce and synchronize follicular wave emergence to improve the results of superovulatory (SOV) treatments in ewes. In Experiment 1 (n = 66), ewes were treated with a progesterone intravaginal implant plus a PGF 2α analogue (group G P4 ), or with the same treatment plus estradiol benzoate (G P4+EB ), a GnRH agonist (G P4+GnRH ), or both, estradiol benzoate and a GnRH agonist (G P4+EB+GnRH ) in a 2 × 2 factorial arrangement. Follicular wave emergence was determined by ultrasound. Follicular wave did not emerge during the studied period in 10 females (one from G P4 , six from G P4+EB and three from G P4+EB+GnRH ). Follicular emergence was less synchronized (P = 0.007) when estradiol was administered (G P4+EB : 103.6 ± 22.0 h), without any interaction with GnRH treatment (G P4+EB+GnRH : 80.1 ± 21.4 h, G P4+GnRH : 52.5 ± 8.7 h, G P4 : 56.6 ± 10.4 h). Estradiol administration delayed the moment of follicular emergence (P = 0.007) and the follicular wave emergence moment in which follicular dominance was achieved (P = 0.009), without interactions between estradiol and GnRH in the moment of follicular wave emergence or dominance. In Experiment 2 (n = 22), two SOV protocols were compared: the best treatment of Experiment 1 (G P4 ) was used to synchronize follicular wave emergence, initiating the SOV treatment 2.5 days later; in the control treatment, SOV treatment started 80 h after a short-term protocol to synchronize ovulation (G control ). The number of corpora lutea (CL) and the evaluation of the collected embryos were performed six days after estrus. Blood samples were collected daily for plasma progesterone determination. Although the number of CL was similar in G control (7.1 ± 1.0) and G P4 (6.9 ± 5.1), the number of structures and viable embryos recovered were greater in G control (P synchronization of follicular wave emergence. When EB was used (alone or

Double insemination and gonadotropin-releasing hormone treatment of repeat-breeding dairy cattle.

Science.gov (United States)

Stevenson, J S; Call, E P; Scoby, R K; Phatak, A P

1990-07-01

Our objective was to determine if double inseminations during the same estrous period of dairy cattle eligible for their third or fourth service (repeat breeders) would improve pregnancy rates equivalent to injections of GnRH given at the time of AI. Repeat-breeding, lactating cows from six herds (five herds in the San Joaquin Valley of central California and one herd in northeast Kansas) were assigned randomly to four treatment groups when detected in estrus: 1) single AI plus no injection, 2) single AI plus 100 micrograms GnRH at AI, 3) double AI plus no injection, or 4) double AI plus 100 micrograms of GnRH at AI. Inseminations were performed according to the a.m.-p.m. rule. The second AI for the double AI treatment was given 12 to 16 h after the first AI. Injections of GnRH were given intramuscularly immediately following the single AI or the first AI of the double AI. Pregnancy rates of cows given a single AI and hormone injection were numerically higher in all six herds than those of their herdmates given only a single AI. In five of six herds, the pregnancy rates of cows given a double AI and hormone injection were numerically higher than pregnancy rates of their herdmates given only a double AI. Overall pregnancy rates for the four treatments were 1) 112/353 (32.1%), 2) 165/406 (41.6%), 3) 119/364 (33.5%), and 4) 135/359 (37.5%). Gonadotropin-releasing hormone increased pregnancy rates of repeat breeders compared with controls given only a single AI. No further benefit beyond the single AI was accrued from the double AI treatment, with or without concurrent hormone administration.

THE USE OF PANAX GINSENG AND ITS ANALOGUES AMONG PHARMACY CUSTOMERS IN ESTONIA: A CROSS-SECTIONAL STUDY.

Science.gov (United States)

Volmer, Dasy; Raal, Ain; Kalle, Raivo; Sõukand, Renata

2016-01-01

The aim of the cross-sectional study was to evaluate the pattern of complementary self-treatment with P. ginseng and its analogues amongst pharmacy customers in Estonia. The study instrument consisted of multiple-choice items related to personal knowledge about and experience with the use of P. ginseng and its analogues. In total, 1233 customers participated in the study. Of study participants, 18.1% reported the use of P. ginseng and its analogues in their lives. P. ginseng preparations were used mostly according to the well- known indications (tiredness, weakness and decreased mental and physical capacity). Of P. ginseng users 44.3% reported positive treatment effects and 12.0% had experienced different side effects. With increase of age (p < 0.01) and at lower levels of education (p = 0.04), the use of ginseng or its analogues decreased. The better the users evaluated their health, the better they perceived the effect of P. ginseng preparations (p < 0.01). This study reported rather frequent use of P. ginseng and its analogues. P. ginseng could be seen in the treatment of conditions, where the use of local medicinal plants has not been established. Further research is needed to learn more about public knowledge and experiences about efficacy and safety of P. ginseng and its analogues.

Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus

DEFF Research Database (Denmark)

Vilsbøll, Tina

2007-01-01

properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development.......The incretin hormones are intestinal peptides that enhance insulin secretion following ingestion of nutrients. Liraglutide is a glucagon-like peptide-1 receptor analogue, which is obtained by derivatising glucagon-like peptide-1 with a fatty acid, providing a compound with pharmacokinetic...

Research progress in combination therapy with pegylated interferon and nucleos(tide analogues in treatment of chronic hepatitis B

Directory of Open Access Journals (Sweden)

YU Yiqi

2015-09-01

Full Text Available Current antiviral treatment strategy for chronic hepatitis B (CHB includes pegylated interferon (PEG-IFN and nucleos(tide analogues (NAs. Whether combination therapy with PEG-IFN and NAs improve therapeutic efficacy has become the key question regarding the antiviral therapy for CHB. This article reviews the recent progress in combination therapy for the management of CHB. The results indicate that the efficacy of simultaneous combination of PEG-IFN and NAs is not superior to that of PEG-IFN monotherapy in terms of HBeAg seroconversion and response after drug withdrawal. Sequential combination or switching therapy in PEG-IFN- or NAs-treated patients, as well as combination with immune cell therapy, is a promising treatment strategy.

Comparison of mild and microdose GnRH agonist flare protocols on IVF outcome in poor responders.

Science.gov (United States)

Karimzadeh, Mohammad Ali; Mashayekhy, Mehri; Mohammadian, Farnaz; Moghaddam, Fatemeh Mansoori

2011-05-01

To compare the IVF outcome of clomiphene citrate/gonadotropin/antagonist (mild protocol) and microdose GnRH agonist flare protocols for poor responders undergoing in vitro fertilization. 159 poor responder patients were randomized and ovarian stimulation was performed with clomiphene citrate, gonadotropin and antagonist (group I) or microdose GnRH agonist flare (group II) protocols. Main outcome was clinical pregnancy rate and secondary outcomes were doses of gonadotropin administration and duration of stimulation. There were no significant differences in age, causes of infertility, basal FSH, BMI, duration of infertility, E(2) level on the day of hCG injection in both groups. Although the cancellation, fertilization, and clinical pregnancy rates were similar in both groups, the endometrial thickness, number of retrieved oocytes, mature oocytes and implantation rate were significantly higher in mild protocol. The doses of gonadotropin administration and duration of stimulation were significantly lower in mild protocol. We recommend mild protocol in assisted reproductive technology cycles for poor responders based on our results regarding less doses of used gonadotropin and a shorter duration of stimulation.

CEC natural analogue working group

International Nuclear Information System (INIS)

Come, B.; Chapman, N.A.

1986-01-01

The second meeting of the CEC Natural Analogue Working Group took place on June 17-19, 1986, hosted by the Swiss NAGRA in Interlaken (CH). A review of recent progress in natural analogue programmes was carried out, and complemented by detailed discussions about geomicrobiology, archaeological analogues, natural colloids, and use of analogues to increase confidence in safety assessments for radioactive waste disposal. A statement drafted by the Group, and the presentations made, are put together in this report

Use of nucleoside (tide) analogues in patients with hepatitis B-related acute liver failure

DEFF Research Database (Denmark)

Dao, Doan Y; Seremba, Emmanuel; Ajmera, Veeral

2012-01-01

The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remains controversial. We determined retrospectively the impact of NAs in a large cohort of patients with HBV-ALF.......The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remains controversial. We determined retrospectively the impact of NAs in a large cohort of patients with HBV-ALF....

Análogos de insulina Insulin analogues

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Manuel E. Licea Puig

2006-12-01

diabetes mellitus (DM. The recombinant technology of deoxyribonucleic acid (DNA has allowed the development of human insulin; however, this has not totally solved the problems related to immunogenecity, among other problems. Therefore, the new technologies are applied to create insulin analogues. It is our purpose to review relevant pharmacological and clinical aspects related to the insulin analogues, as well as their usefulness in the treatment of DM. The insulin analogues result from biochemical modifications of human insulin. These modifications of the insulin molecule alter not only the absorption, but also the beginning and duration of the action, which offer advantages over the conventional insulins. At present, there are three rapid acting insulin analogues: insulin lispro, insulin aspart and glulisine; and three long acting analogues; glargine, detemir and albulin. Albulin is the latest long acting analogue reported. At present, it is being subjected to various in vitro and in vivo studies. Besides, there have been developed diverse formulations where the rapid acting insulin analogues are premixed with the long acting analogues. The rapid acting insulin analogues have showed a modest global benefit against the conventional insulins in type 1 diabetics. The long acting analogues focus their attention in those persons with DM with nocturnal hypoglycemic episodes. Longer term studies are necessary to confirm the safety and benefits of these preparations, as well as to determine their effect on the micro- and macroangiopathic complications of DM.

Effects of Huang Bai (Phellodendri Cortex and Three Other Herbs on GnRH and GH Levels in GT1–7 and GH3 Cells

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Sun Haeng Lee

2016-01-01

Full Text Available The present study was to evaluate the effects of Huang Bai, Zhi Mu, Mai Ya, and Xia Ku Cao on hormone using the GT1–7 and GH3 cells. The GT1–7 and GH3 cell lines were incubated with DW; DMSO; and 30, 100, or 300 μg/mL of one of the four extract solutions in serum-free media for 24 hours. The MTT assay was performed to determine the cytotoxicity of the four herbs. The GT1–7 and GH3 cells were incubated in DW, estradiol (GT1–7 only, or noncytotoxic herb solutions in serum-free medium for 24 hours. A quantitative RT-PCR and western blot were performed to measure the GnRH expression in GT1–7 cells and GH expression in GH3 cells. Huang Bai, Zhi Mu, Xia Ku Cao, and Mai Ya inhibited the GnRH mRNA expression in GT1–7 cells, whereas Huang Bai enhanced GH mRNA expression in GH3 cells. Additionally, Xia Ku Cao inhibited GnRH protein expression in GT1–7 cells and Huang Bai promoted GH protein expression in GH3 cells. The findings suggest that Huang Bai can delay puberty by inhibiting GnRH synthesis in the hypothalamus while also accelerating growth by promoting GH synthesis and secretion in the pituitary.

Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

OpenAIRE

Shimshoni, JA; Winkler, I; Golan, E; Nutt, D

2016-01-01

3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-...

Isolation and structural identification of a novel minoxidil analogue in an illegal dietary supplement: triaminodil.

Science.gov (United States)

Lee, Ji Hyun; Park, Han Na; Park, Hyoung Joon; Kim, Nam Sook; Park, Sung-Kwan; Lee, Jongkook; Baek, Sun Young

2018-01-01

A new minoxidil analogue was detected in an illegal dietary supplement advertised as a hair-growth treatment. The analogue was identified using ultra-performance liquid chromatography (UPLC), high-resolution mass spectrometry (LC-HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. The compound was structurally elucidated as a minoxidil analogue in which the piperidinyl group of minoxidil was replaced with a pyrrolidinyl group corresponding to a molecular formula of C 8 H 13 N 5 O. The new analogue has been named triaminodil. As this is the first report of the compound, there are no chemical, toxicology or pharmacological data available.

Occurrence and profiles of bisphenol analogues in municipal sewage sludge in China

International Nuclear Information System (INIS)

Song, Shanjun; Song, Maoyong; Zeng, Luzhe; Wang, Thanh; Liu, Runzeng; Ruan, Ting; Jiang, Guibin

2014-01-01

Extensive use of bisphenol A and its analogues has caused increasing concern over the potential adverse health impacts of these chemicals. In this study, the presence and profiles of 13 bisphenols (BPs) were investigated in 52 municipal sewage sludge samples collected from 30 cities in China. Tetrabromobisphenol A was the most frequently observed analogue (geometric mean: 20.5 ng/g dw). Bisphenol A (4.69 ng/g dw), bisphenol S (3.02 ng/g dw), and bisphenol F (3.84 ng/g dw) were found with similar frequency. Other BP analogues such as tetrachlorobisphenol A, bisphenol AF, bisphenol E, and dihydroxybiphenyl were identified for the first time in sewage sludge in China. Significant correlations were found among BP concentrations, but no relationships were found with wastewater treatment plant characteristics. Profiles of the relative estradiol equivalents suggested that the estrogenic potential of BP mixtures may be associated with the occurrence and contributions of specific analogues. -- Highlights: • The profiles of various bisphenols were studied initially in sludge in China. • Analogous abundances were found for BPA, BPS and BPF. • Halo-substituted BPs have similar portions with BPA and its ascendant alternatives. • BPAF, TCBPA, BPE and DHBP were identified for the first time in sludge in China. -- We analyzed the profiles of bisphenol analogues in 52 sewage sludge samples with several bisphenols identified for the first time in wastewater treatment plants in China

Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus

DEFF Research Database (Denmark)

Vilsbøll, Tina

2007-01-01

The incretin hormones are intestinal peptides that enhance insulin secretion following ingestion of nutrients. Liraglutide is a glucagon-like peptide-1 receptor analogue, which is obtained by derivatising glucagon-like peptide-1 with a fatty acid, providing a compound with pharmacokinetic propert...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development....... properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...

Serum CA 125 concentrations in women with endometriosis or ...

African Journals Online (AJOL)

releasing hormone (GnRH) agonist analogue therapy in women with endometriosis and uterine fibroids. Serum concentrations of this cell surface antigen did not correlate with uterine volume and appeared to have no value in the assessment of ...

CEC Natural Analogue Working Group

International Nuclear Information System (INIS)

Come, B.; Chapman, N.A.

1989-01-01

The central theme for the third meeting of the CEC analogue working group was ''How can analogue data be used for performance assessments, both in support of the results and for presentation to the public''. This report puts together the most recent achievements in this field, together with a review of on-going natural analogue programmes

A silyl andrographolide analogue suppresses Wnt/β-catenin signaling pathway in colon cancer.

Science.gov (United States)

Reabroi, Somrudee; Chairoungdua, Arthit; Saeeng, Rungnapha; Kasemsuk, Teerapich; Saengsawang, Witchuda; Zhu, Weiming; Piyachaturawat, Pawinee

2018-05-01

Hyperactivation of Wnt/β-catenin signaling implicated in oncogenesis of colorectal cancer (CRC) is a potential molecular target for chemotherapy. An andrographolide analogue, 3A.1 (19-tert-butyldiphenylsilyl-8, 17-epoxy andrographolide) has previously been reported to be potently cytotoxic toward cancer cells by unknown molecular mechanisms. The present study explored the anti-cancer activity of analogue 3A.1 on Wnt/β-catenin signaling in colon cancer cells (HT29 cells) which were more sensitive to the others (HCT116 and SW480 cells). Analogue 3A.1 inhibited viability of HT29 cells with IC 50 value of 11.1 ± 1.4 μM at 24 h, which was more potent than that of the parent andrographolide. Analogue 3A.1 also suppressed the proliferation of HT29 cells and induced cell apoptosis in a dose-dependent manner. Its apoptotic activity was accompanied with increased expressions of proteins related to DNA damages; PARP-1 and γ-H2AX. In addition, analogue 3A.1 significantly inhibited T-cell factor and lymphoid enhancer factor (TCF/LEF) promoter activity of Wnt/β-catenin signaling. Accordingly, the expressions of Wnt target genes and β-catenin protein were suppressed. Moreover, analogue 3A.1 increased the activity of GSK-3β kinase, which is a negative regulator responsible for degradation of intracellular β-catenin. This mode of action was further supported by the absence of the effects after treatment with a GSK-3β inhibitor, and over-expression of a mutant β-catenin (S33Y). Our findings reveal, for the first time, an insight into the molecular mechanism of the anti-cancer activity of analogue 3A.1 through the inhibition of Wnt/β-catenin/GSK-3β pathway and provide a therapeutic potential of the andrographolide analogue 3A.1 in CRC treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height

OpenAIRE

Tanaka, Toshiaki; Naiki, Yasuhiro; Horikawa, Reiko

2012-01-01

Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin?) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean d...

Clinical Value of Basal Serum Progesterone Prior to Initiate Ovarian Hyper-Stimulation with GnRH Antagonists: A Retrospective Cohort Study.

Science.gov (United States)

Faulisi, Sonia; Reschini, Marco; Borroni, Raffaella; Paffoni, Alessio; Busnelli, Andrea; Somigliana, Edgardo

2017-01-01

The routine assessment of day 3 serum progesterone prior to initiation of ovarian hyper-stimulation with the use of GnRH antagonists is under debate. In this study, we evaluated the clinical utility of this policy. Retrospective cohort study of women undergoing in vitro fertilization (IVF) with the use of GnRH antagonists aimed at determining the frequency of cases with progesterone levels exceeding the recommended threshold of 1,660 pg/ml and at evaluating whether this assessment may be predictive of pregnancy. Serum progesterone exceeded the recommended threshold in one case (0.3%, 95% CI 0.01-1.5). The median (interquartile range) basal progesterone in women who did (n = 95) and did not (n = 217) become pregnant were 351 (234-476) and 380 (237-531) pg/ml, respectively (p = 0.28). The 90th percentile of the basal progesterone distribution in women who became pregnant was 660 pg/ml. Cases with serum progesterone exceeding this threshold in successful and unsuccessful cycles were 10 (10%) and 30 (14%), respectively (p = 0.47). The capacity of basal progesterone to predict pregnancy was evaluated using receiver operating characteristic curve (area under the curve = 0.54, 95% CI 0.47-0.61, p = 0.28). No graphically evident threshold emerged. Routine day 3 serum progesterone assessment in IVF cycles with the use of GnRH antagonists is not justified. Further evidence is warranted prior to claiming its systematic use. © 2016 S. Karger AG, Basel.

Karyometric changes of neurons of hypothalamus and ependyma nuclei of the third cerebral ventricle of sheep following administration of Gn-RH and subsequent irradiation

International Nuclear Information System (INIS)

Stanikova, A.; Arendarcik, J.; Tokos, M.; Balun, J.; Chlebovsky, O.

1983-01-01

A karyometric analysis was used for the study of changes in the cell nucleus volume of the neurons of nucleus paraventricularis, nucleus arcuatus, and the ependyma of the third cerebral ventricle of sheep after the administration of Gn-RH, followed by exposure to X rays. The test animals included 12 ewes in physiological anoestrus and two rams. The trials were conducted in spring. The first group of four ewes and two rams were left as controls; in the ewes of the second group the hypothalamo-hypophysial region was irradiated with 516.5 mC/kg (200 R);in the four ewes of the third group, ovaries were directly irradiated at laparotomy with 64.4 mC/kg (250 R). The ewes of the second and third groups were treated with i.m. administration of 400 μg Gn-RH per head before irradiation. The excisions were collected and processed the tenth day from irradiation. The karyometric analysis was performed at 3000-fold magnification, 200 cells being measured in each sample. Changes in neurosecretory cells were described in the regions of nucleus paraventricularis, nucleus arcuatus and in the ependyma of the third cerebral ventricle. The results of the karyometric analysis of nucleus paraventricularis and nucleus arcuatus suggest that the administration of Gn-RH and irradiation of the hypothalamo-hypophysial region, and direct irradiation of the ovaries stimulated the studied cerebral structures. The changes observed in the ependyma of the third cerebral ventricle after the administration of Gn-RH and subsequent irradiation of the hypothalamo-hypophysial region were insignificant; it was only after direct irradiation of the ovaries that these cells were inhibited indirectly through the feedback mechanism. (author)

The effects of a slow release GnRH agonist implant on male rabbits

DEFF Research Database (Denmark)

Goericke-Pesch, Sandra Kathrin; Groeger, Gesa; Wehrend, Axel

2015-01-01

Surgical castration is done in male pet rabbits for reproduction control, to reduce inter-male aggression and to control hyper-sexuality, territory marking and aggression against humans. Alternatives to surgical castration are requested because of a relatively great anaesthetic risk in rabbits....... Long-term application of a GnRH agonist implant results in a fully reversible "hormonal" castration in male dogs, cats, boars and many other species. Therefore, the present study using New Zealand White hybrid and German Giant rabbits aimed to investigate the effects of a 4.7mg deslorelin implant...

Analogue alternative the electronic analogue computer in Britain and the USA, 1930-1975

CERN Document Server

Small, James S

2013-01-01

We are in the midst of a digital revolution - until recently, the majority of appliances used in everyday life have been developed with analogue technology. Now, either at home or out and about, we are surrounded by digital technology such as digital 'film', audio systems, computers and telephones. From the late 1940s until the 1970s, analogue technology was a genuine alternative to digital, and the two competing technologies ran parallel with each other. During this period, a community of engineers, scientists, academics and businessmen continued to develop and promote the analogue computer.

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

in normal responder IVF patients. We here present a novel approach for luteal support after a GnRHa trigger. METHODS Normal responder patients who failed at least one previous IVF attempt, during which a conventional hCG trigger was used, were consecutively enrolled in the study. A GnRH antagonist...

Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

Directory of Open Access Journals (Sweden)

Cristina Alvarez-Escola

2016-11-01

Full Text Available In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH and insulin-like growth factor (IGF1 levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status. The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission.

A Sleeping Beauty DNA transposon-based genetic sensor for functional screening of vitamin D3 analogues

DEFF Research Database (Denmark)

Staunstrup, Nicklas Heine; Sharma, Nynne; Bak, Rasmus Otkjær

2011-01-01

Analogues of vitamin D3 are extensively used in the treatment of various illnesses, such as osteoporosis, inflammatory skin diseases, and cancer. Functional testing of new vitamin D3 analogues and formulations for improved systemic and topical administration is supported by sensitive screening me...

Systematic Review of the Cost Effectiveness of Insulin Analogues in Type 1 and Type 2 Diabetes Mellitus.

Science.gov (United States)

Shafie, Asrul Akmal; Ng, Chin Hui; Tan, Yui Ping; Chaiyakunapruk, Nathorn

2017-02-01

Insulin analogues have a pharmacokinetic advantage over human insulin and are increasingly used to treat diabetes mellitus. A summary of their cost effectiveness versus other available treatments was required. Our objective was to systematically review the published cost-effectiveness studies of insulin analogues for the treatment of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). We searched major databases and health technology assessment agency reports for economic evaluation studies published up until 30 September 2015. Two reviewers performed data extraction and assessed the quality of the data using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. Seven of the included studies assessed short-acting insulin analogues, 12 assessed biphasic insulin analogues, 30 assessed long-acting insulin analogues and one assessed a combination of short- and long-acting insulin analogues. Only 17 studies involved patients with T1DM, all were modelling studies and 12 were conducted in Canada. The incremental cost-effectiveness ratios (ICERs) for short-acting insulin analogues ranged from dominant to $US435,913 per quality-adjusted life-year (QALY) gained, the ICERs for biphasic insulin analogues ranged from dominant to $US57,636 per QALY gained and the ICERs for long-acting insulin analogues ranged from dominant to $US599,863 per QALY gained. A total of 15 studies met all the CHEERS guidelines reporting quality criteria. Only 26 % of the studies assessed heterogeneity in their analyses. Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM. The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues.

NARCIS (Netherlands)

Rolleman, E.J.; Melis, M.; Valkema, R.; Boerman, O.C.; Krenning, E.P.; Jong, M. de

2010-01-01

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides

Growth Hormone Supplementation in the Luteal Phase Before Microdose GnRH Agonist Flare Protocol for In Vitro Fertilization.

Science.gov (United States)

Dunne, Caitlin; Seethram, Ken; Roberts, Jeffrey

2015-09-01

Growth hormone (GH) acts in both early and late follicular development to stimulate the proliferation and differentiation of granulosa cells and to increase the production of estradiol in animal and human ovaries. Investigators have therefore explored GH supplementation to improve outcomes in women undergoing in vitro fertilization, with the greatest interest in women with diminished ovarian reserve. Recent meta-analyses indicate that GH supplementation can be beneficial for poor responders undergoing IVF. In most studies, GH has been given concomitantly with gonadotropins during the follicular phase; this may not be optimal, since follicular recruitment begins during the preceding luteal phase. We therefore wished to examine the effect of GH supplementation in the luteal phase before controlled ovarian stimulation (COH) with a microdose GnRH agonist flare (MDF) protocol in women undergoing in vitro fertilization. We performed a retrospective matched case-control study of patients undergoing treatment at a private IVF facility between June 2012 and July 2013. Patients identified as poor responders to COH were offered adjuvant GH treatment as part of their ovarian stimulation regimen. The patients in the experimental group chose to take GH, 3.33 mg daily by subcutaneous injection for 14 days, before starting COH. All patients had an MDF stimulation protocol using 450 IU of follicle stimulating hormone (FSH) daily. A total of 42 women were included in the study. There were 14 women in the experimental group (GH) and 28 controls (C) matched for age, BMI, and day 3 FSH level. There was no difference between the groups in clinical pregnancy rate (GH = 29%, C = 32%, P = 0.99), number of mature oocytes retrieved (GH = 2.5, C = 5.0, P = 0.13), cycle cancellation rate (GH = 21%, C = 14%, P = 0.88), duration of COH (GH = 10.1, C = 10.1, P = 0.93), or mean peak estradiol level (GH = 4174 pmol/L, C = 5105 pmol/L, P = 0.44). The administration of growth hormone during the

Natural Analogue Synthesis Report

Energy Technology Data Exchange (ETDEWEB)

A. M. Simmons

2002-05-01

The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport

NATURAL ANALOGUE SYNTHESIS REPORT

International Nuclear Information System (INIS)

Simmons, A.M.

2004-01-01

The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the Yucca Mountain Site Description (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature along with results of quantitative studies conducted specifically for the Yucca Mountain Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement-drift degradation, waste-form degradation, waste-package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated-zone (SZ) transport, impact of radionuclide release on the biosphere

Transdermal delivery of a melanotropic peptide hormone analogue

International Nuclear Information System (INIS)

Dawson, B.V.; Hadley, M.E.; Kreutzfeld, K.; Dorr, R.T.; Hruby, V.J.; Al-Obeidi, F.; Don, S.

1988-01-01

We previously reported that topical application of [Nl3 4 ,D-Phe 7 ]alpha-MSH, a superpotent analogue of alpha-melanocyte stimulating hormone, to mice induces a darkening of follicular melanocytes throughout the skin. We now report that the melanotropin analogue can be delivered across mouse but not rat skin in an in vitro model system. Passage of the analogue from the topically applied vehicle (polyethylene glycol) across the skin into a subcutaneous receiving vessel was demonstrated by both bioassay as well as by radioimmunoassay. The bioassay data demonstrate that percutaneous absorption of the melanotropin did not result in loss of biological activity of the peptide. The differential penetration of the peptide across rodent skin reveals that one cannot predict percutaneous absorption of a substance across the stratum corneum from studies on a single species. The present results are the first to demonstrate, by direct quantitative measurements, that a bioactive peptide can be delivered across the vertebrate integument in vitro. These studies point out the potential of a topically applied melanotropin for tanning of the skin and possibly for treatment of certain hypopigmentary disorders

Design and implementation of an integrated architecture for massive parallel data treatment of analogue signals supplied by silicon detectors of very high spatial resolution

International Nuclear Information System (INIS)

Michel, J.

1993-02-01

This doctorate thesis studies an integrated architecture designed to a parallel massive treatment of analogue signals supplied by silicon detectors of very high spatial resolution. The first chapter is an introduction presenting the general outline and the triggering conditions of the spectrometer. Chapter two describes the operational structure of a microvertex detector made of Si micro-plates associated to the measuring chains. Information preconditioning is related to the pre-amplification stage, to the pile-up effects and to the reduction in the time characteristic due to the high counting rates. The chapter three describes the architecture of the analogue delay buffer, makes an analysis of the intrinsic noise and presents the operational testings and input/output control operations. The fourth chapter is devoted to the description of the analogue pulse shape processor and gives also the testings and the corresponding measurements on the circuit. Finally, the chapter five deals with the simplest modeling of the entire conditioning chain. Also, the testings and measuring procedures are here discussed. In conclusion the author presents some prospects for improving the signal-to-noise ratio by summation of the de-convoluted micro-paths. 78 refs., 78 figs., 1 annexe

Insulin biosimilars: the impact on rapid-acting analogue-based therapy.

Science.gov (United States)

Franzè, S; Cilurzo, F; Minghetti, P

2015-04-01

The impending expiration of patent protection for recombinant insulins provides the opportunity to introduce cost-saving copies, named biosimilars, onto the market. Although there is broad experience in the production and characterisation of insulins, the development of copies is still a challenge. In this paper, the main features of insulins and the EU regulatory framework for their biosimilar products are reviewed. The main focus is on rapid-acting insulin analogues (Humalog(®); Novolog(®)/NovoRapid(®); Apidra(®)). Since they differ by one or two amino acids in chain B, production of one biosimilar for all three drug products is not feasible. However, from post-marketing-collected clinical data, rapid-acting insulin analogues seem to have similar therapeutic efficacy. It is reasonable to suppose that, for prescription to treatment-naïve patients, the cheaper biosimilar would be the preferred choice of physicians, either spontaneously or induced by health insurance. Therefore, its introduction will affect the market share of all the other rapid-acting insulin analogues.

Progesterone concentration, pregnancy and calving rate in Simmental dairy cows after oestrus synchronisation and hCG treatment during the early luteal phase.

Science.gov (United States)

Šuluburić, Adam; Milanović, Svetlana; Vranješ-Đurić, Sanja; Jovanović, Ivan B; Barna, Tomislav; Stojić, Milica; Fratrić, Natalija; Szenci, Ottó; Gvozdić, Dragan

2017-09-01

Early embryonic development may be negatively affected by insufficient progesterone (P4) production. Therefore, the aim of our study was to increase P4 by gonadotropin-releasing hormone (GnRH) and/or human chorionic gonadotropin (hCG) treatments after inducing oestrus by prostaglandin (PG) treatment. Lactating Simmental dairy cows (n = 110), between 1 to 5 lactations, with an average milk production of 6,500 1/305 days, at 40-80 days postpartum were used and grouped as follows: (1) PG + GnRH treatment at AI (GnRH group), (2) PG + hCG treatment at day 7 after AI (hCG group), (3) PG + GnRH at AI + hCG treatment at day 7 after AI (GnRH/hCG group), and (4) spontaneous oestrus (C: control group). All animals were double inseminated (at the time of oestrus detection and 12 ± 2 h thereafter). Blood serum and milk samples were collected at the day of observed oestrus (day 0), and 14, 21 and 28 days after AI. Serum P4 was determined using a commercial radioimmunoassay (RIA) test (INEP, Zemun), and milk P4 was determined using enzyme-linked immunoassay (ELISA) test (NIV Novi Sad). Pregnancy status was confirmed by ultrasonography between days 28 and 35 after AI. Differences of serum or milk P4 medians, pregnancy (and calving) rate were determined using Dunn's Multiple Comparison Tests and Z test, respectively. Serum P4 medians were significantly higher at days 14, 21 and 28 after AI in the hCG-treated animals, indicating increased luteal activity, with a similar tendency in whole milk P4 values. Treatment with hCG during the early luteal phase significantly contributed to the maintenance of gestation at days 28-35 after AI, and also increased the calving rate in Simmental dairy cows.

Luteinizing hormone-releasing hormone analogue (Buserelin) treatment for central precocious puberty: a multi-centre trial.

Science.gov (United States)

Werther, G A; Warne, G L; Ennis, G; Gold, H; Silink, M; Cowell, C T; Quigley, C; Howard, N; Antony, G; Byrne, G C

1990-02-01

A multi-centre open trial of Buserelin, a luteinizing hormone-releasing hormone (LHRH) analogue, was conducted in 13 children with central precocious puberty. Eleven children (eight girls and three boys), aged 3.4-10.2 years at commencement, completed the required 12 month period of treatment. Initially all patients received the drug by intranasal spray in a dose of 1200 micrograms/day, but by the end of the 12 month period two were having daily subcutaneous injections and three were receiving an increased dose intranasally. The first month of treatment was associated in one boy with increased aggression and masturbation, and in the girls with an increase in the prevalence of vaginal bleeding. Thereafter, however, both behavioural abnormalities and menstruation were suppressed. Median bone age increased significantly during the study, but without any significant change in the ratio of height age to bone age. The median predicted adult height for the group therefore did not alter significantly over the twelve months of the study. Buserelin treatment caused a reduction in the peak luteinizing hormone and follicle-stimulating hormone (FSH) responses to LHRH, mostly to prepubertal levels, and also suppressed basal FSH. In the first weeks of treatment, the girls' serum oestradiol levels rose significantly and then fell to prepubertal or early pubertal levels. A similar pattern was seen for serum testosterone levels. Serum somatomedin-C levels, however, showed little fluctuation over the course of the study. Buserelin treatment was safe and well accepted, and offers the promise of improved linear growth potential in precocious puberty.

A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy and Heart Failure

DEFF Research Database (Denmark)

Aubdool, Aisah A; Thakore, Pratish; Argunhan, Fulye

2017-01-01

cardiovascular disease in two distinct murine models of hypertension and heart failure in vivoMethods -The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin using a CGRP receptor antagonist. The effect of the αAnalogue on Angiotensin II (AngII)-induced hypertension......, Western blot and histology. Results -The AngII-induced hypertension was attenuated by co-treatment with the αAnalogue (50nmol/kg/day, s.c., at a dose selected for lack of long term hypotensive effects at baseline). The αAnalogue protected against vascular, renal and cardiac dysfunction, characterised...... failure. It preserved heart function, assessed by echocardiography, whilst protecting against adverse cardiac remodelling and apoptosis. Moreover, treatment with the αAnalogue was well-tolerated with neither signs of desensitisation nor behavioural changes. Conclusions -These findings, in two distinct...

Overnight Levels of Luteinizing Hormone, Follicle-Stimulating Hormone and Growth Hormone before and during Gonadotropin-Releasing Hormone Analogue Treatment in Short Boys Born Small for Gestational Age

NARCIS (Netherlands)

van der Kaay, Danielle C. M.; de Jong, Frank H.; Rose, Susan R.; Odink, Roelof J. H.; Bakker-van Waarde, Willie M.; Sulkers, Eric J.; Hokken-Koelega, Anita C. S.

2009-01-01

Aims: To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone

Effects of recombinant LH treatment on folliculogenesis and responsiveness to FSH stimulation

DEFF Research Database (Denmark)

Durnerin, Cedrin I; Erb, K; Fleming, R

2008-01-01

at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration. RESULTS: The LH treatment was associated with increased small antral follicles prior to FSH stimulation (P = 0.007), and an increased yield of normally fertilized (2 PN) embryos (P = 0...... in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist. METHODS: We employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high......-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured...

The effect of synthetic ceramide analogues on gastritis and esophagitis in rats.

Science.gov (United States)

Kim, Sung Hyo; Um, Seung In; Nam, Yoonjin; Park, Sun Young; Dong, Je Hyun; Ko, Sung Kwon; Sohn, Uy Dong; Lee, Sang Joon

2016-09-01

The effects of ceremide analogues on esophagitis and gastritis in rats were examined. Gastritis induced by indomethacin was significantly reduced after CY3325 and CY3723 treatment, whereas other analogues had no effect. The amount of malondialdehyde in gastritis was significantly reduced by CY3325 or CY 3723. CY3325 or CY 3723 decreased the glutathione levels in gastritis. The myeloperoxidase level in gastritis is increased, and its increment was decreased by CY3325 and CY3723. In reflux esophagitis, the ulceration was decreased by CY3325, CY3723. The gastric volume and acid output are reduced, whereas the pH value is increased by CY3325 or CY3723 after esophagitis. These results suggest that ceramide analogues, CY3325 and CY3723, can prevent the development of gastritis and reflux esophagitis in rats.

Andrographolide and analogues in cancer prevention.

Science.gov (United States)

Mishra, Siddhartha Kumar; Tripathi, Swati; Shukla, Archana; Oh, Seung Hyun; Kim, Hwan Mook

2015-01-01

Andrographis paniculata is a medicinal plant traditionally used for treatment of cough and cold, fever, laryngitis, and several infectious diseases. Extracts of A. paniculata have shown versatile potency against various diseases including cancer. The active biomolecules of A. paniculata mainly are lactone and diterpene. Andrographolide and analogues have been widely used for prevention of different diseases. Andrographolides have shown potent antiinflammatory and anticancer activities. It showed potentials as chemopreventive agents by suppressing growth of cancer cells by inhibiting NF-kappaB, PI3K/AKT and other kinase pathways and by inducing apoptosis. Andrographolide induced both intrinsic and extrinsic apoptosis pathway in different cancer cells via expression of different anti-apoptotic protein like Bax, p53, and activated caspases. Andrographolide was successfully used as an antineoplastic drug in cancer chemotherapy. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide and analogues need to be subjected to further clinical and biomedical studies in cancer chemoprevention. Andrographolide could be potent anticancer agent when used in combination with other chemotherapeutic agents.

Effect of resynchronization with GnRH or progesterone (P4) intravaginal device (CIDR) on Day 23 after timed artificial insemination on cumulative pregnancy and embryonic losses in CIDR-GnRH synchronized Nili-Ravi buffaloes.

Science.gov (United States)

Arshad, Usman; Qayyum, Arslan; Hassan, Mubbashar; Husnain, Ali; Sattar, Abdul; Ahmad, Nasim

2017-11-01

The objective of the present study was to determine the effect of resynchronization on Day 23 with either GnRH or P4 (controlled internal drug release device containing progesterone; CIDR) on pregnancy rate, cumulative pregnancy, and embryonic and fetal losses in CIDR-GnRH synchronized Nili-Ravi buffaloes. Buffaloes (n = 181) of mixed parity, lactating, 181 ± 73 days postpartum, a body condition score (BCS) of 3.2 ± 0.5 (scale of 1-5), and 450-600 kg weight were subjected to synchronization and resynchronization. All buffaloes received CIDR on Day -9.5. In addition, GnRH was injected 36 h after CIDR removal, and timed artificial insemination (TAI) was performed 18 h later (Day 0). On Day 23, buffaloes were randomly assigned to receive one of the following treatments: 1) CON (n = 63), 2) P4 (n = 55), and 3) GnRH (n = 63) for resynchronization (2nd AI). Pregnancy rate, and embryonic and fetal losses were monitored by serial ultrasonography on Days 30, 45, 60, and 90 after synchronization (1st TAI), respectively. The pregnancy rate in GnRH-treated buffaloes remained significantly and consistently higher (P  0.05) between the OVS and CIDR groups; whereas the, cumulative pregnancy rate in GnRH + OVS buffaloes (81%) after 1st and 2 nd AI when determined on Day 64 was higher (P losses were significantly lower (P losses were fewer and did not differ (P > 0.05) due to treatments on Day 60 or 90 post 1st AI. In conclusion, 1) the pregnancy rate and cumulative pregnancy rate in GnRH-treated buffaloes were higher than in CON buffaloes on Day 64 after synchronization and resynchronization, and 2) embryonic and fetal losses were lower in GnRH-treated buffaloes than in CON buffaloes when determined from Day 31-90 post 1st TAI. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of analogues to build technologists' confidence: NAnet

International Nuclear Information System (INIS)

Noseck, Ulrich

2008-01-01

The relevance of analogues to radioactive waste management stems from the long timescales that have to be considered. Periods up to a million or more years into the future need to be considered and these are beyond experimental investigation and human experience. Within the last years the term 'Natural Analogue' has got a much wider meaning and includes man-made analogues as well. The role of natural analogues in the safety case depends amongst others on the time scale to be covered. Therefore, it is useful to classify them by the time period addressed in the study. Here it is referred to: industrial analogues which started earliest 150 years ago, archaeological analogues, which cover time frames between the past 10 000 and 150 years, and geological analogues, which usually cover time frames of more than 10 000 years and in most cases more than million years. The current interest in analogues in different countries is reflected by several recent review projects with emphasis on the application of natural analogue study results in performance assessment. The most recent international review was performed within the 5. EURATOM Framework of the EC by the NAnet project, a network on the review of natural analogue studies with emphasis on the application of analogues in long-term safety assessment and communication. The overall aim of the NAnet project was to review the past and present use and understanding of natural analogues, and to make recommendations for their future use. The project covered 'traditional' natural analogue studies, such as large-scale investigations of radionuclide transport around uranium ore bodies, and process or mechanistic analogue studies such as those examining natural glass and bentonite clay stability. To complete the picture, a restricted range of other studies of natural systems which employ a similar philosophy to analogues was also included in the scope. These included studies which have examined radionuclide transport and retardation

In silico and in vitro characterization of anti-amyloidogenic activity of vitamin K3 analogues for Alzheimer's disease.

Science.gov (United States)

Huy, Pham Dinh Quoc; Yu, Yao-Chung; Ngo, Son Tung; Thao, Tran Van; Chen, Chin-Piao; Li, Mai Suan; Chen, Yi-Cheng

2013-04-01

Aggregation of amyloid-beta (Aβ) has been proposed as the main cause of Alzheimer's disease (AD). Vitamin K deficiency has been linked to the pathogenesis of AD. Therefore, 15 synthesized vitamin K3 (VK3) analogues were studied for their anti-amyloidogenic activity. Biological and spectroscopic assays were used to characterize the effect of VK3 analogues on amyloidogenic properties of Aβ, such as aggregation, free radical formation, and cell viability. Molecular dynamics simulation was used to calculate the binding affinity and mode of VK3 analogue binding to Aβ. Both numerical and experimental results showed that several VK3 analogues, including VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224 could effectively inhibit Aβ aggregation and conformational conversion. The calculated inhibition constants were in the μM range for VK3-10, VK3-6, and VK3-9 which was similar to the IC50 of curcumin. Cell viability assays indicated that VK3-9 could effectively reduce free radicals and had a protective effect on cytotoxicity induced by Aβ. The results clearly demonstrated that VK3 analogues could effectively inhibit Aβ aggregation and protect cells against Aβ induced toxicity. Modified VK3 analogues can possibly be developed as effective anti-amyloidogenic drugs for the treatment of AD. VK3 analogues effectively inhibit Aβ aggregation and are highly potent as anti-amyloidogenic drugs for therapeutic treatment of AD. Copyright © 2012 Elsevier B.V. All rights reserved.

The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo-controlled study.

Science.gov (United States)

Leather, A T; Studd, J W; Watson, N R; Holland, E F

1999-02-01

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.

Natural and archaeological analogues: a review

International Nuclear Information System (INIS)

Brookins, D.G.

1987-01-01

In this chapter natural analogues in the geomedia for various aspects of radioactive waste disposal are discussed. Particular reference is made to the Okla Natural Reactor in Gabon. Igneous contact zones are discussed and natural analogues of waste-form materials. The importance of archaeological remains and anthropogenic materials left by man, in assessing weathering conditions and serving as radioactive waste analogues, is also emphasised. (UK)

Neurochemical binding profiles of novel indole and benzofuran MDMA analogues.

Science.gov (United States)

Shimshoni, Jakob A; Winkler, Ilan; Golan, Ezekiel; Nutt, David

2017-01-01

3,4-Methylenedioxy-N-methylamphetamine (MDMA) has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) in numerous clinical trials. In the present study, we have characterized the neurochemical binding profiles of three MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; 1-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (1-(1H-indol-5-yl)-2-methylamino-propan-1-ol, 5-IT). These compounds were screened as potential second-generation anti-PTSD drugs, against a battery of human and non-human receptors, transporters, and enzymes, and their potencies as 5-HT 2 receptor agonist and monoamine uptake inhibitors determined. All MDMA analogues displayed high binding affinities for 5-HT 2a,b,c and NE α2 receptors, as well as significant 5-HT, DA, and NE uptake inhibition. 5-APB revealed significant agonist activity at the 5-HT 2a,b,c receptors, while 6-MAPB, 5-MAPB, and 5-IT exhibited significant agonist activity at the 5-HT 2c receptor. There was a lack of correlation between the results of functional uptake and the monoamine transporter binding assay. MDMA analogues emerged as potent and selective monoamine oxidase A inhibitors. Based on 6-MAPB favorable pharmacological profile, it was further subjected to IC 50 determination for monoamine transporters. Overall, all MDMA analogues displayed higher monoamine receptor/transporter binding affinities and agonist activity at the 5-HT 2a,c receptors as compared to MDMA.

Women with oligo-/amenorrhoea and polycystic ovaries have identical responses to GnRH stimulation regardless of their androgen status: comparison of the Rotterdam and Androgen Excess Society diagnostic criteria.

Science.gov (United States)

Lewandowski, Krzysztof C; Cajdler-Luba, Agata; Bieńkiewicz, Małgorzata; Lewiński, Andrzej

2011-01-01

As increased frequency of gonadotrophin-releasing hormone (GnRH) pulses is characteristic for polycystic ovary syndrome (PCOS), we assessed gonadotrophin response to GnRH in women with PCOS with normal and raised androgens and in regularly menstruating controls. The study involved 155 subjects: PCOS, n=121, age (mean±SD) 24.8±5.4 yrs, BMI 24.5±6.0 kg/m2, all with oligo-/amenorrhoea and PCO morphology, and 34 controls. Gonadotrophins were measured in early follicular phase after GnRH stimulation (0, 30 and 60 minutes). Fifty four (41.9%) women with PCOS had androgens (testosterone, androstendione, dihydroepiandrosterone sulphate) within the reference range, and would fulfil the "Rotterdam", but not the Androgen Excess Society PCOS criteria. Baseline and stimulated LH concentrations were higher in PCOS (9.09±5.56 vs 4.83±1.71 IU/l, 35.48±31.4 vs 16.30±6.68 IU/l, 33.86±31.8 vs 13.45±5.2 IU/l, at 0, 30 and 60 min post GnRH, respectively, pPCOS increased further after GnRH stimulation. ROC analysis revealed that LH30min/FSH30min >2.11 or LH60min/FSH60min >1.72 had 78.3% and 87.5% sensitivity and 81.7% and 81.3% specificity for diagnosis of PCOS. Both baseline and GnRH-stimulated LH and FSH concentrations were similar in women with PCOS and raised androgens and with androgens within the reference range (p=0.71 and p=0.20 for LH and FSH, respectively). Regardless of their androgen status, women with PCO morphology and oligo-/amenorrhoea have higher baseline and GnRH-stimulated LH concentrations and higher GnRH-stimulated LH/FSH ratio than controls, suggestive of similar underlying mechanism accounting for menstrual irregularities. These observations support validity of PCOS diagnostic criteria based on the Rotterdam consensus.

Split-time artificial insemination in beef cattle: III. Comparing fixed-time artificial insemination to split-time artificial insemination with delayed administration of GnRH in 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

2017-09-01

This experiment was designed to compare pregnancy rates in postpartum beef cows following split-time (STAI) or fixed-time (FTAI) artificial insemination. Estrus was synchronized for 671 cows at seven locations following administration of the 7-d CO-Synch + CIDR protocol (100 μg GnRH + CIDR insert [1.38 g progesterone] on d 0; 25 mg prostaglandin F 2α [PG] at CIDR removal on d 7). Cows were assigned to treatments that were balanced across locations based on age, body condition score, and days postpartum at the time treatments were initiated. All cows in treatment 1 (n = 333; FTAI) were inseminated at 66 h after PG and GnRH was administered concurrent with insemination regardless of estrus expression. For cows in treatment 2 (n = 338; STAI), inseminations were performed at 66 or 90 h after PG, and estrous status was recorded at these times. Cows in the STAI treatment that exhibited estrus by 66 h were inseminated at that time and did not receive GnRH, whereas AI was delayed 24 h until 90 h after PG for cows that failed to exhibit estrus by 66 h. Gonadotropin-releasing hormone (100 μg) was administered concurrent with AI at 90 h only to cows failing to exhibit estrus. Estrus expression that occurred during the 24 h delay period among cows assigned to the STAI treatment increased the total proportion of cows that expressed estrus prior to insemination (1 = 60%; 2 = 86%; P cows inseminated at 66 h that exhibited estrus did not differ between treatments (1 = 58%; 2 = 58%; P = 0.93); however, pregnancy rates among non-estrous cows at 66 h were improved (1 = 35%; 2 = 51%; P = 0.01) among cows assigned to the STAI treatment when insemination was postponed by 24 h. Consequently, total AI pregnancy rate tended to be higher for cows that received STAI (1 = 49%; 2 = 56%; P = 0.06). In summary, following administration of the 7-d CO-Synch + CIDR protocol, total estrous response increased and pregnancy rates resulting from AI

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

International Nuclear Information System (INIS)

Morgan, Kevin; Meyer, Colette; Miller, Nicola; Sims, Andrew H; Cagnan, Ilgin; Faratian, Dana; Harrison, David J; Millar, Robert P; Langdon, Simon P

2011-01-01

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. 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 125 I-ligand binding and stimulation of 3 H-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. 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 3 H-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. Breast cancers exhibit a range of GnRH-R immunostaining, with higher levels of

Novel Indole-based Tambjamine-Analogues Induce Apoptotic Lung Cancer Cell Death through p38 Mitogen-Activated Protein Kinase Activation.

Science.gov (United States)

Manuel-Manresa, Pilar; Korrodi-Gregório, Luís; Hernando, Elsa; Villanueva, Alberto; Martínez-García, David; Rodilla, Ananda M; Ramos, Ricard; Fardilha, Margarida; Moya, Juan; Quesada, Roberto; Soto-Cerrato, Vanessa; Pérez-Tomás, Ricardo

2017-07-01

Lung cancer has become the leading killer cancer worldwide, due to late diagnosis and lack of efficient anticancer drugs. We have recently described novel natural-derived tambjamine analogues that are potent anion transporters capable of disrupting cellular ion balance, inducing acidification of the cytosol and hyperpolarization of cellular plasma membranes. Although these tambjamine analogues were able to compromise cell survival, their molecular mechanism of action remains largely unknown. Herein we characterize the molecular cell responses induced by highly active indole-based tambjamine analogues treatment in lung cancer cells. Expression changes produced after compounds treatment comprised genes related to apoptosis, cell cycle, growth factors and its receptors, protein kinases and topoisomerases, among others. Dysregulation of BCL2 and BIRC5 /survivin genes suggested the apoptotic pathway as the induced molecular cell death mechanism. In fact, activation of several proapoptotic markers (caspase-9, caspase-3, and PARP) and reversion of the cytotoxic effect upon treatment with an apoptosis inhibitor (Z-VAD-FMK) were observed. Moreover, members of the Bcl-2 protein family suffered changes after tambjamine analogues treatment, with a concomitant protein decrease towards the prosurvival members. Besides this, it was observed cellular accumulation of ROS upon compound treatment and an activation of the stress-kinase p38 MAPK route that, when inhibited, reverted the cytotoxic effect of the tambjamine analogues. Finally, a significant therapeutic effect of these compounds was observed in subcutaneous and orthotopic lung cancer mice models. Taken together, these results shed light on the mechanism of action of novel cytotoxic anionophores and demonstrate the therapeutic effects against lung cancer. Mol Cancer Ther; 16(7); 1224-35. ©2017 AACR . ©2017 American Association for Cancer Research.

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

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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.

Journal of Biosciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

... releasing hormone (GnRH) would revolutionize drug formulation and delivery for a peptide analogue. This review examines some of the molecular targets that may change contraceptive choices in the future. Author Affiliations. Usha Natraj1. Institute for Research in Reproduction, JM Street, Parel, Mumbai 400 012, India ...

A Short Term Analogue Memory

DEFF Research Database (Denmark)

Shah, Peter Jivan

1992-01-01

A short term analogue memory is described. It is based on a well-known sample-hold topology in which leakage currents have been minimized partly by circuit design and partly by layout techniques. Measurements on a test chip implemented in a standard 2.4 micron analogue CMOS process show a droop...

Cytotoxicity Study of Cyclopentapeptide Analogues of Marine Natural Product Galaxamide towards Human Breast Cancer Cells

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Jignesh Lunagariya

2017-01-01

Full Text Available Herein, we report the cytotoxicity of cyclopentapeptide analogues of marine natural product galaxamide towards breast carcinoma cells and the underlying mechanisms. We examined the effect of the novel galaxamide analogues on cancer cell proliferation by MTT assay and also further examined the most active compound for morphological changes using Hoechst33342 staining technique, induction of apoptosis, cell cycle phases, mitochondrial membrane potential (MMP, and reactive oxygen species (ROS generation using flow cytometry in human breast cancer MCF-7 cells in vitro. Galaxamide and its analogues effectively induced toxicity in human hepatocellular carcinoma HepG2, human breast carcinoma MCF-7, human epitheloid cervix carcinoma HeLa, and human breast carcinoma MB-MDA-231 cell lines. Amongst them, compound 3 exhibited excellent toxicity towards MCF-7 cells. This galaxamide analogue significantly induced apoptosis in a dose-dependent manner in MCF-7 cells involves cell cycle arrest in the G1 phase, a reduction of MMP, and a marked increase in generation of ROS. Particularly, compound 3 of galaxamide analogues might be a potential candidate for the treatment of breast cancer.

The mucosal toxicity of different benzalkonium chloride analogues evaluated with an alternative test using slugs.

Science.gov (United States)

Adriaens, E; Dierckens, K; Bauters, T G; Nelis, H J; van Goethem, F; Vanparys, P; Remon, J P

2001-07-01

The objective of this study was to evaluate the mucosal toxicity of different benzalkonium chloride (BAC) analogues using slugs as the alternative test organism. The effect of different BAC analogues on the mucosal tissue of slugs was determined from the protein, lactate dehydrogenase, and alkaline phosphatase released from the foot mucosa after treatment. Additionally, mucus production and reduction in body weight of the slugs were measured. The eye irritation potency of the molecules was evaluated with the Bovine Corneal Opacity and Permeability (BCOP) assay. The antimicrobial activity of the different BAC analogues was also assessed. All BAC analogues induced severe damage to the mucosal epithelium of the slugs, and the irritation increased with decreasing alkyl chain length: BAC-C16 or = BAC-C16 > BAC-C12. The BAC-C14 exhibited higher activity than the BAC-mix. The toxicity and activity of BAC analogues depend on the alkyl chain length. The use of BAC-C14 as a conservative agent in pharmaceutical preparations instead of the BAC-mix should be considered.

Socially regulated reproductive development: analysis of GnRH-1 and kisspeptin neuronal systems in cooperatively breeding naked mole-rats (Heterocephalus glaber).

Science.gov (United States)

Zhou, Shuzhi; Holmes, Melissa M; Forger, Nancy G; Goldman, Bruce D; Lovern, Matthew B; Caraty, Alain; Kalló, Imre; Faulkes, Christopher G; Coen, Clive W

2013-09-01

In naked mole-rat (NMR) colonies, breeding is monopolized by the queen and her consorts. Subordinates experience gonadal development if separated from the queen. To elucidate the neuroendocrine factors underlying reproductive suppression/development in NMRs, we quantified plasma gonadal steroids and GnRH-1- and kisspeptin-immunoreactive (ir) neurons in subordinate adults and in those allowed to develop into breeders, with or without subsequent gonadectomy. In males and females, respectively, plasma testosterone and progesterone are higher in breeders than in subordinates. No such distinction occurs for plasma estradiol; its presence after gonadectomy and its positive correlation with adrenal estradiol suggest an adrenal source. Numbers of GnRH-1-ir cell bodies do not differ between gonad-intact breeders and subordinates within or between the sexes. As in phylogenetically related guinea pigs, kisspeptin-ir processes pervade the internal and external zones of the median eminence. Their distribution is consistent with actions on GnRH-1 neurons at perikaryal and/or terminal levels. In previously investigated species, numbers of kisspeptin-ir cell bodies vary from substantial to negligible according to sex and/or reproductive state. NMRs are exceptional: irrespective of sex, reproductive state, or presence of gonads, substantial numbers of kisspeptin-ir cell bodies are detected in the rostral periventricular region of the third ventricle (RP3V) and in the anterior periventricular (PVa), arcuate, and dorsomedial hypothalamic nuclei. Nevertheless, the greater number in the RP3V/PVa of female breeders compared with female subordinates or male breeders suggests that emergence from a hypogonadotrophic state in females may involve kisspeptin-related mechanisms similar to those underlying puberty or seasonal breeding in other species. Copyright © 2013 Wiley Periodicals, Inc.

Analogue to Digital and Digital to Analogue Converters (ADCs and DACs): A Review Update

CERN Document Server

Pickering, J.

2015-06-15

This is a review paper updated from that presented for CAS 2004. Essentially, since then, commercial components have continued to extend their performance boundaries but the basic building blocks and the techniques for choosing the best device and implementing it in a design have not changed. Analogue to digital and digital to analogue converters are crucial components in the continued drive to replace analogue circuitry with more controllable and less costly digital processing. This paper discusses the technologies available to perform in the likely measurement and control applications that arise within accelerators. It covers much of the terminology and 'specmanship' together with an application-oriented analysis of the realisable performance of the various types. Finally, some hints and warnings on system integration problems are given.

Quantum analogue computing.

Science.gov (United States)

Kendon, Vivien M; Nemoto, Kae; Munro, William J

2010-08-13

We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest

International Nuclear Information System (INIS)

Ujiki, Michael B.; Milam, Ben; Ding Xianzhong; Roginsky, Alexandra B.; Salabat, M. Reza; Talamonti, Mark S.; Bell, Richard H.; Gu Wenxin; Silverman, Richard B.; Adrian, Thomas E.

2006-01-01

Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer

A novel approach towards the synthesis of pyrophosphate analogues of farnesyl pyrophosphate

NARCIS (Netherlands)

Valentijn, A.R.P.M.; Berg, O. van den; Marel, G.A. van der; Cohen, L.H.; Boom, J.H. van

1994-01-01

The synthesis of two new analogues (i.e. 3 and 4) of farnesyl pyrophosphate (FPP) containing a phosphonophosphate and a phosphonophosphonate moiety was accomplished via the phosphonomorpholidate. The latter was easily obtained by treatment of a phosphonic chloride with morpholine.

Observational Study to Assess the Therapeutic Value of Four Ovarian Hyperstimulation Protocols in IVF After Pituitary Suppression with GnRH Antagonists in Normally Responding Women.

Science.gov (United States)

Ana, Monzó; Vicente, Montañana; María, Rubio José; Trinidad, García-Gimeno; Alberto, Romeu

2011-02-22

To compare the clinical results of four different protocols of COH for IVF-ICSI in normovulatory women, using in all cases pituitary suppression with GnRH antagonists. A single center, open label, parallel-controlled, prospective, post-authorization study under the approved conditions for use where 305 normal responders women who were candidates to COH were assigned to r-FSH +hp-hMG (n = 51, Group I), hp-hMG (n = 61, Group II), fixed-dose r-FSH (n = 118, Group III), and r-FSH with potential dose adjustment (n = 75, Group IV) to subsequently undergo IVF-ICSI. During stimulation, Group IV needed significantly more days of stimulation as compared to Group II [8.09 ± 1.25 vs. 7.62 ± 1.17; P women undergoing pituitary suppression with GnRH antagonists.

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

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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

An Analogue of the Antibiotic Teicoplanin Prevents Flavivirus Entry In Vitro

NARCIS (Netherlands)

De Burghgraeve, Tine; Kaptein, Suzanne J. F.; Ayala Nunez, Nilda V.; Mondotte, Juan A.; Pastorino, Boris; Printsevskaya, Svetlana S.; de Lamballerie, Xavier; Jacobs, Michael; Preobrazhenskaya, Maria; Gamarnik, Andrea V.; Smit, Jolanda M.; Neyts, Johan

2012-01-01

There is an urgent need for potent inhibitors of dengue virus (DENV) replication for the treatment and/or prophylaxis of infections with this virus. We here report on an aglycon analogue of the antibiotic teicoplanin (code name LCTA-949) that inhibits DENV-induced cytopathic effect (CPE) in a

BALANOL ANALOGUES

DEFF Research Database (Denmark)

1997-01-01

The present invention relates to a solid phase methodology for the preparation of a combinatorial library of structural analogues of the natural product balanol (ophiocordin, azepinostatin), which is a protein kinase C (PKC) and protein kinase A (PKA) inhibitor. The method comprises solid...

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.

Anti-Mullerian hormone levels do not predict response to pulsatile GnRH in women with hypothalamic amenorrhea.

Science.gov (United States)

Billington, Emma O; Corenblum, Bernard

2016-09-01

Pulsatile GnRH is used to induce ovulation in women with hypothalamic amenorrhea (HA), but tools to predict response are lacking. We assessed whether baseline AMH levels are associated with response to pulsatile GnRH in 16 women with HA. AMH levels were compared between non-responders and women who achieved follicular development or pregnancy. Median AMH for the cohort was 2.2 ng/mL. AMH levels were undetectable or low in four women, normal in nine and high in three. Follicular development was observed in 13 (81%) women (82% of cycles) and pregnancy achieved in 10 (63%) women (29% of cycles). All four women with low or undetectable AMH had follicular response and three achieved pregnancy. Of the 12 women with normal or high AMH, 10 had a follicular response and seven achieved pregnancy. Median AMH levels were comparable in those who achieved follicular development and those who did not (2.2 ng/mL versus 1.3 ng/mL, p = 0.78) and in those who became pregnant and those who did not (2.2 ng/mL versus 1.9 ng/mL, p = 0.52). In summary, low AMH does not preclude response to ovulation induction in women with HA, suggesting that ovarian potential may not be the primary determinant of AMH concentrations in this population.

Cephalostatin analogues--synthesis and biological activity.

Science.gov (United States)

Flessner, Timo; Jautelat, Rolf; Scholz, Ulrich; Winterfeldt, Ekkehard

2004-01-01

Starting off in the early 90's the field of cephalostatin analogues has continually expanded over the last 10 years. First syntheses prepared symmetric analogues like 14b (119) and 26 (65), which were subsequently desymmetrized to provide analogues like beta-hydroxy ketone 31 (19). Importantly the straightforward approach provided already compounds with mu-molar potency and the same pattern of activity as cephalostatin 1 (1) (see Chapter 2.1). Chemically more demanding, two new methods for the directed synthesis of (bissteroidal) pyrazines were devised and subsequently applied to a wide variety of differently functionalized coupling partners. These new methods allowed for the synthesis of various analogues (Chapter 2.2.; and, last but not least, for the totals synthesis of several cephalostatin natural products; Chapter 1.). Functionalization and derivatization of the 12-position was performed (Chapter 2.1 and 3) and synthetic approaches to establish the D-ring double bond were successfully investigated (Chapter 3). [figure: see text] Dealing synthetically with the spiroketal moiety, novel oxidative opening procedures on monomeric delta 14, 15-steroids were devised as well as intensive studies regarding spiroketal synthesis and spiroketal rearrangements were conducted (Chapter 3.2. and 4.). Last but not least direct chemical modification of ritterazines and cephalostatins were studied, which provided a limited number of ritterazine analogues (Chapter 4.). All these synthetic activities towards analogues are summarized in Fig. 18. During this period of time the growing number of cephalostatins and ritterazines on the one hand and of analogues on the other hand provided several SAR trends, which can guide future analogue synthesis. The combined SAR findings are displayed in Fig. 19. So far it is apparent that: Additional methoxylations or hydroxylations in the steroidal A ring core structure (1-position) are slightly decreasing activity (compare cephalostatin 1 1 to

Analogue to Digital and Digital to Analogue (AD/DA) Conversion Techniques: An Overview

CERN Multimedia

CERN. Geneva

2002-01-01

The basic ideas behind modern Analogue to Digital and Digital to Analogue (AD/DA) conversion methods will be introduced: a general view of the importance of these devices will be given, along with the digital representation of time-varying, real-world analogue signals. Some CERN applications will be outlined. The variety of conversion methods, their limitations, error sources and measurement methods will form the major part of this presentation. A review of the technological progress in this field over the last 30 years will be presented, concluding with the present 'state of the art' and a quick look at what is just around the corner. This Technical Training Seminar is in the framework of the FEED-2002 Lecture Series, and it is a prerequisite to attending to any of the FEED-2002 Terms. FEED-2002 is a two-term course that will review the techniques dealing with closed loop systems, focussing on time-invariant linear systems. (free attendance, no registration required) More information on the FEED-2002 ...

Doppler of the uterine arteries combined with endometrial thickness correlate well with the degree of pituitary suppression in women treated with long-acting GnRH agonists.

Science.gov (United States)

Geber, Selmo; Vaintraub, Marco Túlio; Rotschild, Gisele; Sampaio, Marcos

2013-02-01

The aim of this study was to evaluate the use of Doppler velocimetry of the uterine arteries and its association to endometrial thickness as a method to confirm pituitary suppression after administration of gonadotropin-releasing hormone analogues in assisted reproduction treatment cycles. A total of 70 patients using gonadotropin-releasing hormone analogues for pituitary suppression for in vitro fertilization treatment were studied. To confirm down-regulation, serum estradiol levels and endometrial thickness were evaluated 10 days after gonadotropin-releasing hormone analogues administration. When estradiol was 30 pg/ml the mean PI was 2.22 ± 0.8 (p = 0.005). For the patients who had endometrial thickness ≤5 mm the mean PI was 2.86 ± 0.82 and for those with endometrial thickness >5 mm the mean PI was 2.17 ± 0.79 (p = 0.004). Using a cut-off point of 2.51 for the pulsatility index, to compare to estradiol levels, we observed a sensitivity of 72.7 % and specificity of 71 %. The combination of Doppler velocimetric and endometrial thickness showed a sensitivity of 94 % and specificity of 82.3 %. Doppler velocimetric analysis of the uterine arteries can be an important tool in the diagnosis of the down-regulation after the use of gonadotropin-releasing hormone analogues and might help simplify assisted reproduction programmes.

Central precocious puberty: from physiopathological mechanisms to treatment.

Science.gov (United States)

Chirico, V; Lacquaniti, A; Salpietro, V; Buemi, M; Salpietro, C; Arrigo, T

2014-01-01

Puberty is a complex, coordinated biological process with multiple levels of regulations. The timing of puberty varies greatly in children and it is influenced by environmental, endocrine and genetic factors. Precocious puberty (PP) is an important issue, affecting between 1 in 5.000-10.000 children. The physiopathological mechanism is still unknown. From an etiological point of view, PP may be subdivided into gonadotropin-releasing hormone (GnRH) -dependent and independent causes. GnRH-dependent PP, often called central precocious puberty (CPP), is based on hypothalamic-pituitary-gonadal axis activation associated with progressive pubertal development, accelerated growth rate and advancement of skeletal age. Conversely, peripheral precocious puberty (PPP) is related to sex steroid exposure, independently of hypothalamic-–pituitary-–gonadal (HPG) axis activation. Kisspeptins play a central role in the modulation of GnRH secretion with peripheral factors that influence the timing of puberty, such as adipokines and endocrine disrupting chemicals. Moreover, PP could be related to genetic disorders, involving pivotal genes of the HPG axis. The standard test used to verify HPG activity is the gonadotropin response to administered GnRH analogs. We describe the physiopathological mechanisms of PP and its clinical implications, analysing diagnostic flow-chart and new potential biomarkers that could reveal PP. An update of the current literature was also carried out regarding the recent novelty for treatment.

International video project on natural analogues

International Nuclear Information System (INIS)

Guentensperger, Marcel

1993-01-01

A natural analogue can be defined as a natural process which has occurred in the past and is studied in order to test predictions about the future evolution of similar processes. In recent years, natural analogues have been used increasingly to test the mathematical models required for repository performance assessment. Analogues are, however, also of considerable use in public relations as they allow many of the principles involved in demonstrating repository safety to be illustrated in a clear manner using natural systems with which man is familiar. The international Natural Analogue Working Group (NAWG), organised under the auspices of the CEC, has recognised that such PR applications are of considerable importance and should be supported from a technical level. At the NAWG meeting in Pitlochry, Scotland (June 1990), it was recommended that the possibilities for making a video film on this topic be investigated and Nagra was requested to take the lead role in setting up such a project

Emission of bisphenol analogues including bisphenol A and bisphenol F from wastewater treatment plants in Korea.

Science.gov (United States)

Lee, Sunggyu; Liao, Chunyang; Song, Geum-Ju; Ra, Kongtae; Kannan, Kurunthachalam; Moon, Hyo-Bang

2015-01-01

Due to the regulation on bisphenol A (BPA) in several industrialized countries, the demand for other bisphenol analogues (BPs) as substitutes for BPA is growing. Eight BPs were determined in sludge from 40 representative wastewater treatment plants (WWTPs) in Korea. Total concentrations of BPs (ΣBP) in sludge ranged from bisphenol F (BPF), suggesting use of BPF in certain industrial products in Korea. No significant correlations were found between BPs and the WWTP characteristics. The average per-capita emissions of BPs ranged from 0.04 (BPP) to 886 g capita(-1) d (BPA) through WWTP discharges. The emission fluxes of ΣBP through industrial WWTPs were 2-3 orders of magnitudes higher than those calculated for domestic WWTPs, indicating that industrial discharges are the major source of BPs into the Korean environment. This is the first nationwide survey of BPs in sludge from Korean WWTPs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Activity of two chlorinated lincomycin analogues against chloroquine-resistant falciparum malaria in owl monkeys.

Science.gov (United States)

Powers, K G; Jacobs, R L

1972-01-01

The chloroquine-resistant Oak Knoll strain of Plasmodium falciparum, recently adapted to the owl monkey (Aotus trivirgatus), was insusceptible to chloroquine therapy. Two chlorinated lincomycin analogues tested in this host-parasite system cured blood-induced infections. Acute infections were treated orally for 7 consecutive days with either 15 or 75 mg of clindamycin hydrochloride (U-21) per kg per day, 10 or 50 mg of N-demethyl-4'-pentyl clindamycin hydrochloride (U-24) per kg per day, or 20 mg of chloroquine base per kg per day. These lincomycin analogues cleared trophozoites from the peripheral blood by the end of the 7-day treatment period. The speed of clearance of parasites was not dose-related, but curative activity appeared dependent upon the amount of drug given as well as the number of daily treatments. The efficacy of U-21 and U-24 is of particular interest since they represent major structural departures from compounds commonly used in the treatment of malaria.

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

Analogue Hawking radiation from astrophysical black-hole accretion

International Nuclear Information System (INIS)

Das, Tapas K

2004-01-01

We show that spherical accretion onto astrophysical black holes can be considered as a natural example of an analogue system. We provide, for the first time, an exact analytical scheme for calculating the analogue Hawking temperature and surface gravity for general relativistic accretion onto astrophysical black holes. Our calculation may bridge the gap between the theory of transonic astrophysical accretion and the theory of analogue Hawking radiation. We show that the domination of the analogue Hawking temperature over the actual Hawking temperature may be a real astrophysical phenomenon, though observational tests of this fact will at best be difficult and at worst might prove to be impossible. We also discuss the possibilities of the emergence of analogue white holes around astrophysical black holes. Our calculation is general enough to accommodate accreting black holes with any mass

Gonadotropin Releasing Hormone (GnRH) Neuron Migration: Initiation, Maintenance and Cessation as Critical Steps to Ensure Normal Reproductive Function

OpenAIRE

Wierman, Margaret E.; Kiseljak-Vassiliades, Katja; Tobet, Stuart

2010-01-01

GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over expression of candidate genes in mouse models. Importan...

Lateral line analogue aids vision in successful predator evasion for the brief squid, Lolliguncula brevis.

Science.gov (United States)

York, Carly A; Bartol, Ian K

2014-07-15

Cephalopods have visual and mechanoreception systems that may be employed to sense and respond to an approaching predator. While vision presumably plays the dominant role, the importance of the lateral line analogue for predator evasion has not been examined in cephalopods. To test the respective roles of vision and the lateral line analogue, brief squid, Lolliguncula brevis, were observed in the presence of summer flounder, Paralichthys dentatus, under light and dark conditions with their lateral line analogue intact and ablated. Hair cell ablation was achieved through a pharmacological technique used for the first time on a cephalopod. The proportion of predator-prey interactions survived was significantly higher in the light non-ablated and light ablated groups compared with the dark ablated group. The mean number of interactions survived varied across treatment groups with the light non-ablated group having significantly more success than the light ablated, dark non-ablated and dark ablated groups. These findings demonstrate that although vision is the primary sense, the lateral line analogue also contributes to predator evasion in squid. © 2014. Published by The Company of Biologists Ltd.

Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues.

Directory of Open Access Journals (Sweden)

Leonie Harmse

Full Text Available Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05. Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05, with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.

Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues.

Science.gov (United States)

Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; van Otterlo, Willem; Penny, Clement

2015-01-01

Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.

Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

Directory of Open Access Journals (Sweden)

Kinga Majchrzak

Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

Synthesis and biological evaluation of febrifugine analogues.

Science.gov (United States)

Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

2014-12-01

A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity.

The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma?

Science.gov (United States)

Guarnotta, Valentina; Martini, Chiara; Davì, Maria Vittoria; Pizza, Genoveffa; Colao, Annamaria; Faggiano, Antongiulio

2018-04-01

Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy. We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines. The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents. The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.

Assessment of six dissimilarity metrics for climate analogues

Science.gov (United States)

Grenier, Patrick; Parent, Annie-Claude; Huard, David; Anctil, François; Chaumont, Diane

2013-04-01

Spatial analogue techniques consist in identifying locations whose recent-past climate is similar in some aspects to the future climate anticipated at a reference location. When identifying analogues, one key step is the quantification of the dissimilarity between two climates separated in time and space, which involves the choice of a metric. In this communication, spatial analogues and their usefulness are briefly discussed. Next, six metrics are presented (the standardized Euclidean distance, the Kolmogorov-Smirnov statistic, the nearest-neighbor distance, the Zech-Aslan energy statistic, the Friedman-Rafsky runs statistic and the Kullback-Leibler divergence), along with a set of criteria used for their assessment. The related case study involves the use of numerical simulations performed with the Canadian Regional Climate Model (CRCM-v4.2.3), from which three annual indicators (total precipitation, heating degree-days and cooling degree-days) are calculated over 30-year periods (1971-2000 and 2041-2070). Results indicate that the six metrics identify comparable analogue regions at a relatively large scale, but best analogues may differ substantially. For best analogues, it is also shown that the uncertainty stemming from the metric choice does generally not exceed that stemming from the simulation or model choice. A synthesis of the advantages and drawbacks of each metric is finally presented, in which the Zech-Aslan energy statistic stands out as the most recommended metric for analogue studies, whereas the Friedman-Rafsky runs statistic is the least recommended, based on this case study.

Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'

DEFF Research Database (Denmark)

Nilsson, Lena; Andersen, A.N.; Lindenberg, Svend

2010-01-01

To enhance oocyte yield and pregnancy outcome in poor responder women undergoing IVF treatment, daily low dose GnRH antagonist administration was given during the late luteal phase to induce luteolysis and possibly secure a more synchronous cohort of recruitable follicles. An open extended pilot...

Modeling the Male Reproductive Endocrine Axis: Potential Role for a Delay Mechanism in the Inhibitory Action of Gonadal Steroids on GnRH Pulse Frequency.

Science.gov (United States)

Ferasyi, Teuku R; Barrett, P Hugh R; Blache, Dominique; Martin, Graeme B

2016-05-01

We developed a compartmental model so we could test mechanistic concepts in the control of the male reproductive endocrine axis. Using SAAM II computer software and a bank of experimental data from male sheep, we began by modeling GnRH-LH feed-forward and LH-T feedback. A key assumption was that the primary control signal comes from a hypothetical neural network (the PULSAR) that emits a digital (pulsatile) signal of variable frequency that drives GnRH secretion in square wave-like pulses. This model produced endocrine profiles that matched experimental observations for the testis-intact animal and for changes in GnRH pulse frequency after castration and T replacement. In the second stage of the model development, we introduced a delay in the negative feedback caused by the aromatization of T to estradiol at the brain level, a concept supported by empirical observations. The simulations showed how changes in the process of aromatization could affect the response of the pulsatile signal to inhibition by steroid feedback. The sensitivity of the PULSAR to estradiol was a critical factor, but the most striking observation was the effect of time delays. With longer delays, there was a reduction in the rate of aromatization and therefore a decrease in local estradiol concentrations, and the outcome was multiple-pulse events in the secretion of GnRH/LH, reflecting experimental observations. In conclusion, our model successfully emulates the GnRH-LH-T-GnRH loop, accommodates a pivotal role for central aromatization in negative feedback, and suggests that time delays in negative feedback are an important aspect of the control of GnRH pulse frequency.

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones.

Science.gov (United States)

Malik, Minnie; Britten, Joy; Cox, Jeris; Patel, Amrita; Catherino, William H

2016-01-01

To determine the effect of GnRH analogues (GnRH-a) leuprolide acetate (LA) and cetrorelix acetate on gonadal hormone-regulated expression of extracellular matrix in uterine leiomyoma three-dimensional (3D) cultures. Laboratory study. University research laboratory. Women undergoing hysterectomy for symptomatic leiomyomas. The 3D cell cultures, protein analysis, Western blot, immunohistochemistry. Expression of extracellular matrix proteins, collagen 1, fibronectin, and versican in leiomyoma cells 3D cultures exposed to E2, P, LA, cetrorelix acetate, and combinations for 24- and 72-hour time points. The 3D leiomyoma cultures exposed to E2 for 24 hours demonstrated an increased expression of collagen-1 and fibronectin, which was maintained for up to 72 hours, a time point at which versican was up-regulated significantly. Although P up-regulated collagen-1 protein (1.29 ± 0.04) within 24 hours of exposure, significant increase in all extracellular matrix (ECM) proteins was observed when the gonadal hormones were used concomitantly. Significant decrease in the amount of ECM proteins was observed on use of GnRH-a, LA and cetrorelix, with 24-hour exposure. Both the compounds also significantly decreased ECM protein concentration despite the presence of E2 or both gonadal hormones. This study demonstrates that GnRH-a directly affect the gonadal hormone-regulated collagen-1, fibronectin, and versican production in their presence. These findings suggest that localized therapy with GnRH-a may inhibit leiomyoma growth even in the presence of endogenous gonadal hormone exposure, thereby providing a mechanism to eliminate the hypoestrogenic side effects associated with GnRH-a therapy. Published by Elsevier Inc.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D₃ analogue in polymorphic light eruption.

Science.gov (United States)

Gruber-Wackernagel, A; Bambach, I; Legat, F J; Hofer, A; Byrne, S N; Quehenberger, F; Wolf, P

2011-07-01

Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)-induced immune suppression. Similar to UV radiation, calcitriol (1,25-dihydroxyvitamin D₃) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties. We performed a randomized double-blinded placebo-controlled intraindividual half-body trial (NCT00871052) to investigate the preventive effect of a calcipotriol-containing cream in PLE. Thirteen patients with PLE (10 women, three men; mean age 37 years) pretreated their skin on two symmetrically located test fields with calcipotriol or placebo cream twice daily for 7 days before the start of photoprovocation testing with solar-simulated UV radiation. We established a specific PLE test score [AA + SI + 0·4 P (range 0-12), where AA is affected area score (range 0-4), SI is skin infiltration score (range 0-4) and P is pruritus score on a visual analogue scale (range 0-10)] to quantify PLE severity. Photoprovocation led to PLE lesions in 12/13 (92%) patients. As shown by the PLE test score, compared with placebo calcipotrial pretreatment significantly reduced PLE symptoms in average by 32% (95% confidence interval 21-44%; P = 0·0022, exact Wilcoxon signed-rank test) throughout the observation period starting at 48 h until 144 h after the first photoprovocation exposure. At 48, 72 and 144 h calcipotriol pretreatment resulted in a lower PLE test score in 7 (58%), 9 (75%) and 10 (83%) of the 12 cases, respectively. Considering all time points together, calcipotriol diminished the PLE test score in all 12 photoprovocable patients (P = 0·0005; Wilcoxon signed-rank test). These results suggest a potential therapeutic benefit of topical 1,25-dihydroxyvitamin D₃ analogues as prophylactic treatment in patients with PLE. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

Synthesis and anticancer evaluation of spermatinamine analogues

KAUST Repository

Moosa, Basem; Sagar, Sunil; Li, Song; Esau, Luke; Kaur, Mandeep; Khashab, Niveen M.

2016-01-01

analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell

Activity of Two Chlorinated Lincomycin Analogues Against Chloroquine-Resistant Falciparum Malaria in Owl Monkeys1

Science.gov (United States)

Powers, Kendall G.; Jacobs, Richard L.

1972-01-01

The chloroquine-resistant Oak Knoll strain of Plasmodium falciparum, recently adapted to the owl monkey (Aotus trivirgatus), was insusceptible to chloroquine therapy. Two chlorinated lincomycin analogues tested in this host-parasite system cured blood-induced infections. Acute infections were treated orally for 7 consecutive days with either 15 or 75 mg of clindamycin hydrochloride (U-21) per kg per day, 10 or 50 mg of N-demethyl-4′-pentyl clindamycin hydrochloride (U-24) per kg per day, or 20 mg of chloroquine base per kg per day. These lincomycin analogues cleared trophozoites from the peripheral blood by the end of the 7-day treatment period. The speed of clearance of parasites was not dose-related, but curative activity appeared dependent upon the amount of drug given as well as the number of daily treatments. The efficacy of U-21 and U-24 is of particular interest since they represent major structural departures from compounds commonly used in the treatment of malaria. PMID:4207758

Insulin analogues in pregnancy and specific congenital anomalies

DEFF Research Database (Denmark)

de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa

2016-01-01

Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant...... women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we...... samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies. Copyright © 2015 John Wiley & Sons, Ltd....

Glucagon-like peptide-1 analogues: An overview

Directory of Open Access Journals (Sweden)

Vishal Gupta

2013-01-01

Full Text Available Abnormalities of the incretin axis have been implicated in the pathogenesis of type 2 diabetes mellitus. Glucagon-like peptide-1 (GLP-1 and gastroinhibitory intestinal peptide constitutes >90% of all the incretin function. Augmentation of GLP-1 results in improvement of beta cell health in a glucose-dependant manner (post-prandial hyperglycemia and suppression of glucagon (fasting hyperglycemia, amongst other beneficial pleiotropic effects. Native GLP-1 has a very short plasma half-life and novel methods have been developed to augment its half life, such that its anti-hyperglycemic effects can be exploited. They can be broadly classified as exendin-based therapies (exenatide, exenatide once weekly, DPP-4-resistant analogues (lixisenatide, albiglutide, and analogues of human GLP-1 (liraglutide, taspoglutide. Currently, commercially available analogues are exenatide, exenatide once weekly, and liraglutide. This review aims to provide an overview of most GLP-1 analogues.

Analogue circuits simulation

Energy Technology Data Exchange (ETDEWEB)

Mendo, C

1988-09-01

Most analogue simulators have evolved from SPICE. The history and description of SPICE-like simulators are given. From a mathematical formulation of the electronic circuit the following analysis are possible: DC, AC, transient, noise, distortion, Worst Case and Statistical.

Corifollitropin alfa compared to daily rFSH or HP-HMG in GnRH antagonist controlled ovarian stimulation protocol for patients undergoing assisted reproduction.

Science.gov (United States)

Souza, Priscila Morais Galvão; Carvalho, Bruno Ramalho de; Nakagawa, Hitomi Miura; Rassi, Thalita Reis Esselin; Barbosa, Antônio César Paes; Silva, Adelino Amaral

2017-06-01

This study aimed to compare the outcomes of controlled ovarian stimulation (COS) with corifollitropin alfa versus daily recombinant follicle-stimulating hormone (rRFSH) or highly purified human menopausal gonadotropin (HP-HMG) in patients undergoing in vitro fertilization (IVF) cycles based on gonadotropin-releasing hormone (GnRH) antagonist protocols. The primary endpoints were total number of oocytes and mature oocytes. This retrospective study looked into 132 controlled ovarian stimulation cycles from IVF or oocyte cryopreservation performed in a private human reproduction center between January 1 and December 31, 2014. Enrollment criteria: women aged 0.05). There were no significant differences in fertilization (76.9% vs. 76.8%, p=1.0), biochemical pregnancy (66.7% vs. 47.2%, p=0.1561) or embryo implantation rates (68.7% vs. 50%, p=0.2588) between the groups using corifollitropin alfa and rFSH or HMG, respectively. Corifollitropin alfa seems to be as effective as rFSH or HP-HMG when used in the first seven days of ovulation induction for patients undergoing assisted reproduction in GnRH antagonist protocols.

Uncertainties and credibility building of safety analyses. Natural analogues

International Nuclear Information System (INIS)

Laciok, A.

2001-07-01

The substance of natural analogues and their studies is defined as a complementary method to laboratory and in-situ experiments and modelling. The role of natural analogues in the processes of development of repositories is defined, mainly in performance assessment of repository system and communication with public. The criteria for identification of natural analogues which should be evaluated in the phase of initiation of new studies are specified. Review part of this report is divided to study of natural analogues and study of anthropogenic and industrial analogues. The main natural analogue studies performed in various countries, in different geological setting, with various aims are characterized. New results acquired in recently finished studies are included: Palmottu (2nd phase of project financed by European Commission), Oklo (results of research financed also by European Commission), Maqarin (3rd phase) and other information obtained from last meetings and workshops of NAWG. In view of the fact that programmes of development of deep repositories in Czech and Slovak Republics are interconnected, the natural analogues studies carried out in the Czech republic are incorporated in separate chapter - study of uranium accumulation in Tertiary clays at Ruprechtov site and study of degradation of natural glasses. In final part the areas of natural analogue studies as an integral part of development of deep geological repository are proposed along with characterization of broader context and aspects of realization of these studies (international cooperation, preparation and evaluation of procedures, communication with public). (author)

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS

Directory of Open Access Journals (Sweden)

Daniel Griffin

2017-12-01

Full Text Available Ovarian hyperstimulation syndrome (OHSS is an iatrogenic complication of controlled ovarian stimulation. The use of gonadotropin releasing hormone (GnRH agonist for the trigger of oocyte maturation is effective in the prevention of OHSS although it may result in a lower pregnancy rate. The use of adjuvant low dose human chorionic gonadotropin (hCG at the time of trigger or at the time of oocyte retrieval may improve pregnancy rates. The goal of this dual trigger study is to evaluate the safety and efficacy of the use of low dose hCG administered at the time of GnRH agonist trigger or 35 h later as well as the potential impact on pregnancy rates. The population will consist of 82 women undergoing IVF treatment who are at risk of developing OHSS. This study will be a single center prospective randomized double-blind placebo controlled trial. The randomization schedule will be administered by the Investigational Drug Services of the University. After controlled ovarian stimulation, induction of oocyte maturation will be achieved using a GnRH agonist and patients will be randomized to receive either low dose hCG 1000 IU at the time of trigger and placebo at oocyte retrieval (Study group or placebo at the time of trigger and hCG 1500 IU at the time of oocyte retrieval (Control group. The main outcomes will be live birth rates and incidence of OHSS. Two ancillary studies will include a quality of life survey and serum assessment of independent corpus luteum function.

ACTINOMYCIN D ANALOGUES

DEFF Research Database (Denmark)

1997-01-01

The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by $g...

Introduction to electronic analogue computers

CERN Document Server

Wass, C A A

1965-01-01

Introduction to Electronic Analogue Computers, Second Revised Edition is based on the ideas and experience of a group of workers at the Royal Aircraft Establishment, Farnborough, Hants. This edition is almost entirely the work of Mr. K. C. Garner, of the College of Aeronautics, Cranfield. As various advances have been made in the technology involving electronic analogue computers, this book presents discussions on the said progress, including some acquaintance with the capabilities of electronic circuits and equipment. This text also provides a mathematical background including simple differen

Trends in the use and cost of human and analogue insulins in a Colombian population, 2011-2015.

Science.gov (United States)

Torres, D R; Portilla, A; Machado-Duque, M E; Machado-Alba, J E

2017-12-01

Diabetes mellitus is a common disease among the general population and imposes considerable costs on health care systems. Insulin is used to treat type 1 diabetes mellitus and as an adjuvant to oral agents in advanced stages of type 2 diabetes mellitus. The objective was to describe the trends in use and cost of human and analogue insulins for Colombian patients. Descriptive retrospective analysis of prescriptions of human and analogue insulins on a monthly basis for the period from July 1, 2011 to February 2, 2015. Information was collected for the database population of two insurance companies. Frequencies and proportions were calculated; estimated economic impact was expressed as net cost and cost per thousand inhabitants per day. During the observation period, there was continuous growth in use of insulin, mainly in analogue forms (34.0% growth). At the start of the study, 10.4% of subjects were using an analogue insulin; this figure was 62.6% at the end of the study. In 2012, the average cost per 1000 inhabitants/day was US$1.7 for analogue and US$0.8 for human insulins. At the end of the observation period these costs had risen to US$9.2 for analogue (441.1% increase) and fallen to US$0.5 for human insulin (58.3% decrease). There has been an increase in the unit cost and frequency of use of insulin analogues for anti-diabetic therapy in Colombian patients. Moreover, there is controversy over whether insulin analogues are a more cost-effective treatment than human insulins for the general diabetic population. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

In vitro structure-activity relationship of Re-cyclized octreotide analogues

Energy Technology Data Exchange (ETDEWEB)

Dannoon, Shorouk F. [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Bigott-Hennkens, Heather M. [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Ma Lixin [Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); International Institute of Nano and Molecular Medicine, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Gallazzi, Fabio [Structural Biology Core, University of Missouri, Columbia, MO 65211 (United States); Lewis, Michael R., E-mail: lewismic@missouri.ed [Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States); Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Jurisson, Silvia S., E-mail: jurissons@missouri.ed [Department of Chemistry, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65211 (United States); Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO 65211 (United States)

2010-07-15

Introduction: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods: Various octreotide analogue sequences and coordination systems (e.g., S{sub 2}N{sub 2} and S{sub 3}N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with {sup 111}In-DOTA-Tyr{sup 3}-octreotide in AR42J rat pancreatic tumor cells yielded IC{sub 50} values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr{sup 3}-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. Results: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr{sup 3}-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS{sub 3} and N{sub 2}S{sub 2} coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of {sup 99m}Tc-cyclized analogue 4.

Influence of GnRH analogue on body mass index in girls with precocious puberty: a prospective study

Directory of Open Access Journals (Sweden)

Heshmat Moaieri

2014-06-01

Conclusion: Gonadotropin-releasing hormone analog (GnRHa therapy in central precocious puberty (CPP is safe for BMI and increasing of BMI is not significant, long- term follow-up study is required to elucidate whether GnRHa treatment affects adult obesity. Using growth hormone concomitantly, the effect on increasing height is significant.

A novel lunar bed rest analogue.

Science.gov (United States)

Cavanagh, Peter R; Rice, Andrea J; Licata, Angelo A; Kuklis, Matthew M; Novotny, Sara C; Genc, Kerim O; Englehaupt, Ricki K; Hanson, Andrea M

2013-11-01

Humans will eventually return to the Moon and thus there is a need for a ground-based analogue to enable the study of physiological adaptations to lunar gravity. An important unanswered question is whether or not living on the lunar surface will provide adequate loading of the musculoskeletal system to prevent or attenuate the bone loss that is seen in microgravity. Previous simulations have involved tilting subjects to an approximately 9.5 degrees angle to achieve a lunar gravity component parallel to the long-axis of the body. However, subjects in these earlier simulations were not weight-bearing, and thus these protocols did not provide an analogue for load on the musculoskeletal system. We present a novel analogue which includes the capability to simulate standing and sitting in a lunar loading environment. A bed oriented at a 9.5 degrees angle was mounted on six linear bearings and was free to travel with one degree of freedom along rails. This allowed approximately 1/6 body weight loading of the feet during standing. "Lunar" sitting was also successfully simulated. A feasibility study demonstrated that the analogue was tolerated by subjects for 6 d of continuous bed rest and that the reaction forces at the feet during periods of standing were a reasonable simulation of lunar standing. During the 6 d, mean change in the volume of the quadriceps muscles was -1.6% +/- 1.7%. The proposed analogue would appear to be an acceptable simulation of lunar gravity and deserves further exploration in studies of longer duration.

Causal structure of analogue spacetimes

International Nuclear Information System (INIS)

Barcelo, Carlos; Liberati, Stefano; Sonego, Sebastiano; Visser, Matt

2004-01-01

The so-called 'analogue models of general relativity' provide a number of specific physical systems, well outside the traditional realm of general relativity, that nevertheless are well-described by the differential geometry of curved spacetime. Specifically, the propagation of perturbations in these condensed matter systems is described by 'effective metrics' that carry with them notions of 'causal structure' as determined by an exchange of quasi-particles. These quasi-particle-induced causal structures serve as specific examples of what can be done in the presence of a Lorentzian metric without having recourse to the Einstein equations of general relativity. (After all, the underlying analogue model is governed by its own specific physics, not necessarily by the Einstein equations.) In this paper we take a careful look at what can be said about the causal structure of analogue spacetimes, focusing on those containing quasi-particle horizons, both with a view to seeing what is different from standard general relativity, and what the similarities might be. For definiteness, and because the physics is particularly simple to understand, we will phrase much of the discussion in terms of acoustic disturbances in moving fluids, where the underlying physics is ordinary fluid mechanics, governed by the equations of traditional hydrodynamics, and the relevant quasi-particles are the phonons. It must however be emphasized that this choice of example is only for the sake of pedagogical simplicity and that our considerations apply generically to wide classes of analogue spacetimes

Natural analogues and radionuclide transport model validation

International Nuclear Information System (INIS)

Lever, D.A.

1987-08-01

In this paper, some possible roles for natural analogues are discussed from the point of view of those involved with the development of mathematical models for radionuclide transport and with the use of these models in repository safety assessments. The characteristic features of a safety assessment are outlined in order to address the questions of where natural analogues can be used to improve our understanding of the processes involved and where they can assist in validating the models that are used. Natural analogues have the potential to provide useful information about some critical processes, especially long-term chemical processes and migration rates. There is likely to be considerable uncertainty and ambiguity associated with the interpretation of natural analogues, and thus it is their general features which should be emphasized, and models with appropriate levels of sophistication should be used. Experience gained in modelling the Koongarra uranium deposit in northern Australia is drawn upon. (author)

The Palmottu analogue project

International Nuclear Information System (INIS)

Ahonen, L.; Blomqvist, R.; Suksi, J.

1993-01-01

The report gives a summary of the results of investigations carried out in 1992 at the Palmottu natural analogue study site, which is a small U-Th mineralization in Nummi-Pusula, southwestern Finland. Additionally, the report includes several separate articles dealing with various aspects of the Palmottu Analogue Project: (1) deep groundwater flow, (2) interpretation of hydraulic connections, (3) characterization of groundwater colloids, (4) uranium mineral-groundwater equilibrium, (5) water-rock interaction and (6) modelling of in situ matrix diffusion. The Palmottu Analogue Project aims at a more profound understanding of radionuclide transport processes in fractured crystalline bedrock. The essential factors controlling transport are groundwater flow and interaction between water and rock. Accordingly, the study includes (1) structural interpretations partly based on geophysical measurements, (2) hydrological studies including hydraulic drill-hole measurements, (3) flow modelling, (4) hydrogeochemical characterization of groundwater, uranium chemistry and colloid chemistry, (5) mineralogical studies, (6) geochemical interpretation and modelling, (7) studies of radionuclide mobilization and retardation including matrix diffusion, and (8) modelling of uranium series data. Palaeohydrogeological aspects, due to the anticipated future glaciation of the Fennoscandian Shield, are of special interest. Quaternary sediments are studied to gain information on post-glacial migration in the overburden. (orig.)

Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy

NARCIS (Netherlands)

I.M. van der Sluis (Inge); A.M. Boot (Annemieke); E.P. Krenning (Eric); S.L.S. Drop (Stenvert); S.M.P.F. de Muinck Keizer-Schrama (Sabine)

2002-01-01

textabstractWe studied bone mineral density (BMD), bone metabolism, and body composition in 47 children with central precocious puberty (n = 36) or early puberty (n = 11) before, during, and after cessation of GnRH agonist. Bone density and body composition were measured with dual

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

Neuroprotective effects of an oxyntomodulin analogue in the MPTP mouse model of Parkinson's disease.

Science.gov (United States)

Liu, WeiZhen; Li, Yanwei; Jalewa, Jaishree; Saunders-Wood, Taylor; Li, Lin; Hölscher, Christian

2015-10-15

Oxyntomodulin is a hormone and a growth factor. It activates two receptors, the Glucagon-like peptide 1 (GLP-1) and the glucagon receptor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first positive results. D-Ser2-oxyntomodulin (Oxy) is a protease resistant oxyntomodulin analogue that has been developed to treat diabetes. Here we demonstrate for the first time that such analogues have neuroprotective effects. The drug showed protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected daily (20 mg/kg i.p.) for 7 days, and Oxy injected once-daily for 14 days i.p. Oxy treatment prevented or reversed the MPTP- induced motor impairment (Rotarod, spontaneous locomotion, swim activity, muscle strength test), the MPTP-induced reduction in Tyrosine Hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, the reduction of the synaptic marker synapstophysin, the inactivation of the growth factor kinase Akt/PKB and of the anti-apoptotic signaling molecule Bcl-2, and the increase of levels of the pro-inflammatory cytokine TNF-α. The results demonstrate that oxyntomodulin analogues show promise as a novel treatment of PD. Copyright © 2015 Elsevier B.V. All rights reserved.

The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

Directory of Open Access Journals (Sweden)

Bryan L Roth

Full Text Available In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS-2-(ethylamino-2-(3-methoxyphenylcyclohexanone and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenylcyclohexanamine and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenylcyclohexyl]piperidine and 1-[1-(4-methoxyphenylcyclohexyl]piperidine, were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects.

Application of natural analogues in the Yucca Mountain project - overview

International Nuclear Information System (INIS)

Simmons, Ardyth M.

2003-01-01

The Natural Analogue Synthesis Report (NASR) [1] provides a compilation of information from analogues that test, corroborate, and add confidence to process models and model predictions pertinent to total system performance assessment (TSPA). The report updated previous work [2] with new literature examples and results of quantitative studies conducted by the Yucca Mountain Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate greater understanding of processes expected to occur during postclosure of a proposed Yucca Mountain repository. Natural analogues, as used here, refer to either natural or anthropogenic systems in which processes similar to those expected to occur in a nuclear waste repository are thought to have occurred over long time periods (decades to millenia) and large spatial scales (up to tens of kilometers). In the past, the YMP has used analogues for testing and building confidence in conceptual and numerical process models in a number of ways. Yucca Mountain mineral alteration phases provided a self-analogue for postclosure alteration [3]. Thermodynamic parameters for silica minerals of the Wairakai, New Zealand geothermal field were added to databases used in geochemical modeling [4]. Scoping calculations of radionuclide transport using the Yucca Mountain TSPA numerical model were conducted for the Peqa Blanca site [5]. Eruption parameters from the Cerro Negro volcano, Nicaragua, were used to verify codes that model ash plume dispersion [6]. Analogues have also been used in supplemental science and performance analyses to provide multiple lines of evidence in support of both analyses and model reports (AMRs) [7]; in screening arguments for inclusion or exclusion of features, events, and processes (FEP)s in TSPAs; in the quantification of uncertainties [7]; in expert elicitations of volcanic and seismic hazards [8, 9] and in peer reviews [10]. Natural analogues may be applied

A review of preserved and preservative-free prostaglandin analogues for the treatment of open-angle glaucoma and ocular hypertension.

Science.gov (United States)

Hommer, A

2010-06-01

Glaucoma affects an increasing number of people worldwide and is the second leading cause of blindness. The aim of antiglaucoma therapy is to maintain a patient's visual function and quality of life. Prostaglandin analogues are first-line topical antiglaucoma therapy. They are effective at lowering intraocular pressure (IOP) and are generally well tolerated, with fewer systemic adverse events compared with the other classes. However, the use of prostaglandin analogues can be associated with ocular adverse effects, such as stinging/burning sensation, dry eyes, iris and periocular hyperpigmentation, and eye lash growth, which can affect patient compliance. Preservatives used in antiglaucoma preparations can have dose-dependent toxic effects, which contribute to adverse effects. The development of preservative-free preparations may reduce such adverse effects and therefore improve patient compliance. Tafluprost is a prostaglandin analogue in a preservative-free formulation that was recently approved for the reduction of elevated IOP in open-angle glaucoma and ocular hypertension. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Degarelix 240/80 mg: a new treatment option for patients with advanced prostate cancer

DEFF Research Database (Denmark)

Boccon-Gibod, Laurent; Iversen, Peter; Persson, Bo-Eric

2009-01-01

levels that can lead to clinical flare in patients with advanced disease. Degarelix (Firmagon is a new GnRH blocker that has recently been approved by the EMEA and US FDA for the treatment of men with hormone-sensitive advanced prostate cancer. In this article, we briefly review the Phase III trial data...

Synthesis and anticancer evaluation of spermatinamine analogues

KAUST Repository

Moosa, Basem

2016-02-04

Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcystiene carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5 - 10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines.

Insulin analogues in type 1 diabetes mellitus: getting better all the time.

Science.gov (United States)

Mathieu, Chantal; Gillard, Pieter; Benhalima, Katrien

2017-07-01

The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. This approach means that glucose sensing needs to be replaced and levels of insulin need to mimic physiological insulin-action profiles, including basal coverage and changes around meals. Training and educating patients are crucial for the achievement of good glycaemic control, but having insulin preparations with action profiles that provide stable basal insulin coverage and appropriate mealtime insulin peaks helps people with type 1 diabetes mellitus to live active lives without sacrificing tight glycaemic control. Insulin analogues enable patients to achieve this goal, as some have fast action profiles, and some have very slow action profiles, which gives people with type 1 diabetes mellitus the tools to achieve dynamic insulin-action profiles that enable tight glycaemic control with a risk of hypoglycaemia that is lower than that with human short-acting and long-acting insulins. This Review discusses the established and novel insulin analogues that are used to treat patients with type 1 diabetes mellitus and provides insights into the future development of insulin analogues.

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

Energy Technology Data Exchange (ETDEWEB)

Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, V 220, Rotterdam (Netherlands); Boerman, Otto C. [Radboud University Hospital, Department of Nuclear Medicine, Nijmegen (Netherlands)

2010-05-15

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

Localisation and mechanism of renal retention of radiolabelled somatostatin analogues

Energy Technology Data Exchange (ETDEWEB)

Melis, Marleen; Krenning, Eric P.; Bernard, Bert F.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Barone, Raffaella [UCL, Centre of Nuclear Medicine and Laboratory of PET, Brussels (Belgium); Visser, Theo J. [Erasmus MC, Department of Internal Medicine, Rotterdam (Netherlands)

2005-10-01

Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionuclide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues. For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1-24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [{sup 111}In-DTPA]octreotide, the effects of three inhibitory substances were explored in rats. Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The anti-megalin immunohistochemical staining pattern showed a strong similarity with the renal [{sup 111}In-DTPA]octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged d-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [{sup 111}In-DTPA]octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control. Renal retention of [{sup 111}In-DTPA]octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part. (orig.)

Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

International Nuclear Information System (INIS)

Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de; Boerman, Otto C.

2010-01-01

This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

Conformationally restrained aromatic analogues of fosmidomycin and FR900098.

Science.gov (United States)

Kurz, Thomas; Schlüter, Katrin; Pein, Miriam; Behrendt, Christoph; Bergmann, Bärbel; Walter, Rolf D

2007-07-01

The synthesis and in-vitro antimalarial activity of conformationally restrained bis(pivaloyloxymethyl) ester analogues of the natural product fosmidomycin is presented. In contrast to alpha-aryl-substituted analogues, conformationally restrained aromatic analogues exhibit only moderate in-vitro antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum. The most active derivative displays an IC(50) value of 47 microM.

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.

Science.gov (United States)

Benavides Valades, Gabriela; Ganswindt, Andre; Annandale, Henry; Schulman, Martin L; Bertschinger, Henk J

2012-08-25

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. 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). 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 (Pelephants. These results indicate that irregular oestrous cycles occur amongst free

Downscaling of surface moisture flux and precipitation in the Ebro Valley (Spain using analogues and analogues followed by random forests and multiple linear regression

Directory of Open Access Journals (Sweden)

G. Ibarra-Berastegi

2011-06-01

Full Text Available In this paper, reanalysis fields from the ECMWF have been statistically downscaled to predict from large-scale atmospheric fields, surface moisture flux and daily precipitation at two observatories (Zaragoza and Tortosa, Ebro Valley, Spain during the 1961–2001 period. Three types of downscaling models have been built: (i analogues, (ii analogues followed by random forests and (iii analogues followed by multiple linear regression. The inputs consist of data (predictor fields taken from the ERA-40 reanalysis. The predicted fields are precipitation and surface moisture flux as measured at the two observatories. With the aim to reduce the dimensionality of the problem, the ERA-40 fields have been decomposed using empirical orthogonal functions. Available daily data has been divided into two parts: a training period used to find a group of about 300 analogues to build the downscaling model (1961–1996 and a test period (1997–2001, where models' performance has been assessed using independent data. In the case of surface moisture flux, the models based on analogues followed by random forests do not clearly outperform those built on analogues plus multiple linear regression, while simple averages calculated from the nearest analogues found in the training period, yielded only slightly worse results. In the case of precipitation, the three types of model performed equally. These results suggest that most of the models' downscaling capabilities can be attributed to the analogues-calculation stage.

Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.

Directory of Open Access Journals (Sweden)

Syed Nuruddin

Full Text Available Research on Alzheimer's disease (AD has indicated an association between hormones of the hypothalamic-pituitary-gonadal (HPG axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh and its receptor (Gnrhr were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate. The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP mutations (tgArcSwe. At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental

Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio

Directory of Open Access Journals (Sweden)

Ryo eNishiguchi

2012-10-01

Full Text Available Gonadotropin-releasing hormone (GnRH is an evolutionarily conserved neuropeptide with 10 amino acid residues, of which several structural variants exist. A molecular form known as GnRH2 ([His5 Trp7 Tyr8]GnRH, also known as chicken GnRH II is widely distributed in vertebrates except for rodents, and has recently been implicated in the regulation of feeding behavior in goldfish. However, the influence of GnRH2 on feeding behavior in other fish has not yet been studied. In the present study, therefore, we investigated the role of GnRH2 in the regulation of feeding behavior in a zebrafish model, and examined its involvement in food intake after intracerebroventricular (ICV administration. ICV injection of GnRH2 at 0.1 and 1 pmol/g body weight (BW induced a marked decrease of food consumption in a dose-dependent manner during 30 min after feeding. Cumulative food intake was significantly decreased by ICV injection of GnRH2 at 1 pmol/g BW during the 30-min post-treatment observation period. The anorexigenic action of GnRH2 was completely blocked by treatment with the GnRH type I receptor antagonist Antide at 50 pmol/g BW. We also examined the effect of feeding condition on the expression level of the GnRH2 transcript in the hypothalamus. Levels of GnRH2 mRNA obtained from fish that had been provided excess food for 7 days were higher than those in fish that had been fed normally. These results suggest that, in zebrafish, GnRH2 acts as an anorexigenic factor, as is the case in goldfish.

U.S. Nuclear Regulatory Commission natural analogue research program

International Nuclear Information System (INIS)

Kovach, L.A.; Ott, W.R.

1995-01-01

This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process

Characterisation of insulin analogues therapeutically available to patients

KAUST Repository

Adams, Gary G.

2018-03-29

The structure and function of clinical dosage insulin and its analogues were assessed. This included \\'native insulins\\' (human recombinant, bovine, porcine), \\'fast-acting analogues\\' (aspart, glulisine, lispro) and \\'slow-acting analogues\\' (glargine, detemir, degludec). Analytical ultracentrifugation, both sedimentation velocity and equilibrium experiments, were employed to yield distributions of both molar mass and sedimentation coefficient of all nine insulins. Size exclusion chromatography, coupled to multi-angle light scattering, was also used to explore the function of these analogues. On ultracentrifugation analysis, the insulins under investigation were found to be in numerous conformational states, however the majority of insulins were present in a primarily hexameric conformation. This was true for all native insulins and two fast-acting analogues. However, glargine was present as a dimer, detemir was a multi-hexameric system, degludec was a dodecamer (di-hexamer) and glulisine was present as a dimer-hexamer-dihexamer system. However, size-exclusion chromatography showed that the two hexameric fast-acting analogues (aspart and lispro) dissociated into monomers and dimers due to the lack of zinc in the mobile phase. This comprehensive study is the first time all nine insulins have been characterised in this way, the first time that insulin detemir have been studied using analytical ultracentrifugation and the first time that insulins aspart and glulisine have been studied using sedimentation equilibrium. The structure and function of these clinically administered insulins is of critical importance and this research adds novel data to an otherwise complex functional physiological protein.

Fungal growth inhibitory properties of new phytosphingolipid analogues.

Science.gov (United States)

Mormeneo, D; Manresa, A; Casas, J; Llebaria, A; Delgado, A

2008-04-01

To study the growth inhibitory properties of a series of phytosphingosine (PHS) and phytoceramide (PHC) analogues. A panel of two yeast (Candida albicans and Saccharomyces cerevisiae) and six moulds (Aspergillus repens, Aspergillus niger, Penicillium chrysogenum, Cladosporium cladosporioides, Arthroderma uncinatum and Penicillium funiculosum) has been used in this study. A series of new PHS and PHC analogues differing at the sphingoid backbone and the functional group at C1 position were synthesized. Among PHS analogues, 1-azido derivative 1c, bearing the natural D-ribo stereochemistry, showed a promising growth inhibitory profile. Among PHC analogues, compound 12, with a bulky N-pivaloyl group and a Z double bond at C3 position of the sphingoid chain, was the most active growth inhibitor. Minimal inhibitory concentration values were in the range of 23-48 micromol l(-1) for 1c and 44-87 micromol l(-1) for 12. Only scattered data on the antifungal activity of phytosphingolipids have been reported in the literature. This is the first time that a series of analogues of this kind are tested and compared to discern their structural requirements for antifungal activity.

Final height after gonadotrophin releasing hormone agonist treatment for central precocious puberty : The Dutch experience

NARCIS (Netherlands)

Mul, D; Oostdijk, W; Otten, BJ; Rouwe, C; Jansen, M; Delemarre-van de Waal, HA; Waelkens, JJJ; Drop, SLS

Final height (FH) data of 96 children (87 girls) treated with GnRH agonist for central precocious puberty were studied. In girls mean FH exceeded initial height prediction by 7.4 (5.7) cm (p <0.001); FH was significantly lower than target height, but still in the genetic target range. When treatment

CO2 Capture with Enzyme Synthetic Analogue

Energy Technology Data Exchange (ETDEWEB)

Cordatos, Harry

2010-11-08

Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

Antineoplastic Activities of MT81 and Its Structural Analogue in Ehrlich Ascites Carcinoma-Bearing Swiss Albino Mice

Directory of Open Access Journals (Sweden)

Sujata Maiti Choudhury

2010-01-01

Full Text Available Many fungal toxins exhibit in vitro and in vivo antineoplastic effects on various cancer cell types. Luteoskyrin, a hydroxyanthraquinone has been proved to be a potent inhibitor against Ehrlich ascites tumor cells. The comparative antitumor activity and antioxidant status of MT81 and its structural analogue [Acetic acid-MT81 (Aa-MT81] having polyhydroxyanthraquinone structure were assessed against Ehrlich ascites carcinoma (EAC tumor in mice. The in vitro cytotoxicity was measured by the viability of EAC cells after direct treatment of the said compounds. In in vivo study, MT81 and its structural analogue were administered (i.p. at the two different doses (5, 7 mg MT81; 8.93, 11.48 mg Aa-MT81/kg body weight for 7 days after 24 hrs. of tumor inoculation. The activities were assessed using mean survival time (MST, increased life span (ILS, tumor volume, viable tumor cell count, peritoneal cell count, protein percentage and hematological parameters. Antioxidant status was determined by malondialdehyde (MDA and reduced glutathione (GSH content, and by the activity of superoxide dismutase (SOD and catalase (CA T. MT81 and its structural analogues increased the mean survival time, normal peritoneal cell count. They decreased the tumor volume, viable tumor cell count, hemoglobin percentage and packed cell volume. Differential counts of WBC, total counts of RBC & WBC that altered by EAC inoculation, were restored in a dose-dependent manner. Increased MDA and decreased GSH content and reduced activity of SOD, and catalase in EAC bearing mice were returned towards normal after the treatment of MT81 and its structural analogue. Being less toxic than parent toxin MT81, the structural analogue showed more prominent antineoplastic activities against EAC cells compared to MT81. At the same time, both compounds exhibit to some extent antioxidant potential for the EAC-bearing mice.

Insulin analogues with improved absorption characteristics.

Science.gov (United States)

Brange, J; Hansen, J F; Langkjaer, L; Markussen, J; Ribel, U; Sørensen, A R

1992-01-01

The insulin preparations available today are not ideal for therapy as s.c. injection does not provide a physiological insulin profile. With the aim to improve the absorption properties recombinant DNA technology has been utilized to design novel insulin molecules with changed physico-chemical characteristics and hence altered subcutaneous absorption kinetics. Soluble, long-acting human insulin analogues in which the isoelectric point has been increased from 5.4 to approx. 7 are absorbed very slowly, providing a more constant basal insulin delivery with lower day-to-day variation than present protracted preparations. In addition they have better storage stability. Rapid-acting human insulin analogues with largely reduced self-association are absorbed substantially faster from subcutaneous tissue than current regular insulin and thus are better suited for bolus injection. The absorption kinetics of these analogues have been able to explain the mechanism behind the dose effect on insulin absorption rate.

Natural analogue working group

International Nuclear Information System (INIS)

Come, B.; Chapman, N.

1986-01-01

A Natural Analogue Working Group was established by the Commission of the European Communities in 1985. The purpose of this group is to bring together modellers with earth scientists and others, so that maximum benefit can be obtained from natural analogue studies with a view to safe geological disposal of radioactive waste. The first meeting of this group was held in Brussels from November 5 to 7, 1985. The discussions mainly concerned the identification of the modellers' needs and of the earth scientists' capacity to provide for them. Following the debates, a written statement was produced by the Group; this document forms the core of the present Report. Notes and outlines of many of the presentations made are grouped in four appendixes. The valuable contribution of all those involved in the meeting is gratefully acknowledged

Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

Science.gov (United States)

Segal, Meirav; Fischer, Bilha

2012-02-28

Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

Evidence That Dopamine Acts via Kisspeptin to Hold GnRH Pulse Frequency in Check in Anestrous Ewes

Science.gov (United States)

Maltby, Matthew J.; Millar, Robert P.; Hileman, Stanley M.; Nestor, Casey C; Whited, Brant; Tseng, Ashlie S.; Coolen, Lique M.; Lehman, Michael N.

2012-01-01

Recent work has implicated stimulatory kisspeptin neurons in the arcuate nucleus (ARC) as important for seasonal changes in reproductive function in sheep, but earlier studies support a role for inhibitory A15 dopaminergic (DA) neurons in the suppression of GnRH (and LH) pulse frequency in the nonbreeding (anestrous) season. Because A15 neurons project to the ARC, we performed three experiments to test the hypothesis that A15 neurons act via ARC kisspeptin neurons to inhibit LH in anestrus: 1) we used dual immunocytochemistry to determine whether these ARC neurons contain D2 dopamine receptor (D2-R), the receptor responsible for inhibition of LH in anestrus; 2) we tested the ability of local administration of sulpiride, a D2-R antagonist, into the ARC to increase LH secretion in anestrus; and 3) we determined whether an antagonist to the kisspeptin receptor could block the increase in LH secretion induced by sulpiride in anestrus. In experiment 1, 40% of this ARC neuronal subpopulation contained D2-R in breeding season ewes, but this increased to approximately 80% in anestrus. In experiment 2, local microinjection of the two highest doses (10 and 50 nmol) of sulpiride into the ARC significantly increased LH pulse frequency to levels 3 times that seen with vehicle injections. Finally, intracerebroventricular infusion of a kisspeptin receptor antagonist completely blocked the increase in LH pulse frequency induced by systemic administration of sulpiride to anestrous ewes. These results support the hypothesis that DA acts to inhibit GnRH (and LH) secretion in anestrus by suppressing the activity of ARC kisspeptin neurons. PMID:23038740

Treatment of ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs, by sildenafil analogue (UK343-664 or nitroglycerin

Directory of Open Access Journals (Sweden)

Sidi Avner

2008-01-01

Full Text Available In patients at risk for sudden ethanol (ETOH intravascular absorption, prompt treatment of pulmonary hypertension (PHTN will minimise the risk of cardiovascular decompensation. We investigated the haemodynamic effects of intravenous ETOH and the pulmonary vasodilatory effects of a sildenafil analogue (UK343-664 and nitroglycerin (NTG during ETOH-induced PHTN in pigs. We studied pulmonary and systemic haemodynamics, and right ventricular rate or time derivate of pressure rise during ventricular contraction ( =dP/dT, as an index of contractility, in 23 pigs. ETOH was infused at a rate of 50 mg/kg/min, titrated to achieve a twofold increase in mean pulmonary arterial pressure (MPAP, and then discontinued. The animals were randomised to receive an infusion of 2 ml/kg ( n = 7 normal saline, a 500-μg/kg bolus of UK343-664 ( n = 8, or NTG 1 μg/kg ( n = 8; each was given over 60 seconds. Following ETOH infusion, dP/dT decreased central venous pressure (CVP, and MPAP increased significantly, resulting in significantly increased pulmonary vascular resistance (PVR. Within 2 minutes after treatment with either drug, CVP, heart rate (HR, and the systemic vascular resistance-to-pulmonary vascular resistance (SVR/PVR ratio returned to baseline. However, at that time, only in the UK343-664 group, MPAP and dP/dT partially recovered and were different from the respective values at PHTN stage. NTG and UK343-664 decreased PVR within 2 minutes, from 1241±579 and 1224±494 dyne · cm/sec 5 , which were threefold-to-fourfold increased baseline values, to 672±308 and 538±203 dyne · cm/sec 5 respectively. However, only in the UK343-664 group, changes from baseline PVR values after treatment were significant compared to the maximal change during target PHTN. Neither drug caused a significant change in SVR. In this model of ETOH-induced PHTN, both UK343-664 and NTG were effective pulmonary vasodilators with a high degree of selectivity. However, the changes from

Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial--ANRS HB02 VAC-ADN.

Science.gov (United States)

Fontaine, H; Kahi, S; Chazallon, C; Bourgine, M; Varaut, A; Buffet, C; Godon, O; Meritet, J F; Saïdi, Y; Michel, M L; Scott-Algara, D; Aboulker, J P; Pol, S

2015-01-01

The antiviral efficacy of nucleos(t)ide analogues whose main limitation is relapse after discontinuation requires long-term therapy. To overcome the risk of relapse and virological breakthrough during long-term therapy, we performed a phase I/II, open, prospective, multicentre trial using a HBV envelope-expressing DNA vaccine. 70 patients treated effectively with nucleos(t)ide analogues for a median of 3 years (HBV DNA 120 IU/mL) or impossibility of stopping treatment at week 48. Reactivation occurred in 97% of each group after a median 28 days without liver failure but with an HBV DNA <2000 IU/mL in 33%; 99% of adverse reactions were mild to moderate. Immune responses were evaluated by enzyme-linked immunosorbent spot and proliferation assays: there was no difference in the percentage of patients with interferon-γ secreting cells and a specific T-cell proliferation to HBcAg but not to HBsAg after reactivation in each group. Although it is fairly well tolerated, the HBV DNA vaccine does not decrease the risk of relapse in HBV-treated patients or the rate of virological breakthrough, and does not restore the anti-HBV immune response despite effective viral suppression by analogues. NCT00536627. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Peri-pubertal gonadotropin-releasing hormone agonist treatment affects sex biased gene expression of amygdala in sheep.

Science.gov (United States)

Nuruddin, Syed; Krogenæs, Anette; Brynildsrud, Ola Brønstad; Verhaegen, Steven; Evans, Neil P; Robinson, Jane E; Haraldsen, Ira Ronit Hebold; Ropstad, Erik

2013-12-01

The nature of hormonal involvement in pubertal brain development has attracted wide interest. Structural changes within the brain that occur during pubertal development appear mainly in regions closely linked with emotion, motivation and cognitive functions. Using a sheep model, we have previously shown that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) receptors, results in exaggerated sex-differences in cognitive executive function and emotional control, as well as sex and hemisphere specific patterns of expression of hippocampal genes associated with synaptic plasticity and endocrine signaling. In this study, we explored effects of this treatment regime on the gene expression profile of the ovine amygdala. The study was conducted with 30 same-sex twin lambs (14 female and 16 male), half of which were treated with the GnRH agonist (GnRHa) goserelin acetate every 4th week, beginning before puberty, until approximately 50 weeks of age. Gene expression profiles of the left and right amygdala were measured using 8×15 K Agilent ovine microarrays. Differential expression of selected genes was confirmed by qRT-PCR (Quantitative real time PCR). Networking analyses and Gene Ontology (GO) Term analyses were performed with Ingenuity Pathway Analysis (IPA), version 7.5 and DAVID (Database for Annotation, Visualization and integrated Discovery) version 6.7 software packages, respectively. GnRHa treatment was associated with significant sex- and hemisphere-specific differential patterns of gene expression. GnRHa treatment was associated with differential expression of 432 (|logFC|>0.3, adj. p value expressed as a result of GnRHa treatment in the male animals. The results indicated that GnRH may, directly and/or indirectly, be involved in the regulation of sex- and hemisphere-specific differential expression of genes in the amygdala. This finding should be considered when long-term peri-pubertal GnRHa treatment is used in children. Copyright �

A Low-cost Multi-channel Analogue Signal Generator

CERN Document Server

Müller, F; The ATLAS collaboration; Shen, W; Stamen, R

2009-01-01

A scalable multi-channel analogue signal generator is presented. It uses a commercial low-cost graphics card with multiple outputs in a standard PC as signal source. Each color signal serves as independent channel to generate an analogue signal. A custom-built external PCB was developed to adjust the graphics card output voltage levels for a specific task, which needed differential signals. The system furthermore comprises a software package to program the signal shape. The signal generator was successfully used as independent test bed for the ATLAS Level-1 Trigger Pre-Processor, providing up to 16 analogue signals.

Use of Insulin Analogues in Children and Adolescents: Topical Issues and Possibilities for Achieving Optimal Type 1 Diabetes Mellitus Compensation

OpenAIRE

О.A. Budreyko

2013-01-01

The review contains an analysis of the data of numerous scientific studies on the results of use of insulin analogues in comprehensive treatment of type 1 diabetes mellitus in children and adolescents. Problem of mitogenic potential of insulin preparations and ways to prevent its realization in clinical practice is discussed. Advisability of the use of insulin analogues glulisine and glargine in children and adolescents is substantiated for achievement of optimal compensation of carbohydrate ...

Serum Level of Antibodies Against Hepatitis B Core Protein Is Associated With Clinical Relapse After Discontinuation of Nucleos(t)ide Analogue Therapy.

Science.gov (United States)

Chi, Heng; Li, Zhandong; Hansen, Bettina E; Yu, Tao; Zhang, Xiaoyong; Sun, Jian; Hou, Jinlin; Janssen, Harry L A; Peng, Jie

2018-06-11

Levels of antibodies against the hepatitis B virus (HBV) core protein (anti-HBc) have been associated with response to nucleos(t)ide analogue and (peg)interferon therapy in patients with chronic HBV infection. We performed a prospective study to determine whether the total serum level of anti-HBc level (immunoglobulins M and G) is associated with clinical relapse after discontinuation of nucleos(t)ide analogue-based therapy. We collected data from patients with chronic HBV infection who discontinued nucleos(t)ide analogue therapy according to pre-specified stopping criteria, recruited from November 2012 through July 2016 at an academic hospital in Guangzhou, China. Patients were followed through February 2017. We performed comprehensive biochemical and virologic tests at every visit, and anti-HBc was quantified for 2 years after treatment cessation (at baseline and weeks 4, 8, 12, 24, 48, and 96). The primary endpoint was clinical relapse, defined as level of HBV DNA >2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal-these were also the criteria for retreatment. We followed 100 patients (71% positive for HB e antigen [HBeAg] at the start of nucleos(t)ide analogue therapy, 43% treated with entecavir or tenofovir) for a median of 2.5 years after stopping therapy. Clinical relapse occurred in 39 patients (in 46% of patients at year 4 after discontinuation). High level of anti-HBc at the end of treatment (hazard ratio [HR], 0.31 per log IU/mL; P=.002) and low level of HB surface antigen (HBsAg) at the end of treatment (HR, 1.71 per log IU/mL; P=.032) were associated with a reduced risk of clinical relapse after adjusting for age, start of nucleos(t)ide analogue therapy HBeAg-status, and consolidation therapy duration. At year 4, 21% of patients with anti-HBc levels at the end of treatment ≥1000 IU/mL developed a clinical relapse compared to 85% of patients with levels level at the end of treatment ≤100 IU/mL was associated

Effect of restricted protein diet supplemented with keto analogues in chronic kidney disease: a systematic review and meta-analysis.

Science.gov (United States)

Jiang, Zheng; Zhang, Xiaoyan; Yang, Lichuan; Li, Zi; Qin, Wei

2016-03-01

To evaluate the efficacy and safety of the restricted protein diet (low or very low protein diet) supplemented with keto analogues in the treatment of chronic kidney disease (CKD). The Cochrane library, PubMed, Embase, CBM and CENTRAL databases were searched and reviewed up to April 2015. Clinical trials were analyzed using RevMan 5.3 software. Seven random control trials, one cross-over trial and one non-randomized concurrent control trial were selected and included in this study according to our inclusion and exclusion criteria. The changes of eGFR, BUN, Scr, albumin, PTH, triglyceride, cholesterol, calcium, phosphorus and nutrition indexes (BMI, lean body mass and mid-arm muscular circumference) before and after treatment were analyzed. The meta-analysis results indicated that, comparing with normal protein diet, low protein diet (LPD) or very low protein diet (vLPD) supplemented with keto analogues (s(v)LPD) could significantly prevent the deterioration of eGFR (P diet supplemented with keto analogues (s(v)LPD) could delay the progression of CKD effectively without causing malnutrition.

[Spermatogenesis of pulsatile gonadotropin-releasing hormone infusion versus gonadotropin therapy in male idiopathic hypogonadotropic hypogonadism].

Science.gov (United States)

Huang, Bingkun; Mao, Jiangfeng; Xu, Hongli; Wang, Xi; Liu, Zhaoxiang; Nie, Min; Wu, Xueyan

2015-05-26

To compare the efficacies of pulsatile gonadotropin-releasing hormone (GnRH) versus human chorionic gonadotropin/human menopausal gonadotropin (HCG/HMG) for spermatogenesis in male idiopathic hypogonadotropic hypogonadism (IHH). For this retrospective study, a total of 92 male IHH outpatients from May 2010 to October 2014 were recruited and categorized into GnRH (n = 40) and HCG/HMG (n = 52) groups. Each subject selected one specific therapy voluntarily. The gonadotropin levels were measured in the first week and monthly post-treatment in GnRH group. And serum total testosterone (TT), testicular volume (TV) and rate of spermatogenesis were observed monthly post-treatment in two groups. Spermatogenesis, TT and TV were compared between two groups. All IHH patients were treated for over 3 months. The median follow-up periods in GnRH and HCG/HMG groups was 8.2 (3.0-18.4) and 9.2 (3.0-18.6) months respectively (P = 0.413). In GnRH group, LH ((0.5 ± 0.6) vs (3.4 ± 2.4) U/L, P treatment. In GnRH group, at the end of follow-up, TT ((1.0 ± 1.0) vs (7.4 ± 5.2) nmol/L, P treatment time for initial sperm appearance than HCG/HMG group ((6.5 ± 3.1) vs (10.8 ± 3.7) months, P = 0.001). Pulsatile GnRH requires a shorter time for initiation of spermatogenesis than gonadotropin therapy in IHH male patients.

Synthesis of an Orthogonal Topological Analogue of Helicene

DEFF Research Database (Denmark)

Wixe, Torbjörn; Wallentin, Carl‐Johan; Johnson, Magnus T.

2013-01-01

The synthesis of an orthogonal topological pentamer analogue of helicene is presented. This analogue forms a tubular structure with its aromatic systems directed parallel to the axis of propagation, which creates a cavity with the potential to function as a host molecule. The synthetic strategy r...

Phosphorylation of inositol 1,4,5-trisphosphate analogues by 3-kinase and dephosphorylation of inositol 1,3,4,5-tetrakisphosphate analogues by 5-phosphatase

NARCIS (Netherlands)

Dijken, Peter van; Lammers, Aleida A.; Ozaki, Shoichiro; Potter, Barry V.L.; Erneux, Christophe; Haastert, Peter J.M. van

1994-01-01

A series of P-32-labeled D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P-4] analogues was enzymically prepared from the corresponding D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-3] analogues using recombinant rat brain Ins(1,4,5)P-3 3-kinase and [gamma-P-32]ATP. Ins(1,4,5)P-3 analogues

On the robustness of entanglement in analogue gravity systems

International Nuclear Information System (INIS)

Bruschi, D E; Friis, N; Fuentes, I; Weinfurtner, S

2013-01-01

We investigate the possibility of generating quantum-correlated quasi-particles utilizing analogue gravity systems. The quantumness of these correlations is a key aspect of analogue gravity effects and their presence allows for a clear separation between classical and quantum analogue gravity effects. However, experiments in analogue systems, such as Bose–Einstein condensates (BECs) and shallow water waves, are always conducted at non-ideal conditions, in particular, one is dealing with dispersive media at non-zero temperatures. We analyse the influence of the initial temperature on the entanglement generation in analogue gravity phenomena. We lay out all the necessary steps to calculate the entanglement generated between quasi-particle modes and we analytically derive an upper bound on the maximal temperature at which given modes can still be entangled. We further investigate a mechanism to enhance the quantum correlations. As a particular example, we analyse the robustness of the entanglement creation against thermal noise in a sudden quench of an ideally homogeneous BEC, taking into account the super-sonic dispersion relations. (paper)

A preliminary feasibility study on natural analogue in Korea

Energy Technology Data Exchange (ETDEWEB)

Kim, Chun Soo; Bae, Dae Seok; Kim, Kyung Su; Koh, Yong Kwon; Park, Byung Yun

2000-03-01

Preliminary study on the assessment of natural analogue study in Korea for the deep geological disposal of high-level radioactive waste was carried out. The project on natural analogue study in other countries are introduced. The uranium-bearing deposit in Okcheon belt are summarized, which reported to be uranium-bearing minerals in order to assess to feasibility for natural analogue study in Korea. Among the uranium-bearing deposits, the Deokpyeong area, reported to be the highest reservoir and grade, are selected as the study site, and the elementary investigation, including survey of radioactivity and geochemistry are carried out. According to the investigation of surface environment, the radioactivity and uranium content in the surface water and shallow groundwater does not show any anormal values. However, the radioactivity is expected to be increased in depth and the groundwater reacted with uranium-bearing graphite formation shows high unanium content, indicating the potential possibility for natural analogue study in Korea. In future, if more detail study are performed, the assessment of natural analogue study in Korea are expected.

Analogue Signal Processing: Collected Papers 1994-95

DEFF Research Database (Denmark)

1996-01-01

This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of Electronics Institute, Technical University of Denmark, in 1994 and 1995.......This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of Electronics Institute, Technical University of Denmark, in 1994 and 1995....

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.

A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

Directory of Open Access Journals (Sweden)

Arno Verlee

2017-02-01

Full Text Available For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonylbenzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues.

On Using Current Steering Logic in Mixed Analogue-digital Circuits

DEFF Research Database (Denmark)

Lehmann, Torsten

1998-01-01

The authors investigate power supply noise in mixed analogue-digital circuits, arising from communication between the analogue and digital parts of the circuit. Current steering techniques and proper buffering are used to show which noise currents can be reduced and which cannot. In addition......, a high-swing current steering buffer for driving analogue switches or external digital signals is proposed....

Should we give up hormone treatment in menopause?

Directory of Open Access Journals (Sweden)

Mehmet Aral Atalay

2013-12-01

Full Text Available The first paper entitled intrauterine insemination (IUI was published in 1962. By time, several methods involving the technique and the ovulation induction schedules have evolved in order to improve the success rates. Although gonadotrophin releasing hormone antagonists (GnRHa is a crucial part of assisted reproductive treatments now, concerns also arouse regarding the need for the use of it in IUI cycles. These drugs may be considered in IUI programs basically in order to prevent premature LH surges and related cycle cancellations. Although administration of a GnRH antagonist almost completely abolishes premature luteinization, it does not substantially improve the pregnancy rate. The decision of using GnRH antagonists in IUI cycles should be based primarily on the local cost/benefit analysis of individual centers. It will be prudent to limit the involvement of the antagonists in ovulation induction protocols to: patients who frequently exhibit premature LH discharges and therefore either fail to complete treatment or result in unsuccessful outcome; initiated cycles intented for IUI but converted to ART; if it is not possible for logistic reasons (weekend to perform the insemination or for medical centers in which a gynecologist on call is not available and in order to decrease clinical task burden resulting from strict cycle monitoring such as serial transvaginal sonography and/or frequent urine tests.

UK Natural Analogue Coordinating Group: fourth annual report

International Nuclear Information System (INIS)

Read, D.; Hooker, P.J.

1992-01-01

HMIP has a research programme investigating some naturally radioactive sites as geochemical analogues of radionuclide migration. All of the analogue sites under investigation, both in the U.K. and overseas, are located where elevated uranium concentrations occur naturally. Coordination of the programme is achieved through the UK Natural Analogue Co-ordinating Group (NACG) which has met three times in this reporting period. The NACG is steered by the British Geological Survey. Its purpose is to ensure that the different research projects have an integrated function aimed at increasing our understanding of natural geochemical processes. Effort is also being expended in testing research models which may be used in such assessments. (author)

In Silico Screening and In Vitro Activity Measurement of Javamide Analogues as Potential p38 MAPK Inhibitors.

Science.gov (United States)

Park, Jae B

2017-12-13

p38 Mitogen-activated protein kinase (p38 MAPK) is a protein kinase critically involved in the progress of inflammation/stress-associated diseases. Our data suggested that javamide analogues may contain strong anti-inflammation activities, but there is little information about their effects on p38 MAPK. Therefore, in this paper, the effects of thirty javamide analogues on p38 MAPK were investigated using in silico screening and in vitro p38 MAPK assay methods. The javamide analogues were synthesized and their chemical structures were confirmed using nuclear magnetic resonance (NMR) spectroscopic methods. Then, the javamide analogues were screened using an in silico modeling program. The screened analogues demonstrated a wide range of binding energy (ΔE; -20 to -39) and several analogues with ΔE; -34 to -39 showed strong binding affinity to p38 MAPK. In vitro p38 MAPK assay, the kinase was significantly inhibited by the analogues with great binding energy (ΔE; -34 to -39) and in silico scores (Avg. score; -27.5 to -29.3). Furthermore, the comparative analysis of both assays showed a positive correlation between the in silico scores and p38 MAPK inhibition. In fact, the javamide analogues with top five in silico scores (Avg. score; -27.5 to -29.3) were found to inhibit p38 MAPK by 27-31% ( p silico score (Avg. score; -29.2) inhibited p38 MAPK (IC 50 = 9.9 μM) a little better than its methyl ester with best in silico score (Avg. score; -29.3). To support the ability to inhibit p38 MAPK, the treatment of javamide-II-ethyl and -methyl esters could suppress the production of IL-8 and MCP-1 protein significantly by 22-73% ( p silico and in vitro assay approach may be a useful and efficient solution as a functional screening approach in searching new lead compounds for targeted molecules.

Factors affecting synchronization and conception rate after the Ovsynch protocol in lactating Holstein cows.

Science.gov (United States)

Galvão, K N; Santos, J E P

2010-06-01

Objectives were to evaluate risk factors affecting ovulatory responses and conception rate to the Ovsynch protocol. Holstein cows, 466, were submitted to the Ovsynch protocol [day 0, GnRH-1; day 7, prostaglandin (PG) F(2alpha); day 9, GnRH-2] and 103 cows were inseminated 12 h after GnRH-2. Information on parity, days in milk at GnRH-1, body condition, milk yield, exposure to heat stress, pre-synchronization with PGF(2alpha) and the use of progesterone insert from GnRH-1 to PGF(2alpha) was collected. Ovaries were scanned to determine responses to treatments. Overall, 54.7%, 10.6%, 2.2%, 81.1%, 9.0%, 91.5% and 36.9% of the cows ovulated to GnRH-1, multiple ovulated to GnRH-1, ovulated before GnRH-2, ovulated to GnRH-2, multiple ovulated to GnRH-2, experienced corpus luteum (CL) regression and conceived, respectively. Ovulation to GnRH-1 was greater in cows without a CL at GnRH-1, cows with follicles >19 mm and cows not pre-synchronized with PGF(2alpha) 14 days before GnRH-1. Multiple ovulations to GnRH-1 increased in cows without CL at GnRH-1 and cows with follicles Conception rate at 42 days after AI increased in cows with body condition score > 2.75 and cows that ovulated to GnRH-2. Strategies that optimize ovulation to GnRH-2, such as increased ovulation to GnRH-1, should improve response to the Ovsynch protocol.

Progesterone concentration and lambing rate of Karakul ewes treated with prostaglandin and GnRH combined with the ram effect during breeding and non-breeding seasons.

Science.gov (United States)

Mirzaei, A; Mohebbi-Fani, M; Omidi, A; Boostani, A; Nazifi, S; Mahmoodian-Fard, H R; Chahardahcherik, M

2017-09-15

The combination of ram effect with two injections of PGF 2α 10-days apart and the same protocol plus an additional injection of GnRH prior to the first injection of PGF 2α were examined in Karakul ewes during breeding and non-breeding seasons, respectively. Plasma progesterone (P 4 ) concentrations (to detect the presence of active corpus luteum), twin lambing, litter size and synchronization of lambing were evaluated. In each study 70 ewes (2-4 years old) were divided to a treatment (n = 40) and a control (n = 30) group. During the breeding season, on days -10 and 0 before ram release, the treatment group was injected intramuscularly with PGF 2α (D-Cloprostenol; 0.15 mg). During the non-breeding season, on day -15 before ram release the treatment group was injected with GnRH (buserelin; 4.2 μg) intramuscularly followed by two injections of PGF 2α on days -10 and 0. In both studies, the rams were released into the ewe flock after the second prostaglandin injection (day 0). Blood samples of ewes were collected on days -10, 0, 20 and 70 of the study in breeding season and on days -15, -10, 0, 20 and 70 during non-breeding season. The treatment group had higher P 4 concentrations compared to the control ewes on day 0 in the breeding season (5.80 ± 0.61 vs. 5.0 ± 0.93 ng/mL) and day -10 in the non-breeding season (3.50 ± 0.33 vs. 2.70 ± 0.35 ng/mL) though the differences were not significant (P > 0.05). Based on plasma P 4 concentrations (>1 ng/mL) on day 70, in the breeding season all control ewes (100%) and 91.9% of the treatment ewes were detected to have active corpus luteum (P = 0.09). An almost inverse result (90% vs. 97.5%; P = 0.2) was detected in the non-breeding season. The lambing rate was higher (P = 0.03) in the treatment group compared to the control ewes during the non-breeding season (90% vs. 70%), but tended to be lower (P = 0.07) in the breeding season (73% vs. 90%). Twin lambing rate was higher in the

Valuing Treatments for Parkinson Disease Incorporating Process Utility: Performance of Best-Worst Scaling, Time Trade-Off, and Visual Analogue Scales.

Science.gov (United States)

Weernink, Marieke G M; Groothuis-Oudshoorn, Catharina G M; IJzerman, Maarten J; van Til, Janine A

2016-01-01

The objective of this study was to compare treatment profiles including both health outcomes and process characteristics in Parkinson disease using best-worst scaling (BWS), time trade-off (TTO), and visual analogue scales (VAS). From the model comprising of seven attributes with three levels, six unique profiles were selected representing process-related factors and health outcomes in Parkinson disease. A Web-based survey (N = 613) was conducted in a general population to estimate process-related utilities using profile-based BWS (case 2), multiprofile-based BWS (case 3), TTO, and VAS. The rank order of the six profiles was compared, convergent validity among methods was assessed, and individual analysis focused on the differentiation between pairs of profiles with methods used. The aggregated health-state utilities for the six treatment profiles were highly comparable for all methods and no rank reversals were identified. On the individual level, the convergent validity between all methods was strong; however, respondents differentiated less in the utility of closely related treatment profiles with a VAS or TTO than with BWS. For TTO and VAS, this resulted in nonsignificant differences in mean utilities for closely related treatment profiles. This study suggests that all methods are equally able to measure process-related utility when the aim is to estimate the overall value of treatments. On an individual level, such as in shared decision making, BWS allows for better prioritization of treatment alternatives, especially if they are closely related. The decision-making problem and the need for explicit trade-off between attributes should determine the choice for a method. Copyright © 2016. Published by Elsevier Inc.

Analogue computer display of accelerator beam optics

International Nuclear Information System (INIS)

Brand, K.

1984-01-01

Analogue computers have been used years ago by several authors for the design of magnetic beam handling systems. At Bochum a small analogue/hybrid computer was combined with a particular analogue expansion and logic control unit for beam transport work. This apparatus was very successful in the design and setup of the beam handling system of the tandem accelerator. The center of the stripper canal was the object point for the calculations, instead of the high energy acceleration tube a drift length was inserted into the program neglecting the weak focusing action of the tube. In the course of the installation of a second injector for heavy ions it became necessary to do better calculations. A simple method was found to represent accelerating sections on the computer and a particular way to simulate thin lenses was adopted. The analogue computer system proved its usefulness in the design and in studies of the characteristics of different accelerator installations over many years. The results of the calculations are in very good agreement with real accelerator data. The apparatus is the ideal tool to demonstrate beam optics to students and accelerator operators since the effect of a change of any of the parameters is immediately visible on the oscilloscope

Letrozole+ GnRH antagonist stimulation protocol in poor ovarian responders undergoing intracytoplasmic sperm injection cycles: An RCT

Directory of Open Access Journals (Sweden)

Mahbod Ebrahimi

2017-08-01

Full Text Available Background: Gonadotropin-releasing hormone (GnRH antagonist protocol has been proposed as a potentially proper option for the patients with limited ovarian reserve. Nevertheless, there is no significant difference in terms of clinical pregnancy between the GnRH antagonist and agonist cycles. The use of aromatase inhibitors such as letrozole was suggested by some studies. Objective: The object of this study was to evaluate the efficacy of letrozole cotreatment with GnRH-antagonist protocol in ovarian stimulation of poor responder patients undergoing intracytoplasmic sperm injection. Materials and Methods: A double-blinded randomized control trial was conducted on 70 infertile women with poor ovarian response based on Bologna criteria in two groups: letrozole+GnRH-antagonist (LA group and placebo+GnRH-antagonist (PA group (n=35/each. The LA group involved at letrozole 2.5 mg daily over 5 days and recombinant human follicle stimulating hormone 225 IU/daily. The PA group received placebo over 5 days and recombinant human follicle stimulating hormone at the same starting day and dose, similar to LA group. GnRH-antagonist was introduced once one or more follicle reached ≥14 mm. The main outcome measures were the number of oocytes retrieved, fertilization rate, implantation rate, cycle cancellation rate, and clinical pregnancy rate. Results: There were no significant differences in demographic characteristics between groups. There were no significant differences between groups regarding the number of oocytes retrieved (p=0.81, number of embryos transferred (p=0.82, fertilization rate (p=0.225, implantation rate (p=0.72, total cycle cancelation rate (p=0.08, and clinical pregnancy rate (p=0.12. Conclusion: The use of letrozole in GnRH-antagonist cycles does not improve clinical outcomes in poor responder patients undergoing intracytoplasmic sperm injection.

Analogue Signal Processing: Collected Papers 1996-97

DEFF Research Database (Denmark)

1997-01-01

This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of the Department of Information Technology, Technical University of Denmark, in 1996 and 1997.......This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of the Department of Information Technology, Technical University of Denmark, in 1996 and 1997....

Chemopreventive properties of curcumin analogues ...

African Journals Online (AJOL)

Chemopreventive properties of curcumin analogues, ... These compounds .... using microscope with 400 × magnification. APC ... Figure 3: Microscopic images of rat colorectal tissue stained with APC rabbit polyclonal antibody with different.

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

Science.gov (United States)

Janáky, T; Juhász, A; Bajusz, S; Csernus, V; Srkalovic, G; Bokser, L; Milovanovic, S; Redding, T W; Rékási, Z; Nagy, A

1992-02-01

In an attempt to produce better cytotoxic analogues, chemotherapeutic antineoplastic radicals including an alkylating nitrogen mustard derivative of D-phenylalanine (D-melphalan), reactive cyclopropane, anthraquinone derivatives [2-(hydroxymethyl)anthraquinone and the anticancer antibiotic doxorubicin], and an antimetabolite (methotrexate) were coupled to suitably modified agonists and antagonists of luteinizing hormone-releasing hormone (LH-RH). Analogues with D-lysine6 and D-ornithine6 or N epsilon-(2,3-diaminopropionyl)-D-lysine and N delta-(2,3-diaminopropionyl)-D-ornithine were used as carriers for one or two cytotoxic moieties. The enhanced biological activities produced by the incorporation of D amino acids into position 6 of the agonistic analogues were further increased by the attachment of hydrophobic cytotoxic groups, resulting in compounds with 10-50 times higher activity than LH-RH. Most of the monosubstituted agonistic analogues showed high affinities for the membrane receptors of human breast cancer cells, while the receptor binding affinities of peptides containing two cytotoxic side chains were lower. Antagonistic carriers [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,D-Lys6,D-Ala10] LH-RH [where Nal(2) is 3-(2-naphthyl)alanine], [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Trp3,Arg5,N epsilon-(2,3-diaminopropionyl)-D-Lys6,D-Ala10]LH-RH, and their D-Pal(3)3 homologs [Pal(3) is 3-(3-pyridyl)alanine] as well as [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,Tyr5,N epsilon-(2,3-diamino-propionyl)-D-Lys6,D-Ala10]LH-RH were linked to cytotoxic compounds. The hybrid molecules inhibited ovulation in rats at doses of 10 micrograms and suppressed LH release in vitro. The receptor binding of cytotoxic analogues was decreased compared to the precursor peptides, although analogues with 2-(hydroxymethyl)anthraquinone hemiglutarate had high affinities. All of the cytotoxic analogues tested inhibited [3H]thymidine incorporation into DNA in cultures of human breast and prostate cancer cell lines

Insulin analogues and severe hypoglycaemia in type 1 diabetes

DEFF Research Database (Denmark)

Kristensen, P L; Hansen, L S; Jespersen, M J

2012-01-01

The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed...

Safety Extension Study Of Leuprolide Acetate (Lupron Depot) In The Treatment Of Central Precocious Puberty

Science.gov (United States)

2014-01-08

Precocious; Leuprolide Acetate; Luteinizing Hormone (LH); Gonadotrophin-releasing Hormone Agonist (GnRHa); Tanner Staging; Depot Formulation; Suppression of LH; Central Precocious Puberty (CPP); Gonadotrophin-releasing Hormone (GnRH); Lupron; GnRH Analog; Pediatrics Central Precocious Puberty

How stakeholders view the use of analogues in safety cases: PAMINA

International Nuclear Information System (INIS)

Atherton, Elizabeth; Bailey, Lucy

2008-01-01

The aim of this presentation is to provide an overview of some research that has been undertaken in the UK to investigate stakeholders' views of analogues. There are various reasons for using analogues including: to try and explain difficult concepts; to compare disposal facility features with familiar and/or natural systems; to provide an alternative, non-numerical line of reasoning to support the Safety Case conclusions; to provide evidence of behaviour over very long timescales, that cannot be achieved in the laboratory. There are some dangers when using analogues that people should be aware of: the analogue conditions may not be the same as those found in a disposal facility, so the analogue may have limited application. Some analogues may have negative implications, for example artefacts that have corroded. Analogues can be taken too far and used in inappropriate ways to try and support an assumption. So it is important to find out how stakeholders view the use of analogues in a safety case. NDA is involved in an EC funded project called Pamina (Performance Assessment Methodologies in Application). The project involves 26 partners from 11 European countries, plus other associated members and runs for 3 years from October 2006 to October 2009. The NDA is involved in several parts of the project: Exploring issues of modelling uncertainty; Evaluating effectiveness of approaches for communicating safety cases with stakeholders. NDA ran a workshop in October 2007 in Manchester. The aims of the workshop were to explore how different methods of communicating aspects of a safety case were received by stakeholders. The workshop presented stakeholders with: Examples of different repository concepts; Descriptions of barrier performance; Different ways of presenting numerical results; Use of natural analogues

Defining reference conditions for acidified waters using a modern analogue approach

International Nuclear Information System (INIS)

Simpson, Gavin L.; Shilland, Ewan M.; Winterbottom, Julie M.; Keay, Janey

2005-01-01

Analogue matching is a palaeolimnological technique that aims to find matches for fossil sediment samples from a set of modern surface sediment samples. Modern analogues were identified that closely matched the pre-disturbance conditions of eight of the UK Acid Waters Monitoring Network (AWMN) lakes using diatom- and cladoceran-based analogue matching. These analogue sites were assessed in terms of hydrochemistry, aquatic macrophytes and macro-invertebrates as to their suitability for defining wider hydrochemical and biological reference conditions for acidified sites within the AWMN. The analogues identified for individual AWMN sites show a close degree of similarity in terms of their hydrochemical characteristics, aquatic macrophytes and, to a lesser extent, macro-invertebrate fauna. The reference conditions of acidified AWMN sites are inferred to be less acidic than today and to support a wider range of acid-sensitive aquatic macrophyte and macro-invertebrate taxa than that recorded in the AWMN lakes over the period of monitoring since 1988. - The use of a palaeolimnological technique to identify modern ecological reference analogues for acidified lakes is demonstrated

Changes in proliferating and apoptotic markers of leiomyoma following treatment with a selective progesterone receptor modulator or gonadotropin-releasing hormone agonist.

Science.gov (United States)

Yun, Bo Seong; Seong, Seok Ju; Cha, Dong Hyun; Kim, Ji Yeon; Kim, Mi-La; Shim, Jeong Yun; Park, Ji Eun

2015-08-01

To evaluate changes in proliferating and apoptotic markers of myoma tissue from patients treated with a selective progesterone receptor modulator (SPRM) or GnRH agonist by measuring expression of PDGF-A mRNA, IGF-1 mRNA, bcl-2 mRNA, and PCNA and caspase-3 protein. Between December 2013 and July 2014, women with symptomatic leiomyoma were divided into control (no treatment before surgery), SPRM (treatment with ulipristal acetate [SPRM] for 3 months before surgery), and GnRHa (treatment with leuprolide acetate [GnRH agonist] for 3 months before surgery) groups. Tissue specimens were collected from the myoma core and normal myometrium of all patients. The expression of mRNA and protein was assessed by quantitative real-time reverse transcriptase-polymerase chain reaction and Western blot. A total of 38 patients were enrolled (control group, n=14; SPRM group, n=13; GnRHa group, n=11). PDGF-A mRNA expression was lower in both the myoma core and normal myometrium tissues of the SPRM compared with the control group, but there was no difference between the control and GnRHa group. There were also no group differences in bcl-2 mRNA or IGF-1 mRNA expression. Both PCNA and caspase-3 protein expression were higher in the leiomyoma tissue of the SPRM compared with the control group, but there was no difference between the control and GnRHa groups in the expression of either protein. Both proliferation and apoptosis were increased in the leiomyoma of patients after SPRM treatment, but there was no change following GnRH agonist treatment, in vivo. However, PDGF-A mRNA was decreased after SPRM treatment, indicating a dual effect of progesterone on the regulation of growth factors. Furthermore, there was an increase in caspase-3 protein, but not bcl-2 mRNA, expression in the SPRM group suggesting that SPRM may exert its effects in pathways other than the bcl-2 apoptotic pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Modern treatment of short bowel syndrome

DEFF Research Database (Denmark)

Jeppesen, Palle B

2013-01-01

Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use.......Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use....

Alligator Rivers Analogue project. Application of scenario development method in evaluation of the Koongarra Analogue. Final Report - Volume 16

Energy Technology Data Exchange (ETDEWEB)

Skagius, K [Kemakta Consultants co., Stockholm (Sweden); Wingefors, S [Swedish Nuclear Power Inspectorate, Stockholm (Sweden)

1993-12-31

The study of natural analogues has been established as one of the most important methods for validation of concepts and models applied for the assessment of long-term performance of repositories for nuclear waste. The objectives of such studies range from detailed investigations of processes and features on a small scale to attempts of explaining the evolution of whole sites. For studies of specific processes it may well be as important to consider the larger scale settings as boundary conditions. This appreciation of context and an integrated view may be as important for evaluation of most natural analogues as for performance assessments. This is more evident the more the evaluation depends on a knowledge about the evolution of the natural analogue. The attempted formulation of scenarios of the Koongarra Analogue has been based on the external conditions and external features. A rapid weathering of the host rock, i.e. the chlorite schist, is assumed to have started around the onset of the Pleistocene Ice Age (ca 1.6 Ma BP). The eventual oxidation and mobilization of the uranium ore could then have occurred under unsaturated or saturated conditions. This leads to the following major scenarios: (1) Uranyl Phosphates formed under unsaturated conditions, with a periodical evolution of the dispersion fan in conjunction with alternating dry (glacial) and wet (interglacial) periods during the Pleistocene Ice Age; (2) Uranyl Phosphates formed under unsaturated conditions as a single event, taking place either early or late during the Pleistocene Ice Age; (3)Uranyl Phosphates formed under saturated conditions, in conjunction with periods of higher and lower flow due to the climatic cycling. Although the original objectives may not have been fully achieved, this work is believed to contribute to a better understanding of the Koongarra Analogue as well as to give a basis for further scenario work

Alligator Rivers Analogue project. Application of scenario development method in evaluation of the Koongarra Analogue. Final Report - Volume 16

Energy Technology Data Exchange (ETDEWEB)

Skagius, K. [Kemakta Consultants co., Stockholm (Sweden); Wingefors, S. [Swedish Nuclear Power Inspectorate, Stockholm (Sweden)

1992-12-31

The study of natural analogues has been established as one of the most important methods for validation of concepts and models applied for the assessment of long-term performance of repositories for nuclear waste. The objectives of such studies range from detailed investigations of processes and features on a small scale to attempts of explaining the evolution of whole sites. For studies of specific processes it may well be as important to consider the larger scale settings as boundary conditions. This appreciation of context and an integrated view may be as important for evaluation of most natural analogues as for performance assessments. This is more evident the more the evaluation depends on a knowledge about the evolution of the natural analogue. The attempted formulation of scenarios of the Koongarra Analogue has been based on the external conditions and external features. A rapid weathering of the host rock, i.e. the chlorite schist, is assumed to have started around the onset of the Pleistocene Ice Age (ca 1.6 Ma BP). The eventual oxidation and mobilization of the uranium ore could then have occurred under unsaturated or saturated conditions. This leads to the following major scenarios: (1) Uranyl Phosphates formed under unsaturated conditions, with a periodical evolution of the dispersion fan in conjunction with alternating dry (glacial) and wet (interglacial) periods during the Pleistocene Ice Age; (2) Uranyl Phosphates formed under unsaturated conditions as a single event, taking place either early or late during the Pleistocene Ice Age; (3)Uranyl Phosphates formed under saturated conditions, in conjunction with periods of higher and lower flow due to the climatic cycling. Although the original objectives may not have been fully achieved, this work is believed to contribute to a better understanding of the Koongarra Analogue as well as to give a basis for further scenario work

Alligator Rivers Analogue project. Application of scenario development method in evaluation of the Koongarra Analogue. Final Report - Volume 16

International Nuclear Information System (INIS)

Skagius, K.; Wingefors, S.

1992-01-01

The study of natural analogues has been established as one of the most important methods for validation of concepts and models applied for the assessment of long-term performance of repositories for nuclear waste. The objectives of such studies range from detailed investigations of processes and features on a small scale to attempts of explaining the evolution of whole sites. For studies of specific processes it may well be as important to consider the larger scale settings as boundary conditions. This appreciation of context and an integrated view may be as important for evaluation of most natural analogues as for performance assessments. This is more evident the more the evaluation depends on a knowledge about the evolution of the natural analogue. The attempted formulation of scenarios of the Koongarra Analogue has been based on the external conditions and external features. A rapid weathering of the host rock, i.e. the chlorite schist, is assumed to have started around the onset of the Pleistocene Ice Age (ca 1.6 Ma BP). The eventual oxidation and mobilization of the uranium ore could then have occurred under unsaturated or saturated conditions. This leads to the following major scenarios: (1) Uranyl Phosphates formed under unsaturated conditions, with a periodical evolution of the dispersion fan in conjunction with alternating dry (glacial) and wet (interglacial) periods during the Pleistocene Ice Age; (2) Uranyl Phosphates formed under unsaturated conditions as a single event, taking place either early or late during the Pleistocene Ice Age; (3)Uranyl Phosphates formed under saturated conditions, in conjunction with periods of higher and lower flow due to the climatic cycling. Although the original objectives may not have been fully achieved, this work is believed to contribute to a better understanding of the Koongarra Analogue as well as to give a basis for further scenario work

Cobalamin analogues in humans

DEFF Research Database (Denmark)

Hardlei, Tore Forsingdal; Obeid, Rima; Herrmann, Wolfgang

2013-01-01

BACKGROUND: Haptocorrin (HC) carries cobalamin analogues (CorA), but whether CorA are produced in the body is unknown. All cobalamins (Cbl) to the foetus are delivered by the Cbl-specific protein transcobalamin (TC), and therefore analysis of cord serum for CorA may help to clarify the origin...

Concise synthesis of new bridged-nicotine analogues

DEFF Research Database (Denmark)

Crestey, François; Hooyberghs, Geert; Kristensen, Jesper Langgaard

2012-01-01

This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively.......This study describes a very efficient strategy for the synthesis of two new bridged-nicotine analogues. Starting from either 4- or 3-chloropyridine the desired tricyclic ring systems are accessed in just three steps in 23% and 40% overall yield, respectively....

Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue

NARCIS (Netherlands)

Fiebrich, H. -B.; van den Berg, G.; Kema, I. P.; Links, T. P.; Kleibeuker, J. H.; van Beek, A. P.; Walenkamp, A. M. E.; Sluiter, W. J.; de Vries, E. G. E.

2010-01-01

P>Background Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels

Climate Analogues for agricultural impact projection and adaptation – a reliability test

Directory of Open Access Journals (Sweden)

Swen P.M. Bos

2015-10-01

Full Text Available The climate analogue approach is often considered a valuable tool for climate change impact projection and adaptation planning, especially for complex systems that cannot be modelled reliably. Important examples are smallholder farming systems using agroforestry or other mixed-cropping approaches. For the projected climate at a particular site of interest, the analogue approach identifies locations where the current climate is similar to these projected conditions. By comparing baseline-analogue site pairs, information on climate impacts and opportunities for adaptation can be obtained. However, the climate analogue approach is only meaningful, if climate is a dominant driver of differences between baseline and analogue site pairs. For a smallholder farming setting on Mt. Elgon in Kenya, we tested this requirement by comparing yield potentials of maize and coffee (obtained from the IIASA Global Agro-ecological Zones dataset among 50 close analogue sites for different future climate scenarios and models, and by comparing local ecological knowledge and farm characteristics for one baseline-analogue pair.Yield potentials among the 50 closest analogue locations varied strongly within all climate scenarios, hinting at factors other than climate as major drivers of what the analogue approach might interpret as climate effects. However, on average future climatic conditions seemed more favourable to maize and coffee cultivation than current conditions. The detailed site comparison revealed substantial differences between farms in important characteristics, such as farm size and presence of cash crops, casting doubt on the usefulness of the comparison for climate change analysis. Climatic constraints were similar between sites, so that no apparent lessons for adaptation could be derived. Pests and diseases were also similar, indicating that climate change may not lead to strong changes in biotic constraints at the baseline site in the near future. From

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.

Synchronization of ovulation and fixed time intrauterine insemination in ewes.

Science.gov (United States)

Deligiannis, C; Valasi, I; Rekkas, C A; Goulas, P; Theodosiadou, E; Lainas, T; Amiridis, G S

2005-02-01

A novel method for oestrus-ovulation synchronization in sheep followed by fixed time insemination is presented herewith. Mature dry ewes (n = 28) of Karagouniko breed being at an unknown stage of the oestrous cycle, were used during the middle of breeding season. The treatment protocol consisted of an initial administration of a GnRH analogue followed 5 days later by a prostaglandin F2alpha injection. Thirty-six hours later a second GnRH injection was administered to synchronize ovulation, and laparoscopic intrauterine insemination was performed 12-14 h later. Three days after insemination, fertile rams were introduced into the flock twice daily and oestrus-mating detection was carried out. For progesterone (P(4)) determination, blood samples were collected on alternate days, starting 2 days before the first GnRH injection and continuing for 17 days after insemination. An additional sample was taken on the day of insemination. Pregnancy diagnosis was carried out by trans-abdominal ultrasonography. Fourteen ewes (50%) conceived at insemination and maintained pregnancy; from the remainder 14 ewes 10 became pregnant at natural service, while four, although they mated at least two to three times, failed to conceive. In response to the first GnRH, P(4) concentration increased at higher levels in ewes that conceived at AI compared with those that failed to conceive (47.54 and 22.44%, respectively; p < 0.05). Significant differences (p < 0.05) in mean P(4) concentration between pregnant and non-pregnant animals were detected 1 day before AI (0.17 +/- 0.06 and 0.26 +/- 0.14 ng/ml, respectively) on the day of AI (0.15 +/- 0.04 and 0.24 +/- 0.08 ng/ml, respectively) as well as 9 and 11 days thereafter (0.48 +/- 0.12 and 0.38 +/- 0.12 ng/ml; 0.68 +/- 0.14 and 0.50 +/- 0.18 ng/ml, respectively). These results indicate that using the proposed protocol, an acceptable conception rate can be achieved which could be further improved by modifying the time intervals between

Potential Application of Curcumin and Its Analogues in the Treatment Strategy of Patients with Primary Epithelial Ovarian Cancer

Science.gov (United States)

Terlikowska, Katarzyna M.; Witkowska, Anna M.; Zujko, Malgorzata E.; Dobrzycka, Bozena; Terlikowski, Slawomir J.

2014-01-01

Recent findings on the molecular basis of ovarian cancer development and progression create new opportunities to develop anticancer medications that would affect specific metabolic pathways and decrease side systemic toxicity of conventional treatment. Among new possibilities for cancer chemoprevention, much attention is paid to curcumin—A broad-spectrum anticancer polyphenolic derivative extracted from the rhizome of Curcuma longa L. According to ClinicalTrials.gov at present there are no running pilot studies, which could assess possible therapeutic benefits from curcumin supplementation to patients with primary epithelial ovarian cancer. Therefore, the goal of this review was to evaluate potential preclinical properties of curcumin and its new analogues on the basis of in vivo and in vitro ovarian cancer studies. Curcumin and its different formulations have been shown to display multifunctional mechanisms of anticancer activity, not only in platinum-resistant primary epithelial ovarian cancer, but also in multidrug resistant cancer cells/xenografts models. Curcumin administered together with platinum-taxane chemotherapeutics have been reported to demonstrate synergistic effects, sensitize resistant cells to drugs, and decrease their biologically effective doses. An accumulating body of evidence suggests that curcumin, due to its long-term safety and an excellent profile of side effects should be considered as a beneficial support in ovarian cancer treatment strategies, especially in patients with platinum-resistant primary epithelial recurrent ovarian cancer or multidrug resistant disease. Although the prospect of curcumin and its formulations as anticancer agents in ovarian cancer treatment strategy appears to be challenging, and at the same time promising, there is a further need to evaluate its effectiveness in clinical studies. PMID:25429431

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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus.

Science.gov (United States)

Hogan, Andrew E; Gaoatswe, Gadintshware; Lynch, Lydia; Corrigan, Michelle A; Woods, Conor; O'Connell, Jean; O'Shea, Donal

2014-04-01

Glucagon-like peptide 1 (GLP-1) is a gut hormone used in the treatment of type 2 diabetes mellitus. There is emerging evidence that GLP-1 has anti-inflammatory activity in humans, with murine studies suggesting an effect on macrophage polarisation. We hypothesised that GLP-1 analogue therapy in individuals with type 2 diabetes mellitus would affect the inflammatory macrophage molecule soluble CD163 (sCD163) and adipocytokine profile. We studied ten obese type 2 diabetes mellitus patients starting GLP-1 analogue therapy at a hospital-based diabetes service. We investigated levels of sCD163, TNF-α, IL-1β, IL-6, adiponectin and leptin by ELISA, before and after 8 weeks of GLP-1 analogue therapy. GLP-1 analogue therapy reduced levels of the inflammatory macrophage activation molecule sCD163 (220 ng/ml vs 171 ng/ml, p < 0.001). This occurred independent of changes in body weight, fructosamine and HbA1c. GLP-1 analogue therapy was associated with a decrease in levels of the inflammatory cytokines TNF-α (264 vs 149 pg/ml, p < 0.05), IL-1β (2,919 vs 748 pg/ml, p < 0.05) and IL-6 (1,379 vs 461 pg/ml p < 0.05) and an increase in levels of the anti-inflammatory adipokine adiponectin (4,480 vs 6,290 pg/ml, p < 0.002). In individuals with type 2 diabetes mellitus, GLP-1 analogue therapy reduces the frequency of inflammatory macrophages. This effect is not dependent on the glycaemic or body weight effects of GLP-1.

Patients' preferences when comparing analogue implant impressions using a polyether impression material versus digital impressions (Intraoral Scan) of dental implants.

Science.gov (United States)

Wismeijer, Daniel; Mans, Ronny; van Genuchten, Michiel; Reijers, Hajo A

2014-10-01

The primary objective of this clinical study was to assess the patients' perception of the difference between an analogue impression approach on the one hand and an intra-oral scan (IO scan) on the other when restoring implants in the non-aesthetic zone. A second objective was to analyse the difference in time needed to perform these two procedures. Thirty consecutive patients who had received 41 implants (Straumann tissue level) in the non-aesthetic zone in an implant-based referral practice setting in the Netherlands. As they were to receive crown and or bridge work on the implants, in one session, the final impressions were taken with both an analogue technique and with an intraoral scan. Patients were also asked if, directly after the treatment was carried out, they would be prepared to fill out a questionnaire on their perception of both techniques. The time involved following these two procedures was also recorded. The preparatory activities of the treatment, the taste of the impression material and the overall preference of the patients were significantly in favour of the IO scan. The bite registration, the scan head and gag reflex positively tended to the IO scan, but none of these effects were significant. The overall time involved with the IO scan was more negatively perceived than the analogue impression. Overall less time was involved when following the analogue impression technique than with the IO scan. The overall preference of the patients in our sample is significantly in favour of the approach using the IO scan. This preference relates mainly to the differences between the compared approaches with respect to taste effects and their preparatory activities. The patients did perceive the duration of IO scan more negatively than the analogue impression approach. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chitosan-based DNA delivery vector targeted to gonadotropin-releasing hormone (GnRH) receptor.

Science.gov (United States)

Boonthum, Chatwalee; Namdee, Katawut; Boonrungsiman, Suwimon; Chatdarong, Kaywalee; Saengkrit, Nattika; Sajomsang, Warayuth; Ponglowhapan, Suppawiwat; Yata, Teerapong

2017-02-10

The main purpose of this study was to investigate the application of modified chitosan as a potential vector for gene delivery to gonadotropin-releasing hormone receptor (GnRHR)-expressing cells. Such design of gene carrier could be useful in particular for gene therapy for cancers related to the reproductive system, gene disorders of sexual development, and contraception and fertility control. In this study, a decapeptide GnRH was successfully conjugated to chitosan (CS) as confirmed by proton nuclear magnetic resonance spectroscopy ( 1 H NMR) and Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The synthesized GnRH-conjugated chitosan (GnRH-CS) was able to condense DNA to form positively charged nanoparticles and specifically deliver plasmid DNA to targeted cells in both two-dimensional (2D) and three-dimensional (3D) cell cultures systems. Importantly, GnRH-CS exhibited higher transfection activity compared to unmodified CS. In conclusion, GnRH-conjugated chitosan can be a promising carrier for targeted DNA delivery to GnRHR-expressing cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analogue Electrical Circuit for Simulation of the Duffing-Holmes Equation

DEFF Research Database (Denmark)

Tamaseviciute, E.; Tamasevicius, A.; Mykolaitis, G.

2008-01-01

An extremely simple second order analogue electrical circuit for simulating the two-well Duffing-Holmes mathematical oscillator is described. Numerical results and analogue electrical simulations are illustrated with the snapshots of chaotic waveforms, phase portraits (Lissajous figures...

Análogos de la somatostatina en el tratamiento de la retinopatía diabética Somatostatin analogues in the treatment of diabetic retinopathy

Directory of Open Access Journals (Sweden)

Juana Elvira Maciques Rodríguez

2012-04-01

Full Text Available La retinopatía diabética constituye un importante problema de salud por la discapacidad visual que provoca. El tratamiento de elección continúa siendo la fotocoagulación láser, pero en ocasiones hay formas avanzadas en que la respuesta es pobre y la evolución tórpida. Se continúan buscando otras alternativas de tratamiento que puedan mejorar la evolución, como son los esteroides y antiangiogénicos. Con el objetivo de reagrupar información actual sobre este grupo de medicamentos (análogos de la somatostatina, los cuales tienen efectos antiangiogénicos y han sido usados en el tratamiento de la retinopatía diabética proliferativa y el edema macular diabético, se realizó esta revisión. Los análogos de la somatostatina han mostrado ser eficaces, fundamentalmente, en el control de los fenómenos hemorrágicos y proliferativos en la retinopatía diabética proliferativa, y al mejorar también la integridad de la barrera hematoretiniana, ofrecen una alternativa de tratamiento para el edema macular diabético, fundamentalmente, cuando la respuesta al láser no resulta favorable.The diabetic retinopathy is an important health problem due to visual disability provoked. The choice treatment still remains the laser photocoagulation, but sometimes there is advanced ways in which the response is poor and the course is torpid. Other alternatives of treatment are look for to improve the course including the steroids and anti-angiogenic. The aim of present review was to regroup the current information on this group of drugs (somatostatin analogues, which has a anti-angiogenic effect and used in the treatment of proliferative diabetic retinopathy and the diabetic macular edema. The somatostatin analogues have shown to be effective, mainly in the control of hemorrhagic and proliferative phenomena and to also improve the integrity of the hematoretinal barrier, offer an alternative of treatment for diabetic macular edema, mainly when the response

3-alkyl fentanyl analogues: Structure-activity-relationship study

OpenAIRE

Vučković, Sonja; Savić-Vujović, Katarina; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Stojanović, Radan; Prostran, Milica

2012-01-01

Introduction. Fentanyl belongs to 4-anilidopiperidine class of synthetic opioid analgesics. It is characterized by high potency, rapid onset and short duration of action. A large number of fentanyl analogues have been synthesized so far, both to establish the structure-activity-relationship (SAR) and to find novel, clinically useful analgesic drugs. Objective. In this study, newly synthesized 3-alkyl fentanyl analogues were examined for analgesic activity and compared with fentanyl. Methods. ...

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.

Rheological and physical characteristics of crustal-scaled materials for centrifuge analogue modelling

Science.gov (United States)

Waffle, Lindsay; Godin, Laurent; Harris, Lyal B.; Kontopoulou, M.

2016-05-01

We characterize a set of analogue materials used for centrifuge analogue modelling simulating deformation at different levels in the crust simultaneously. Specifically, we improve the rheological characterization in the linear viscoelastic region of materials for the lower and middle crust, and cohesive synthetic sands without petroleum-binding agents for the upper crust. Viscoelastic materials used in centrifuge analogue modelling demonstrate complex dynamic behaviour, so viscosity alone is insufficient to determine if a material will be an effective analogue. Two series of experiments were conducted using an oscillating bi-conical plate rheometer to measure the storage and loss moduli and complex viscosities of several modelling clays and silicone putties. Tested materials exhibited viscoelastic and shear-thinning behaviour. The silicone putties and some modelling clays demonstrated viscous-dominant behaviour and reached Newtonian plateaus at strain rates clays demonstrated elastic-dominant power-law relationships. Based on these results, the elastic-dominant modelling clay is recommended as an analogue for basement cratons. Inherently cohesive synthetic sands produce fine-detailed fault and fracture patterns, and developed thrust, strike-slip, and extensional faults in simple centrifuge test models. These synthetic sands are recommended as analogues for the brittle upper crust. These new results increase the accuracy of scaling analogue models to prototype. Additionally, with the characterization of three new materials, we propose a complete lithospheric profile of analogue materials for centrifuge modelling, allowing future studies to replicate a broader range of crustal deformation behaviours.

Impacto do uso de anÃlogos de GnRH sobre o tecido e metabolismo Ãsseo de pacientes endometrÃoticas

OpenAIRE

Danyelle Craveiro de Aquino

2005-01-01

Este trabalho tem por objetivo avaliar mulheres portadoras de endometriose em uso de anÃlogos de GnRH investigando o metabolismo Ãsseo e massa Ãssea atravÃs da dosagem de marcadores sÃricos e realizaÃÃo de ultra-sonometria do calcÃneo, respectivamente. Trata-se de estudo observacional transversal tipo caso â controle prospectivo. Foi desenvolvido na Maternidade-Escola Assis Chateaubriand (MEAC) â UFC. Foram avaliadas 99 mulheres, divididas em 3 grupos, sendo 32 portadoras de endometriose diag...

Immunohistochemical evidence for the involvement of gonadotropin releasing hormone in neuroleptic and cataleptic effects of haloperidol in mice.

Science.gov (United States)

Fegade, Harshal A; Umathe, Sudhir N

2016-04-01

Blockade of dopamine D2 receptor by haloperidol is attributed for neuroleptic and cataleptic effects; and also for the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH agonist is reported to exhibit similar behavioural effects as that of haloperidol, and pre-treatment with GnRH antagonist is shown to attenuate the effects of haloperidol, suggesting a possibility that GnRH might mediate the effects of haloperidol. To substantiate such possibility, the influence of haloperidol on GnRH immunoreactivity (GnRH-ir) in the brain was studied in vehicle/antide pre-treated mice by peroxidase-antiperoxidase method. Initially, an earlier reported antide-haloperidol interaction in rat was confirmed in mice, wherein haloperidol (250μg/kg, i.p.) exhibited suppression of conditioned avoidance response (CAR) on two-way shuttle box, and induced catalepsy in bar test; and pre-treatment with antide (50μg/kg, s.c., GnRH antagonist) attenuated both effects of haloperidol. Immunohistochemical study was carried out to identify GnRH-ir in the brain, isolated 1h after haloperidol treatment to mice pre-treated with vehicle/antide. The morphometric analysis of microphotographs of brain sections revealed that haloperidol treatment increased integrated density units of GnRH-ir in various regions of the limbic system. Considering basal GnRH-ir in vehicle treated group as 100%, the increase in GnRH-ir after haloperidol treatment was by 100.98% in the medial septum; 54.26% in the bed nucleus of the stria terminalis; 1152.85% in the anteroventral periventricular nucleus; 120.79% in the preoptic area-organum vasculosum of the lamina terminalis and 138.82% in the arcuate nucleus. Antide did not influence basal and haloperidol induced increase in GnRH-ir in any of the regions. As significant increase in GnRH-ir after haloperidol treatment was observed in such regions of the brain which are reported to directly or indirectly communicate with the hippocampus and basal

Labelling and evaluation of new stabilised neurotensin (8-13) analogues for SPET

International Nuclear Information System (INIS)

Chavatte, K.; Terriere, D.; Jeannin, L.

1998-01-01

Neurotensin (8-13) analogues were biologically stabilised by replacement of the peptide bond between amino acids 8 and 9 by the reduced ψ(CH 2 -NH) isostere. DTPA analogues for In-111 labelling and 2-bromo-phenyl-acetyl analogues for radioiodination, showed receptor affinities in the low nanomolar range in combination with a biological half live in human plasma up to 275 minutes. Biodistribution studies in male Wistar rats of metabolically stabilised and non-stabilised 111 In-DTPA-NT(8-13) analogues showed a major clearance from the blood through the kidneys. 125 I-labelled Neurotensin (8-13) analogues showed accumulation up to 2.2% of the injected dose per g tissue in the liver which might be an important disadvantage when diagnosis of tumours in the gut is aimed. It is strongly suggested that stabilised neurotensin (8-13) analogues whether labelled with In-111, I-123 and the near future with Tc-99m, may act as new potential peptidergic radiopharmaceuticals for SPET diagnosis of different NT-receptor positive tumours like non-endocrine pancreas carcinoma, small cell lung carcinoma or colon adeno carcinoma. It is enticing to speculate that metabolically stabilised Neurotensin (8-13) analogues labelled with an appropriate isotope might be useful in therapy of different human cancers. (author)

Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus.

Science.gov (United States)

Fullerton, Birgit; Siebenhofer, Andrea; Jeitler, Klaus; Horvath, Karl; Semlitsch, Thomas; Berghold, Andrea; Plank, Johannes; Pieber, Thomas R; Gerlach, Ferdinand M

2016-06-30

Short-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates. To assess the effects of short-acting insulin analogues versus regular human insulin in adults with type 1 diabetes. We carried out the electronic searches through Ovid simultaneously searching the following databases: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 14 April 2015), EMBASE (1988 to 2015, week 15), the Cochrane Central Register of Controlled Trials (CENTRAL; March 2015), ClinicalTrials.gov and the European (EU) Clinical Trials register (both March 2015). We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues with regular human insulins in the treatment of adults with type 1 diabetes who were not pregnant. Two review authors independently extracted data and assessed trials for risk of bias, and resolved differences by consensus. We graded overall study quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. We used random-effects models for the main analyses and presented the results as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes. We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in

Thymidine analogues to assess microperfusion in human tumors

International Nuclear Information System (INIS)

Janssen, Hilde L.; Ljungkvist, Anna S.; Rijken, Paul F.; Sprong, Debbie; Bussink, Jan; Kogel, Albert J. van der; Haustermans, Karin M.; Begg, Adrian C.

2005-01-01

Purpose: To validate the use of the thymidine analogues as local perfusion markers in human tumors (no labeling indicates no perfusion) by comparison with the well-characterized perfusion marker Hoechst 33342. Methods and Materials: Human tumor xenografts from gliomas and head-and-neck cancers were injected with iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) and the fluorescent dye Hoechst 33342. In frozen sections, each blood vessel was scored for the presence of IdUrd/BrdUrd labeling and Hoechst in surrounding cells. The percentage of analogue-negative vessels was compared with the fraction of Hoechst-negative vessels. Collocalization of the two markers was also scored. Results: We found considerable intertumor variation in the fraction of perfused vessels, measured by analogue labeling, both in the human tumor xenografts and in a series of tumor biopsies from head-and-neck cancer patients. There was a significant correlation between the Hoechst-negative and IdUrd/BrdUrd-negative vessels in the xenografts (r 85, p = 0.0004), despite some mismatches on a per-vessel basis. Conclusions: Thymidine analogues can be successfully used to rank tumors according to their fraction of perfused vessels. Whether this fraction correlates with the extent of acute hypoxia needs further confirmation

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

Analogues of estradiol as potential breast tumor imaging agents

International Nuclear Information System (INIS)

Gibson, R.E.; Rzeszotarski, W.J.; Ferriera, N.L.; Jagoda, E.M.; Reba, R.C.; Eckelman, W.C.

1984-01-01

The radioiodinated analogue of estradiol, 11β-methoxy-17α-[/sup 125/I]iodovinylestradiol (MIVE/sub 2/), has been shown to be a good candidate for the imaging of estrogen dependent breast tumors. Although there has been no extensive study on the sensitivity of radiotracers of this type, the authors have not observed localization of the radiotracer in metastatic lesions containing less than 20 fmole estrogen receptor/mg protein or in bone metasteses. In order to improve the sensitivity, they have examined several structural analogues of moxestrol (the parent structure for MIVE/sub 2/) for affinity to the ER isolated from immature rat uterus. The 11β-ethyl analogue (EEE/sub 2/) of ethynyl estradiol (EE/sub 2/) exhibits the highest affinity with the 11β-methyl analogue second best. Although the lipophilicity is also very high this compound should not be much more lipophilic than 16-iodoestradiol or MIVE/sub 2/ since the introduction of iodine increases the log P by greater than 1. The distribution of the tritiated derivative of EEE/sub 2/ is under study

Iodination and stability of somatostatin analogues: comparison of iodination techniques. A practical overview.

Science.gov (United States)

de Blois, Erik; Chan, Ho Sze; Breeman, Wouter A P

2012-01-01

For iodination ((125/127)I) of tyrosine-containing peptides, chloramin-T, Pre-Coated Iodo-Gen(®) tubes and Iodo-Beads(®) (Pierce) are commonly used for in vitro radioligand investigations and there have been reliant vendors hereof for decades. However, commercial availability of these radio-iodinated peptides is decreasing. For continuation of our research in this field we investigated and optimized (radio-)iodination of somatostatin analogues. In literature, radioiodination using here described somatostatin analogues and iodination techniques are described separately. Here we present an overview, including High Performance Liquid Chromatography (HPLC) separation and characterisation by mass spectrometry, to obtain mono- and di-iodinated analogues. Reaction kinetics of (125/127)I iodinated somatostatin analogues were investigated as function of reaction time and concentration of reactants, including somatostatin analogues, iodine and oxidizing agent. To our knowledge, for the here described somatostatin analogues, no (127)I iodination and optimization are described. (Radio-)iodinated somatostatin analogues could be preserved with a >90% radiochemical purity for 1 month after reversed phase HPLC-purification.

Nanostructured self-assembly materials from neat and aqueous solutions of C18 lipid pro-drug analogues of Capecitabine—a chemotherapy agent. Focus on nanoparticulate cubosomes™ of the oleyl analogue

Energy Technology Data Exchange (ETDEWEB)

Gong, Xiaojuan; Moghaddam, Minoo J.; Sagnella, Sharon M.; Conn, Charlotte E.; Mulet, Xavier; Danon, Stephen J.; Waddington, Lynne J.; Drummond, Calum J.

2014-09-24

A series of prodrug analogues based on the established chemotherapy agent, 5-fluorouracil, have been prepared and characterized. C18 alkyl and alkenyl chains with increasing degree of unsaturation were attached to the N⁴ position of the 5-fluorocytosine (5-FC) base via a carbamate bond. Physicochemical characterization of the prodrug analogues was carried out using a combination of differential scanning calorimetry, cross-polarized optical microscopy, X-ray diffraction and small-angle X-ray scattering. The presence of a monounsaturated oleyl chain was found to promote lyotropic liquid crystalline phase formation in excess water with a fluid lamellar phase observed at room temperature and one or more bicontinuous cubic phases at 37 °C. The bulk phase was successfully dispersed into liposomes or cubosomes at room and physiological temperature respectively. In vitro toxicity of the nanoparticulate 5-FCOle dispersions was evaluated against several normal and cancer cell types over a 48 h period and exhibited an IC₅₀ of -100 μM against all cell types. The in vivo efficacy of 5-FCOle cubosomes was assessed against the highly aggressive mouse 4T1 breast cancer model and compared to Capecitabine (a water-soluble commercially available 5-FU prodrug) delivered at the same dosages. After 21 days of treatment, the 0.5 mmol 5-FCOle treatment group exhibited a significantly smaller average tumour volume than all other treatment groups including Capecitabine at similar dosage. These results exemplify the potential of self-assembled amphiphile prodrugs for delivery of bioactives in vivo.

The chicken type III GnRH receptor homologue is predominantly expressed in the pituitary, and exhibits similar ligand selectivity to the type I receptor

Science.gov (United States)

Joseph, Nerine T; Morgan, Kevin; Sellar, Robin; McBride, Derek; Millar, Robert P; Dunn, Ian C

2009-01-01

Two GnRH isoforms (cGnRH-I and GnRH-II) and two GnRH receptor subtypes (cGnRH-R-I and cGnRH-R-III) occur in chickens. Differential roles for these molecules in regulating gonadotrophin secretion or other functions are unclear. To investigate this we cloned cGnRH-R-III from a broiler chicken and compared its structure, expression and pharmacological properties with cGnRH-R-I. The broiler cGnRH-R-III cDNA was 100% identical to the sequence reported in the red jungle fowl and white leghorn breed. Pituitary cGnRH-R-III mRNA was ∼1400-fold more abundant than cGnRH-R-I mRNA. Northern analysis indicated a single cGnRH-R-III transcript. A pronounced sex and age difference existed, with higher pituitary transcript levels in sexually mature females versus juvenile females. In contrast, higher expression levels occurred in juvenile males versus sexually mature males. Functional studies in COS-7 cells indicated that cGnRH-R-III has a higher binding affinity for GnRH-II than cGnRH-I (Kd: 0·57 vs 19·8 nM) with more potent stimulation of inositol phosphate production (ED50: 0·8 vs 4·38 nM). Similar results were found for cGnRH-R-I, (Kd: 0·51 vs 10·8 nM) and (ED50: 0·7 vs 2·8 nM). The initial rate of internalisation was faster for cGnRH-R-III than cGnRH-R-I (26 vs 15·8%/min). Effects of GnRH antagonists were compared at the two receptors. Antagonist #27 distinguished between cGnRH-R-I and cGnRH-R-III (IC50: 2·3 vs 351 nM). These results suggest that cGnRH-R-III is probably the major mediator of pituitary gonadotroph function, that antagonist #27 may allow delineation of receptor subtype function in vitro and in vivo and that tissue-specific recruitment of cGnRH-R isoforms has occurred during evolution. PMID:19380456

Prepubertal Development of Gonadotropin-Releasing Hormone Neuron Activity Is Altered by Sex, Age, and Prenatal Androgen Exposure.

Science.gov (United States)

Dulka, Eden A; Moenter, Suzanne M

2017-11-01

Gonadotropin-releasing hormone (GnRH) neurons regulate reproduction though pulsatile hormone release. Disruption of GnRH release as measured via luteinizing hormone (LH) pulses occurs in polycystic ovary syndrome (PCOS), and in young hyperandrogenemic girls. In adult prenatally androgenized (PNA) mice, which exhibit many aspects of PCOS, increased LH is associated with increased GnRH neuron action potential firing. How GnRH neuron activity develops over the prepubertal period and whether this is altered by sex or prenatal androgen treatment are unknown. We hypothesized GnRH neurons are active before puberty and that this activity is sexually differentiated and altered by PNA. Dams were injected with dihydrotestosterone (DHT) on days 16 to 18 post copulation to generate PNA mice. Action potential firing of GFP-identified GnRH neurons in brain slices from 1-, 2-, 3-, and 4-week-old and adult mice was monitored. GnRH neurons were active at all ages tested. In control females, activity increased with age through 3 weeks, then decreased to adult levels. In contrast, activity did not change in PNA females and was reduced at 3 weeks. Activity was higher in control females than males from 2 to 3 weeks. PNA did not affect GnRH neuron firing rate in males at any age. Short-term action potential patterns were also affected by age and PNA treatment. GnRH neurons are thus typically more active during the prepubertal period than adulthood, and PNA reduces prepubertal activity in females. Prepubertal activity may play a role in establishing sexually differentiated neuronal networks upstream of GnRH neurons; androgen-induced changes during this time may contribute to the adult PNA, and possibly PCOS, phenotype. Copyright © 2017 Endocrine Society.

From BPA to its analogues: Is it a safe journey?

Science.gov (United States)

Usman, Afia; Ahmad, Masood

2016-09-01

Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful? Copyright © 2016. Published by Elsevier Ltd.

Patterns of ovarian and oestrous activity and induction of cyclic activity during the post-partum period in Egyptian buffaloes

International Nuclear Information System (INIS)

Aboul-Ela, M.B.; Shafie, M.M.

1988-01-01

This report covers three studies. In the first study, ovarian and oestrous activity were monitored in 47 buffaloes for 90 days following parturition. Failure to resume ovarian cyclicity after calving was found to be the main reason for the delay in conception. High incidence of ovulatory anoestrus (64%) constitutes also a major problem in Egyptian buffaloes. In the second study, buffaloes with inactive ovaries were treated at 90 days post-partum with either GnRH or progesterone, given either intravaginally (PRID) or orally (CAP). Both GnRH and PRID were effective in inducing ovulation but GnRH administration was followed by a high incidence of silent ovulation. Within the 35 days following treatment, about 50% of the PRID treated animals got in calf vs. 44 and 22% for GnRH and CAP treated animals, respectively. In the third study, buffaloes were treated with either 6 or 12μg GnRH at either 7 or 15 days post-partum. GnRH treatment resulted in significant reductions in the intervals from calving to first ovulation, first detected oestrus and time to first rise in serum progesterone concentration (> 1 ng/mL). (author). 26 refs, 5 figs, 4 tabs

Design of a saturated analogue and digital current transducer

International Nuclear Information System (INIS)

Pross, Alexander

2002-01-01

This project describes the development of a new analogue and digital current transducer, providing a range of new theoretical design methods for these novel devices. The main control feature is the limit cycling operation, and the novel use of the embedded sigma-delta modulator sensor structure to derive a low component count digital sensor. The research programme was initiated into the design, development and evaluation of a novel non-Hall sensing analogue and digital current transducer. These transducers are used for measurement of high currents in power systems applications. The investigation is concerned with a new design which uses a magnetic ferrite core without an air gap for current measurement. The motivation for this work was to design a new control circuit which provides a low component count, and utilises the non-linear properties of the magnetic ferrite core to transmit direct current. The use of a limit cycle control circuit was believed to be particularly suitable for the analogue and digital transducers, for two main reasons: the low component count, and the output signal is directly digital. In line with the motivations outlined above, the outcome of the research has witnessed the design, development and evaluation of a practically realisable analogue and digital current transducer. The design procedure, which is documented in this thesis, is considered to be a major contribution to the field of transducers design and development using a control systems approach. Mathematical models for both analogue and digital transducers were developed and the resulting model based predictions were found to be in good agreement with measured results. Simplification of the new model sensing device was achieved by approximating the non-linear ferrite core using FFT analysis. This is also considered to be a significant contribution. The development analogue and digital current censors employed a sampled data control systems design and utilised limit cycling

Natural analogues, paradigm for manmade repositories for radioactive wastes

International Nuclear Information System (INIS)

Pavelescu, M.; Pavelescu, A.

2004-01-01

Natural analogues are given by nature. They show the results of natural processes which have lasted thousands or millions of years. They provide an excellent example of what could happen in an underground site, offering in the same time the opportunity to test by observation and measurement, many of the geochemical processes that are expected to influence in a realistic and appropriate way, the predicted reliability of the radioactive waste repository over long periods of geological time. The natural analogue studies attempt to understand the multiprocessing complexity of the natural system, which contrasts with the limitations of the laboratory experiments and bring arguments to overcome the difficult time scale issue. By this the natural analogues are a useful paradigm for manmade repository for radioactive wastes. The paper discusses the implicit link in the public mind between natural analogues and manmade waste repository with an accent of the positive impact on public acceptance. It is also discussed the decisive qualities of the natural analogues concerning providing valid long term data and increasing the confidence of the public for manmade repositories. The debate is conducting in terms of sustainable development, having at base high-level principles in order to protect humans and their environment, both now and in the future, from potential hazards arising from such wastes. Safe radwaste management involves the application of technology and resources in a regulated manner so that the public, workers and the environment are protected in accordance with the accepted national and international standards. There are at least seven high-level principles which are mentioned in the paper. It is presented the general concept of the deep geological repository, very important for an acceptable solution for the management of nuclear waste, what is a prerequisite for a renewal of nuclear power. Further are introduced natural and archaeological (manufactured) analogue

The Impact of Polyether Chain Length on the Iron Clearing Efficiency and Physiochemical Properties of Desferrithiocin Analogues

Science.gov (United States)

Bergeron, Raymond J.; Bharti, Neelam; Wiegand, Jan; McManis, James S.; Singh, Shailendra; Abboud, Khalil A.

2010-01-01

(S)-2-(2,4-Dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (2) was abandoned in clinical trials as an iron chelator for the treatment of iron overload disease because of its nephrotoxicity. However, subsequent investigations revealed that replacing the 4′-(HO) of 2 with a 3,6,9-trioxadecyloxy group, ligand 4, increased iron clearing efficiency (ICEa) and ameliorated the renal toxicity of 2. This compelled a closer look at additional polyether analogues, the subject of this work. The 3,6,9,12-tetraoxatridecyloxy analogue of 4, chelator 5, an oil, had twice the ICE in rodents of 4, although its ICE in primates was reduced relative to 4. The corresponding 3,6-dioxaheptyloxy analogue of 2, 6 (a crystalline solid), had high ICEs in both the rodent and primate models. It significantly decorporated hepatic, renal, and cardiac iron, with no obvious histopathologies. These findings suggest that polyether chain length has a profound effect on ICE, tissue iron decorporation, and ligand physiochemical properties. PMID:20232803

Cetrorelix suppresses the preovulatory LH surge and ovulation induced by ovulation-inducing factor (OIF present in llama seminal plasma

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Letelier Claudia

2011-05-01

Full Text Available Abstract Background The purpose of the study was to determine if the effect of llama OIF on LH secretion is mediated by stimulation of the hypothalamus or pituitary gland. Methods Using a 2-by-2 factorial design to examine the effects of OIF vs GnRH with or without a GnRH antagonist, llamas with a growing ovarian follicle greater than or equal to 8 mm were assigned randomly to four groups (n = 7 per group and a pre-treated with 1.5 mg of GnRH antagonist (cetrorelix acetate followed by 1 mg of purified llama OIF, b pre-treated with 1.5 mg of cetrorelix followed by 50 micrograms of GnRH, c pre-treated with a placebo (2 ml of saline followed by 1 mg of purified llama OIF or d pre-treated with a placebo (2 ml of saline followed by 50 micrograms of GnRH. Pre-treatment with cetrorelix or saline was given as a single slow intravenous dose 2 hours before intramuscular administration of either GnRH or OIF. Blood samples for LH measurement were taken every 15 minutes from 1.5 hours before to 8 hours after treatment. The ovaries were examined by ultrasonography to detect ovulation and CL formation. Blood samples for progesterone measurement were taken every-other-day from Day 0 (day of treatment to Day 16. Results Ovulation rate was not different (P = 0.89 between placebo+GnRH (86% and placebo+OIF groups (100%; however, no ovulations were detected in llamas pre-treated with cetrorelix. Plasma LH concentrations surged (P Conclusion Cetrorelix (GnRH antagonist inhibited the preovulatory LH surge induced by OIF in llamas suggesting that LH secretion is modulated by a direct or indirect effect of OIF on GnRH neurons in the hypothalamus.

Natural analogues for containment-providing barriers for a HLW repository in salt

Energy Technology Data Exchange (ETDEWEB)

Wolf, J.; Noseck, U.

2015-06-15

In 2005, a German research project was started to develop a novel approach to prove safety for a HLW repository in a salt formation, to refine the safety concept, to identify open scientific issues and to define necessary R&D work. This project aimed at identifying the key information for a HLW repository in salt. One important question is how this information may be best fulfilled by natural analogue studies. This question is answered by starting a review of the required key information needs of the safety case (post-closure phase) in order to assess whether or not these requirements can be supported by natural analogues information. In order to structure the review and to address the key elements of the safety concepts, three types of natural analogues are distinguished: (i) natural analogues for the integrity of the geological barrier, (ii) natural analogues for the integrity of the geotechnical barriers and (iii) natural analogues for release scenarios. For the safety case in salt type (i) and (ii) are of highest importance and are treated in this paper. The assessment documented in this paper on the one hand indicates the high potential benefit of natural analogues for a safety case in salt and on the other hand helps to focus the available human and financial resources for the safety case on the most safety-relevant aspects. (authors)

Attitudes and preferences in patients with acromegaly on long-term treatment with somatostatin analogues

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Cecilia Follin

2016-08-01

Full Text Available Introduction: Patients with acromegaly can be treated with surgery, medical therapy and/or radiation therapy. For the patients not being cured with surgery, treatment with somatostatin analogues (SSAs is the primary therapy. SSA can be taken by self- or partner-administered injections in addition to being given by a nurse at a clinic. The aim was to assess if patients with acromegaly prefer self-injections and to investigate their attitudes towards long-term medical therapy. Method: All patients in the southern medical region of Sweden with a diagnosis of acromegaly and treated with SSA were eligible for the study (n = 24. The study is based on a questionnaire asking about the patients’ attitudes and preferences for injections with SSA, including their attitudes towards self-injection with SSA. Results: The patients’ (23 included median age was 68.5 years and the patients had been treated with SSA for 13 (1–38 years. One patient was currently self-injecting. All of the other patients were receiving injections from a nurse at a clinic. Three patients preferred self-injections, one preferred partner injections and 19 patients did not prefer self- or partner injections. The most frequent arguments to not preferring self-injections were ‘feeling more secure with an educated nurse’ and ‘preferring regular contact with a specialised nurse’. Conclusion: Patients with acromegaly prefer regular contact with the endocrine team to the independence offered by self-injections. These findings might mirror the patients’ desires for continuity and safety. We need to address patients’ concerns regarding injections with SSA and support them in their choices.

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

Science.gov (United States)

Tutton, P J; Barkla, D H

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours.

In Silico Screening and In Vitro Activity Measurement of Javamide Analogues as Potential p38 MAPK Inhibitors

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Jae B. Park

2017-12-01

Full Text Available p38 Mitogen-activated protein kinase (p38 MAPK is a protein kinase critically involved in the progress of inflammation/stress-associated diseases. Our data suggested that javamide analogues may contain strong anti-inflammation activities, but there is little information about their effects on p38 MAPK. Therefore, in this paper, the effects of thirty javamide analogues on p38 MAPK were investigated using in silico screening and in vitro p38 MAPK assay methods. The javamide analogues were synthesized and their chemical structures were confirmed using nuclear magnetic resonance (NMR spectroscopic methods. Then, the javamide analogues were screened using an in silico modeling program. The screened analogues demonstrated a wide range of binding energy (ΔE; −20 to −39 and several analogues with ΔE; −34 to −39 showed strong binding affinity to p38 MAPK. In vitro p38 MAPK assay, the kinase was significantly inhibited by the analogues with great binding energy (ΔE; −34 to −39 and in silico scores (Avg. score; −27.5 to −29.3. Furthermore, the comparative analysis of both assays showed a positive correlation between the in silico scores and p38 MAPK inhibition. In fact, the javamide analogues with top five in silico scores (Avg. score; −27.5 to −29.3 were found to inhibit p38 MAPK by 27–31% (p < 0.05 better than those with less scores (ΔE < −27.0. Especially, javamide-II-O-ethyl ester with relatively high in silico score (Avg. score; −29.2 inhibited p38 MAPK (IC50 = 9.9 μM a little better than its methyl ester with best in silico score (Avg. score; −29.3. To support the ability to inhibit p38 MAPK, the treatment of javamide-II-ethyl and -methyl esters could suppress the production of IL-8 and MCP-1 protein significantly by 22–73% (p < 0.05 in the differentiated THP-1 cells, and the inhibition was slightly stronger by the ethyl ester than the methyl ester. Altogether, this study suggests that javamide-II-O-ethyl ester may

Optoelectronic properties of higher acenes, their BN analogue and substituted derivatives

International Nuclear Information System (INIS)

Armaković, Stevan; Armaković, Sanja J.; Holodkov, Vladimir; Pelemiš, Svetlana

2016-01-01

We have investigated optoelectronic properties of higher acenes: pentacene, hexacene, heptacene, octacene, nonacene, decacene and their boron-nitride (BN) analogues, within the framework of density functional theory (DFT). We have also investigated the optoelectronic properties of acenes modified by BN substitution. Calculated optoelectronic properties encompasses: oxidation and reduction potentials, electron and hole reorganization energies and energy difference between excited first singlet and triplet states ΔE(S_1−T_1). Oxidation and reduction potentials indicate significantly better stability of BN analogues, comparing with their all-carbon relatives. Although higher acenes possess lower electron and hole reorganization energies, with both best values much lower than 0.1 eV, their BN analogues also have competitive values of reorganization energies, especially for holes for which reorganization energy is also lower than 0.1 eV. On the other hand ΔE(S_1−T_1) is much better for BN analogues, having values that indicate that BN analogues are possible applicable for thermally activated delayed fluorescence. - Highlights: • Optoelectronic properties of structures based on higher acenes have been investigated. • Oxidation and reduction potentials together with reorganization energies are calculated. • TADF is analyzed through calculation of ΔE(S_1−T_1), which is much better for BN analogues. • Reorganization energies of acenes improve with the increase of number of benzene rings.

In vivo activity of native GnRHs and their analogues on ovulation in the American catfish, Clarias gariepinus (Burchell)

Czech Academy of Sciences Publication Activity Database

Szabó, T.; Radics, F.; Barth, Tomislav; Horváth, L.

2007-01-01

Roč. 38, č. 2 (2007), s. 140-146 ISSN 1355-557X R&D Projects: GA MZe QF3028; GA MZe QF3029 Institutional research plan: CEZ:AV0Z40550506 Keywords : GnRH * ovulation * African catfish Subject RIV: CC - Organic Chemistry Impact factor: 1.067, year: 2007

Cross-reactivity of amphetamine analogues with Roche Abuscreen radioimmunoassay reagents

International Nuclear Information System (INIS)

Cody, J.T.

1990-01-01

Cross-reactivity of amphetamine analogues with the Abuscreen amphetamine radioimmunoassay reagents was determined for both the standard and high specificity antibody systems. Compounds tested included 2-methoxyamphetamine, 4-hydroxymethamphetamine, 2,5-dimethoxyamphetamine (DMA), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-bromo-2,5-dimethoxy-beta-phenethylamine (BDMPEA), 3,4,5-trimethoxyamphetamine (TMA), 3,4-methylenedioxyamphetamine (MDA), N,N-dimethyl-3,4-methylenedioxyamphetamine and N-hydroxy-3,4-methylenedioxyamphetamine (N-OH MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxy-4-methylamphetamine (DOM), and 3,4,5-trimethoxyphenethylamine (mescaline). Blank negative reference material was spiked with 1,000 to 100,000 ng/mL of the amphetamine analogue and used as sample in the assays. MDA was the only analogue that showed cross reactivity equal to or greater than that of amphetamine. None of the other analogue compounds demonstrated a positive result at even the highest concentration; however several showed depressed counts at various concentration levels

Use of Insulin Analogues in Children and Adolescents: Topical Issues and Possibilities for Achieving Optimal Type 1 Diabetes Mellitus Compensation

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О.A. Budreyko

2013-03-01

Full Text Available The review contains an analysis of the data of numerous scientific studies on the results of use of insulin analogues in comprehensive treatment of type 1 diabetes mellitus in children and adolescents. Problem of mitogenic potential of insulin preparations and ways to prevent its realization in clinical practice is discussed. Advisability of the use of insulin analogues glulisine and glargine in children and adolescents is substantiated for achievement of optimal compensation of carbohydrate metabolism due to their high efficiency and adequate level of safety, confirmed by the regulations of international consensuses (ISPAD and IDF.

Biomimetic synthesis, antimicrobial, antileishmanial and antimalarial activities of euglobals and their analogues.

Science.gov (United States)

Bharate, Sandip B; Bhutani, Kamlesh K; Khan, Shabana I; Tekwani, Babu L; Jacob, Melissa R; Khan, Ikhlas A; Singh, Inder Pal

2006-03-15

In the present communication, naturally occurring phloroglucinol-monoterpene adducts, euglobals G1-G4 (3b/a and 4a/b) and 16 new analogues (13a/b-18a/b and 19-22) were synthesized by biomimetic approach. These synthetic compounds differ from natural euglobals in the nature of monoterpene and acyl functionality. All of these compounds were evaluated for their antibacterial, antifungal, antileishmanial and antimalarial activities. Analogue 17b possessed good antibacterial activity against methicillin-resistant Staphylococcus aureus, while analogues 19-22 possessed potent antifungal activity against Candida glabrata with IC50s ranging from 1.5 to 2.5 microg/mL. Euglobals along with all synthesized analogues exhibited antileishmanial activity. Amongst these, euglobal G2 (3a), G3 (4a) and analogues 13a and 14a showed potent antileishmanial activity with IC50s ranging from 2.8 to 3.9 microg/mL. Analogue 16a possessed antimalarial activity against chloroquine sensitive D6 clone of Plasmodium falciparum. None of the compounds showed toxicity against mammalian kidney fibroblasts (vero cells) upto the concentration of 4.76 microg/ml.

The role of positron emission tomography/computed tomography imaging with radiolabeled choline analogues in prostate cancer.

Science.gov (United States)

Navarro-Pelayo Láinez, M M; Rodríguez-Fernández, A; Gómez-Río, M; Vázquez-Alonso, F; Cózar-Olmo, J M; Llamas-Elvira, J M

2014-11-01

prostate cancer is the most frequent solid malignant tumor in Western Countries. Positron emission tomography/x-ray computed tomography imaging with radiolabeled choline analogues is a useful tool for restaging prostate cancer in patients with rising prostate-specific antigen after radical treatment (in whom conventional imaging techniques have important limitations) as well as in the initial assessment of a selected group of prostate cancer patients. For this reason a literature review is necessary in order to evaluate the usefulness of this imaging test for the diagnosis and treatment of prostate cancer. a MEDLINE (PubMed way) literature search was performed using the search parameters: «Prostate cancer» and «Choline-PET/CT». Other search terms were «Biochemical failure» and/or «Staging» and/or «PSA kinetics». English and Spanish papers were selected; original articles, reviews, systematic reviews and clinical guidelines were included. according to available data, radiolabeled choline analogues plays an important role in the management of prostate cancer, especially in biochemical relapse because technique accuracy is properly correlated with prostate-specific antigen values and kinetics. Although is an emerging diagnostic technique useful in treatment planning of prostate cancer, final recommendations have not been submitted. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

The Planetary Terrestrial Analogues Library (PTAL)

Science.gov (United States)

Werner, S. C.; Dypvik, H.; Poulet, F.; Rull Perez, F.; Bibring, J.-P.; Bultel, B.; Casanova Roque, C.; Carter, J.; Cousin, A.; Guzman, A.; Hamm, V.; Hellevang, H.; Lantz, C.; Lopez-Reyes, G.; Manrique, J. A.; Maurice, S.; Medina Garcia, J.; Navarro, R.; Negro, J. I.; Neumann, E. R.; Pilorget, C.; Riu, L.; Sætre, C.; Sansano Caramazana, A.; Sanz Arranz, A.; Sobron Grañón, F.; Veneranda, M.; Viennet, J.-C.; PTAL Team

2018-04-01

The Planetary Terrestrial Analogues Library project aims to build and exploit a spectral data base for the characterisation of the mineralogical and geological evolution of terrestrial planets and small solar system bodies.

Curcumin and Its Analogue Induce Apoptosis in Leukemia Cells and Have Additive Effects with Bortezomib in Cellular and Xenograft Models

Directory of Open Access Journals (Sweden)

L. I. Nagy

2015-01-01

Full Text Available Combination therapy of bortezomib with other chemotherapeutics is an emerging treatment strategy. Since both curcumin and bortezomib inhibit NF-κB, we tested the effects of their combination on leukemia cells. To improve potency, a novel Mannich-type curcumin derivative, C-150, was synthesized. Curcumin and its analogue showed potent antiproliferative and apoptotic effects on the human leukemia cell line, HL60, with different potency but similar additive properties with bortezomib. Additive antiproliferative effects were correlated well with LPS-induced NF-κB inhibition results. Gene expression data on cell cycle and apoptosis related genes, obtained by high-throughput QPCR, showed that curcumin and its analogue act through similar signaling pathways. In correlation with in vitro results similar additive effect could be obsereved in SCID mice inoculated systemically with HL60 cells. C-150 in a liposomal formulation given intravenously in combination with bortezomib was more efficient than either of the drugs alone. As our novel curcumin analogue exerted anticancer effects in leukemic cells at submicromolar concentration in vitro and at 3 mg/kg dose in vivo, which was potentiated by bortezomib, it holds a great promise as a future therapeutic agent in the treatment of leukemia alone or in combination.

Luciferase-Specific Coelenterazine Analogues for Optical Contamination-Free Bioassays

OpenAIRE

Ryo Nishihara; Masahiro Abe; Shigeru Nishiyama; Daniel Citterio; Koji Suzuki; Sung Bae Kim

2017-01-01

Spectral overlaps among the multiple optical readouts commonly cause optical contamination in fluorescence and bioluminescence. To tackle this issue, we created five-different lineages of coelenterazine (CTZ) analogues designed to selectively illuminate a specific luciferase with unique luciferase selectivity. In the attempt, we found that CTZ analogues with ethynyl or styryl groups display dramatically biased bioluminescence to specific luciferases and pHs by modifying the functional groups ...

Synthesis and antioxidant activity of peptide-based ebselen analogues.

Science.gov (United States)

Satheeshkumar, Kandhan; Mugesh, Govindasamy

2011-04-18

A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration. Copyright �

Conjugate dynamical systems: classical analogue of the quantum energy translation

International Nuclear Information System (INIS)

Torres-Vega, Gabino

2012-01-01

An aspect of quantum mechanics that has not been fully understood is the energy shift generated by the time operator. In this study, we introduce the use of the eigensurfaces of dynamical variables and commutators in classical mechanics to study the classical analogue of the quantum translation of energy. We determine that there is a conjugate dynamical system that is conjugate to Hamilton's equations of motion, and then we generate the analogue of the time operator and use it in the translation of points along the energy direction, i.e. the classical analogue of the Pauli theorem. The theory is illustrated with a nonlinear oscillator model. (paper)

Luciferase-Specific Coelenterazine Analogues for Optical Contamination-Free Bioassays.

Science.gov (United States)

Nishihara, Ryo; Abe, Masahiro; Nishiyama, Shigeru; Citterio, Daniel; Suzuki, Koji; Kim, Sung Bae

2017-04-19

Spectral overlaps among the multiple optical readouts commonly cause optical contamination in fluorescence and bioluminescence. To tackle this issue, we created five-different lineages of coelenterazine (CTZ) analogues designed to selectively illuminate a specific luciferase with unique luciferase selectivity. In the attempt, we found that CTZ analogues with ethynyl or styryl groups display dramatically biased bioluminescence to specific luciferases and pHs by modifying the functional groups at the C-2 and C-6 positions of the imidazopyradinone backbone of CTZ. The optical contamination-free feature was exemplified with the luciferase-specific CTZ analogues, which illuminated anti-estrogenic and rapamycin activities in a mixture of optical probes. This unique bioluminescence platform has great potential for specific and high throughput imaging of multiple optical readouts in bioassays without optical contamination.

Truncated somatostatin receptor 5 may modulate therapy response to somatostatin analogues--Observations in two patients with acromegaly and severe headache

DEFF Research Database (Denmark)

Marina, Djordje; Burman, Pia; Klose, Marianne

2015-01-01

BACKGROUND: Somatotropinomas have unique "fingerprints" of somatostatin receptor (sst) expression, which are targets in treatment of acromegaly with somatostatin analogues (SSAs). However, a significant expression of sst is not always related to the biochemical response to SSAs. Headache is a com...

Sensitivity of groundwater recharge using climatic analogues and HYDRUS-1D

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B. Leterme

2012-08-01

Full Text Available The sensitivity of groundwater recharge to different climate conditions was simulated using the approach of climatic analogue stations, i.e. stations presently experiencing climatic conditions corresponding to a possible future climate state. The study was conducted in the context of a safety assessment of a future near-surface disposal facility for low and intermediate level short-lived radioactive waste in Belgium; this includes estimation of groundwater recharge for the next millennia. Groundwater recharge was simulated using the Richards based soil water balance model HYDRUS-1D and meteorological time series from analogue stations. This study used four analogue stations for a warmer subtropical climate with changes of average annual precipitation and potential evapotranspiration from −42% to +5% and from +8% to +82%, respectively, compared to the present-day climate. Resulting water balance calculations yielded a change in groundwater recharge ranging from a decrease of 72% to an increase of 3% for the four different analogue stations. The Gijon analogue station (Northern Spain, considered as the most representative for the near future climate state in the study area, shows an increase of 3% of groundwater recharge for a 5% increase of annual precipitation. Calculations for a colder (tundra climate showed a change in groundwater recharge ranging from a decrease of 97% to an increase of 32% for four different analogue stations, with an annual precipitation change from −69% to −14% compared to the present-day climate.

Optoelectronic properties of higher acenes, their BN analogue and substituted derivatives

Energy Technology Data Exchange (ETDEWEB)

Armaković, Stevan, E-mail: stevan.armakovic@df.uns.ac.rs [University of Novi Sad, Faculty of Sciences, Department of Physics, Trg Dositeja Obradovića 4, 21000, Novi Sad (Serbia); Armaković, Sanja J. [University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000, Novi Sad (Serbia); Holodkov, Vladimir [Educons University, Faculty of Sport and Tourism - TIMS, Radnička 30a, 21000, Novi Sad (Serbia); Pelemiš, Svetlana [University of East Sarajevo, Faculty of Technology, Karakaj bb, 75400, Zvornik, Republic of Srpska, Bosnia and Herzegovina (Bosnia and Herzegovina)

2016-02-15

We have investigated optoelectronic properties of higher acenes: pentacene, hexacene, heptacene, octacene, nonacene, decacene and their boron-nitride (BN) analogues, within the framework of density functional theory (DFT). We have also investigated the optoelectronic properties of acenes modified by BN substitution. Calculated optoelectronic properties encompasses: oxidation and reduction potentials, electron and hole reorganization energies and energy difference between excited first singlet and triplet states ΔE(S{sub 1}−T{sub 1}). Oxidation and reduction potentials indicate significantly better stability of BN analogues, comparing with their all-carbon relatives. Although higher acenes possess lower electron and hole reorganization energies, with both best values much lower than 0.1 eV, their BN analogues also have competitive values of reorganization energies, especially for holes for which reorganization energy is also lower than 0.1 eV. On the other hand ΔE(S{sub 1}−T{sub 1}) is much better for BN analogues, having values that indicate that BN analogues are possible applicable for thermally activated delayed fluorescence. - Highlights: • Optoelectronic properties of structures based on higher acenes have been investigated. • Oxidation and reduction potentials together with reorganization energies are calculated. • TADF is analyzed through calculation of ΔE(S{sub 1}−T{sub 1}), which is much better for BN analogues. • Reorganization energies of acenes improve with the increase of number of benzene rings.

Liposomes containing alkylated methotrexate analogues for phospholipase A(2) mediated tumor targeted drug delivery

DEFF Research Database (Denmark)

Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde

2009-01-01

of alkylated compounds in liposomes, it was demonstrated that the MTX-analogue partitioned into the water phase and thereby became available for cell uptake. It was concluded that liposomes containing alkylated MTX-analogues show promise as a drug delivery system, although the MTX-analogue needs to be more......Two lipophilic methotrexate analogues have been synthesized and evaluated for cytotoxicity against KATO III and HT-29 human colon cancer cells. Both analogues contained a C-16-alkyl chain attached to the gamma-carboxylic acid and one of the analogues had an additional benzyl group attached...... cytotoxicity was incorporated into liposomes that were designed to be particularly Susceptible to a liposome degrading enzyme, secretory phospholipase A(2) (sPLA(2)), which is found in high concentrations in tumors of several different cancer types. Liposome incorporation was investigated by differential...

Seasonal heat stress: Clinical implications and hormone treatments for the fertility of dairy cows.

Science.gov (United States)

De Rensis, F; Garcia-Ispierto, I; López-Gatius, F

2015-09-15

Heat stress has consequences on both the physiology and reproductive performance of cows, but the most dramatic effect for dairy producers is the decrease produced in fertility. The effects of heat stress on fertility include an increased number of days open, reduced conception rate, and larger number of cows suffering different types of anestrus. Once becomes pregnant, heat stress affects also the reproductive success of the cow through its direct effects on the ovary, uterus, gametes, embryo, and early fetus. This article reviews current knowledge of the effects of heat stress on fertility in dairy cows and the hormonal strategies used to mitigate these effects at the farm level. Administration of GnRH at the moment of artificial insemination can improve the conception rate. Breeding synchronization protocols for fixed-time insemination may reduce the calving conception interval and the number of services per conception. Progesterone-based protocols seem resolve better the reproductive disorders related to a hot environment (anestrus) than GnRH-based protocols. The use of combinations of GnRH, eCG, and hCG in progesterone-based protocols can improve results. Progesterone supplementation during the late embryonic and/or early fetal period would be useful in curtailing pregnancy losses, mainly in single pregnancies, whereas a more positive effect of treatment with GnRH than progesterone has been found in twin pregnancies. Melatonin therapy is emerging as a promising strategy to improve the natural reproductive performance of cows suffering conditions of heat stress. Copyright © 2015 Elsevier Inc. All rights reserved.

Cetrorelix suppresses the preovulatory LH surge and ovulation induced by ovulation-inducing factor (OIF) present in llama seminal plasma.

Science.gov (United States)

Silva, Mauricio E; Smulders, Juan P; Guerra, Monserrat; Valderrama, Ximena P; Letelier, Claudia; Adams, Gregg P; Ratto, Marcelo H

2011-05-30

The purpose of the study was to determine if the effect of llama OIF on LH secretion is mediated by stimulation of the hypothalamus or pituitary gland. Using a 2-by-2 factorial design to examine the effects of OIF vs GnRH with or without a GnRH antagonist, llamas with a growing ovarian follicle greater than or equal to 8 mm were assigned randomly to four groups (n = 7 per group) and a) pre-treated with 1.5 mg of GnRH antagonist (cetrorelix acetate) followed by 1 mg of purified llama OIF, b) pre-treated with 1.5 mg of cetrorelix followed by 50 micrograms of GnRH, c) pre-treated with a placebo (2 ml of saline) followed by 1 mg of purified llama OIF or d) pre-treated with a placebo (2 ml of saline) followed by 50 micrograms of GnRH. Pre-treatment with cetrorelix or saline was given as a single slow intravenous dose 2 hours before intramuscular administration of either GnRH or OIF. Blood samples for LH measurement were taken every 15 minutes from 1.5 hours before to 8 hours after treatment. The ovaries were examined by ultrasonography to detect ovulation and CL formation. Blood samples for progesterone measurement were taken every-other-day from Day 0 (day of treatment) to Day 16. Ovulation rate was not different (P = 0.89) between placebo+GnRH (86%) and placebo+OIF groups (100%); however, no ovulations were detected in llamas pre-treated with cetrorelix. Plasma LH concentrations surged (P llamas suggesting that LH secretion is modulated by a direct or indirect effect of OIF on GnRH neurons in the hypothalamus.

Synthesis of the 4’-desmethoxy analogue of RU79115

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MICHEL KLICH

2004-11-01

Full Text Available The synthesis, and biological activity in vitro of the 4’-desmethoxy analogue (3 of RU 79115 (2 is described. Comparison of the biological activity of the two analogues clearly indicated the importance of the 4’-methoxy group in conferring good gyrase B inhibitory activity as well as antibacterial activity.

Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner

DEFF Research Database (Denmark)

Sandrini, Michael; Clausen, Anders; On, Stephen L. W.

2007-01-01

To investigate the bactericidal activity of antiviral and anticancer nucleoside analogues against a variety of pathogenic bacteria and characterize the activating enzymes, deoxyribonucleoside kinases (dNKs). Several FDA-approved nucleoside analogue drugs were screened for their potential bacteric......-specific manner. Therefore, nucleoside analogues have a potential to be employed as antibiotics in the fight against emerging multiresistant bacteria....

Reasoning by analogy: rational foundation of natural analogue studies

International Nuclear Information System (INIS)

Petit, J.-C.

1992-01-01

Long-term extrapolations concerning the safety of a nuclear waste repository cannot be satisfactorily made on the sole basis of short-term laboratory investigations. Most nuclear countries have hence developed an approach relying on the following research directions: 1. laboratory experiments; 2. in situ testing; 3. modeling; and 4. natural analogues, which are the only means by which very slow mechanisms can be identified and by which long-term predictions of models can be tested for pertinence (if not truly validated). Although the field of natural analogues has grown very rapidly in recent years, receiving support from varied specialists and institutions involved in radioactive waste disposal, there is not yet a full consensus on their actual usefulness. More problematic is the criticism sometimes made that analogical reasoning is not ''true science'' and that information retrieved from the study of natural analogues will always remain questionable. The present paper gives some clues about the exact status of reasoning by analogy, compared to more ''scientific'' ways of deriving information from investigated systems. It is not a thorough discussion of this very complex, and by far too philosophical issue but we hope, at least, to present to readers of papers devoted to natural analogue studies arguments showing that this approach has some sound foundation. (author)

Effect of restricted protein diet supplemented with keto analogues in end-stage renal disease: a systematic review and meta-analysis.

Science.gov (United States)

Jiang, Zheng; Tang, Yi; Yang, Lichuan; Mi, Xuhua; Qin, Wei