A Patient Friendly Corifollitropin Alfa Protocol without Routine Pituitary Suppression in Normal Responders

PubMed Central

Wang, Huai-Ling; Lai, Hsing-Hua; Chuang, Tzu-Hsuan; Shih, Yu-Wei; Huang, Shih-Chieh; Lee, Meng-Ju; Chen, Shee-Uan

2016-01-01

The release of corifollitropin alfa simplifies daily injections of short-acting recombinant follicular stimulating hormone (rFSH), and its widely-used protocol involves short-acting gonadotropins supplements and a fixed GnRH antagonist regimen, largely based on follicle size. In this study, the feasibility of corifollitropin alfa without routine pituitary suppression was evaluated. A total of 288 patients were stimulated by corifollitropin alfa on cycle day 3 following with routine serum hormone monitoring and follicle scanning every other day after 5 days of initial stimulation, and a GnRH antagonist (0.25 mg) was only used prophylactically when the luteinizing hormone (LH) was ≧ 6 IU/L (over half of the definitive LH surge). The incidence of premature LH surge (≧ 10 IU/L) was 2.4% (7/288) before the timely injection of a single GnRH antagonist, and the elevated LH level was dropped down from 11.9 IU/L to 2.2 IU/L after the suppression. Two hundred fifty-one patients did not need any antagonist (87.2% [251/288]) throughout the whole stimulation. No adverse effects were observed regarding oocyte competency (fertilization rate: 78%; blastocyst formation rate: 64%). The live birth rate per OPU cycle after the first cryotransfer was 56.3% (161/286), and the cumulative live birth rate per OPU cycle after cyrotransfers was 69.6% (199/286). Of patients who did and did not receive GnRH antagonist during stimulation, no significant difference existed in the cumulative live birth rates (78.4% vs. 68.3%, p = 0.25). The results demonstrated that the routine GnRH antagonist administration is not required in the corifollitropin-alfa cycles using a flexible and hormone-depended antagonist regimen, while the clinical outcome is not compromised. This finding reveals that the use of a GnRH antagonist only occasionally may be needed. PMID:27100388

A Patient Friendly Corifollitropin Alfa Protocol without Routine Pituitary Suppression in Normal Responders.

PubMed

Wang, Huai-Ling; Lai, Hsing-Hua; Chuang, Tzu-Hsuan; Shih, Yu-Wei; Huang, Shih-Chieh; Lee, Meng-Ju; Chen, Shee-Uan

2016-01-01

The release of corifollitropin alfa simplifies daily injections of short-acting recombinant follicular stimulating hormone (rFSH), and its widely-used protocol involves short-acting gonadotropins supplements and a fixed GnRH antagonist regimen, largely based on follicle size. In this study, the feasibility of corifollitropin alfa without routine pituitary suppression was evaluated. A total of 288 patients were stimulated by corifollitropin alfa on cycle day 3 following with routine serum hormone monitoring and follicle scanning every other day after 5 days of initial stimulation, and a GnRH antagonist (0.25 mg) was only used prophylactically when the luteinizing hormone (LH) was ≧ 6 IU/L (over half of the definitive LH surge). The incidence of premature LH surge (≧ 10 IU/L) was 2.4% (7/288) before the timely injection of a single GnRH antagonist, and the elevated LH level was dropped down from 11.9 IU/L to 2.2 IU/L after the suppression. Two hundred fifty-one patients did not need any antagonist (87.2% [251/288]) throughout the whole stimulation. No adverse effects were observed regarding oocyte competency (fertilization rate: 78%; blastocyst formation rate: 64%). The live birth rate per OPU cycle after the first cryotransfer was 56.3% (161/286), and the cumulative live birth rate per OPU cycle after cyrotransfers was 69.6% (199/286). Of patients who did and did not receive GnRH antagonist during stimulation, no significant difference existed in the cumulative live birth rates (78.4% vs. 68.3%, p = 0.25). The results demonstrated that the routine GnRH antagonist administration is not required in the corifollitropin-alfa cycles using a flexible and hormone-depended antagonist regimen, while the clinical outcome is not compromised. This finding reveals that the use of a GnRH antagonist only occasionally may be needed.

In vitro assessment of thyroid hormone disrupting activities in drinking water sources along the Yangtze River.

PubMed

Hu, Xinxin; Shi, Wei; Zhang, Fengxian; Cao, Fu; Hu, Guanjiu; Hao, Yingqun; Wei, Si; Wang, Xinru; Yu, Hongxia

2013-02-01

The thyroid hormone disrupting activities of drinking water sources from the lower reaches of Yangtze River were examined using a reporter gene assay based on African green monkey kidney fibroblast (CV-1) cells. None of the eleven tested samples showed thyroid receptor (TR) agonist activity. Nine water samples exhibited TR antagonist activities with the equivalents referring to Di-n-butyl phthalate (DNBP) (TR antagonist activity equivalents, ATR-EQ(50)s) ranging from 6.92 × 10(1) to 2.85 × 10(2) μg DNBP/L. The ATR-EQ(50)s and TR antagonist equivalent ranges (ATR-EQ(30-80) ranges) for TR antagonist activities indicated that the water sample from site WX-8 posed the greatest health risks. The ATR-EQ(80)s of the water samples ranging from 1.56 × 10(3) to 6.14 × 10(3) μg DNBP/L were higher than the NOEC of DNBP. The results from instrumental analysis showed that DNBP might be responsible for the TR antagonist activities in these water samples. Water sources along Yangtze River had thyroid hormone disrupting potential. Copyright © 2012 Elsevier Ltd. All rights reserved.

Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules.

PubMed

Mackenzie, Louise S

2018-01-01

Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism. Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people. This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution. © 2018 Elsevier Inc. All rights reserved.

Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists.

PubMed

Ma, Vu; Bannon, Anthony W; Baumgartner, Jamie; Hale, Clarence; Hsieh, Faye; Hulme, Christopher; Rorrer, Kirk; Salon, John; van Staden, Carlo; Tempest, Paul

2006-10-01

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bajusz, S.; Janaky, T.; Csernus, V.J.

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Ofmore » the peptides prepared, (D-Mel{sup 6})LH-RH (SB-05) and (Ac-D-Nal(2){sup 1},D-Phe(pCl){sup 2},D-Pal(3){sup 3},Arg{sup 5},D-Mel{sup 6},D-Ala{sup 10})LH-RH (SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine) possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel{sup 6} analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.« less

Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor

PubMed Central

van Koppen, Chris J; de Gooyer, Marcel E; Karstens, Willem-Jan; Plate, Ralf; Conti, Paolo GM; van Achterberg, Tanja AE; van Amstel, Monique GA; Brands, Jolanda HGM; Wat, Jesse; Berg, Rob JW; Lane, J Robert D; Miltenburg, Andre MM; Timmers, C Marco

2012-01-01

BACKGROUND AND PURPOSE Graves' disease (GD) is an autoimmune disease in which the thyroid is overactive, producing excessive amounts of thyroid hormones, caused by thyroid-stimulating hormone (TSH) receptor-stimulating immunoglobulins (TSIs). Many GD patients also suffer from thyroid eye disease (Graves' ophthalmopathy or GO), as TSIs also activate TSH receptors in orbital tissue. We recently developed low molecular weight (LMW) TSH receptor antagonists as a novel therapeutic strategy for the treatment of GD and GO. Here, we determined the molecular pharmacology of a prototypic, nanomolar potent LMW TSH receptor antagonist, Org 274179-0. EXPERIMENTAL APPROACH Using CHO cells heterogeneously expressing human TSH receptors and rat FRTL-5 cells endogenously expressing rat TSH receptors, we determined the potency and efficacy of Org 274179-0 at antagonizing TSH- and TSI-induced TSH receptor signalling and its cross-reactivity at related follicle-stimulating hormone and luteinizing hormone receptors. We analysed the allosteric mode of interaction of Org 274179-0 and determined whether it is an inverse agonist at five naturally occurring, constitutively active TSH receptor mutants. KEY RESULTS Nanomolar concentrations of Org 274179-0 completely inhibited TSH (and TSI)-mediated TSH receptor activation with little effect on the potency of TSH, in accordance with an allosteric mechanism of action. Conversely, increasing levels of TSH receptor stimulation only marginally reduced the antagonist potency of Org 274179-0. Org 274179-0 fully blocked the increased basal activity of all the constitutively active TSH receptor mutants tested with nanomolar potencies. CONCLUSIONS AND IMPLICATIONS Nanomolar potent TSH receptor antagonists like Org 274179-0 have therapeutic potential for the treatment of GD and GO. PMID:22014107

COMPARISON OF THE EFFECTS OF TWO AR ANTAGONISTS ON ANDROGEN DEPENDENT TISSUES WEIGHTS AND HORMONE LEVELS IN MALE RATS AND ON EXPRESSION OF THREE ANDROGEN DEPENDENT GENES IN THE VENTRAL PROSTATE

EPA Science Inventory

Comparison of the effects of two AR antagonists on tissue weights and hormone levels in male rats and on expression of three androgen dependent genes in the ventral prostate
VS Wilson, CR Wood, GA Held, CS Lambright, JS Ostby, JR Furr, LE Gray Jr. US EPA, ORD, NHEERL, RTD, ...

Gonadotropin-releasing hormone antagonist in in vitro fertilization superovulation.

PubMed

Seng, Shay Way; Ong, Kee Jiet; Ledger, W L

2006-11-01

The use of gonadotropin-releasing hormone (GnRH) antagonists in in vitro fertilization superovulation remains controversial. The GnRH agonist 'long protocol' has been seen as the gold standard for many years. Comparisons and meta-analyses of the efficacy of GnRH antagonists and agonists have been largely inconclusive, with the dataset being contaminated with outdated reports of poorer efficacy with GnRH antagonists, which have stemmed from studies of their use as a second-line drug in older women and women who were poor responders. This work cannot reflect the actual clinical effectiveness of GnRH antagonist and must be interpreted with care. The major advantages of GnRH antagonists use in superovulation include a gentler and more patient-friendly stimulation cycle with less hypoestrogenic side effects, with the potential to lower the risk of ovarian hyperstimulation and enhanced embryo growth. Our current clinical experience with GnRH antagonists in in vitro fertilization is limited, although there are a growing number of in vitro fertilization centers embracing this new technology. There is a clear need for a modern, suitably powered clinical trial to demonstrate the place of GnRH antagonist-based superovulation protocols and in subgroups of patients, such as polycystic ovary syndrome or poor responders.

Relaxin receptor antagonist AT-001 synergizes with docetaxel in androgen-independent prostate xenografts.

PubMed

Neschadim, Anton; Pritzker, Laura B; Pritzker, Kenneth P H; Branch, Donald R; Summerlee, Alastair J S; Trachtenberg, John; Silvertown, Joshua D

2014-06-01

Androgen hormones and the androgen receptor (AR) pathway are the main targets of anti-hormonal therapies for prostate cancer. However, resistance inevitably develops to treatments aimed at the AR pathway resulting in androgen-independent or hormone-refractory prostate cancer (HRPC). Therefore, there is a significant unmet need for new, non-androgen anti-hormonal strategies for the management of prostate cancer. We demonstrate that a relaxin hormone receptor antagonist, AT-001, an analog of human H2 relaxin, represents a first-in-class anti-hormonal candidate treatment designed to significantly curtail the growth of androgen-independent human prostate tumor xenografts. Chemically synthesized AT-001, administered subcutaneously, suppressed PC3 xenograft growth by up to 60%. AT-001 also synergized with docetaxel, standard first-line chemotherapy for HRPC, to suppress tumor growth by more than 98% in PC3 xenografts via a mechanism involving the downregulation of hypoxia-inducible factor 1 alpha and the hypoxia-induced response. Our data support developing AT-001 for clinical use as an anti-relaxin hormonal therapy for advanced prostate cancer.

Influence of histamine and serotonin antagonists on the growth of xenografted human colorectal tumors.

PubMed

Barkla, D H; Tutton, P J

1981-12-01

Four lines of human colorectal cancer were established and serially propagated as subcutaneous xenographs in immunosuppressed inbred CBA/Lac mice. Established xenografts were then used to investigate the influence of a serotonin antagonist (BW 501c) and a histamine H2 receptor antagonists (Cimetidine) on xenograft growth. The growth of each of the four tumor lines was significantly inhibited by BW 501c throughout the treatment, whereas the growth of only two tumor lines was significantly inhibited by Cimetidine treatment. The response of individual tumor lines was not predictable on the basis of either tumor histopathology or the natural growth rate of the untreated xenograft. A number of alternative, but not mutually exclusive, hypotheses are suggested to explain the results. One hypothesis proposes that colorectal tumors are composed of subpopulations of tumor cells that are variously dependent on or independent of amine hormones. Another hypothesis is that tumor cells exhibit temporal changes in hormone sensitivity to amine hormones during treatment. Finally, it is suggested that serotonin and/or histamine H2 antagonists may be useful in preventing the repopulation of colorectal carcinomas following antineoplastic therapy with the use of conventional drugs.

Effects of gonadotropin-releasing hormone agonist/recombinant follicle-stimulating hormone versus gonadotropin-releasing hormone antagonist/recombinant follicle-stimulating hormone on follicular fluid levels of adhesion molecules during in vitro fertilization.

PubMed

Fornaro, Felice; Cobellis, Luigi; Mele, Daniela; Tassou, Argyrò; Badolati, Barbara; Sorrentino, Simona; De Lucia, Domenico; Colacurci, Nicola

2007-01-01

To compare the effects of GnRH-agonist/recombinant rFSH versus GnRH-antagonist/recombinant FSH stimulation on follicular fluid levels of soluble intercellular adhesion molecule (sICAM)-1 and vascular cell adhesion molecule-1 (sVCAM-1) during in vitro fertilization (IVF). Prospective, randomized study. University hospital. Seventy-three women underwent IVF. GnRH-agonist/rFSH or GnRH-antagonist/rFSH administration and collection of follicular fluid from 3 small (11-14 mm in diameter) and 3 large (18-21 mm in diameter) follicles on the day of oocyte retrieval. Follicular fluid levels of sICAM-1 and sVCAM-1 and intrafollicular estradiol and progesterone were also measured. Women who underwent GnRH-agonist/rFSH showed higher concentrations of sICAM-1 in both small and large follicles were compared with patients who received GnRH-antagonist/rFSH treatment; follicular fluid levels of sVCAM-1 were similar between the 2 stimulation protocols. Content of sICAM-1 in small and large follicles positively correlated with the number of follicles of > or =15 mm and the number of oocytes that were retrieved in both study groups. Concentrations of follicular fluid sVCAM-1 and progesterone were higher in large than in small follicles and were correlated positively to each other in both follicular classes. In IVF, GnRH-agonist/rFSH is associated with higher follicular fluid levels of sICAM-1 compared with GnRH-antagonist/rFSH regimen. Intrafollicular sICAM-1 content may predict ovarian response, and sVCAM-1 appears as an indicator of the degree of follicular luteinization.

Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor.

PubMed

Chen, Chen; Wu, Dongpei; Guo, Zhiqiang; Xie, Qiu; Reinhart, Greg J; Madan, Ajay; Wen, Jenny; Chen, Takung; Huang, Charles Q; Chen, Mi; Chen, Yongsheng; Tucci, Fabio C; Rowbottom, Martin; Pontillo, Joseph; Zhu, Yun-Fei; Wade, Warren; Saunders, John; Bozigian, Haig; Struthers, R Scott

2008-12-11

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

Decrease in the AgNOR number in Dunning R3327 prostate cancers after treatment with an agonist and antagonist of luteinizing hormone-releasing hormone.

PubMed Central

Szepeshazi, K.; Korkut, E.; Schally, A. V.

1991-01-01

The argyrophilic staining of the nucleolar organizer region (AgNOR) in cells of Dunning R3327 rat prostate tumors was studied and the effect of hormonal treatments on their appearance was analyzed. The nuclei of the control tumor cells contained 4.1 +/- 0.17 AgNOR granules. Treatment of rats for 8 weeks with luteinizing hormone-releasing hormone (LH-RH) agonist (D-Trp-6-LH-RH) and antagonist SB-75 induced a marked inhibition of tumor growth and decreased significantly (P less than 0.01) the number of Ag-NORs in the tumors to 2.89 +/- 0.10 AgNOR granules/cell in the group given the agonist and to 2.82 +/- 0.10 after therapy with the highest dose of the antagonist. A reduced AgNOR number (3.14 +/- 0.16) also was found after 3 days of treatment with SB-75 (P less than 0.05), but the AgNORs returned to near control values 1 week after the short-term therapy, showing the reversibility of these changes. These results suggest that the AgNOR method, which was widely tested on human tumors in the past few years, can be a valuable technique in experimental tumor pathology and useful in the evaluation of the effects of various treatments. Images Figure 1 PMID:1827237

Screening the Tox21 10K library for thyroid stimulating hormone receptor agonist and antagonist activity (SOT annual meeting)

EPA Science Inventory

Thyroid-stimulating hormone (TSH) regulates thyroid hormone (TH) production via binding to its receptor (TSHR). The roles of TSHR in human pathologies including hyper/hypothyroidism, Grave’s disease, and thyroid cancer are known, but it is currently unknown whether TSHR is an imp...

Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells.

PubMed

Ziegler, C G; Ullrich, M; Schally, A V; Bergmann, R; Pietzsch, J; Gebauer, L; Gondek, K; Qin, N; Pacak, K; Ehrhart-Bornstein, M; Eisenhofer, G; Bornstein, S R

2013-05-22

Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences.

PubMed

Roved, Jacob; Westerdahl, Helena; Hasselquist, Dennis

2017-02-01

Males and females differ in both parasite load and the strength of immune responses and these effects have been verified in humans and other vertebrates. Sex hormones act as important modulators of immune responses; the male sex hormone testosterone is generally immunosuppressive while the female sex hormone estrogen tends to be immunoenhancing. Different sets of T-helper cells (Th) have important roles in adaptive immunity, e.g. Th1 cells trigger type 1 responses which are primarily cell-mediated, and Th2 cells trigger type 2 responses which are primarily humoral responses. In our review of the literature, we find that estrogen and progesterone enhance type 2 and suppress type 1 responses in females, whereas testosterone suppresses type 2 responses and shows an inconsistent pattern for type 1 responses in males. When we combine these patterns of generally immunosuppressive and immunoenhancing effects of the sex hormones, our results imply that the sex differences in immune responses should be particularly strong in immune functions associated with type 2 responses, and less pronounced with type 1 responses. In general the hormone-mediated sex differences in immune responses may lead to genetic sexual conflicts on immunity. Thus, we propose the novel hypothesis that sexually antagonistic selection may act on immune genes shared by the sexes, and that the strength of this sexually antagonistic selection should be stronger for type 2- as compared with type 1-associated immune genes. Finally, we put the consequences of sex hormone-induced effects on immune responses into behavioral and ecological contexts, considering social mating system, sexual selection, geographical distribution of hosts, and parasite abundance. Copyright © 2016 Elsevier Inc. All rights reserved.

High exposure to progesterone between the end of menstruation and the day of triggering final oocyte maturation is associated with a decreased probability of pregnancy in patients treated by in vitro fertilization and intracytoplasmic sperm injection.

PubMed

Kyrou, Dimitra; Kolibianakis, Efstratios M; Fatemi, Human M; Camus, Michel; Tournaye, Herman; Tarlatzis, Basil C; Devroey, Paul

2011-10-01

To investigate the association between the probability of pregnancy and hormone exposure between the end of menstruation and the day of triggering final oocyte maturation (menstruation-free interval). Prospective study. University. One hundred women (aged ≤ 39 years) stimulated with a fixed dose of recombinant follicle-stimulating hormone (200 IU). Daily gonadotropin-releasing hormone antagonist (GnRH, 0.25 mg) used from day 6 of stimulation onward, final oocyte maturation triggered by administration of 10,000 IU of human chorionic gonadotropin (hCG) as soon as ≥ 3 follicles ≥ 17 mm were present, and hormone assessment performed at initiation of stimulation, on the first day after menstruation had stopped, on the day of antagonist initiation, and on the day of hCG administration. The association between hormone exposure during the menstruation-free interval and the probability of ongoing pregnancy. The exposure to progesterone during the menstruation-free interval was statistically significantly higher in patients who did not become pregnant compared with those who did (4.20 ± 2.54 vs. 3.13 ± 1.14, respectively). Binary logistic regression confirmed the adverse effect of the increased exposure to progesterone for the achievement of pregnancy. In recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in vitro fertilization/intracytoplasmic sperm injection cycles, a lower probability of pregnancy is associated with a higher exposure to progesterone during the menstruation-free interval. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Thyroid hormone disrupting activities associated with phthalate esters in water sources from Yangtze River Delta.

PubMed

Shi, Wei; Zhang, Feng-Xian; Hu, Guan-Jiu; Hao, Ying-Qun; Zhang, Xiao-Wei; Liu, Hong-Ling; Wei, Si; Wang, Xin-Ru; Giesy, John P; Yu, Hong-Xia

2012-07-01

Thyroid hormone disrupting compounds in water sources is a concern. Thyroid hormone (TH) agonist and antagonist activities of water sources from the Yangtze River, Huaihe River, Taihu Lake and ground water in the Yangtze River Delta region were evaluated by use of a TH reporter gene assay based on the green monkey kidney fibroblast (CV-1). While weak TH receptor (TR) agonist potency was observed in only one of 15 water sources, antagonist potency was present in most of the water sources. TR antagonist equivalents could be explained by the presence of dibutyl phthalate (DBP), with concentrations ranging from 2.8×10(1) to 1.6×10(3) μg DBP /L (ATR-EQ(50)s). None of the ground waters exhibited TH agonist potencies while all of the samples from Taihu Lake displayed notable TR antagonist potencies. To identify the responsible thyroid active compounds, instrumental analysis was conducted to measure a list of potential thyroid-disrupting chemicals, including organochlorine (OC) pesticides and phthalate esters. Combining the results of the instrumental analysis with those of the bioassay, DBP was determined to account for 17% to 144% of ATR-EQ(50)s in water sources. Furthermore, ATR-EQ(20-80) ranges for TR antagonist activities indicated that samples from locations WX-1 and WX-2 posed the greatest health concern and the associated uncertainty may warrant further investigation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders.

PubMed

Contoreggi, Carlo; Rice, Kenner C; Chrousos, George

2004-01-01

Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in 'somatic' disorders. Some rare forms of Cushing's disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of 'psychosomatic' disorders.

Comparison of mechanisms of action of luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix and LHRH agonist triptorelin on the gene expression of pituitary LHRH receptors in rats

PubMed Central

Kovacs, Magdolna; Schally, Andrew V.

2001-01-01

The mechanisms through which luteinizing hormone (LH)-releasing hormone (LHRH) antagonists suppress pituitary gonadotroph functions and LHRH-receptor (LHRH-R) expression are incompletely understood. Consequently, we investigated the direct effect of LHRH antagonist cetrorelix in vitro on the expression of the pituitary LHRH-R gene and its ability to counteract the exogenous LHRH and the agonist triptorelin in the regulation of this gene. We also compared the effects of chronic administration of cetrorelix and triptorelin on the LHRH-R mRNA level and gonadotropin secretion in ovariectomized (OVX) and normal female rats. The exposure of pituitary cells in vitro to 3-min pulses of 1 nM LHRH or 0.1 nM triptorelin for 5 h increased the LHRH-R mRNA level by 77–88%. Continuous perfusion of the cells with 50 nM cetrorelix did not cause any significant changes, but prevented the stimulatory effect of LHRH pulses on the receptor mRNA expression. In OVX rats, 10 days after administration of a depot formulation of cetrorelix, releasing 100 μg of peptide daily, the elevated LHRH-R mRNA level was decreased by 73%, whereas daily injection of 100 μg of triptorelin caused a 41% suppression. In normal female rats, cetrorelix treatment suppressed the LHRH-R mRNA level by 33%, but triptorelin increased it by 150%. The highly elevated serum LH levels in OVX rats and the normal LH concentration of cycling rats were rapidly and completely suppressed by cetrorelix. Triptorelin decreased the serum LH in OVX rats to the precastration level, but had no effect on basal LH in normal rats. Our results confirm that LHRH antagonists, such as cetrorelix, inhibit the gene expression of pituitary LHRH-R indirectly, by counteracting the stimulatory effect of LHRH. A rapid suppression of serum LH by LHRH antagonists would be advantageous in the treatment of sex hormone-dependent tumors and other conditions. PMID:11593037

Comparison of the ultrashort gonadotropin-releasing hormone agonist-antagonist protocol with microdose flare -up protocol in poor responders: a preliminary study.

PubMed

Berker, Bülent; Duvan, Candan İltemir; Kaya, Cemil; Aytaç, Ruşen; Satıroğlu, Hakan

2010-01-01

To determine the potential effect of the ultrashort gonadotropin-releasing hormone (GnRH) agonist/GnRH antagonist protocol versus the microdose GnRH agonist protocol in poor responders undergoing intracytoplasmic sperm injection (ICSI). The patients in the Agonist-Antagonist Group (n=41) were administered the ultrashort GnRH-agonist/ antagonist protocol, while the patients in the Microdose Group (n=41) were stimulated according to the microdose flare-up protocol. The mean number of mature oocytes retrieved was the primary outcome measure. Fertilization rate, implantation rate per embryo and clinical pregnancy rates were secondary outcome measures. There was no differenc between the mean number of mature oocytes retrieved in the two groups. There were also no statistical differences between the two groups in terms of peak serum E2 level, canceled cycles, endometrial thickness on hCG day, number of 2 pronucleus and number of embryos transferred. However, the total gonadotropin consumption and duration of stimulation were significantly higher with the Agonist-Antagonist Group compared with the Microdose Group. The implantation and clinical pregnancy rates were similar between the two groups. Despite the high dose of gonadotropin consumption and longer duration of stimulation with the ultrashort GnRH agonist/ antagonist protocol, it seems that the Agonist-Antagonist Protocol is not inferior to the microdose protocol in poor responders undergoing ICSI.

Gonadotrophin-releasing activity of neurohypophysial hormones: II. The pituitary oxytocin receptor mediating gonadotrophin release differs from that of corticotrophs.

PubMed

Evans, J J; Catt, K J

1989-07-01

Neurohypophysial hormones stimulate gonadotrophin release from dispersed rat anterior pituitary cells in vitro, acting through receptors distinct from those which mediate the secretory response to gonadotrophin-releasing hormone (GnRH). The LH response to oxytocin was not affected by the presence of the phosphodiesterase inhibitor, methyl isobutylxanthine, but was diminished in the absence of extracellular calcium and was progressively increased as the calcium concentration in the medium was raised to normal. In addition, the calcium channel antagonist, nifedipine, suppressed oxytocin-stimulated secretion of LH. It is likely that the mechanisms of LH release induced by GnRH and neurohypophysial hormones are similar, although stimulation of gonadotrophin secretion is mediated by separate receptor systems. Oxytocin was more active than vasopressin in releasing LH, but less active in releasing ACTH. The highly selective oxytocin agonist, [Thr4,Gly7]oxytocin, elicited concentration-dependent secretion of LH but had little effect on corticotrophin secretion. The neurohypophysial hormone antagonist analogues, [d(CH2)5Tyr(Me)2]vasopressin, [d(CH2)5Tyr(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2Val4,Cit8]vasopressin, inhibited the LH response to both oxytocin and vasopressin. However, [d(CH2)5Tyr(Me)2]vasopressin was much less effective in inhibiting the ACTH response to the neurohypophysial hormones, and [d(CH2)5Tyr-(Me)2,Orn8]vasotocin and [d(CH2)5D-Tyr(Et)2,Val4,Cit8]vasopressin exhibited no inhibitory activity against ACTH release. Thus, agonist and antagonist analogues of neurohypophysial hormones display divergent activities with regard to LH and ACTH responses, and the neuropeptide receptor mediating gonadotroph activation is clearly different from that on the corticotroph. Whereas the corticotroph receptor is a vasopressin-type receptor an oxytocin-type receptor is responsible for gonadotrophin release by neurohypophysial hormones.

Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.

PubMed Central

Halmos, G; Schally, A V; Pinski, J; Vadillo-Buenfil, M; Groot, K

1996-01-01

Antagonists of luteinizing hormone-releasing hormone (LH-RH), unlike the LH-RH agonists, suppress gonadotropins and sex steroid secretion immediately after administration, without initial stimulatory effects. [Ac-D-Nal(2)1,D-Ph(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-R H (SB-75; Cetrorelix) is a modern, potent antagonistic analog of LH-RH. In this study, the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries were investigated after a single injection of Cetrorelix at a dose of 100 microg per rat. To determine whether the treatment with Cetrorelix can affect the concentration of measurable LH-RH binding sites, we applied an in vitro method to desaturate LH-RH receptors by chaotropic agents such as manganous chloride (MnCl2) and ammonium thiocyanate (NH4SCN). Our results show that the percentages of occupied LH-RH receptors at 1, 3, and 6 h after administration of Cetrorelix were approximately 28%, 14%, and 10%, respectively, of total receptors. At later time intervals, we could not detect occupied LH-RH binding sites. Ligand competition assays, following in vitro desaturation, demonstrated that rat pituitary LH-RH receptors were significantly (P < 0.01) down-regulated for at least 72 h after administration of Cetrorelix. The lowest receptor concentration was found 3-6 h after Cetrorelix treatment and a recovery in receptor number began within approximately 24 h. The down-regulation of LH-RH binding sites induced by Cetrorelix was accompanied by serum LH and testosterone suppression. Higher LH-RH receptor concentrations coincided with elevated serum hormone levels at later time intervals. Our results indicate that administration of LH-RH antagonist Cetrorelix produces a marked down-regulation of pituitary receptors for LH-RH and not merely an occupancy of binding sites. PMID:8637885

Gonadotrophin-releasing hormone antagonists for assisted conception.

PubMed

Al-Inany, H G; Abou-Setta, A M; Aboulghar, M

2006-07-19

Gonadotrophin-releasing hormone antagonists produce immediate suppression of gonadotrophin secretion, hence, they can be given after starting gonadotrophin administration. This has resulted in dramatic reduction in the duration of treatment cycle. Two different regimes have been described. The multiple-dose protocol involves the administration of 0.25 mg cetrorelix (or ganirelix) daily from day six to seven of stimulation, or when the leading follicle is 14 to15 mm, until human chorionic gonadotrophin (HCG) administration and the single-dose protocol involves the single administration of 3 mg cetrorelix on day seven to eight of stimulation. Assuming comparable clinical outcome, these benefits would justify a change from the standard long protocol of GnRH agonists to the new GnRH antagonist regimens. To evaluate the evidence regarding the efficacy of gonadotrophin-releasing hormone (GnRH) antagonists with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception. We searched Cochrane Menstrual Disorders and Subfertility Group's Specialised Register, MEDLINE and EMBASE databases from 1987 to February 2006, and handsearched bibliographies of relevant publications and reviews, and abstracts of scientific meetings. We also contacted manufacturers in the field. Randomized controlled studies comparing different protocols of GnRH antagonists with GnRH agonists in assisted conception cycles were included in this review. Two authors independently assessed trial quality and extracted data. If relevant data were missing or unclear, the authors have been consulted Twenty seven RCTs comparing the GnRH antagonist to the long protocol of GnRH agonist fulfilled the inclusion criteria. Clinical pregnancy rate was significantly lower in the antagonist group. (OR = 0.84, 95% CI = 0.72 - 0.97). The ongoing pregnancy/ live-birth rate showed the same significant lower pregnancy in the antagonist group (P = 0.03; OR 0.82, 95% CI 0.69 to 0.98).However, there was statistically significant reduction in incidence of severe OHSS with antagonist protocol. The relative risk ratio was (P = 0.01; RR 0.61, 95% CI 0.42 to 0.89). In addition, interventions to prevent OHSS (e.g. coasting, cycle cancellation) were administered more frequently in the agonist group (P = 0.03; OR 0.44, 95% CI 0.21 to 0.93). GnRH antagonist protocol is a short and simple protocol with good clinical outcome with significant reduction in incidence of severe ovarian hyperstimulation syndrome and amount of gonadotrophins but the lower pregnancy rate compared to the GnRH agonist long protocol necessitates counseling subfertile couples before recommending change from GnRH agonist to antagonist..

Suppression of meiosis of male germ cells by an antagonist of luteinizing hormone-releasing hormone.

PubMed Central

Szende, B; Redding, T W; Schally, A V

1990-01-01

Male nude mice were implanted with osmotic minipumps releasing 50 micrograms of a potent antagonist of luteinizing hormone-releasing hormone (LH-RH) per day [N-Ac-[D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-RH] (SB-75) [Nal(2), 3-(2-naphthyl)alanine; Phe(pCl), 4-chlorophenylalanine; Pal(3), 3-(3-pyridyl)alanine; Cit, citrulline], or they were treated with s.c. injections of SB-75 (25 micrograms twice a day). Another group of nude mice received an injection of microcapsules of the agonist [D-Trp6]LH-RH liberating 25 micrograms/day. One month after the initiation of treatment, the testicular weights were significantly reduced and the blood testosterone values were at castration levels in all treated groups. Histologically, only the testicles of the mice treated with SB-75 released from minipumps showed a significant decrease of meiosis. The most advanced forms of germ cells were spermatogonia in 26%, spermatocytes in 17%, and round spermatids in 35% of the seminiferous tubules. Only 22% of the tubules contained elongated spermatids. The suppression of meiotic activity by this modern LH-RH antagonist can possibly be used for the development of methods for male contraception and for the protection of germ cells against the damage caused by cytotoxic drugs and x-radiation. Images PMID:2405399

Comparison of the ultrashort gonadotropin-releasing hormone agonist-antagonist protocol with microdose flare -up protocol in poor responders: a preliminary study

PubMed Central

Berker, Bülent; Duvan, Candan İltemir; Kaya, Cemil; Aytaç, Ruşen; Şatıroğlu, Hakan

2010-01-01

Objective To determine the potential effect of the ultrashort gonadotropin-releasing hormone (GnRH) agonist/GnRH antagonist protocol versus the microdose GnRH agonist protocol in poor responders undergoing intracytoplasmic sperm injection (ICSI). Material and Methods The patients in the Agonist-Antagonist Group (n=41) were administered the ultrashort GnRH-agonist/ antagonist protocol, while the patients in the Microdose Group (n=41) were stimulated according to the microdose flare-up protocol. The mean number of mature oocytes retrieved was the primary outcome measure. Fertilization rate, implantation rate per embryo and clinical pregnancy rates were secondary outcome measures. Results There was no differenc between the mean number of mature oocytes retrieved in the two groups. There were also no statistical differences between the two groups in terms of peak serum E2 level, canceled cycles, endometrial thickness on hCG day, number of 2 pronucleus and number of embryos transferred. However, the total gonadotropin consumption and duration of stimulation were significantly higher with the Agonist-Antagonist Group compared with the Microdose Group. The implantation and clinical pregnancy rates were similar between the two groups. Conclusion Despite the high dose of gonadotropin consumption and longer duration of stimulation with the ultrashort GnRH agonist/ antagonist protocol, it seems that the Agonist-Antagonist Protocol is not inferior to the microdose protocol in poor responders undergoing ICSI. PMID:24591934

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

PubMed

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.

Hormonal induction of spawning in 4 species of frogs by coinjection with a gonadotropin-releasing hormone agonist and a dopamine antagonist

PubMed Central

2010-01-01

Background It is well known that many anurans do not reproduce easily in captivity. Some methods are based on administration of mammalian hormones such as human chorionic gonadotropin, which are not effective in many frogs. There is a need for simple, cost-effective alternative techniques to induce spawning. Methods Our new method is based on the injection of a combination of a gonadotropin-releasing hormone (GnRH) agonist and a dopamine antagonist. We have named this formulation AMPHIPLEX, which is derived from the combination of the words amphibian and amplexus. This name refers to the specific reproductive behavior of frogs when the male mounts and clasps the female to induce ovulation and to fertilize the eggs as they are laid. Results We describe the use of the method and demonstrate its applicability for captive breeding in 3 different anuran families. We tested several combinations of GnRH agonists with dopamine antagonists using Lithobates pipiens. The combination of des-Gly10, D-Ala6, Pro-LHRH (0.4 microrams/g body weight) and metoclopramide (10 micrograms/g BWt. MET) was most effective. It was used in-season, after short-term captivity and in frogs artificially hibernated under laboratory conditions. The AMPHIPLEX method was also effective in 3 Argentinian frogs, Ceratophrys ornata, Ceratophrys cranwelli and Odontophrynus americanus. Conclusion Our approach offers some advantages over other hormonally-based techniques. Both sexes are injected only once and at the same time, reducing handling stress. AMPHIPLEX is a new reproductive management tool for captive breeding in Anura. PMID:20398399

Modulatory in vitro effect of stress hormones on the cytokine response of rainbow trout and gilthead sea bream head kidney stimulated with Vibrio anguillarum bacterin.

PubMed

Khansari, Ali Reza; Parra, David; Reyes-López, Felipe E; Tort, Lluís

2017-11-01

In fish, the stress response and their consequences in the immune system have been widely described. Recently, a differential cytokine regulation between rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) was reported after treatment with stress hormones together with their receptor antagonists. Nevertheless, there is no evidence of whether antagonists for stress hormone receptors may influence the interaction between hormones and cytokines after bacterial administration. Thus, the aim of our study was to evaluate the cytokine expression in the presence of stress hormones (cortisol, ACTH, adrenaline), hormone receptor antagonists and inactivated Vibrio anguillarum bacterin in rainbow trout and gilthead sea bream head kidney primary cell culture (HKPCC). Mifepristone, spironolactone, propranolol and phentolamine were used to block GR, MR, MC2R, and β-/α-adrenoreceptors. Our results showed an expected increase of the pro-inflammatory and anti-inflammatory response after inactivated V. anguillarum bacterin treatment in both species. Cortisol, ACTH and adrenaline did not modulate the expression of immune-related genes in rainbow trout, while in sea bream cortisol was able to reduce the stimulated gene expression of all cytokines. This effect was only restored to basal expression level in IL-1β and TNF-α by mifepristone. ACTH reduced both pro-inflammatory and anti-inflammatory cytokine expression, excluding IL-1β, only in sea bream. Adrenaline enhanced the expression of IL-1β and TGF-β1 stimulated by inactivated V. anguillarum in sea bream, and the effect was diminished by propranolol. In sum, our results confirm that the immunoendocrine differences reported at gene expression profile between two teleost species are also observed after exposure to inactivated V. anguillarum bacterin, suggesting that stress hormones would differentially modulate the immune response against pathogens in teleost species. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Selection of a melanine concentrating hormone receptor-1 (MCHR1) antagonists' focused library and its biological screening with AequoScreen].

PubMed

Flachner, Beáta; Hajdú, István; Dobi, Krisztina; Lorincz, Zsolt; Cseh, Sándor; Dormán, György

2013-01-01

Target focused libraries can be rapidly selected by 2D virtual screening methods from multimillion compounds' repositories if structures of active compounds are available. In the present study a multi-step virtual and in vitro screening cascade is reported to select Melanin Concentrating Hormone Receptor-1 (MCHR1) antagonists. The 2D similarity search combined with physicochemical parameter filtering is suitable for selecting candidates from multimillion compounds' repository. The seeds of the first round virtual screening were collected from the literature and commercial databases, while the seeds of the second round were the hits of the first round. In vitro screening underlined the efficiency of our approach, as in the second screening round the hit rate (8.6 %) significantly improved compared to the first round (1.9%), reaching the antagonist activity even below 10 nM.

Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis.

PubMed

Ferguson, James Walter; Therapondos, George; Newby, David E; Hayes, Peter Clive

2003-07-01

Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed Central

Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

1991-01-01

Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]LH-RH (SB-75) on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 micrograms of antagonist SB-75 per day were compared with microcapsules of agonist [D-Trp6]LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate carcinoma. During 8 weeks of treatment, tumor growth was decreased by [D-Trp6]LH-RH and all three doses of SB-75 as compared to untreated controls. The highest dose of SB-75 (71.4 micrograms/day) caused a greater inhibition of prostate cancer growth than [D-Trp6]LH-RH as based on measurement of tumor volume and percentage change in tumor volume. Doses of 23.8 and 47.6 micrograms of SB-75 per day induced a partial and submaximal decrease, respectively, in tumor weight and volume. Tumor doubling time was the longest (50 days) with the high dose of SB-75 vs. 15 days for controls. The body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received SB-75, and testosterone levels were decreased to nondetectable values in the case of the two higher doses of SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of SB-75. Therapy with microgranules of SB-75 significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The results indicate that antagonist SB-75, released from sustained delivery systems, can produce a state of chemical castration and effectively inhibit the growth of experimental prostate cancers. The efficacy of the antagonist SB-75 in inhibiting androgen-dependent Dunning prostatic carcinoma and the absence of side effects suggest its possible usefulness for the treatment of hormone-sensitive tumors. PMID:1992476

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed

Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

1991-02-01

Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]LH-RH (SB-75) on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 micrograms of antagonist SB-75 per day were compared with microcapsules of agonist [D-Trp6]LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate carcinoma. During 8 weeks of treatment, tumor growth was decreased by [D-Trp6]LH-RH and all three doses of SB-75 as compared to untreated controls. The highest dose of SB-75 (71.4 micrograms/day) caused a greater inhibition of prostate cancer growth than [D-Trp6]LH-RH as based on measurement of tumor volume and percentage change in tumor volume. Doses of 23.8 and 47.6 micrograms of SB-75 per day induced a partial and submaximal decrease, respectively, in tumor weight and volume. Tumor doubling time was the longest (50 days) with the high dose of SB-75 vs. 15 days for controls. The body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received SB-75, and testosterone levels were decreased to nondetectable values in the case of the two higher doses of SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of SB-75. Therapy with microgranules of SB-75 significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The results indicate that antagonist SB-75, released from sustained delivery systems, can produce a state of chemical castration and effectively inhibit the growth of experimental prostate cancers. The efficacy of the antagonist SB-75 in inhibiting androgen-dependent Dunning prostatic carcinoma and the absence of side effects suggest its possible usefulness for the treatment of hormone-sensitive tumors.

An ethylene-induced regulatory module delays rose flower senescence by regulating cytokinin content

USDA-ARS?s Scientific Manuscript database

In many plant species, including rose (Rosa hybrida), flower senescence is promoted by the gaseous hormone, ethylene, and inhibited by cytokinin (CTK) class of hormones. However, the molecular mechanisms underlying these antagonistic effects are not well understood. In this current study, we charact...

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.

PubMed

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.

On the horizon: new options for contraception.

PubMed

Reifsnider, E

1997-01-01

Future contraceptives include refinements of existing contraceptives and totally new methods. New formulations of oral contraceptives, subdermal hormonal implants, injectable hormones, vaginal spermicides, and intrauterine devices (IUDs) are being tested around the world. New methods that are not yet available include the use of vaginal preparations containing sperm-immobilizing agents, gonadotrophin releasing hormone agonists and antagonists, vaccines against ova and sperm, and endogenous hormones. Male contraceptive methods use hormones to suppress testosterone and vaccines to immobilize sperm. The availability of all future contraceptives is dependent on ample funds for research, development, and testing, and such funds are in jeopardy.

Effects of hormones on platelet aggregation.

PubMed

Farré, Antonio López; Modrego, Javier; Zamorano-León, José J

2014-04-01

Platelets and their activation/inhibition mechanisms play a central role in haemostasis. It is well known agonists and antagonists of platelet activation; however, during the last years novel evidences of hormone effects on platelet activation have been reported. Platelet functionality may be modulated by the interaction between different hormones and their platelet receptors, contributing to sex differences in platelet function and even in platelet-mediated vascular damage. It has suggested aspects that apparently are well established should be reviewed. Hormones effects on platelet activity are included among them. This article tries to review knowledge about the involvement of hormones in platelet biology and activity.

The common molecular players in plant hormone crosstalk and signaling.

PubMed

Ohri, Puja; Bhardwaj, Renu; Bali, Shagun; Kaur, Ravinderjit; Jasrotia, Shivam; Khajuria, Anjali; Parihar, Ripu D

2015-01-01

Plant growth and development is under the control of mutual interactions among plant hormones. The five classical categories of plant hormones include auxins, cytokinins, gibberellins, abscisic acid and ethylene. Additionally, newer classes of plant hormones have been recognized like brassinosteroids, jasmonic acid, salicylic acid and polyamines. These hormones play significant roles in regulating the plant growth and development. Various receptors and key signaling components of these hormones have been studied and identified. At genetic level, crosstalk among the various plant hormones is found to be antagonistic or synergistic. In addition, components of signaling pathway of one plant hormone interact with the signaling components of other hormone. Thus, an attempt has been made to review the literature regarding the role of plant hormones in plant physiology and the common molecular players in their signaling and crosstalk.

Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

PubMed

Tritos, Nicholas A; Biller, Beverly M K

2017-02-01

To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n = 141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

A nonpeptidyl growth hormone secretagogue.

PubMed

Smith, R G; Cheng, K; Schoen, W R; Pong, S S; Hickey, G; Jacks, T; Butler, B; Chan, W W; Chaung, L Y; Judith, F

1993-06-11

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

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.

PubMed

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.

Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

NASA Astrophysics Data System (ADS)

Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

1992-06-01

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

Effect of naloxone treatment on luteinizing hormone and testosterone concentrations in boars with high and low libido

USDA-ARS?s Scientific Manuscript database

The objective was to determine the effects of naloxone, an opioid peptide receptor antagonist on circulating concentrations of luteinizing hormone (LH) and testosterone in boars characterized as having high (n = 8) or low libido (n = 8) based on the willingness to mount an artificial sow and allow s...

Diapause hormone in the Helicoverpa/Heliothis complex: a review of gene expression, peptide structure and activity, analog and antagonist development, and the receptor

USDA-ARS?s Scientific Manuscript database

This review summarizes recent studies focusing on diapause hormone (DH) in the Helicoverpa/Heliothis complex of agricultural pests. Moths in this complex overwinter in pupal diapause, a form of developmental arrest used to circumvent unfavorable seasons. DH was originally reported in the silkmoth ...

Action of specific thyroid hormone receptor α(1) and β(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat.

PubMed

van Beeren, Hermina C; Kwakkel, Joan; Ackermans, Mariëtte T; Wiersinga, Wilmar M; Fliers, Eric; Boelen, Anita

2012-12-01

The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) α(1) and β(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TRα(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TRα(1) or TRβ(1) regulated genes in central and peripheral thyroid hormone metabolism. Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T(3)) and thyroxine (T(4)) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1). Amio treatment decreased serum T(3), while serum T(4) and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSHβ and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T(3) concentration decreased substantially compared to Dron and control rats (50%, p<0.01), but liver T(4) concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups. Our results suggest an important role for TRα1 in the regulation of hypothalamic TRH mRNA expression, whereas TRβ plays a dominant role in pituitary and liver thyroid hormone metabolism.

Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence

PubMed Central

Gomez, Juan L.; Cunningham, Christopher L.; Finn, Deborah A.; Young, Emily A.; Helpenstell, Lily K.; Schuette, Lindsey M.; Fidler, Tara L.; Kosten, Therese A.; Ryabinin, Andrey E.

2015-01-01

An effort has been mounted to understand the mechanisms of alcohol dependence in a way that may allow for greater efficacy in treatment. It has long been suggested that drugs of abuse seize fundamental reward pathways and disrupt homeostasis to produce compulsive drug seeking behaviors. Ghrelin, an endogenous hormone that affects hunger state and release of growth hormone, has been shown to increased alcohol intake following administration, while antagonists decrease intake. Using rodent models of dependence, the current study examined the effects of two ghrelin receptor antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, on dependence-induced alcohol self-administration. In two experiments adult male C57BL/6J mice and Wistar rats were made dependent via intermittent ethanol vapor exposure. In another experiment, adult male C57BL/6J mice were made dependent using the intragastric alcohol consumption (IGAC) procedure. Ghrelin receptor antagonists were given prior to voluntary ethanol drinking. Ghrelin antagonists reduced ethanol intake, preference, and operant self-administration of ethanol and sucrose across these models, but did not decrease food consumption in mice. In experiments 1 and 2, voluntary drinking was reduced by ghrelin receptor antagonists, however this reduction did not persist across days. Despite the transient effects to ghrelin antagonists, the drugs had renewed effectiveness following a break in administration as seen in experiment 1. The results show the ghrelin system as a potential target for studies of alcohol abuse. Further research is needed to determine the central mechanisms of these drugs and their influence on addiction in order to design effective pharmacotherapies. PMID:26051399

Supplementation with a recombinant human chorionic gonadotropin microdose leads to similar outcomes in ovarian stimulation with recombinant follicle-stimulating hormone using either a gonadotropin-releasing hormone agonist or antagonist for pituitary suppression.

PubMed

Cavagna, Mario; Maldonado, Luiz Guilherme Louzada; de Souza Bonetti, Tatiana Carvalho; de Almeida Ferreira Braga, Daniela Paes; Iaconelli, Assumpto; Borges, Edson

2010-06-01

To compare the outcomes of protocols for ovarian stimulation with recombinant hCG microdose, with GnRH agonists and antagonists for pituitary suppression. Prospective nonrandomized clinical trial. A private assisted reproduction center. We studied 182 patients undergoing intracytoplasmic sperm injection (ICSI) cycles, allocated into two groups: GnRH agonist group, in which patients received a GnRH agonist (n = 73), and a GnRH antagonist group, in which patients were administered a GnRH antagonist for pituitary suppression (n = 109). Pituitary suppression with GnRH agonist or GnRH antagonist. Ovarian stimulation carried out with recombinant FSH and supplemented with recombinant hCG microdose. Total dose of recombinant FSH and recombinant hCG administered; E(2) concentrations and endometrial width on the day of hCG trigger; number of follicles aspirated, oocytes and mature oocytes retrieved; fertilization, pregnancy (PR), implantation, and miscarriage rates. The total dose of recombinant FSH and recombinant hCG administered were similar between groups, as were the E(2) concentrations and endometrial width. The number of follicles aspirated, oocytes, and metaphase II oocytes collected were also comparable. There were no statistically significant differences in fertilization, PR, implantation, and miscarriage rates in the GnRH agonist and GnRH antagonist groups. When using recombinant hCG microdose supplementation for controlled ovarian stimulation (COS), there are no differences in laboratory or clinical outcomes with the use of either GnRH antagonist or agonist for pituitary suppression. Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

The use of gonadotrophin-releasing hormone antagonists in polycystic ovarian disease.

PubMed

Lubin, V; Charbonnel, B; Bouchard, P

1998-12-01

Polycystic ovarian disease (PCOD) is characterized by anovulation, eventually high luteinizing hormone (LH) levels, with increased LH pulse frequency, and hyperandrogenism. As the aetiology of the disease is still unknown, gonadotrophin-releasing hormone (GnRH) antagonists, competitive inhibitors of GnRH for its receptor, are interesting tools in order to study and treat the role of increased LH levels and pulse frequency in this disease. Their administration provokes a rapid decrease in bioactive and immunoactive LH followed by a slower decrease in follicle-stimulating hormone (FSH). In patients with PCOD, the suppression of gonadotrophin secretion eradicates the symptoms of the disease as long as the treatment lasts. Several authors have suggested that increased plasma LH levels have deleterious effects on the fertility of women with PCOD. Indeed, fewer spontaneous pregnancies with more miscarriages are observed when plasma LH levels are high. Assisted reproduction techniques such as in vitro fertilization (IVF) have provided other clues to the role of the LH secretory pattern in women with PCOD. The number of oocytes retrieved, the fertilization rate and the cleavage rate are lower in PCOD patients undergoing IVF and this is inversely correlated with FSH:LH ratio. These abnormalities are corrected when endogenous secretion of LH is suppressed. On the other hand, implantation and pregnancy rates after IVF are similar to those observed in control women. New GnRH antagonists are devoid of side effects and suppress LH secretion within a few hours without a flare-up effect. This action lasts for 10-100 hours. When GnRH antagonists are associated with i.v. pulsatile GnRH, this combination both suppresses the effect of endogenous GnRH and because of the competition for GnRH receptors restores a normal frequency of LH secretion. We have studied two women with PCOD, administering first 10 mg s.c. every 72 hours for 7 days of the GnRH antagonist Nal-Glu, then adding on top i.v. pulsatile GnRH: 10 micrograms/pulse every 90 minutes for 15 days. We thus succeeded in normalizing LH secretion pattern and observed a significant decline in testosterone levels. We failed to induce appropriate ovarian response and ovulation. In conclusion, the combination of GnRH antagonist and GnRH pulsatile treatment can re-establish normal LH secretory pattern in patients with PCOD. The failure to induce ovulation with this regimen suggests the existence of an inherent ovarian defect in women with PCOD.

ESR1 ligand binding domain mutations in hormone-resistant breast cancer

PubMed Central

Toy, Weiyi; Shen, Yang; Won, Helen; Green, Bradley; Sakr, Rita A.; Will, Marie; Li, Zhiqiang; Gala, Kinisha; Fanning, Sean; King, Tari A.; Hudis, Clifford; Chen, David; Taran, Tetiana; Hortobagyi, Gabriel; Greene, Geoffrey; Berger, Michael; Baselga, Jose; Chandarlapaty, Sarat

2013-01-01

Seventy percent of breast cancers express estrogen receptor (ER) and most of these are sensitive to ER inhibition. However, many such tumors become refractory to inhibition of estrogen action in the metastatic setting for unknown reasons. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER+ breast tumors and identified mutations in the ligand binding domain (LBD) of ESR1 in 14/80 cases. These included highly recurrent mutations p.Tyr537Ser/Asn and p.Asp538Gly. Molecular dynamics simulations suggest the Tyr537Ser and Asp538Gly structures lead to hydrogen bonding of the mutant amino acid with Asp351, thus favoring the receptor’s agonist conformation. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may have significant therapeutic benefit. PMID:24185512

Attenuated Stress Response to Acute Restraint and Forced Swimming Stress in Arginine Vasopressin 1b Receptor Subtype (Avpr1b) Receptor Knockout Mice and Wild-Type Mice Treated with a Novel Avpr1b Receptor Antagonist

PubMed Central

Roper, J A; Craighead, M; O’Carroll, A-M; Lolait, S J

2010-01-01

Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin-releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic-pituitary-adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild-type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress-induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild-type mice that had been pre-treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint-stressed knockout male mice, and in Avpr1b-antagonist-treated male wild-type mice. By contrast, plasma CORT levels were not reduced in acutely restraint-stressed female knockout animals, or in female wild-type animals pre-treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic-pituitary-adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors. PMID:20846299

Attenuated stress response to acute restraint and forced swimming stress in arginine vasopressin 1b receptor subtype (Avpr1b) receptor knockout mice and wild-type mice treated with a novel Avpr1b receptor antagonist.

PubMed

Roper, J A; Craighead, M; O'Carroll, A-M; Lolait, S J

2010-11-01

Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin-releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic-pituitary-adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild-type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress-induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild-type mice that had been pre-treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint-stressed knockout male mice, and in Avpr1b-antagonist-treated male wild-type mice. By contrast, plasma CORT levels were not reduced in acutely restraint-stressed female knockout animals, or in female wild-type animals pre-treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic-pituitary-adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors. © 2010 The Authors. Journal of Neuroendocrinology © 2010 Blackwell Publishing Ltd.

A NOVEL CELL LINE, MDA-KB2, THAT STABLY EXPRESSES AN ANDROGEN AND GLUCOCORTICOID RESPONSIVE REPORTER FOR THE DETECTION OF HORMONE RECEPTOR AGONISTS AND ANTAGONISTS

EPA Science Inventory

The U.S. Environmental Protection Agency has proposed that in vitro assays for estrogen receptor (ER) and androgen receptor (AR) mediated actions be included in a Tier I screening battery to detect hormonally active chemicals. Herein we describe the development of a novel stab...

Three-dimensional quantitative structure-activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists.

PubMed

Morales-Bayuelo, Alejandro; Ayazo, Hernan; Vivas-Reyes, Ricardo

2010-10-01

Comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were performed on a series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists (MCHR1 antagonists). Molecular superimposition of antagonists on the template structure was performed by database alignment method. The statistically significant model was established on sixty five molecules, which were validated by a test set of ten molecules. The CoMSIA model yielded the best predictive model with a q(2) = 0.639, non cross-validated R(2) of 0.953, F value of 92.802, bootstrapped R(2) of 0.971, standard error of prediction = 0.402, and standard error of estimate = 0.146 while the CoMFA model yielded a q(2) = 0.680, non cross-validated R(2) of 0.922, F value of 114.351, bootstrapped R(2) of 0.925, standard error of prediction = 0.364, and standard error of estimate = 0.180. CoMFA analysis maps were employed for generating a pseudo cavity for LeapFrog calculation. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. The results show the variability of steric and electrostatic contributions that determine the activity of the MCHR1 antagonist, with these results we proposed new antagonists that may be more potent than previously reported, these novel antagonists were designed from the addition of highly electronegative groups in the substituent di(i-C(3)H(7))N- of the bicycle [4.1.0] heptanes, using the model CoMFA which also was used for the molecular design using the technique LeapFrog. The data generated from the present study will further help to design novel, potent, and selective MCHR1 antagonists. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

A Suppressive Antagonism Evidences Progesterone and Estrogen Receptor Pathway Interaction with Concomitant Regulation of Hand2, Bmp2 and ERK during Early Decidualization

PubMed Central

Mestre-Citrinovitz, Ana C.; Kleff, Veronika; Vallejo, Griselda

2015-01-01

Progesterone receptor and estrogen receptor participate in growth and differentiation of the different rat decidual regions. Steroid hormone receptor antagonists were used to study steroid regulation of decidualization. Here we describe a suppressive interaction between progesterone receptor (onapristone) and estrogen receptor (ICI182780) antagonists and their relation to a rescue phenomenon with concomitant regulation of Hand2, Bmp2 and p-ERK1/2 during the early decidualization steps. Phenotypes of decidua development produced by antagonist treatments were characterized by morphology, proliferation, differentiation, angiogenesis and expression of signaling molecules. We found that suppression of progesterone receptor activity by onapristone treatment resulted in resorption of the implantation sites with concomitant decrease in progesterone and estrogen receptors, PCNA, KI67 antigen, DESMIN, CCND3, CX43, Prl8a2, and signaling players such as transcription factor Hand2, Bmp2 mRNAs and p-ERK1/2. Moreover, FGF-2 and Vegfa increased as a consequence of onapristone treatment. Implantation sites from antagonist of estrogen receptor treated rats developed all decidual regions, but showed an anomalous blood vessel formation at the mesometrial part of the decidua. The deleterious effect of onapristone was partially counteracted by the impairment of estrogen receptor activity with rescue of expression levels of hormone steroid receptors, proliferation and differentiation markers, and the induction of a probably compensatory increase in signaling molecules Hand2, Bmp2 and ERK1/2 activation compared to oil treated controls. This novel drug interaction during decidualization could be applied to pathological endometrial cell proliferation processes to improve therapies using steroid hormone receptor targets. PMID:25897495

[Obesity: a review of currently used antiobesity drugs and new compounds in clinical development].

PubMed

Zieba, Remigiusz

2007-10-19

This review summarizes data on currently used antiobesity drugs and new compounds under clinical development. Three antiobesity drugs are currently accepted for long-term use. Sibutramine is a noradrenaline and serotonin reuptake inhibitor which reduces body weight by about 4-5 kg but increases heart rate and arterial blood pressure. Orlistat is a gastrointestinal lipase inhibitor which results in mean weight loss by about 3 kg and reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance; however, adverse gastrointestinal effects have been observed. Rimonabant is an endocannabinoid CB1 receptor antagonist which induces a 4-5 kg mean weight loss and improves glycemic and lipid profiles, but it induces anxiety and depressive disorders. Unfortunately, there are no data on the chronic administration of these drugs. Other drugs can induce weight loss, e.g. some antidepressants, antiseizure agents, and antidiabetic drugs. The moderate efficacy of currently used antiobesity drugs has led to an intense effort to identify new, safe antiobesity drugs with better therapeutic profiles. The new antiobesity drugs under clinical development include: 1) agents that affect neurotransmitters in the central nervous system, including noradrenaline and dopamine reuptake inhibitors (bupropion, radafaxine), selective 5HT2C receptor agonists (lorcaserin), and selective 5HT6 receptor antagonists, 2) agents that modulate the activity of neuropeptides influencing food intake, including leptin analogues, human ciliary neurotrophic factor (Axokine), neuropeptide Y antagonists, and melanine-concentrating hormone antagonists, 3) agents that affect the peripheral satiety signals and brain-gut axis, e.g. selective cholecystokinin receptor A agonists, PYY3-36, agents decreasing ghrelin activity, 4) thermogenic agents, e.g. selective beta3 receptor agonists and selective thyroid hormone receptor beta agonists, and 5) others, e.g. human growth hormone fragment (AOD9604) and gastrointestinal lipase inhibitor (cetilistat).

Occurrence of thyroid hormone activities in drinking water from eastern China: contributions of phthalate esters.

PubMed

Shi, Wei; Hu, Xinxin; Zhang, Fengxian; Hu, Guanjiu; Hao, Yingqun; Zhang, Xiaowei; Liu, Hongling; Wei, Si; Wang, Xinru; Giesy, John P; Yu, Hongxia

2012-02-07

Thyroid hormone is essential for the development of humans. However, some synthetic chemicals with thyroid disrupting potentials are detectable in drinking water. This study investigated the presence of thyroid active chemicals and their toxicity potential in drinking water from five cities in eastern China by use of an in vitro CV-1 cell-based reporter gene assay. Waters were examined from several phases of drinking water processing, including source water, finished water from waterworks, tap water, and boiled tap water. To identify the responsible compounds, concentrations and toxic equivalents of a list of phthalate esters were quantitatively determined. None of the extracts exhibited thyroid receptor (TR) agonist activity. Most of the water samples exhibited TR antagonistic activities. None of the boiled water displayed the TR antagonistic activity. Dibutyl phthalate accounted for 84.0-98.1% of the antagonist equivalents in water sources, while diisobutyl phthalate, di-n-octyl phthalate and di-2-ethylhexyl phthalate also contributed. Approximately 90% of phthalate esters and TR antagonistic activities were removable by waterworks treatment processes, including filtration, coagulation, aerobic biodegradation, chlorination, and ozonation. Boiling water effectively removed phthalate esters from tap water. Thus, this process was recommended to local residents to reduce certain potential thyroid related risks through drinking water.

Microdose gonadotropin-releasing hormone agonist flare-up protocol versus multiple dose gonadotropin-releasing hormone antagonist protocol in poor responders undergoing intracytoplasmic sperm injection-embryo transfer cycle.

PubMed

Kahraman, Korhan; Berker, Bulent; Atabekoglu, Cem Somer; Sonmezer, Murat; Cetinkaya, Esra; Aytac, Rusen; Satiroglu, Hakan

2009-06-01

To compare the efficacy of microdose GnRH agonist (GnRH-a) flare-up and multiple dose GnRH antagonist protocols in patients who have a poor response to a long luteal GnRH-a protocol. Prospective, randomized, clinical study. University hospital. Forty-two poor responder patients undergoing intracytoplasmic sperm injection (ICSI)-embryo transfer cycle. Twenty-one patients received microdose leuprolide acetate (LA) (50 microg twice daily) starting on the second day of withdrawal bleeding. The other 21 patients received 0.25 mg of cetrorelix daily when the leading follicle reached 14 mm in diameter. Serum E(2) levels, number of growing follicles and mature oocytes, embryo quality, dose of gonadotropin used, cancellation, fertilization, implantation rate and pregnancy rate (PR). The mean serum E(2) concentration on the day of hCG administration was significantly higher in the microdose GnRH-a group than in the GnRH antagonist group (1,904 vs. 1,362 pg/mL). The clinical PRs per started cycle of microdose GnRH-a and GnRH antagonist groups were 14.2% and 9.5%, respectively. There were no statistically significant differences in the other ovulation induction characteristics, fertilization and implantation rates. Microdose GnRH-a flare-up protocol and multiple dose GnRH antagonist protocol seem to have similar efficacy in improving treatment outcomes of poor responder patients.

Efficacy of corifollitropin alfa followed by recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist protocol for Korean women undergoing assisted reproduction.

PubMed

Park, Hyo Young; Lee, Min Young; Jeong, Hyo Young; Rho, Yong Sook; Song, Sang Jin; Choi, Bum-Chae

2015-06-01

To evaluate the effect of a gonadotropin-releasing hormone (GnRH) antagonist protocol using corifollitropin alfa in women undergoing assisted reproduction. Six hundred and eighty-six in vitro fertilization-embryo transfer (IVF)/intracytoplasmic sperm injection (ICSI) cycles were analyzed. In 113 cycles, folliculogenesis was induced with corifollitropin alfa and recombinant follicle stimulating hormone (rFSH), and premature luteinizing hormone (LH) surges were prevented with a GnRH antagonist. In the control group (573 cycles), premature LH surges were prevented with GnRH agonist injection from the midluteal phase of the preceding cycle, and ovarian stimulation was started with rFSH. The treatment duration, quality of oocytes and embryos, number of embryo transfer (ET) cancelled cycles, risk of ovarian hyperstimulation syndrome (OHSS), and the chemical pregnancy rate were evaluated in the two ovarian stimulation protocols. There were no significant differences in age and infertility factors between treatment groups. The treatment duration was shorter in the corifollitropin alfa group than in the control group. Although not statistically significant, the mean numbers of matured (86.8% vs. 85.1%) and fertilized oocytes (84.2% vs. 83.1%), good embryos (62.4% vs. 60.3%), and chemical pregnancy rates (47.2% vs. 46.8%) were slightly higher in the corifollitropin alfa group than in the control group. In contrast, rates of ET cancelled cycles and the OHSS risk were slightly lower in the corifollitropin alfa group (6.2% and 2.7%) than in the control group (8.2% and 3.5%), although these differences were also not statistically significant. Although no significant differences were observed, the use of corifollitropin alfa seems to offer some advantages to patients because of its short treatment duration, safety, lower ET cancellation rate and reduced risk of OHSS.

Effects of an Antagonistic Analog of Growth Hormone-Releasing Hormone on Endometriosis in a Mouse Model and In Vitro.

PubMed

Köster, Frank; Jin, Li; Shen, Yuanming; Schally, Andrew V; Cai, Ren-Zhi; Block, Norman L; Hornung, Daniela; Marschner, Gabriele; Rody, Achim; Engel, Jörg B; Finas, Dominique

2017-11-01

Endometriosis is a benign gynecologic disorder causing dysmenorrhea, pelvic pain, and subfertility. Receptors for the growth hormone-releasing hormone (GHRH) were found in endometriotic tissues. Antagonists of GHRH have been used to inhibit the growth of endometriotic endometrial stromal cells. In this study, the GHRH receptor splice variant (SV) 1 was detected in human endometrial tissue samples by Western blots and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The highest messenger RNA (mRNA) and protein levels of SV1 were found in eutopic endometrium from patients with endometriosis compared to ectopic endometriotic tissues and endometrium from normal patients. The highest expression for GHRH mRNA was found by qRT-PCR in ectopic endometriosis lesions. In an in vivo mouse model with human endometrial explants from patients with endometriosis, 10 μg MIA-602 per day resulted in significantly smaller human endometrial xenotransplants after 4 weeks compared to mice treated with vehicle. The endometrial tissues expressed SV1 before and after xenotransplantation. The proliferation of endometrial stromal cells as well as the endometriosis cell lines 12-Z and 49-Z was decreased by exposure to 1 μM MIA-602 after 72 hours. The protein levels of epithelial growth factor receptors in 12-Z and 49-Z cell lines were reduced 48 and 72 hours after the administration of 1 μM MIA-602. MIA-602 decreased the activation of the MAP-kinases ERK-1/2. Our study demonstrates the presence of SV1 receptor as a target for treatment with GHRH antagonist in endometriosis. Endometrial tissues respond to MIA-602 with inhibition of proliferation in vitro and in vivo. The use of MIA-602 could be an effective supplement to the treatment strategies in endometriosis.

Structural insight into the activation of a class B G-protein-coupled receptor by peptide hormones in live human cells

PubMed Central

Seidel, Lisa; Zarzycka, Barbara; Zaidi, Saheem A; Katritch, Vsevolod; Coin, Irene

2017-01-01

The activation mechanism of class B G-protein-coupled receptors (GPCRs) remains largely unknown. To characterize conformational changes induced by peptide hormones, we investigated interactions of the class B corticotropin-releasing factor receptor type 1 (CRF1R) with two peptide agonists and three peptide antagonists obtained by N-truncation of the agonists. Surface mapping with genetically encoded photo-crosslinkers and pair-wise crosslinking revealed distinct footprints of agonists and antagonists on the transmembrane domain (TMD) of CRF1R and identified numerous ligand-receptor contact sites, directly from the intact receptor in live human cells. The data enabled generating atomistic models of CRF- and CRF(12-41)-bound CRF1R, further explored by molecular dynamics simulations. We show that bound agonist and antagonist adopt different folds and stabilize distinct TMD conformations, which involves bending of helices VI and VII around flexible glycine hinges. Conservation of these glycine hinges among all class B GPCRs suggests their general role in activation of these receptors. DOI: http://dx.doi.org/10.7554/eLife.27711.001 PMID:28771403

Pituitary block with gonadotrophin-releasing hormone antagonist during intrauterine insemination cycles: a systematic review and meta-analysis of randomised controlled trials.

PubMed

Vitagliano, A; Saccone, G; Noventa, M; Borini, A; Coccia, M E; Nardelli, G B; Saccardi, C; Bifulco, G; Litta, P S; Andrisani, A

2018-06-03

Several randomised controlled trials (RCTs) have investigated the usefulness of pituitary block with gonadotrophin-releasing hormone (GnRH) antagonists during intrauterine insemination (IUI) cycles, with conflicting results. The aim of the present systematic review and meta-analysis of RCTs was to evaluate the effectiveness of GnRH antagonist administration as an intervention to improve the success of IUI cycles. Electronic databases (MEDLINE, Scopus, EMBASE, Sciencedirect) and clinical registers were searched from their inception until October 2017. Randomised controlled trials of infertile women undergoing one or more IUI stimulated cycles with GnRH antagonists compared with a control group. The primary outcomes were ongoing pregnancy/live birth rate (OPR/LBR) and clinical pregnancy rate (CPR). Pooled results were expressed as odds ratio (OR) or mean differences with 95% confidence interval (95% CI). Sources of heterogeneity were investigated through sensitivity and subgroups analysis. The body of evidence was rated using GRADE methodology. Publication bias was assessed with funnel plot, Begg's and Egger's tests. Fifteen RCTs were included (3253 IUI cycles, 2345 participants). No differences in OPR/LBR (OR 1.14, 95% CI 0.82-1.57, P = 0.44) and CPR (OR 1.28, 95% CI 0.97-1.69, P = 0.08) were found. Sensitivity and subgroup analyses did not provide statistical changes in pooled results. The body of evidence was rated as low (GRADE 2/4). No publication bias was detected. Pituitary block with GnRH antagonists does not improve OPR/LBR and CPR in women undergoing IUI cycles. Pituitary block with GnRH antagonists does not improve the success of IUI cycles. © 2018 Royal College of Obstetricians and Gynaecologists.

Prolonged inhibition of luteinizing hormone and testosterone levels in male rats with the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed Central

Bokser, L; Bajusz, S; Groot, K; Schally, A V

1990-01-01

Inhibitory effects of the potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1,4-chloro-D-phenylalanine2,3- (3-pyridyl)-D- alanine3,D-citrulline6,D-alanine10]luteinizing hormone-releasing hormone (SB-75) free of edematogenic effects were investigated in male rats. In a study to determine the effect on luteinizing hormone levels in castrated male rats, SB-75 was injected s.c. in doses of 0.625, 1.25, 2.5, 5.0, and 10 micrograms. Blood samples were taken at different intervals for 48 hr. All doses of SB-75 significantly decreased luteinizing hormone levels for greater than 6 hr (P less than 0.01); this inhibition lasted for greater than 24 hr (P less than 0.01) with a dose of 5.0 micrograms and greater than 48 hr with 10 micrograms (P less than 0.05). Serum testosterone levels were also measured in intact male rats injected with SB-75 in doses of 25, 50, and 100 micrograms. All doses produced a dramatic fall in testosterone to castration levels 6 hr after injection (P less than 0.01); this inhibition of serum testosterone was maintained for greater than 72 hr, but only the 100-micrograms dose could keep testosterone in the castration range for greater than 24 hr (P less than 0.01). In another study using a specific RIA, we obtained the pharmacokinetic release pattern of SB-75 from two sustained delivery formulations of SB-75 pamoate microgranules and examined their effect on serum testosterone. After a single i.m. injection of 20 mg of one batch of microgranules, a large peak corresponding to SB-75 at 45.8 ng/ml was observed, corresponding to the "burst" effect. Levels of the analog decreased to 19.6 ng/ml on day 2, gradually reached a concentration of 4.7 ng/ml on day 7, and kept declining thereafter. Testosterone levels were reduced on day 1 (P less than 0.01) and were maintained at low values for greater than 7 days (P less than 0.05). In rats injected with 10 mg of SB-75 pamoate microgranules of the second batch, SB-75 serum levels rose to 33 ng/ml 3 hr after administration and then fell gradually to approximately 3.4 ng/ml on day 16, but a second small peak was seen on day 28. Subsequently, the analog levels decreased slowly to 2.9 ng/ml on day 42. At this time, testosterone serum levels were still significantly lower than in controls. These overall results demonstrate the efficacy of SB-75 in the suppression of the pituitary-gonadal axis. This modern luteinizing hormone-releasing hormone antagonist can possibly be used for treating sex hormone-sensitive cancers and other disorders. PMID:2205853

Prolonged inhibition of luteinizing hormone and testosterone levels in male rats with the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed

Bokser, L; Bajusz, S; Groot, K; Schally, A V

1990-09-01

Inhibitory effects of the potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1,4-chloro-D-phenylalanine2,3- (3-pyridyl)-D- alanine3,D-citrulline6,D-alanine10]luteinizing hormone-releasing hormone (SB-75) free of edematogenic effects were investigated in male rats. In a study to determine the effect on luteinizing hormone levels in castrated male rats, SB-75 was injected s.c. in doses of 0.625, 1.25, 2.5, 5.0, and 10 micrograms. Blood samples were taken at different intervals for 48 hr. All doses of SB-75 significantly decreased luteinizing hormone levels for greater than 6 hr (P less than 0.01); this inhibition lasted for greater than 24 hr (P less than 0.01) with a dose of 5.0 micrograms and greater than 48 hr with 10 micrograms (P less than 0.05). Serum testosterone levels were also measured in intact male rats injected with SB-75 in doses of 25, 50, and 100 micrograms. All doses produced a dramatic fall in testosterone to castration levels 6 hr after injection (P less than 0.01); this inhibition of serum testosterone was maintained for greater than 72 hr, but only the 100-micrograms dose could keep testosterone in the castration range for greater than 24 hr (P less than 0.01). In another study using a specific RIA, we obtained the pharmacokinetic release pattern of SB-75 from two sustained delivery formulations of SB-75 pamoate microgranules and examined their effect on serum testosterone. After a single i.m. injection of 20 mg of one batch of microgranules, a large peak corresponding to SB-75 at 45.8 ng/ml was observed, corresponding to the "burst" effect. Levels of the analog decreased to 19.6 ng/ml on day 2, gradually reached a concentration of 4.7 ng/ml on day 7, and kept declining thereafter. Testosterone levels were reduced on day 1 (P less than 0.01) and were maintained at low values for greater than 7 days (P less than 0.05). In rats injected with 10 mg of SB-75 pamoate microgranules of the second batch, SB-75 serum levels rose to 33 ng/ml 3 hr after administration and then fell gradually to approximately 3.4 ng/ml on day 16, but a second small peak was seen on day 28. Subsequently, the analog levels decreased slowly to 2.9 ng/ml on day 42. At this time, testosterone serum levels were still significantly lower than in controls. These overall results demonstrate the efficacy of SB-75 in the suppression of the pituitary-gonadal axis. This modern luteinizing hormone-releasing hormone antagonist can possibly be used for treating sex hormone-sensitive cancers and other disorders.

Effects of melanocortin-4 receptor agonists and antagonists on expression of genes related to reproduction in spotted scat, Scatophagus argus.

PubMed

Jiang, Dong-Neng; Li, Jian-Tao; Tao, Ya-Xiong; Chen, Hua-Pu; Deng, Si-Ping; Zhu, Chun-Hua; Li, Guang-Li

2017-05-01

Melanocortin-4 receptor (Mc4r) function related to reproduction in fish has not been extensively investigated. Here, we report on gene expression changes by real-time PCR following treatment with Mc4r agonists and antagonists in the spotted scat (Scatophagus argus). Using in vitro incubated hypothalamus, the Mc4r nonselective agonist NDP-MSH ([Nle 4 , D-Phe 7 ]-α-melanocyte stimulating hormone; 10 -6 M) and selective agonist THIQ (N-[(3R)-1, 2, 3, 4-Tetrahydroisoquinolinium-3-ylcarbonyl]- (1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl) piperidin-1-yl]-2-oxoethylamine; 10 -7 M) significantly increased the expression of gnrh (Gonadotropin releasing hormone), while the Mc4r nonselective antagonist SHU9119 (Ac-Nle-[Asp-His-DPhe/DNal(2')-Arg-Trp-Lys]-NH2; 10 -6 M) and selective antagonist Ipsen 5i (compound 5i synthesized in Ipsen Research Laboratories; 10 -6 M) significantly inhibited gnrh expression after 3 h of incubation. In incubated pituitary tissue, NDP-MSH and THIQ significantly increased the expression of fshb (Follicle-stimulating hormone beta subunit) and lhb (Luteinizing hormone beta subunit), while SHU9119 and Ipsen 5i significantly decreased fshb and lhb expression after 3 h of incubation. During the in vivo experiment, THIQ (1 mg/kg bw) significantly increased gnrh expression in hypothalamic tissue, as well as the fshb and lhb expression in pituitary tissue 12 h after abdominal injection. Furthermore, Ipsen 5i (1 mg/kg bw) significantly inhibited gnrh expression in hypothalamic tissue, as well as fshb and lhb gene expression in pituitary tissue 12 h after abdominal injection. In summary, Mc4r singling appears to stimulate gnrh expression in the hypothalamus, thereby modulating the synthesis of Fsh and Lh in the pituitary. In addition, Mc4r also appears to directly regulate fshb and lhb levels in the pituitary in spotted scat. Our study suggests that Mc4r, through the hypothalamus and pituitary, participates in reproductive regulation in fish.

Endocrine control of osmoregulation in teleost fish

USGS Publications Warehouse

McCormick, S.D.

2001-01-01

SYNOPSIS. As the primary link between environmental change and physiological response, the neuroendocrinesystem is a critical part of osmoregulatory adaptations. Cortisol has been viewpd as 'the' seawater-adapting hormone in fish and prolactin as 'the' fresh water adapting hormone. Recent evidence indicates that the growth hormone/insulin-like growth factor I axis is also important in seawater adaptation in several teleosts of widely differing evolutionary lineages. In salmonids, growth hormone acts in synergy with cortisol to increase seawater tolerance, at least partly through the upregulation of gill cortisol receptors. Cortisol under some conditions may promote ion uptake and interacts with prolactin during acclimation to fresh water. The osmoregulatory actions of growth hormone and prolactin are antagonistic. In some species, thyroid hormones support the action of growth hormone and cortisol in promoting seawater acclimation. Although a broad generalization that holds for all teleosts is unlikely, our current understanding indicates that growth hormone promotes acclimation to seawater, prolactin promotes acclimation to fresh water, and cortisol interacts with both of these hormones thus having a dual osmoregulatory function.

Calcium antagonism: aldosterone and vascular responses to catecholamines and angiotensin II in man.

PubMed

Elliott, H L

1993-12-01

Effects of calcium antagonists on pressor mechanisms: A number of differences have been reported in the variable extent to which calcium antagonists interfere with various pressor mechanisms. In theory, high lipid solubility, membrane-binding characteristics and a prolonged duration of action appear to be requirements for a calcium antagonist to affect mechanisms such as vasodilation, endogenous vasoconstrictor responses, hormone release and natriuretic activity. Reduction in peripheral vascular resistance: A reduction in peripheral vascular resistance is fundamental to the antihypertensive effect not only of calcium antagonists but also of angiotensin converting enzyme inhibitors and alpha 1-adrenoceptor antagonists. However, only the calcium antagonists interfere directly with the pressor responses mediated by both the adrenergic nervous system and the renin-angiotensin system. Mechanism of lacidipine effects: Preliminary results with the new dihydropyridine calcium antagonist lacidipine indicate that it not only has vasodilator activity but that it also interferes with both adrenergic and non-adrenergic endogenous vasoconstrictor mechanisms. This may provide additional potentially beneficial cardiovascular effects, particularly in relation to left ventricular hypertrophy and dysfunction.

The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats

PubMed Central

Kawata, Mitsuhiro; Escobar, Carolina

2017-01-01

Abstract Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood–brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day. PMID:28275717

Dual suppression with oral contraceptive pills in GnRH antagonist cycles for patients with polycystic ovary syndrome undergoing intracytoplasmic sperm injection.

PubMed

Ozmen, B; Sükür, Y E; Seval, M M; Ateş, C; Atabekoğlu, C S; Sönmezer, M; Berker, B

2014-12-01

To evaluate the effects of a gonadotropin-releasing hormone (GnRH) antagonist protocol, with or without oral contraceptive pill (OCP) pretreatment, in patients with polycystic ovary syndrome (PCOS) undergoing intracytoplasmic sperm injection (ICSI). In this retrospective cohort study, 410 infertile patients with PCOS were assessed in their first ICSI cycles between January 2006 and June 2013. In Group A (n=208), patients underwent a long luteal GnRH agonist protocol, and in Groups B (n=143) and C (n=59), patients underwent a GnRH antagonist protocol. The patients in Group C also received OCPs containing 30mg of ethinyl oestradiol and 3mg of drospirenone prior to treatment. The main outcome measures were pregnancy and ovarian hyperstimulation syndrome (OHSS) rates. Demographic features, body mass index, duration of infertility, serum baseline hormone levels, cycle outcomes, multiple pregnancy rates, miscarriage rates, OHSS rates, total number of Grade A embryos and total number of transferred embryos were comparable between the groups. Clinical pregnancy rates were 27.4%, 26.6% and 23.7% in Groups A, B and C, respectively (p=0.853). OCP pretreatment was found to have no beneficial or adverse effects in patients with PCOS undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Degarelix Injection

MedlinePlus

... injection is used to treat advanced prostate cancer (cancer that begins in the prostate [a male reproductive gland]). Degarelix injection is in a class of medications called gonadotropin-releasing hormone (GnRH) receptor antagonists. It works by decreasing the amount of ...

New approaches to male non-hormonal contraception

PubMed Central

Nya-Ngatchou, Jean-Jacques; Amory, John K.

2012-01-01

A non-hormonal male contraceptive is a contraceptive that does not involve the administration of hormones or hormone blockers. This review will focus on the use of lonidamine derivatives and inhibitors of retinoic acid biosynthesis and function as approaches to male non-hormonal contraception. Two current lonidamine derivatives, Adjudin and H2-gamendazole, are in development as male contraceptives. These potent anti-spermatogenic compounds impair the integrity of the apical ectoplasmic specialization, resulting in premature spermiation and infertility. Another approach to male contraceptive development is the inhibition of retinoic acid in the testes, as retinoic acid signaling is necessary for spermatogenesis. The administration of the retinoic acid receptor antagonist BMS-189453 reversibly inhibits spermatogenesis in mice. Similarly, oral dosing of WIN 18,446, which inhibits testicular retinoic acid biosynthesis, effectively contracepts rabbits. Hopefully, one of these approaches to non-hormonal male contraception will prove to be safe and effective in future clinical trials. PMID:22995542

Reproductive corticotropin releasing hormone, implantation, and fetal immunotolerance.

PubMed

Kalantaridou, Sophia N; Zoumakis, Emmanouil; Weil, Stacie; Lavasidis, Lazaros G; Chrousos, George P; Makrigiannakis, Antonis

2007-01-01

The fundamental process of implantation involves a series of steps leading to effective cross-talk between invasive trophoblast cells and the maternal endometrium. The molecular interactions at the embryo-maternal interface during the time of blastocyst adhesion and subsequent invasion are not fully understood. Embryonic trophoblast and maternal decidual cells produce corticotropin-releasing hormone (CRH) and express Fas ligand (FasL), a proapoptotic cytokine. Fas and its ligand are pivotal in the regulation of immune tolerance. Trophoblast and decidual CRH play crucial roles in implantation, as well as in the anti-rejection process that protects the fetus from the maternal immune system, primarily by killing activated T cells through Fas-FasL interaction. The potential use of CRH antagonists is presently under intense investigation. CRH antagonists have been used experimentally to elucidate the role of CRH in blastocyst implantation and invasion, early fetal immunotolerance, and premature labor.

The Role of DNA Methyltransferase in the Progression of Breast Cancer of a Hormone Independent Phenotype

DTIC Science & Technology

1999-09-01

cycle with alternating rounds of proliferation and apoptosis. The greatest increase in mitotic index occurs during the luteal phase of the cycle...for the mitogenic actions of progesterone on breast tissue during the luteal phase of the reproductive cycle (72, 95). Progestins induce growth hormone...antagonist show ductal hyperplasia. Ablation of the GH/IGF1 axis in mice with human breast cancer xenografts, or transplant of xenografts into GH- deficient

Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site.

PubMed

Kassotis, Christopher D; Iwanowicz, Luke R; Akob, Denise M; Cozzarelli, Isabelle M; Mumford, Adam C; Orem, William H; Nagel, Susan C

2016-07-01

Currently, >95% of end disposal of hydraulic fracturing wastewater from unconventional oil and gas operations in the US occurs via injection wells. Key data gaps exist in understanding the potential impact of underground injection on surface water quality and environmental health. The goal of this study was to assess endocrine disrupting activity in surface water at a West Virginia injection well disposal site. Water samples were collected from a background site in the area and upstream, on, and downstream of the disposal facility. Samples were solid-phase extracted, and extracts assessed for agonist and antagonist hormonal activities for five hormone receptors in mammalian and yeast reporter gene assays. Compared to reference water extracts upstream and distal to the disposal well, samples collected adjacent and downstream exhibited considerably higher antagonist activity for the estrogen, androgen, progesterone, glucocorticoid and thyroid hormone receptors. In contrast, low levels of agonist activity were measured in upstream/distal sites, and were inhibited or absent at downstream sites with significant antagonism. Concurrent analyses by partner laboratories (published separately) describe the analytical and geochemical profiling of the water; elevated conductivity as well as high sodium, chloride, strontium, and barium concentrations indicate impacts due to handling of unconventional oil and gas wastewater. Notably, antagonist activities in downstream samples were at equivalent authentic standard concentrations known to disrupt reproduction and/or development in aquatic animals. Given the widespread use of injection wells for end-disposal of hydraulic fracturing wastewater, these data raise concerns for human and animal health nearby. Copyright © 2016 Elsevier B.V. All rights reserved.

Endocrine disrupting activities of surface water associated with a West Virginia oil and gas industry wastewater disposal site

USGS Publications Warehouse

Kassotis, Christopher D.; Iwanowicz, Luke R.; Akob, Denise M.; Cozzarelli, Isabelle M.; Mumford, Adam; Orem, William H.; Nagel, Susan C.

2016-01-01

Currently, >95% of end disposal of hydraulic fracturing wastewater from unconventional oil and gas operations in the US occurs via injection wells. Key data gaps exist in understanding the potential impact of underground injection on surface water quality and environmental health. The goal of this study was to assess endocrine disrupting activity in surface water at a West Virginia injection well disposal site. Water samples were collected from a background site in the area and upstream, on, and downstream of the disposal facility. Samples were solid-phase extracted, and extracts assessed for agonist and antagonist hormonal activities for five hormone receptors in mammalian and yeast reporter gene assays. Compared to reference water extracts upstream and distal to the disposal well, samples collected adjacent and downstream exhibited considerably higher antagonist activity for the estrogen, androgen, progesterone, glucocorticoid and thyroid hormone receptors. In contrast, low levels of agonist activity were measured in upstream/distal sites, and were inhibited or absent at downstream sites with significant antagonism. Concurrent analyses by partner laboratories (published separately) describe the analytical and geochemical profiling of the water; elevated conductivity as well as high sodium, chloride, strontium, and barium concentrations indicate impacts due to handling of unconventional oil and gas wastewater. Notably, antagonist activities in downstream samples were at equivalent authentic standard concentrations known to disrupt reproduction and/or development in aquatic animals. Given the widespread use of injection wells for end-disposal of hydraulic fracturing wastewater, these data raise concerns for human and animal health nearby.

Aldosterone antagonists in heart failure.

PubMed

Miller, Susan E; Alvarez, René J

2013-01-01

Chronic, systolic heart failure is an increasing and costly health problem, and treatments based on pathophysiology have evolved that include the use of aldosterone antagonists. Advances in the understanding of neurohormonal responses to heart failure have led to better pharmacologic treatments. The steroid hormone aldosterone has been associated with detrimental effects on the cardiovascular system, such as ventricular remodeling and endothelial dysfunction. This article will review the literature and guidelines that support the use of aldosterone antagonists in the treatment of chronic, systolic heart failure. Aldosterone antagonists are life-saving drugs that have been shown to decrease mortality in patients with New York Heart Association class III to IV heart failure and in patients with heart failure after an acute myocardial infarction. Additional studies are being conducted to determine if the role of aldosterone antagonists can be expanded to patients with less severe forms of heart failure. Aldosterone antagonists are an important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of systolic heart failure. These drugs have been shown to decrease mortality and reduce hospital readmission rates. The major complication of aldosterone antagonists is hyperkalemia, which can be avoided with appropriate patient selection and diligent monitoring.

Characterization of Estrogen and Androgen Activity of Food Contact Materials by Different In Vitro Bioassays (YES, YAS, ERα and AR CALUX) and Chromatographic Analysis (GC-MS, HPLC-MS)

PubMed Central

Osorio, Veronica; Grininger, Angelika; Richter, Alexander; Bergmair, Johannes; Pyerin, Michael; Washüttl, Michael; Tacker, Manfred

2014-01-01

Endocrine active substances (EAS) show structural similarities to natural hormones and are suspected to affect the human endocrine system by inducing hormone dependent effects. Recent studies with in vitro tests suggest that EAS can leach from packaging into food and may therefore pose a risk to human health. Sample migrates from food contact materials were tested for estrogen and androgen agonists and antagonists with different commonly used in vitro tests. Additionally, chemical trace analysis by GC-MS and HPLC-MS was used to identify potential hormone active substances in sample migrates. A GC-MS method to screen migrates for 29 known or potential endocrine active substances was established and validated. Samples were migrated according to EC 10/2011, concentrated by solid phase extraction and tested with estrogen and androgen responsive reporter gene assays based on yeast cells (YES and YAS) or human osteoblast cells (ERα and AR CALUX). A high level of agreement between the different bioassays could be observed by screening for estrogen agonists. Four out of 18 samples tested showed an estrogen activity in a similar range in both, YES and ERα CALUX. Two more samples tested positive in ERα CALUX due to the lower limits of detection in this assay. Androgen agonists could not be detected in any of the tested samples, neither with YAS nor with AR CALUX. When testing for antagonists, significant differences between yeast and human cell-based bioassays were noticed. Using YES and YAS many samples showed a strong antagonistic activity which was not observed using human cell-based CALUX assays. By GC-MS, some known or supposed EAS were identified in sample migrates that showed a biological activity in the in vitro tests. However, no firm conclusions about the sources of the observed hormone activity could be obtained from the chemical results. PMID:25000404

The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin.

PubMed

Arce, Joan-Carles; Klein, Bjarke M; La Marca, Antonio

2014-06-01

The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n = 155 and n = 188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2 ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (≥15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p = 0.025) and 31% versus 49% (p = 0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p = 0.074; antagonist protocol: 34% versus 23%, p = 0.075; overall population: 34% versus 22%, p = 0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders.

Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (SB-75).

PubMed

Bokser, L; Srkalovic, G; Szepeshazi, K; Schally, A V

1991-08-01

The reversibility of the antifertility effects induced by long-term administration of the LH-RH antagonistic analog [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-LH-RH (SB-75) was investigated in male and female rats. Male rats were implanted with osmotic minipumps releasing 50 micrograms of SB-75/day for 60 days. The control rats were implanted with minipumps containing only vehicle. The treatment with the antagonist caused a significant decrease in the weights of the testes, seminal vesicles and ventral prostates (p less than 0.01) and reduced serum LH and testosterone levels (p less than 0.01). The histology of the testes from the treated rats showed that spermatogenesis was totally depressed. No mature elongated or round spermatids were found in the seminiferous tubules, spermatocytes being the most advanced germ cell form in 100% of the testicular tubules. These changes indicate that a total spermatogenetic arrest occurred in the treated animals. Ninety days after cessation of treatment with the LH-RH antagonist, there was a complete recovery of the weights of the testes, seminal vesicles and ventral prostates and LH and testosterone returned to control levels. Histological studies revealed a complete recovery of spermatogenesis, with 99.2% of seminiferous tubules containing mature elongated spermatids. Immediately after the discontinuation of treatment with SB-75, a significant down-regulation of the pituitary LH-RH receptors was found, but 90 days later, this phenomenon was completely reversed. Female rats were injected every 3 weeks for 6 weeks with SB-75 microcapsules, at a dose calculated to release 27 micrograms/day of the antagonist. The treatment with SB-75 disrupted the normal estrous cycle. Body weights were not affected, but ovarian and uterine weights were significantly decreased (p less than 0.01 and p less than 0.05, respectively) in the animals treated with the antagonist. Treated rats had significantly lower LH (p less than 0.05) and estradiol (p less than 0.01) levels than controls. The histology of the ovaries from the SB-75-treated group showed that the ratio of small to large maturing follicles increased significantly (p less than 0.01) and corpora lutea were absent. Two months after the cessation of treatment, a complete recovery in the organ weights and in hormonal levels was observed and no histological differences were found between the ovaries in treated and untreated rats. These collective results indicate that the suppression of gonadal function induced by the treatment with LH-RH antagonist SB-75 is completely reversible both in male and female animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a

PubMed Central

Casanueva, Felipe F.; Camiña, Jesus P.; Carreira, Marcos C.; Pazos, Yolanda; Varga, Jozsef L.; Schally, Andrew V.

2008-01-01

Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1–29)NH2 (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wild-type HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of 125I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1–42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control. PMID:19088192

Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a.

PubMed

Casanueva, Felipe F; Camiña, Jesus P; Carreira, Marcos C; Pazos, Yolanda; Varga, Jozsef L; Schally, Andrew V

2008-12-23

Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH(2) (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wild-type HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of (125)I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.

Neuroprotective effects of testosterone metabolites and dependency on receptor action on the morphology of somatic motoneurons following the death of neighboring motoneurons.

PubMed

Cai, Yi; Chew, Cory; Muñoz, Fernando; Sengelaub, Dale R

2017-06-01

Partial depletion of spinal motoneuron populations induces dendritic atrophy in neighboring motoneurons, and treatment with testosterone is neuroprotective, attenuating induced dendritic atrophy. In this study we examined whether the protective effects of testosterone could be mediated via its androgenic or estrogenic metabolites. Furthermore, to assess whether these neuroprotective effects were mediated through steroid hormone receptors, we used receptor antagonists to attempt to prevent the neuroprotective effects of hormones after partial motoneuron depletion. Motoneurons innervating the vastus medialis muscles of adult male rats were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, some saporin-injected rats were treated with either dihydrotestosterone or estradiol, alone or in combination with their respective receptor antagonists, or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Compared with intact normal animals, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons. Dendritic atrophy was attenuated with both dihydrotestosterone and estradiol treatment to a degree similar to that seen with testosterone, and attenuation of atrophy was prevented by receptor blockade. Together, these findings suggest that neuroprotective effects on motoneurons can be mediated by either androgenic or estrogenic hormones and require action via steroid hormone receptors, further supporting a role for hormones as neurotherapeutic agents in the injured nervous system. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 691-707, 2017. © 2016 Wiley Periodicals, Inc.

A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.

PubMed

Peluffo, M C; Stanley, J; Braeuer, N; Rotgeri, A; Fritzemeier, K-H; Fuhrmann, U; Buchmann, B; Adevai, T; Murphy, M J; Zelinski, M B; Lindenthal, B; Hennebold, J D; Stouffer, R L

2014-07-01

Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3-4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus-oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3-4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests and blood lipid profiles. Several mRNAs encoding proteins involved in PGE2 synthesis, metabolism and signaling increase (P < 0.05) in the periovulatory follicle after administration of an ovulatory hCG bolus. PGE2 signaling through PTGER2 induces cumulus cell expansion and production of hyaluronic acid, which are critical events for fertilization. Moreover, chronic administration of a selective PTGER2 antagonist resulted in a significant (P < 0.05 versus vehicle-treated controls) contraceptive effect without altering steroid hormone patterns or menstrual cyclicity during a 5-months contraceptive trial. Fertility recovered as early as 1 month after ending treatment. This is a proof-of-concept study in a non-human primate model. Further investigations are warranted to elucidate the mechanism(s) of PTGER2 antagonist action in the primate ovary. Although PTGER2 antagonist treatment did not produce any obvious undesirable effects, improvements in the mode of administration, as well as the efficacy of these compounds, are necessary to consider such a contraceptive for women. Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity. Even though hormonal contraceptives are effective for women, concerns remain regarding their side-effects and long-term use because of the widespread actions of such steroidal products in many tissues. Moreover, some women cannot take hormones for medical reasons. Thus, development of non-hormonal contraceptives for women is warranted. Supported by Bayer HealthCare Pharmaceuticals, The Eunice Kennedy Shriver NICHD Contraceptive Development and Research Center (U54 HD055744), NIH Office of the Director (Oregon National Primate Research Center P51 OD011092), and a Lalor Foundation Postdoctoral Basic Research Fellowship (MCP). The use of the Leica confocal was supported by grant number S10RR024585. Some of the authors (N.B., A.R., K.-H.F., U.F., B.B. and B.L.) are employees of Bayer Healthcare Pharma.

Regulation of prostate cancer by hormone-responsive G protein-coupled receptors.

PubMed

Wang, Wei; Chen, Zhao-Xia; Guo, Dong-Yu; Tao, Ya-Xiong

2018-06-15

Regulation of prostate cancer by androgen and androgen receptor (AR), and blockade of AR signaling by AR antagonists and steroidogenic enzyme inhibitors have been extensively studied. G protein-coupled receptors (GPCRs) are a family of membrane receptors that regulate almost all physiological processes. Nearly 40% of FDA-approved drugs in the market target GPCRs. A variety of GPCRs that mediate reproductive function have been demonstrated to be involved in the regulation of prostate cancer. These GPCRs include gonadotropin-releasing hormone receptor, luteinizing hormone receptor, follicle-stimulating hormone receptor, relaxin receptor, ghrelin receptor, and kisspeptin receptor. We highlight here GPCR regulation of prostate cancer by these GPCRs. Further therapeutic approaches targeting these GPCRs for the treatment of prostate cancer are summarized. Copyright © 2018. Published by Elsevier Inc.

A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1.

PubMed

Patterson, James T; Ottaway, Nickki; Gelfanov, Vasily M; Smiley, David L; Perez-Tilve, Diego; Pfluger, Paul T; Tschöp, Matthias H; Dimarchi, Richard D

2011-02-18

Ex-4 (9-39)a is a well characterized GLP-1 receptor antagonist that suffers from two notable limitations, its nonhuman amino acid sequence and its relatively short in vivo duration of action. Comparable N-terminal shortening of human GLP-1 lessens agonism but does not provide a high potency antagonist. Through a series of GLP-1/Ex-4 hybrid peptides, the minimal structural changes required to generate a pure GLP-1-based antagonist were identified as Glu16, Val19, and Arg20, yielding an antagonist of approximately 3-fold greater in vitro potency compared with Ex-4 (9-39)a. The structural basis of antagonism appears to result from stabilization of the α helix combined with enhanced electrostatic and hydrophobic interactions with the extracellular domain of the receptor. Site-specific acylation of the human-based antagonist yielded a peptide of increased potency as a GLP-1 receptor antagonist and 10-fold greater selectivity relative to the GIP receptor. The acylated antagonist demonstrated sufficient duration of action to maintain inhibitory activity when administered as a daily subcutaneous injection. The sustained pharmacokinetics and enhanced human sequence combine to form an antagonist optimized for clinical study. Daily administration of this antagonist by subcutaneous injection to diet-induced obese mice for 1 week caused a significant increase in food intake, body weight, and glucose intolerance, demonstrating endogenous GLP-1 as a relevant hormone in mammalian energy balance in the obese state.

Peptide hormones and lung cancer.

PubMed

Moody, T W

2006-03-01

Several peptide hormones have been identified which alter the proliferation of lung cancer. Small cell lung cancer (SCLC), which is a neuroendocrine cancer, produces and secretes gastrin releasing peptide (GRP), neurotensin (NT) and adrenomedullin (AM) as autocrine growth factors. GRP, NT and AM bind to G-protein coupled receptors causing phosphatidylinositol turnover or elevated cAMP in SCLC cells. Addition of GRP, NT or AM to SCLC cells causes altered expression of nuclear oncogenes, such as c-fos, and stimulation of growth. Antagonists have been developed for GRP, NT and AM receptors which function as cytostatic agents and inhibit SCLC growth. Growth factor antagonists, such as the NT1 receptor antagonist SR48692, facilitate the ability of chemotherapeutic drugs to kill lung cancer cells. It remains to be determined if GRP, NT and AM receptors will served as molecular targets, for development of new therapies for the treatment of SCLC patients. Non-small cell lung cancer (NSCLC) cells also have a high density of GRP, NT, AM and epidermal growth factor (EGF) receptors. Several NSCLC patients with EGF receptor mutations respond to gefitinib, a tyrosine kinase inhibitor. Gefitinib relieves NSCLC symptoms, maintaining stable disease in patients who are not eligible for systemic chemotherapy. It is important to develop new therapeutic approaches using translational research techniques for the treatment of lung cancer patients.

GnRH antagonist, cetrorelix, for pituitary suppression in modern, patient-friendly assisted reproductive technology.

PubMed

Tur-Kaspa, Ilan; Ezcurra, Diego

2009-10-01

Gonadotropin-releasing hormone (GnRH) analogues are used routinely to prevent a premature luteinizing hormone (LH) surge in women undergoing assisted reproductive technology (ART) treatments. In contrast to GnRH agonists, antagonists produce rapid and reversible suppression of LH with no initial flare effect. To review the role of cetrorelix, the first GnRH antagonist approved for the prevention of premature LH surges during controlled ovarian stimulation in modern ART. A review of published literature on cetrorelix. Both multiple- and single-dose cetrorelix protocols were shown to be at least as effective as long GnRH agonist regimens for pituitary suppression in Phase II/III clinical trials. Furthermore, cetrorelix co-treatment resulted in similar live birth rates but a shorter duration of gonadotropin stimulation, a lower total gonadotropin dose requirement and lower incidence of ovarian hyperstimulation syndrome compared with long agonist regimens. A single-dose cetrorelix protocol further decreased the number of injections required. Preliminary studies have also produced promising data on the use of cetrorelix in modified ART protocols, such as frozen embryo transfer and donor oocyte recipient cycles. Cetrorelix offers a potential therapeutic alternative to GnRH agonists during controlled ovarian stimulation and has become an integral part of modern, patient-friendly reproductive medicine.

New approaches to male non-hormonal contraception.

PubMed

Nya-Ngatchou, Jean-Jacques; Amory, John K

2013-03-01

A non-hormonal male contraceptive is a contraceptive that does not involve the administration of hormones or hormone blockers. This review will focus on the use of lonidamine derivatives and inhibitors of retinoic acid biosynthesis and function as approaches to male non-hormonal contraception. Two current lonidamine derivatives, adjudin and H2-gamendazole, are in development as male contraceptives. These potent anti-spermatogenic compounds impair the integrity of the apical ectoplasmic specialization, resulting in premature spermiation and infertility. Another approach to male contraceptive development is the inhibition of retinoic acid in the testes, as retinoic acid signaling is necessary for spermatogenesis. The administration of the retinoic acid receptor antagonist BMS-189453 reversibly inhibits spermatogenesis in mice. Similarly, oral dosing of WIN 18,446, which inhibits testicular retinoic acid biosynthesis, effectively contracepts rabbits. Hopefully, one of these approaches to non-hormonal male contraception will prove to be safe and effective in future clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

Complex Actions of Thyroid Hormone Receptor Antagonist NH-3 on Gene Promoters in Different Cell Lines

PubMed Central

Shah, Vanya; Nguyen, Phuong; Nguyen, Ngoc-Ha; Togashi, Marie; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

2014-01-01

It is desirable to obtain new antagonists for thyroid hormone (TRs) and other nuclear receptors (NRs). We previously used X-ray structural models of TR ligand binding domains (LBDs) to design compounds, such as NH-3, that impair coactivator binding to activation function 2 (AF-2) and block thyroid hormone (triiodothyronine, T3) actions. However, TRs bind DNA and are transcriptionally active without ligand. Thus, NH-3 could modulate TR activity via effects on other coregulator interaction surfaces, such as activation function (AF-1) and corepressor binding sites. Here, we find that NH-3 blocks TR-LBD interactions with coactivators and corepressors and also inhibits activities of AF-1 and AF-2 in transfections. While NH-3 lacks detectable agonist activity at T3-activated genes in GC pituitary cells it nevertheless activates spot 14 (S14) in HTC liver cells with the latter effect accompanied by enhanced histone H4 acetylation and coactivator recruitment at the S14 promoter. Surprisingly, T3 promotes corepressor recruitment to target promoters. NH-3 effects vary; we observe transient recruitment of N-CoR to S14 in GC cells and dismissal and rebinding of N-CoR to the same promoter in HTC cells. We propose that NH-3 will generally behave as an antagonist by blocking AF-1 and AF-2 but that complex effects on coregulator recruitment may result in partial/mixed agonist effects that are independent of blockade of T3 binding in some contexts. These properties could ultimately be utilized in drug design and development of new selective TR modulators. PMID:18930112

Photodynamic therapy using hemagglutinating virus of Japan envelope (HVJ-E): a novel therapeutic approach for the treatment of hormone antagonistic prostate cancer

NASA Astrophysics Data System (ADS)

Inai, Mizuho; Yamauchi, Masaya; Honda, Norihiro; Hazama, Hisanao; Tachikawa, Shoji; Nakamura, Hiroyuki; Nishida, Tomoki; Yasuda, Hidehiro; Kaneda, Yasufumi; Awazu, Kunio

2015-03-01

Traditional treatment options for prostate cancer are insufficient to cure advanced drug-resistant prostate cancer. Thus, as an alternative form of cancer therapy, photodynamic therapy (PDT) has become the main subject of intense investigation as a possible treatment modality. In this study, ultraviolet-inactivated viral vector, called hemagglutinating virus of Japan envelope (HVJ-E) was utilized to establish an effective delivery system for photosensitizer. Lipidated protoporphyrin IX (PpIX lipid) was inserted in HVJ-E by centrifugation to create a new drug delivering system that allows selective accumulation of photosensitizers in cancer cells. To study in vitro drug release mechanism of porphyrus envelope, the ultra-high voltage electron microscope tomography was applied. Next, to evaluate the photodynamic efficiency of porphyrus envelope for hormone antagonistic prostate cancer cells (PC-3), uptake of porphyrus envelope derived PpIX lipid and PpIX induced from exogenously administered precursor of 5-aminolevulinic acid hydrochloride (5-ALA) were compared by measuring fluorescence intensity of PpIX. Finally, to evaluate the efficacy of porphyrus envelope-PDT, laser light at a wavelength of 405 nm was irradiated to PC-3 cells. As a result, incorporation of porphyrus envelope-derived PpIX lipid occurred via membrane fusion, giving the highest fluorescence intensity when compared to 5-ALA-induced PpIX. Also, results from PDT experiment revealed the 28.6 × 103-fold and 206-fold increase in therapeutic efficacy when compared to those of PDT using 5-ALA induced PpIX and PpIX lipid, respectively. Our findings suggest how porphyrus envelope can induce efficient accumulation of PpIX lipid, which can enhance the therapeutic efficacy of PDT against hormone antagonistic prostate cancer.

Anti-androgenic effects of S-40542, a novel non-steroidal selective androgen receptor modulator (SARM) for the treatment of benign prostatic hyperplasia.

PubMed

Nejishima, Hiroaki; Yamamoto, Noriko; Suzuki, Mika; Furuya, Kazuyuki; Nagata, Naoya; Yamada, Shizuo

2012-10-01

Selective androgen receptor modulators (SARMs) would provide alternative therapeutic agent for androgen-related diseases. We identified a tetrahydroquinoline (THQ) derivative, 1-(8-nitro-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl) ethane-1, 2-diol (S-40542) as a novel SARM antagonist. Affinity for nuclear receptors of S-40542 was evaluated in receptor-binding studies. Androgen receptor (AR) transcriptional activity of S-40542 was investigated by luciferase reporter assay in DU145AR cells. Normal and benign prostatic hyperplasia (BPH) model rats were repeatedly treated with S-40542 and flutamide. The tissue weights of prostate and levator ani muscle as well as blood levels of testosterone and luteinizing hormone were measured. S-40542 bound to the AR with high affinity. S-40542 at relatively high concentrations increased the transcriptional activity. This agent also showed a concentration-dependent AR antagonistic action in the presence of 1 nM 5α-dihydrotestosterone. Repeated treatment with S-40542 and flutamide decreased dose-dependently the weights of the prostate to a similar extent. In contrast, the tissue weight-reducing effect by S-40542 treatment on the levator ani muscle was much weaker than that of flutamide. S-40542 had little effect on the blood level of testosterone and luteinizing hormone, whereas flutamide increased the level of both hormones. Furthermore, S-40542 decreased dose-dependently prostate weight of BPH rats. The current results indicate that S-40542 possesses the prostate-selective SARM activity, suggestive of clinical benefit against benign prostate hyperplasia. THQ compounds may be useful for the research of mode of action of SARMs and for the development of safe SARM antagonists. Copyright © 2012 Wiley Periodicals, Inc.

Synthetic gene network restoring endogenous pituitary–thyroid feedback control in experimental Graves’ disease

PubMed Central

Saxena, Pratik; Charpin-El Hamri, Ghislaine; Folcher, Marc; Zulewski, Henryk; Fussenegger, Martin

2016-01-01

Graves’ disease is an autoimmune disorder that causes hyperthyroidism because of autoantibodies that bind to the thyroid-stimulating hormone receptor (TSHR) on the thyroid gland, triggering thyroid hormone release. The physiological control of thyroid hormone homeostasis by the feedback loops involving the hypothalamus–pituitary–thyroid axis is disrupted by these stimulating autoantibodies. To reset the endogenous thyrotrophic feedback control, we designed a synthetic mammalian gene circuit that maintains thyroid hormone homeostasis by monitoring thyroid hormone levels and coordinating the expression of a thyroid-stimulating hormone receptor antagonist (TSHAntag), which competitively inhibits the binding of thyroid-stimulating hormone or the human autoantibody to TSHR. This synthetic control device consists of a synthetic thyroid-sensing receptor (TSR), a yeast Gal4 protein/human thyroid receptor-α fusion, which reversibly triggers expression of the TSHAntag gene from TSR-dependent promoters. In hyperthyroid mice, this synthetic circuit sensed pathological thyroid hormone levels and restored the thyrotrophic feedback control of the hypothalamus–pituitary–thyroid axis to euthyroid hormone levels. Therapeutic plug and play gene circuits that restore physiological feedback control in metabolic disorders foster advanced gene- and cell-based therapies. PMID:26787873

Endocrine-Disrupting Effects of Pesticides through Interference with Human Glucocorticoid Receptor.

PubMed

Zhang, Jianyun; Zhang, Jing; Liu, Rui; Gan, Jay; Liu, Jing; Liu, Weiping

2016-01-05

Many pesticides have been identified as endocrine-disrupting chemicals (EDCs) due to their ability to bind sex-steroid hormone receptors. However, little attention has been paid to the ability of pesticides to interfere with other steroid hormone receptors such as glucocorticoid receptor (GR) that plays a critical role in metabolic, endocrine, immune, and nervous systems. In this study, the glucocorticoidic and antiglucocorticoidic effects of 34 pesticides on human GR were investigated using luciferase reporter gene assay. Surprisingly, none of the test chemicals showed GR agonistic activity, but 12 chemicals exhibited apparent antagonistic effects. Bifenthrin, λ-cyhalothrin, cypermethrin, resmethrin, o,p'-DDT, p,p'-DDT, methoxychlor, ethiofencarb, and tolylfluanid showed remarkable GR antagonistic properties with RIC20 values lower than 10(-6) M. The disruption of glucocorticoid-responsive genes in H4IIE and J774A.1 cells was further evaluated on these 12 GR antagonists. In H4IIEcells, four organochlorine insecticides, bifenthrin, and 3-PBA decreased cortisol-induced PEPCK gene expression, while o,p'-DDT and methoxychlor inhibited cortisol-stimulated Arg and TAT gene expression. Cypermethrin and tolyfluanid attenuated cortisol-induced TAT expression. In J774A.1 cells, λ-cyhalothrin, resmethrin, 3-PBA, o,p'-DDT, p,p'-DDT, p,p'-DDE, methoxychlor- and tolylfluanid-reduced cortisol-stimulated GILZ expression. Furthermore, molecular docking simulation indicated that different interactions may stabilize the binding between molecules and GR. Our findings suggest that comprehensive screening and evaluation of GR antagonists and agonists should be considered to better understand the health and ecological risks of man-made chemicals such as pesticides.

Receptors for luteinizing hormone-releasing hormone (LHRH) in benign prostatic hyperplasia (BPH) as potential molecular targets for therapy with LHRH antagonist cetrorelix.

PubMed

Rozsa, Bernadett; Nadji, Mehrdad; Schally, Andrew V; Dezso, Balazs; Flasko, Tibor; Toth, Gyorgy; Mile, Melinda; Block, Norman L; Halmos, Gabor

2011-04-01

The majority of men will develop symptoms of benign prostatic hyperplasia (BPH) after 70 years of age. Various studies indicate that antagonists of LHRH, such as cetrorelix, exert direct inhibitory effects on BPH mediated by specific LHRH receptors. Our aim was to investigate the mRNA for LHRH and LHRH receptors and the expression of LHRH receptors in specimens of human BPH. The expression of mRNA for LHRH (n=35) and LHRH receptors (n=55) was investigated by RT-PCR in surgical specimens of BPH, using specific primers. The characteristics of binding sites for LHRH on 20 samples were determined by ligand competition assays. The LHRH receptor expression was also examined in 64 BPH specimens by immunohistochemistry. PCR products for LHRH were found in 18 of 35 (51%) BPH tissues and mRNA for LHRH receptors was detected in 39 of 55 (71%) BPH specimens. Eighteen of 20 (90%) samples showed a single class of high affinity binding sites for [D-Trp(6) ]LHRH with a mean K(d) of 4.04 nM and a mean B(max) of 527.6 fmol/mg membrane protein. LHRH antagonist cetrorelix showed high affinity binding to LHRH receptors in BPH. Positive immunohistochemical reaction for LHRH receptors was present in 42 of 64 (67%) BPH specimens. A high incidence of LHRH receptors in BPH supports the use of LHRH antagonists such as cetrorelix, for treatment of patients with lower urinary tract symptoms from BPH. Copyright © 2010 Wiley-Liss, Inc.

Growth hormone-releasing hormone promotes survival of cardiac myocytes in vitro and protects against ischaemia-reperfusion injury in rat heart.

PubMed

Granata, Riccarda; Trovato, Letizia; Gallo, Maria Pia; Destefanis, Silvia; Settanni, Fabio; Scarlatti, Francesca; Brero, Alessia; Ramella, Roberta; Volante, Marco; Isgaard, Jorgen; Levi, Renzo; Papotti, Mauro; Alloatti, Giuseppe; Ghigo, Ezio

2009-07-15

The hypothalamic neuropeptide growth hormone-releasing hormone (GHRH) stimulates GH synthesis and release in the pituitary. GHRH also exerts proliferative effects in extrapituitary cells, whereas GHRH antagonists have been shown to suppress cancer cell proliferation. We investigated GHRH effects on cardiac myocyte cell survival and the underlying signalling mechanisms. Reverse transcriptase-polymerase chain reaction analysis showed GHRH receptor (GHRH-R) mRNA in adult rat ventricular myocytes (ARVMs) and in rat heart H9c2 cells. In ARVMs, GHRH prevented cell death and caspase-3 activation induced by serum starvation and by the beta-adrenergic receptor agonist isoproterenol. The GHRH-R antagonist JV-1-36 abolished GHRH survival action under both experimental conditions. GHRH-induced cardiac cell protection required extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide-3 kinase (PI3K)/Akt activation and adenylyl cyclase/cAMP/protein kinase A signalling. Isoproterenol strongly upregulated the mRNA and protein of the pro-apoptotic inducible cAMP early repressor, whereas GHRH completely blocked this effect. Similar to ARVMs, in H9c2 cardiac cells, GHRH inhibited serum starvation- and isoproterenol-induced cell death and apoptosis through the same signalling pathways. Finally, GHRH improved left ventricular recovery during reperfusion and reduced infarct size in Langendorff-perfused rat hearts, subjected to ischaemia-reperfusion (I/R) injury. These effects involved PI3K/Akt signalling and were inhibited by JV-1-36. Our findings suggest that GHRH promotes cardiac myocyte survival through multiple signalling mechanisms and protects against I/R injury in isolated rat heart, indicating a novel cardioprotective role of this hormone.

Update on the male hormonal contraceptive agents.

PubMed

Walton, Melanie; Anderson, Richard A

2004-09-01

There remains a need for new acceptable and effective male contraceptives to increase the choice for couples throughout the world. There have been no recent advances in available male contraceptive methods although a number of promising approaches have been identified, of which the hormonal approach is currently undergoing clinical investigation. In recent years the pace of research in this area has quickened significantly with increasing interest and now investment by the pharmaceutical industry. This is vital if the work undertaken so far by the public sector is to be transformed into a commercial reality. The hormonal approach is based on suppression of pituitary gonadotropin secretion resulting in a reversible reduction in spermatogenesis with azoospermia in all men being the ultimate aim. Without stimulation by luteinising hormone from the pituitary, testicular testosterone production also ceases. Therefore, androgen administration to restore physiological levels is an essential component of all male hormonal contraceptive regimes. Male hormonal contraceptives can consist of testosterone alone, or either a progestogen or gonadotropin-releasing hormone antagonist with 'add-back' testosterone. This article reviews the current state of progress in this field.

Intraportal infusion of ghrelin could inhibit glucose-stimulated GLP-1 secretion by enteric neural net in Wistar rat.

PubMed

Zhang, Xiyao; Li, Wensong; Li, Ping; Chang, Manli; Huang, Xu; Li, Qiang; Cui, Can

2014-01-01

As a regulator of food intake and energy metabolism, the role of ghrelin in glucose metabolism is still not fully understood. In this study, we determined the in vivo effect of ghrelin on incretin effect. We demonstrated that ghrelin inhibited the glucose-stimulated release of glucagon-like peptide-1 (GLP-1) when infused into the portal vein of Wistar rat. Hepatic vagotomy diminished the inhibitory effect of ghrelin on glucose-stimulated GLP-1 secretion. In addition, phentolamine, a nonselective α receptor antagonist, could recover the decrease of GLP-1 release induced by ghrelin infusion. Pralmorelin (an artificial growth hormone release peptide) infusion into the portal vein could also inhibit the glucose-stimulated release of GLP-1. And growth hormone secretagogue receptor antagonist, [D-lys3]-GHRP-6, infusion showed comparable increases of glucose stimulated GLP-1 release compared to ghrelin infusion into the portal vein. The data showed that intraportal infusion of ghrelin exerted an inhibitory effect on GLP-1 secretion through growth hormone secretagogue receptor 1α (GHS1α receptor), which indicated that the downregulation of ghrelin secretion after food intake was necessary for incretin effect. Furthermore, our results suggested that the enteric neural net involved hepatic vagal nerve and sympathetic nerve mediated inhibition effect of ghrelin on incretin effect.

Comparison of corifollitropin alfa and daily recombinant follicle-stimulating hormone in poor responder patients undergoing in vitro fertilization cycles.

PubMed

Akarsu, Süleyman; Demir, Sibel; Gode, Funda; Işık, Ahmet Zeki

2017-12-01

The aim of this study was to compare the effect of corifollitropin alfa (CFA) and recombinant follicle-stimulating hormone (rFSH) in poor-responder patients undergoing antagonist cycles. The study was a retrospective analysis of the treatment results of 214 poor responder patients who had been admitted to the In Vitro Fertilization Unit of İzmir Medical Park Hospital between November 2014 and November 2016. Intracytoplasmic sperm injections were performed in 38 patients (group 1) with CFA, and the remaining 176 (group 2) with rFSH for controlled ovarian hyperstimulation. The age, body mass index, anti-müllerian hormone level, duration of infertility, duration of induction and antral follicle number were similar in the two groups. There was no difference in the total aspirated oocyte counts, mature oocyte ratio, fertilization rate, implantation rate, and clinical pregnancy rates between the two groups. The implantation rate was 9/38 (23.6%) in group 1 and 42/176 (23.8%) in group 2, whereas the clinical pregnancy rates were 16.3% and 17.2%, respectively. No difference was found in terms of oocyte count, fertilization rate, implantation rate, and clinical pregnancy rates of CFA or rFSH use in the antagonist cycles in poor-responder patients.

GPER modulators: Opportunity Nox on the heels of a class Akt.

PubMed

Prossnitz, Eric R

2018-02-01

The (patho)physiology of estrogen and its receptors is complex. It is therefore not surprising that therapeutic approaches targeting this hormone include stimulation of its activity through supplementation with either the hormone itself or natural or synthetic agonists, inhibition of its activity through the use of antagonists or inhibitors of its synthesis, and tissue-selective modulation of its activity with biased ligands. The physiology of this hormone is further complicated by the existence of at least three receptors, the classical nuclear estrogen receptors α and β (ERα and ERβ), and the 7-transmembrane G protein-coupled estrogen receptor (GPER/GPR30), with overlapping but distinct pharmacologic profiles, particularly of anti-estrogenic ligands. GPER-selective ligands, as well as GPER knockout mice, have greatly aided our understanding of the physiological roles of GPER. Such ligands have revealed that GPER activation mediates many of the rapid cellular signaling events (including Ca 2+ mobilization, ERK and PI3K/Akt activation) associated with estrogen activity, as opposed to the nuclear ERs that are traditionally described to function as ligand-induced transcriptional factors. Many of the salutary effects of estrogen throughout the body are reproduced by the GPER-selective agonist G-1, which, owing to its minimal effects on reproductive tissues, can be considered a non-feminizing estrogenic compound, and thus of potential therapeutic use in both women and men. On the contrary, until recently GPER-selective antagonists had predominantly found preclinical application in cancer models where estrogen stimulates cell growth and survival. This viewpoint changed recently with the discovery that GPER is associated with aging, particularly that of the cardiovascular system, where the GPER antagonist G36 reduced hypertension and GPER deficiency prevented cardiac fibrosis and vascular dysfunction with age, through the downregulation of Nox1 and as a consequence superoxide production. Thus, similar to the classical ERs, both agonists and antagonists of GPER may be of therapeutic benefit depending on the disease or condition to be treated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Xiao-Min, E-mail: rxm200318@gmail.com; Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn; Gao, Yu, E-mail: francesscototti@gmail.com

2013-05-01

Polybrominated diphenyl ethers (PBDEs) have been shown to disrupt thyroid hormone (TH) functions in experimental animals, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to TH receptors (TRs). However, previous data on TH receptor binding and TH activity of OH-PBDEs were very limited and sometimes inconsistent. In the present paper, we examined the binding potency of ten OH-PBDEs with different degrees of bromination to TR using a fluorescence competitive binding assay. The results showed that the ten OH-PBDEs bound to TR with potency that correlated to their bromination level. We further examined their effectmore » on TR using a coactivator binding assay and GH3 cell proliferation assay. Different TR activities of OH-PBDEs were observed depending on their degree of bromination. Four low-brominated OH-PBDEs (2′-OH-BDE-28, 3′-OH-BDE-28, 5-OH-BDE-47, 6-OH-BDE-47) were found to be TR agonists, which recruited the coactivator peptide and enhanced GH3 cell proliferation. However, three high-brominated OH-PBDEs (3-OH-BDE-100, 3′-OH-BDE-154, 4-OH-BDE-188) were tested to be antagonists. Molecular docking was employed to simulate the interactions of OH-PBDEs with TR and identify the structural determinants for TR binding and activity. According to the docking results, low-brominated OH-PBDEs, which are weak binders but TR agonists, bind with TR at the inner side of its binding pocket, whereas high-brominated compounds, which are potent binders but TR antagonists, reside at the outer region. These results indicate that OH-PBDEs have different activities on TR (agonistic or antagonistic), possibly due to their different binding geometries with the receptor. - Highlights: ► Thyroid hormone (TH) activity of OH-PBDEs with different Br number was evaluated. ► Four different experimental approaches were employed to investigate the mechanism. ► Low-brominated OH-PBDEs were agonists, but high-brominated ones were antagonists. ► Low-brominated OH-PBDEs bind to TH receptor differently than high-brominated ones.« less

Gibberellin Signaling: a Wake-up Call for Seed Germination

USDA-ARS?s Scientific Manuscript database

Making an appropriate decision to germinate is essential for the survival of plant species and is important for proper stand establishment in crop plants. Germination is regulated by the antagonistic effects to two plant hormones in Arabidopsis thaliana: abscisic acid (ABA) induces dormancy and repr...

Quality of life and psychosocial and physical well-being among 1,023 women during their first assisted reproductive technology treatment: secondary outcome to a randomized controlled trial comparing gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist protocols.

PubMed

Toftager, Mette; Sylvest, Randi; Schmidt, Lone; Bogstad, Jeanette; Løssl, Kristine; Prætorius, Lisbeth; Zedeler, Anne; Bryndorf, Thue; Pinborg, Anja

2018-01-01

To compare self-reported quality of life, psychosocial well-being, and physical well-being during assisted reproductive technology (ART) treatment in 1,023 women allocated to either a short GnRH antagonist or long GnRH agonist protocol. Secondary outcome of a prospective phase 4, open-label, randomized controlled trial. Four times during treatment a questionnaire on self-reported physical well-being was completed. Further, a questionnaire on self-reported quality of life and psychosocial well-being was completed at the day of hCG testing. Fertility clinics at university hospitals. Women referred for their first ART treatment were randomized in a 1:1 ratio and started standardized ART protocols. Gonadotropin-releasing hormone analogue; 528 women allocated to a short GnRH antagonist protocol and 495 women allocated to a long GnRH agonist protocol. Self-reported quality of life, psychosocial well-being, and physical well-being based on questionnaires developed for women receiving ART treatment. Baseline characteristics were similar, and response rates were 79.4% and 74.3% in the GnRH antagonist and GnRH agonist groups, respectively. Self-reported quality of life during ART treatment was rated similar and slightly below normal in both groups. However, women in the GnRH antagonist group felt less emotional (adjusted odds ratio [AOR] 0.69), less limited in their everyday life (AOR 0.74), experienced less unexpected crying (AOR 0.71), and rated quality of sleep better (AOR 1.55). Further, women receiving GnRH agonist treatment felt worse physically. Women in a short GnRH antagonist protocol rated psychosocial and physical well-being during first ART treatment better than did women in a long GnRH agonist protocol. However, the one item on self-reported general quality of life was rated similarly. NCT00756028. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Growth hormone-releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan-induced chronic prostatitis.

PubMed

Popovics, Petra; Cai, Renzhi; Sha, Wei; Rick, Ferenc G; Schally, Andrew V

2018-05-21

Inflammation plays a key role in the etiology of benign prostatic hyperplasia (BPH) through multiple pathways involving the stimulation of proliferation by cytokines and growth factors as well as the induction of the focal occurrence of epithelial-to-mesenchymal transition (EMT). We have previously reported that GHRH acts as a prostatic growth factor in experimental BPH and in autoimmune prostatitis models and its blockade with GHRH antagonists offer therapeutic approaches for these conditions. Our current study was aimed at the investigation of the beneficial effects of GHRH antagonists in λ-carrageenan-induced chronic prostatitis and at probing the downstream molecular pathways that are implicated in GHRH signaling. To demonstrate the complications triggered by recurrent/chronic prostatic inflammation in Sprague-Dawley rats, 50 μL 3% carrageenan was injected into both ventral prostate lobes two times, 3 weeks apart. GHRH antagonist, MIA-690, was administered 5 days after the second intraprostatic injection at 20 μg daily dose for 4 weeks. GHRH-induced signaling events were identified in BPH-1 and in primary prostate epithelial (PrEp) cells at 5, 15, 30, and 60 min with Western blot. Inflammation induced prostatic enlargement and increased the area of the stromal compartment whereas treatment with the GHRH antagonist significantly reduced these effects. This beneficial activity was consistent with a decrease in prostatic GHRH, inflammatory marker COX-2, growth factor IGF-1 and inflammatory and EMT marker TGF-β1 protein levels and the expression of multiple genes related to EMT. In vitro, GHRH stimulated multiple pathways involved in inflammation and growth in both BPH-1 and PrEp cells including NFκB p65, AKT, ERK1/2, EGFR, STAT3 and increased the levels of TGF-β1 and Snail/Slug. Most interestingly, GHRH also stimulated the transactivation of the IGF receptor. The study demonstrates that GHRH antagonists could be beneficial for the treatment of prostatic inflammation and BPH in part by inhibiting the growth-promoting and inflammatory effects of locally produced GHRH. © 2018 Wiley Periodicals, Inc.

Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells.

PubMed

Lin, Hung-Yun; Hsieh, Meng-Ti; Cheng, Guei-Yun; Lai, Hsuan-Yu; Chin, Yu-Tang; Shih, Ya-Jung; Nana, André Wendindondé; Lin, Shin-Ying; Yang, Yu-Chen S H; Tang, Heng-Yuan; Chiang, I-Jen; Wang, Kuan

2017-09-01

Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin α v β 3 for nonpeptide hormones. Interaction between hormones and integrin α v β 3 can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin α v β 3 . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin α v β 3 blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. . © 2017 New York Academy of Sciences.

Ghrelin and leptin interplay in prevention of testicular damage due to cryptochidism

USDA-ARS?s Scientific Manuscript database

Ghrelin, the endogenous ligand to the growth hormone secretagogue receptor (ghsr), is centrally implicated in body weight homeostasis. A novel murine model for ghrelin and its physiologic antagonist, leptin, was developed at this institution. Mice with a deletion of ghsr (ghsr -/-) or a targeted dis...

Contribution to More Patient-Friendly ART Treatment: Efficacy of Continuous Low-Dose GnRH Agonist as the Only Luteal Support—Results of a Prospective, Randomized, Comparative Study

PubMed Central

Pirard, Céline; Loumaye, Ernest; Wyns, Christine

2015-01-01

Background. The aim of this pilot study was to evaluate intranasal buserelin for luteal phase support and compare its efficacy with standard vaginal progesterone in IVF/ICSI antagonist cycles. Methods. This is a prospective, randomized, open, parallel group study. Forty patients underwent ovarian hyperstimulation with human menopausal gonadotropin under pituitary inhibition with gonadotropin-releasing hormone antagonist, while ovulation trigger and luteal support were achieved using intranasal GnRH agonist (group A). Twenty patients had their cycle downregulated with buserelin and stimulated with hMG, while ovulation trigger was achieved using 10,000 IU human chorionic gonadotropin with luteal support by intravaginal progesterone (group B). Results. No difference was observed in estradiol levels. Progesterone levels on day 5 were significantly lower in group A. However, significantly higher levels of luteinizing hormone were observed in group A during the entire luteal phase. Pregnancy rates (31.4% versus 22.2%), implantation rates (22% versus 15.4%), and clinical pregnancy rates (25.7% versus 16.7%) were not statistically different between groups, although a trend towards higher rates was observed in group A. No luteal phase lasting less than 10 days was recorded in either group. Conclusion. Intranasal administration of buserelin is effective for providing luteal phase support in IVF/ICSI antagonist protocols. PMID:25945092

Gonadotropin-releasing hormone antagonist use in controlled ovarian stimulation and intrauterine insemination cycles in women with polycystic ovary syndrome.

PubMed

Ertunc, Devrim; Tok, Ekrem C; Savas, Aysun; Ozturk, Ilay; Dilek, Saffet

2010-03-01

To observe the effects of ganirelix on controlled ovarian stimulation and intrauterine insemination (COS/IUI) cycles in women with polycystic ovary syndrome (PCOS). Prospective, randomized, controlled clinical study. An academic clinical research center. Women with PCOS and anovulatory infertility undergoing COS/IUI. Recombinant FSH therapy was started on day 3. In women assigned to the control group (n = 47), treatment was continued up to the day of hCG administration. In patients assigned to receive GnRH antagonist (n = 42), ganirelix was added when the leading follicle was > or =14 mm. Pregnancy rates, serum E(2), P, and LH levels, and follicle numbers at hCG day, prevalence of premature luteinization, and cost of stimulation. Serum E(2), P, and LH levels were significantly lower in the ganirelix group. Although premature luteinization and cycle cancellation was encountered less in the ganirelix group, the pregnancy rates per cycle were similar (15.4% vs. 10.7%). Patients would pay 6,153 dollars more for each pregnancy when using ganirelix. Gonadotropin-releasing hormone antagonist resulted in more monofollicular development, less premature luteinization, and less cycle cancellation in IUI cycles of patients with PCOS; however, the cost of stimulation increased without an improvement in pregnancy rates. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Risks, benefits, and approaches to hormonal blockade in prostate cancer. Highlights from the European Association of Urology Meeting, March 20-24, 2015, Madrid, Spain.

PubMed

Barkin, Jack

2015-06-01

Several abstracts presented at the 2015 European Association of Urology Meeting highlighted new developments in hormone therapy for prostate cancer management. One abstract described how the luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone (GnRH) agonist leuprolide, but not the LHRH/GnRH antagonist degarelix, induced plaque instability in a mouse model. A second abstract showed that in patients with a history of severe cardiovascular disease, degarelix was associated with fewer cardiovascular events than treatment with an LHRH agonist. A third abstract showed how primary androgen-deprivation therapy was linked with increased all-cause mortality in a US registry. A fourth abstract showed that in the ANAMEN study, cognitive performance was not significantly affected by 6 months of treatment with GnRH agonists. Last, a fifth abstract showed that low-dose prednisone, with or without abiraterone, was associated with an overall low incidence of corticosteroid-associated adverse events.

Peptide processing and biology in human disease.

PubMed

Kovac, Suzana; Shulkes, Arthur; Baldwin, Graham S

2009-02-01

To describe recent advances in the processing of gastrointestinal hormones, and the consequences for human disease of mutations in the enzymes involved. Although gastrointestinal prohormones were long regarded as devoid of biological activity, recent data indicate that the prohormones for both gastrin and gastrin-releasing peptide are bioactive, through different receptors from the mature hormones. Mutations in the family of prohormone convertases responsible for the initial steps in the processing of gastrointestinal hormones are associated with several different pathophysiological conditions in humans. Human mutational studies, when taken together with the phenotypes observed in mice deficient in the prohormone convertases, emphasize the crucial importance of the processing enzymes in mammalian biology. Although the phenotypes may often be ascribed to defective production of a mature hormone or growth factor, the recognition that the precursors are independently bioactive suggests that the increased precursor concentrations may also contribute to the symptoms. The observation that the precursors often act through different receptors from the mature hormones may permit the development of precursor-selective antagonists for therapeutic use.

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.

PubMed

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

Identification of Thyroid Receptor Ant/Agonists in Water Sources Using Mass Balance Analysis and Monte Carlo Simulation

PubMed Central

Shi, Wei; Wei, Si; Hu, Xin-xin; Hu, Guan-jiu; Chen, Cu-lan; Wang, Xin-ru; Giesy, John P.; Yu, Hong-xia

2013-01-01

Some synthetic chemicals, which have been shown to disrupt thyroid hormone (TH) function, have been detected in surface waters and people have the potential to be exposed through water-drinking. Here, the presence of thyroid-active chemicals and their toxic potential in drinking water sources in Yangtze River Delta were investigated by use of instrumental analysis combined with cell-based reporter gene assay. A novel approach was developed to use Monte Carlo simulation, for evaluation of the potential risks of measured concentrations of TH agonists and antagonists and to determine the major contributors to observed thyroid receptor (TR) antagonist potency. None of the extracts exhibited TR agonist potency, while 12 of 14 water samples exhibited TR antagonistic potency. The most probable observed antagonist equivalents ranged from 1.4 to 5.6 µg di-n-butyl phthalate (DNBP)/L, which posed potential risk in water sources. Based on Monte Carlo simulation related mass balance analysis, DNBP accounted for 64.4% for the entire observed antagonist toxic unit in water sources, while diisobutyl phthalate (DIBP), di-n-octyl phthalate (DNOP) and di-2-ethylhexyl phthalate (DEHP) also contributed. The most probable observed equivalent and most probable relative potency (REP) derived from Monte Carlo simulation is useful for potency comparison and responsible chemicals screening. PMID:24204563

Focus on the short- and long-term effects of ghrelin on energy homeostasis.

PubMed

De Vriese, Carine; Perret, Jason; Delporte, Christine

2010-06-01

The endogenous ligand for the growth hormone secretagogue receptor, ghrelin, is a 28-amino-acid peptide acylated with an octanoyl group at the serine in position 3. Most of the circulating ghrelin results from its synthesis and secretion by the X/A-like endocrine cells from the stomach and proximal small intestine. Besides its potent growth hormone secretory action, ghrelin is a highly pleiotropic hormone, contributing significantly to the regulation of appetite and food intake control, gastrointestinal motility, gastric acid secretion, endocrine and exocrine pancreatic secretions, cell proliferation, glucose and lipid metabolism, and cardiovascular and immunologic processes. The purpose of this review is to consider the orexigenic effects of ghrelin on short-term regulation of food intake and long-term regulation of body weight, the implications of genetic ghrelin and growth hormone secretagogue receptor polymorphism, and the use of antagonists and agonists of ghrelin in pathophysiological conditions. Copyright 2010 Elsevier Inc. All rights reserved.

Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure based modeling methods

PubMed Central

Politi, Regina; Rusyn, Ivan; Tropsha, Alexander

2016-01-01

The thyroid hormone receptor (THR) is an important member of the nuclear receptor family that can be activated by endocrine disrupting chemicals (EDC). Quantitative Structure-Activity Relationship (QSAR) models have been developed to facilitate the prioritization of THR-mediated EDC for the experimental validation. The largest database of binding affinities available at the time of the study for ligand binding domain (LBD) of THRβ was assembled to generate both continuous and classification QSAR models with an external accuracy of R2=0.55 and CCR=0.76, respectively. In addition, for the first time a QSAR model was developed to predict binding affinities of antagonists inhibiting the interaction of coactivators with the AF-2 domain of THRβ (R2=0.70). Furthermore, molecular docking studies were performed for a set of THRβ ligands (57 agonists and 15 antagonists of LBD, 210 antagonists of the AF-2 domain, supplemented by putative decoys/non-binders) using several THRβ structures retrieved from the Protein Data Bank. We found that two agonist-bound THRβ conformations could effectively discriminate their corresponding ligands from presumed non-binders. Moreover, one of the agonist conformations could discriminate agonists from antagonists. Finally, we have conducted virtual screening of a chemical library compiled by the EPA as part of the Tox21 program to identify potential THRβ-mediated EDCs using both QSAR models and docking. We concluded that the library is unlikely to have any EDC that would bind to the THRβ. Models developed in this study can be employed either to identify environmental chemicals interacting with the THR or, conversely, to eliminate the THR-mediated mechanism of action for chemicals of concern. PMID:25058446

Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel 1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid CYP3A4 time-dependent inhibition.

PubMed

Igawa, Hideyuki; Takahashi, Masashi; Shirasaki, Mikio; Kakegawa, Keiko; Kina, Asato; Ikoma, Minoru; Aida, Jumpei; Yasuma, Tsuneo; Okuda, Shoki; Kawata, Yayoi; Noguchi, Toshihiro; Yamamoto, Syunsuke; Fujioka, Yasushi; Kundu, Mrinalkanti; Khamrai, Uttam; Nakayama, Masaharu; Nagisa, Yasutaka; Kasai, Shizuo; Maekawa, Tsuyoshi

2016-06-01

Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q-u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats. Copyright © 2016 Elsevier Ltd. All rights reserved.

The growth hormone-releasing hormone (GHRH) antagonist JV-1-36 inhibits proliferation and survival of human ectopic endometriotic stromal cells (ESCs) and the T HESC cell line.

PubMed

Annunziata, Marta; Grande, Cristina; Scarlatti, Francesca; Deltetto, Francesco; Delpiano, Elena; Camanni, Marco; Ghigo, Ezio; Granata, Riccarda

2010-08-01

To determine the effect of the GHRH antagonist JV-1-36 on proliferation and survival of primary ectopic human endometriotic stromal cells (ESCs) and the T HESC cell line. Prospective laboratory study. University hospital. 22 women with endometriosis (aged 34.8+/-5.7 years) undergoing therapeutic laparoscopy. Eutopic (n=10) and ectopic (n=22) endometrial tissues were collected from women who underwent therapeutic laparoscopic surgery for endometriosis (stage III/IV). Expression of GHRH, GHRH receptor (GHRH-R) and GHRH-R splice variant (SV) 1 mRNA was determined by reverse-transcription polymerase chain reaction (RT-PCR). The ESC proliferation was assessed by 5-bromo-2-deoxyuridine incorporation, cell survival by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and Trypan blue assay. The T HESC survival was evaluated by MTT, cyclic adenosine monophosphate (cAMP) levels by ELISA, extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation by Western blot, and insulin-like growth factor (IGF)-2 mRNA by real-time PCR. The ESCs and T HESCs, but not normal endometrial tissues, expressed GHRH-R mRNA; SV1 mRNA was determined in normal endometrial tissues, ESCs, and T HESCs; GHRH mRNAwas found in T HESCs; JV-1-36 inhibited ESC proliferation and ESC and T HESC survival. In T HESCs, JV-1-36 reduced cAMP production and ERK1/2 phosphorylation but had no effect on IGF-2 mRNA expression. The GHRH antagonist JV-1-36 inhibits endometriotic cell proliferation and survival, suggesting that GHRH antagonist may represent promising tools for treatment of endometriosis. Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buoso, Erica; Galasso, Marilisa; Ronfani, Melania

We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity andmore » protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system. - Highlights: • RACK1 expression can be induced by AR agonists with a consequent enhancement of the response to LPS. • RACK1 can be negatively modulated by the AR antagonists DDT and its main metabolite p,p′DDE. • RACK1 can be a relevant target of EDCs, representing a bridge between the endocrine system and the immune system.« less

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

PubMed

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 < 40 years submitted to COS with corifollitropin alfa 100µg or 150µg (n = 26) and rFSH or HP-HMG in the first seven days of treatment with daily doses of 150-225 IU (n = 106); all subjects were on GnRH antagonist protocols. The groups had similar mean ages and duration of stimulation. The mean number ± standard deviation of total aspirated oocytes and MII oocytes was 11.9±10 and 10.3±7.9 in the corifollitropin alfa group, and 10.9±7.2 and 8.6±5.7 in the group on rFSH or HMG (p>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.

Ethylene-induced transcriptional and hormonal responses at the onset of sugarcane ripening

PubMed Central

Cunha, Camila P.; Roberto, Guilherme G.; Vicentini, Renato; Lembke, Carolina G.; Souza, Glaucia M.; Ribeiro, Rafael V.; Machado, Eduardo C.; Lagôa, Ana M. M. A.; Menossi, Marcelo

2017-01-01

The effects of ethephon as a sugarcane ripener are attributed to ethylene. However, the role of this phytohormone at the molecular level is unknown. We performed a transcriptome analysis combined with the evaluation of sucrose metabolism and hormone profiling of sugarcane plants sprayed with ethephon or aminoethoxyvinylglycine (AVG), an ethylene inhibitor, at the onset of ripening. The differential response between ethephon and AVG on sucrose level and sucrose synthase activity in internodes indicates ethylene as a potential regulator of sink strength. The correlation between hormone levels and transcriptional changes suggests ethylene as a trigger of multiple hormone signal cascades, with approximately 18% of differentially expressed genes involved in hormone biosynthesis, metabolism, signalling, and response. A defence response elicited in leaves favoured salicylic acid over the ethylene/jasmonic acid pathway, while the upper internode was prone to respond to ethylene with strong stimuli on ethylene biosynthesis and signalling genes. Besides, ethylene acted synergistically with abscisic acid, another ripening factor, and antagonistically with gibberellin and auxin. We identified potential ethylene target genes and characterized the hormonal status during ripening, providing insights into the action of ethylene at the site of sucrose accumulation. A molecular model of ethylene interplay with other hormones is proposed. PMID:28266527

A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques

PubMed Central

Peluffo, M.C.; Stanley, J.; Braeuer, N.; Rotgeri, A.; Fritzemeier, K.-H.; Fuhrmann, U.; Buchmann, B.; Adevai, T.; Murphy, M.J.; Zelinski, M.B.; Lindenthal, B.; Hennebold, J.D.; Stouffer, R.L.

2014-01-01

STUDY QUESTION Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? SUMMARY ANSWER This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. WHAT IS KNOWN ALREADY The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus–oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. STUDY DESIGN, SIZE, DURATION First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3–4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus–oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3–4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. PARTICIPANTS/MATERIALS, SETTING, METHODS Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests and blood lipid profiles. MAIN RESULTS AND THE ROLE OF CHANCE Several mRNAs encoding proteins involved in PGE2 synthesis, metabolism and signaling increase (P < 0.05) in the periovulatory follicle after administration of an ovulatory hCG bolus. PGE2 signaling through PTGER2 induces cumulus cell expansion and production of hyaluronic acid, which are critical events for fertilization. Moreover, chronic administration of a selective PTGER2 antagonist resulted in a significant (P < 0.05 versus vehicle-treated controls) contraceptive effect without altering steroid hormone patterns or menstrual cyclicity during a 5-months contraceptive trial. Fertility recovered as early as 1 month after ending treatment. LIMITATIONS, REASONS FOR CAUTION This is a proof-of-concept study in a non-human primate model. Further investigations are warranted to elucidate the mechanism(s) of PTGER2 antagonist action in the primate ovary. Although PTGER2 antagonist treatment did not produce any obvious undesirable effects, improvements in the mode of administration, as well as the efficacy of these compounds, are necessary to consider such a contraceptive for women. WIDER IMPLICATIONS OF THE FINDINGS Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity. Even though hormonal contraceptives are effective for women, concerns remain regarding their side-effects and long-term use because of the widespread actions of such steroidal products in many tissues. Moreover, some women cannot take hormones for medical reasons. Thus, development of non-hormonal contraceptives for women is warranted. STUDY FUNDING/COMPETING INTEREST(S) Supported by Bayer HealthCare Pharmaceuticals, The Eunice Kennedy Shriver NICHD Contraceptive Development and Research Center (U54 HD055744), NIH Office of the Director (Oregon National Primate Research Center P51 OD011092), and a Lalor Foundation Postdoctoral Basic Research Fellowship (MCP). The use of the Leica confocal was supported by grant number S10RR024585. Some of the authors (N.B., A.R., K.-H.F., U.F., B.B. and B.L.) are employees of Bayer Healthcare Pharma. PMID:24781425

Mitochondrial distribution and activity in human mature oocytes: gonadotropin-releasing hormone agonist versus antagonist for pituitary down-regulation.

PubMed

Dell'Aquila, Maria Elena; Ambruosi, Barbara; De Santis, Teresa; Cho, Yoon Sung

2009-01-01

To analyze the effects of GnRH agonists versus antagonists on mitochondrial distribution and activity in human mature oocytes. Randomized research experimental study. Academic basic research laboratory and hospital-based fertility center. Two hundred twenty-five supernumerary mature oocytes from 44 patients. Fluorescent staining and confocal laser scanning microscopy on oocytes after the use of either GnRH agonist (group A) or GnRH antagonist (group B). Oocyte mitochondrial distribution pattern and activity using MitoTracker Orange CMTM Ros. More oocytes showing polarized mitochondrial distribution pattern were found in group A than in group B (35% vs. 14%). In group B, hCG rather than GnRH agonist, for ovulation induction, resulted in more oocytes showing heterogeneous (57% vs. 14%), in particular polarized (24% vs. 0) mitochondrial distribution. In groups A and B, fluorescence intensity did not vary according to mitochondrial distribution pattern. However, fluorescence intensity was higher in oocytes with polarized and large granules configurations in group B compared to group A. The GnRH agonist and antagonist may have different effects on oocyte mitochondrial distribution pattern and activity. The GnRH antagonist may induce mitochondrial hyperactivity, which may be detrimental to the oocyte.

Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.

PubMed

Wu, Mingwei; Li, Yan; Fu, Xinmei; Wang, Jinghui; Zhang, Shuwei; Yang, Ling

2014-09-01

Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q²) = 0.509, non-cross-validated correlation coefficient (R²(ncv)) = 0.841 and the predicted correlation coefficient (R²(pred)) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.

Sex differences in the analgesic effects of ICI 182,780 and Flutamide on ureteral calculosis in rats.

PubMed

Affaitati, Giannapia; Ceccarelli, Ilaria; Fiorenzani, Paolo; Rossi, Cosmo; Pace, Maria Caterina; Passavanti, Maria Beatrice; Aurilio, Caterina; Sorda, Giuseppina; Danielli, Barbara; Giamberardino, Maria Adele; Aloisi, Anna Maria

2011-01-01

To better define the involvement of gonadal hormones in the sex differences observed in experimental visceral pain, we administered antagonists of estrogen receptors (ICI 182,780 [ICI]) or androgen receptors (Flutamide [FLU]) to adult male and female rats suffering from artificial ureteral calculosis. Subjects were divided into groups and treated with one of the substances (ICI, FLU) or sweet almond oil (OIL, vehicle) for 5 days, starting 2 days before surgery. On day 3, animals underwent surgery, with half receiving an artificial calculosis (Stone) and half only a sham procedure. The animals' behavior (number and duration of ureteral crises) and blood hormone levels (estradiol and testosterone) were determined in all groups. In OIL-treated rats the number and duration of crises were higher in females than in males. The administration of ICI or FLU resulted in hormonal effects in males and behavioral effects in females. In males ICI treatment increased estradiol plasma levels and FLU increased testosterone plasma levels; in females ICI and FLU treatments both decreased the number and duration of the ureteral crises. These results, confirming previous findings of higher sensitivity of females than males to urinary tract pain, showed the modulatory effects of estrogen and androgen antagonists on the behavioral responses induced by pain but only in females. Copyright © 2010 Elsevier Inc. All rights reserved.

[A male contraceptive injection can be available within 5 years].

PubMed

Gottlieb, C; Aanesen, A

1999-09-22

After more than two decades of attempts to develop a safe male contraceptive, the goal now seems attainable. Spermatogenesis, which is dependent on endogenous testosterone production in the testes, may be controlled by such exogenous steroid hormones as testosterone, gestagens, or combinations of them. The recent development of gonadotrophin-releasing hormone (GnRH) antagonists has provided an added means of depressing testosterone production. Other targets for interference with male fertility are the germinal epithelium (e.g. using the cottonseed oil product, Gossypol, or Triptyrigeum Wilfordii extract), or the maturing sperm in the epididymis (using immunoactive substances).

Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore

Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. Wemore » have determined the crystal structure of the complex between PTHrP (residues 1-108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an {alpha}-helical structure extending from residues 14-29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor.« less

SPECIES DIFFERENCES IN ANDROGEN AND ESTROGEN RECEPTOR STRUCTURE AND FUNCTION AMONG VERTEBRATES AND INVERTEBRATES FOR INTERSPECIES EXTRAPOLATION OF ENDOCRINE DISRUPTING CHEMICALS

EPA Science Inventory

In vitro screening assays designed to identify hormone minics or antagonists, including the EDSTAC Tier 1 Screening (TIS) Battery, typically use only mammalian estrogen (ER) and androgen receptors (AR). However, there is uncertainty concerning species differences in binding affin...

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

PubMed Central

Trägårdh, M; Lindén, D; Ploj, K; Johansson, A; Turnbull, A; Carlsson, B; Antonsson, M

2017-01-01

In this study, we present the translational modeling used in the discovery of AZD1979, a melanin‐concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body‐composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non‐parametric input estimation (e.g., predicting energy intake from longitudinal body‐weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose‐prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly. PMID:28556607

Proceedings of the 1972 Lyndon B. Johnson Space Center Endocrine Program Conference

NASA Technical Reports Server (NTRS)

1974-01-01

Subjects covered during the Endocrine Program Conference include the following: (1) endocrine/metabolic studies on the Apollo 16 crewmen; (2) changes in glucose, insulin, and growth hormone levels associated with bed rest; (3) circadian rhythms of heart rate and body temperature during 56 days of bed rest; (4) stress-induced changes in corticosteroid metabolism in man; (5) present status of physiological studies on parathyroid hormone and vitamin D; (6) antagonistic effect of lithium on antidiuretic hormone action; (7) proposed Skylab body-fluid volumes study; (8) daily rhythmic changes in serotonin content in areas of the mouse brain and norepinephrine content in areas of the hamster brain; (9) studies of sodium homeostasis during simulated weightlessness; and (10) application of the water immersion model to man.

Identification of Antibody and Small Molecule Antagonists of Ferroportin-Hepcidin Interaction

PubMed Central

Ross, Sandra L.; Biswas, Kaustav; Rottman, James; Allen, Jennifer R.; Long, Jason; Miranda, Les P.; Winters, Aaron; Arvedson, Tara L.

2017-01-01

The iron exporter ferroportin and its ligand, the hormone hepcidin, control fluxes of stored and recycled iron for use in a variety of essential biochemical processes. Inflammatory disorders and malignancies are often associated with high hepcidin levels, leading to ferroportin down-regulation, iron sequestration in tissue macrophages and subsequent anemia. The objective of this research was to develop reagents to characterize the expression of ferroportin, the interaction between ferroportin and hepcidin, as well as to identify novel ferroportin antagonists capable of maintaining iron export in the presence of hepcidin. Development of investigative tools that enabled cell-based screening assays is described in detail, including specific and sensitive monoclonal antibodies that detect endogenously-expressed human and mouse ferroportin and fluorescently-labeled chemically-synthesized human hepcidin. Large and small molecule antagonists inhibiting hepcidin-mediated ferroportin internalization were identified, and unique insights into the requirements for interaction between these two key iron homeostasis molecules are provided. PMID:29209212

Roles of the locus coeruleus and adrenergic receptors in brain-mediated hypothalamic-pituitary-adrenal axis responses to intracerebroventricular alcohol.

PubMed

Selvage, Dan

2012-06-01

Alcohol activates the hypothalamic-pituitary-adrenal (HPA) axis through its actions in both the periphery and the central nervous system (CNS). The studies presented here were designed to test the CNS-specific noradrenergic mechanisms by which alcohol stimulates HPA activity in the male rat. We used an experimental paradigm in which a small, nontoxic amount (5 μl) of alcohol was slowly microinfused intracerebroventricularly (icv). Alcohol was administered icv to animals with lesions of the locus coeruleus (LC) or in animals pretreated with α- or β-adrenergic receptor antagonists. Hormonal HPA activation was determined by measuring secretion of the pituitary stress hormone adrenocorticotropin (ACTH). Neuronal activation was determined by quantification of the expression of the transcription factor c-fos (Fos). As expected, icv alcohol stimulated ACTH secretion from the pituitary and Fos expression in the paraventricular nucleus of the hypothalamus (PVN). Bilateral electrolytic LC lesions blocked the ability of icv alcohol to stimulate ACTH secretion. Pretreatment with icv propranolol increased basal ACTH secretion levels, but icv alcohol did not increase this effect. Propranolol also blunted icv alcohol-induced PVN Fos expression. A low dose of phenoxybenzamine, an α-adrenergic receptor antagonist, did not affect the ability of icv alcohol to stimulate ACTH release. However, a higher dose of the drug was able to block the ACTH response to icv alcohol. Despite this, phenoxybenzamine did not inhibit alcohol-induced Fos expression. Icv pretreatment with corynanthine, a selective α-1 adrenergic receptor antagonist, modestly raised basal ACTH levels and blocked the icv alcohol-induced secretion of this hormone. These results indicate that the LC and norepinephrine play important roles in HPA activation caused by icv alcohol administration, but that the specific adrenergic receptor subtypes involved in this phenomenon still need to be identified. Copyright © 2012 by the Research Society on Alcoholism.

Neonatal Exposure to Bisphenol A Alters Reproductive Parameters and Gonadotropin Releasing Hormone Signaling in Female Rats

PubMed Central

Fernández, Marina; Bianchi, Maria; Lux-Lantos, Victoria; Libertun, Carlos

2009-01-01

Background Bisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins, and polystyrene and is found in many products. Several reports have revealed potent in vivo effects, because BPA acts as an estrogen agonist and/or antagonist and as an androgen and thyroid hormone antagonist. Objectives We analyzed the effects of neonatal exposure to BPA on the reproductive axis of female Sprague-Dawley rats. Methods Female rats were injected subcutaneusly, daily, from postnatal day 1 (PND1) to PND10 with BPA [500 μg/50 μL (high) or 50 μg/50 μL (low)] in castor oil or with castor oil vehicle alone. We studied body weight and age at vaginal opening, estrous cycles, and pituitary hormone release in vivo and in vitro, as well as gonadotropin-releasing hormone (GnRH) pulsatility at PND13 and in adults. We also analyzed two GnRH-activated signaling pathways in the adults: inositol-triphosphate (IP3), and extracellular signal-regulated kinase1/2 (ERK1/2). Results Exposure to BPA altered pituitary function in infantile rats, lowering basal and GnRH-induced luteinizing hormone (LH) and increasing GnRH pulsatility. BPA dose-dependently accelerated puberty onset and altered estrous cyclicity, with the high dose causing permanent estrus. In adults treated neonatally with BPA, GnRH-induced LH secretion in vivo was decreased and GnRH pulsatility remained disrupted. In vitro, pituitary cells from animals treated with BPA showed lower basal LH and dose-dependently affected GnRH-induced IP3 formation; the high dose also impaired GnRH-induced LH secretion. Both doses altered ERK1/2 activation. Conclusions Neonatal exposure to BPA altered reproductive parameters and hypothalamic–pituitary function in female rats. To our knowledge, these results demonstrate for the first time that neonatal in vivo BPA permanently affects GnRH pulsatility and pituitary GnRH signaling. PMID:19479018

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models.

PubMed

Whitesell, Luke; Santagata, Sandro; Mendillo, Marc L; Lin, Nancy U; Proia, David A; Lindquist, Susan

2014-12-23

The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.

Delay of iris flower senescence by cytokinins and jasmonates.

PubMed

van Doorn, Wouter G; Çelikel, Fisun G; Pak, Caroline; Harkema, Harmannus

2013-05-01

It is not known whether tepal senescence in Iris flowers is regulated by hormones. We applied hormones and hormone inhibitors to cut flowers and isolated tepals of Iris × hollandica cv. Blue Magic. Treatments with ethylene or ethylene antagonists indicated lack of ethylene involvement. Auxins or auxin inhibitors also did not change the time to senescence. Abscisic acid (ABA) hastened senescence, but an inhibitor of ABA synthesis (norflurazon) had no effect. Gibberellic acid (GA3 ) slightly delayed senescence in some experiments, but in other experiments it was without effect, and gibberellin inhibitors [ancymidol or 4-hydroxy-5-isopropyl-2-methylphenyltrimethyl ammonium chloride-1-piperidine carboxylate (AMO-1618)] were ineffective as well. Salicylic acid (SA) also had no effect. Ethylene, auxins, GA3 and SA affected flower opening, therefore did reach the flower cells. Jasmonates delayed senescence by about 2.0 days. Similarly, cytokinins delayed senescence by about 1.5-2.0 days. Antagonists of the phosphatidylinositol signal transduction pathway (lithium), calcium channels (niguldipine and verapamil), calmodulin action [fluphenazine, trifluoroperazine, phenoxybenzamide and N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide hydrochloride (W-7)] or protein kinase activity [1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7), N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8) and N-(2-aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9)] had no effect on senescence, indicating no role of a few common signal transduction pathways relating to hormone effects on senescence. The results indicate that tepal senescence in Iris cv. Blue Magic is not regulated by endogenous ethylene, auxin, gibberellins or SA. A role of ABA can at present not be excluded. The data suggest the hypothesis that cytokinins and jasmonates are among the natural regulators. Copyright © Physiologia Plantarum 2012.

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist*

PubMed Central

Song, Chin-Hee; Yang, Su Hui; Park, Eunsook; Cho, Suk Hee; Gong, Eun-Yeung; Khadka, Daulat Bikram; Cho, Won-Jea; Lee, Keesook

2012-01-01

Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4–2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer. PMID:22798067

[Anthology of the first clinical studies with hypothalamic hormones: a story of successful international cooperation].

PubMed

Schally, Andrew V; Gual, Carlos

2002-01-01

Our early pioneering clinical trials in Mexico with natural and synthetic thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Highly purified TRH of porcine origin was shown to stimulate Thyrotropin (TSH) release in hypothyroid cretins. Subsequent tests with synthetic TRH also demonstrated significant increases in plasma TSH in normal men and women as well as in patients with primary hypothyroidism and other endocrine disorders. Even more extensive clinical studies were carried out with highly purified natural porcine LH-RH. Subjects with normal basal serum levels of gonadotropins, low levels (men and women pretreated with steroids) and high levels (e.g. post menopausal women) all responded to LH-RH with a release of LH and FSH. The results of these early studies with the natural LH-RH were confirmed by the use of synthetic LH-RH. These investigations made in Mexico with TRH and LH-RH preceded all other clinical studies by a wide margin. Subsequently various clinical investigations with LH-RH agonists and antagonists were also carried out. All these studies played a major role in introducing hypothalamic-releasing hormones into clinical medicine.

Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs.

PubMed

Ufnal, Marcin; Skrzypecki, Janusz

2014-04-01

Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure. Copyright © 2014 Elsevier Ltd. All rights reserved.

An ABI3-interactor of conifers responds to multiple hormones.

PubMed

Zeng, Ying; Zhao, Tiehan; Kermode, Allison

2013-11-01

CnAIP2 (Callitropsis nootkatensis ABI3-Interacting Protein 2) was previously identified as a protein that interacts with the yellow-cedar ABI3 protein. CnAIP2 plays important roles during several key transitions of the plant lifecycle and acts as a global regulator with functions opposite to those of ABI3 proteins. Here we report that the CnAIP2 gene promoter is strongly upregulated by all of the major plant hormones. Young Arabidopsis seedlings expressing a chimeric CnAIP2pro-GUS construct were subjected to exogenously applied hormones; the maximum fold-enhancement of GUS activity was as high as 47-fold, and each hormone showed a distinctive cell/tissue-specific pattern of GUS induction. By far the greatest response was elicited by the synthetic auxin 2,4-D (47-fold induction); the other hormones tested stimulated GUS activities by 8- to 21-fold. The CnAIP2 promoter also responded to glucose and salt (NaCl), albeit to a lesser extent (2- to 3-fold induction). As well as acting in an antagonistic way to the global regulator ABI3, CnAIP2 appears to participate in multiple hormonal crosstalk pathways to carry out its functions.

Peptide processing and biology in human disease

PubMed Central

Kovac, Suzana; Shulkes, Arthur; Baldwin, Graham S.

2008-01-01

Purpose of review To describe recent advances in the processing of gastrointestinal hormones, and the consequences for human disease of mutations in the enzymes involved. Recent findings Although gastrointestinal prohormones were long regarded as devoid of biological activity, recent data indicates that the prohormones for both gastrin and gastrin-releasing peptide are bioactive, through different receptors from the mature hormones. Mutations in the family of prohormone convertases responsible for the initial steps in the processing of gastrointestinal hormones are associated with several different pathophysiological conditions in humans. Summary Human mutational studies, when taken together with the phenotypes observed in mice deficient in the prohormone convertases, emphasize the crucial importance of the processing enzymes in mammalian biology. Although the phenotypes may often be ascribed to defective production of a mature hormone or growth factor, the recognition that the precursors are independently bioactive suggests that the increased precursor concentrations may also contribute to the symptoms. The observation that the precursors often act through different receptors from the mature hormones may permit the development of precursor-selective antagonists for therapeutic use. PMID:19104240

TIMED DAILY ADMINISTRATION OF HORMONES AND ANTAGONISTS OF NEUROENDOCRINE RECEPTORS ALTER DAY-NIGHT RHYTHMS OF ALLOGRAFT REJECTION IN THE GULF KILLIFISH, FUNDULUS GRANDIS. (R823881)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

CLONING AND IN VITRO EXPRESSION AND CHARACTERIZATION OF THE ANDROGEN RECEPTOR AND ISOLATION OF ESTROGEN RECEPTOR α FROM THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

EPA Science Inventory

In vitro screening assays designed to identify hormone mimics or antagonists typically use mammalian (rat, human) estrogen (ER) and androgen receptors (AR). Although we know that the amino acid sequences of steroid receptors in nonmammalian vertebrates are not identical to the ma...

CLONING, EXPRESSION AND CHARACTERIZATION OF THE ANDROGEN RECEPTOR AND ISOLATION OF ESTROGEN RECEPTOR ALPHA FROM THE FATHEAD MINNOW (PIMEPHALES PROMELAS)

EPA Science Inventory

In vitro screening assays designed to identify hormone mimics or antagonists, including those recommended for use in the EPA's Tier 1 screening battery, typically use mammalian estrogen (ER) and androgen receptors (AR) such as rat or human. Although we know that the amino acid s...

Analogs of sulfakinin-related peptides demonstrate reduction in food intake in the red flour beetle, Tribolium castaneum, while putative antagonists increase consumption

USDA-ARS?s Scientific Manuscript database

The insect sulfakinins (SKs) constitute a family of neuropeptides that display both structural and functional similarities to the mammalian hormones gastrin and cholecystokinin (CCK). As a multifunctional neuropeptide, SKs are involved in muscle contractions as well as food intake regulation in many...

Analysis of thyroid hormone receptor {beta}A mRNA expression in Xenopus laevis tadpoles as a means to detect agonism and antagonism of thyroid hormone action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Opitz, Robert; Lutz, Ilka; Nguyen, Ngoc-Ha

2006-04-01

Amphibian metamorphosis represents a unique biological model to study thyroid hormone (TH) action in vivo. In this study, we examined the utility of thyroid hormone receptors {alpha} (TR{alpha}) and {beta}A (TR{beta}A) mRNA expression patterns in Xenopus laevis tadpoles as molecular markers indicating modulation of TH action. During spontaneous metamorphosis, only moderate changes were evident for TR{alpha} gene expression whereas a marked up-regulation of TR{beta}A mRNA occurred in hind limbs (prometamorphosis), head (late prometamorphosis), and tail tissue (metamorphic climax). Treatment of premetamorphic tadpoles with 1 nM 3,5,3'-triiodothyronine (T3) caused a rapid induction of TR{beta}A mRNA in head and tail tissue withinmore » 6 to 12 h which was maintained for at least 72 h after initiation of T3 treatment. Developmental stage had a strong influence on the responsiveness of tadpole tissues to induce TR{beta}A mRNA during 24 h treatment with thyroxine (0, 1, 5, 10 nM T4) or T3 (0, 1, 5, 10 nM). Premetamorphic tadpoles were highly sensitive in their response to T4 and T3 treatments, whereas sensitivity to TH was decreased in early prometamorphic tadpoles and strongly diminished in late prometamorphic tadpoles. To examine the utility of TR{beta}A gene expression analysis for detection of agonistic and antagonistic effects on T3 action, mRNA expression was assessed in premetamorphic tadpoles after 48 h of treatment with the synthetic agonist GC-1 (0, 10, 50, 250 nM), the synthetic antagonist NH-3 (0, 40, 200, 1000 nM), and binary combinations of NH-3 (0, 40, 200, 1000 nM) and T3 (1 nM). All tested concentrations of GC-1 as well as the highest concentration of NH-3 caused an up-regulation of TR{beta}A expression. Co-treatment with NH-3 and T3 revealed strong antagonistic effects by NH-3 on T3-induced TR{beta}A mRNA up-regulation. Results of this study suggest that TR{beta}A mRNA expression analysis could serve as a sensitive molecular testing approach to study effects of environmental compounds on the thyroid system in X. laevis tadpoles.« less

Activity of binary mixtures of drospirenone with progesterone and 17α-ethinylestradiol in vitro and in vivo.

PubMed

Rossier, Nadine Madeleine; Chew, Geraldine; Zhang, Kun; Riva, Francesco; Fent, Karl

2016-05-01

Despite potential exposure of aquatic organisms to mixtures of steroid hormones, very little is known on their joint activity in fish. Drospirenone (DRS) is a new synthetic progestin used in contraceptive pills in combination with 17α-ethinylestradiol (EE2). Here we systematically analyzed effects of DRS in binary mixtures with progesterone (P4) and EE2. First, we determined the in vitro activity of single compounds in recombinant yeast assays that express the human progesterone, androgen, or estrogen receptor, followed by determination of mixture activities of DRS and P4, DRS and EE2, as well as medroxyprogesterone acetate (MPA) and dydrogesterone (DDG). Mixtures of DRS and P4, as well as of DRS and EE2 showed additive progestogenic and androgenic activities. However, DDG and MPA showed non-additive progestogenic and androgenic activities. We then analyzed the in vivo activity of single compounds and mixtures of DRS and P4, as well as DRS and EE2, by assessing transcriptional changes of up to 14 selected target genes in zebrafish embryos at 48h post fertilization (hpf), and in eleuthero-embryos at 96hpf and 144hpf. DRS, P4, and EE2 led to significant transcriptional alteration of genes, including those encoding hormone receptors (pgr, esr1), a steroidogenic enzyme (hsd17b3), and estrogenic markers (vtg1, cyp19b), in particular at 144 hpf. In general, DRS showed stronger transcriptional changes than P4. In mixtures of DRS and P4, they were mainly non-additive (antagonistic interaction). In mixtures of DRS and EE2, transcriptional responses of esr1, vtg1 and cyp19b were dominated by EE2, suggesting an antagonistic interaction or independent action. Equi-effective mixtures of DRS and EE2, based on progesterone receptor transcripts, showed antagonistic interactions. Our data suggest that interactions in mixtures assessed in vitro in recombinant yeast cannot be translated to the in vivo situation. The receptor-based responses did not correspond well to the transcriptional responses in embryos which are much more complex due to the interplay between hormonal pathways, receptor crosstalk, and hormonal feedback loops. Copyright © 2016 Elsevier B.V. All rights reserved.

Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods

DOE Office of Scientific and Technical Information (OSTI.GOV)

Politi, Regina; Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599; Rusyn, Ivan, E-mail: iir@unc.edu

2014-10-01

The thyroid hormone receptor (THR) is an important member of the nuclear receptor family that can be activated by endocrine disrupting chemicals (EDC). Quantitative Structure–Activity Relationship (QSAR) models have been developed to facilitate the prioritization of THR-mediated EDC for the experimental validation. The largest database of binding affinities available at the time of the study for ligand binding domain (LBD) of THRβ was assembled to generate both continuous and classification QSAR models with an external accuracy of R{sup 2} = 0.55 and CCR = 0.76, respectively. In addition, for the first time a QSAR model was developed to predict bindingmore » affinities of antagonists inhibiting the interaction of coactivators with the AF-2 domain of THRβ (R{sup 2} = 0.70). Furthermore, molecular docking studies were performed for a set of THRβ ligands (57 agonists and 15 antagonists of LBD, 210 antagonists of the AF-2 domain, supplemented by putative decoys/non-binders) using several THRβ structures retrieved from the Protein Data Bank. We found that two agonist-bound THRβ conformations could effectively discriminate their corresponding ligands from presumed non-binders. Moreover, one of the agonist conformations could discriminate agonists from antagonists. Finally, we have conducted virtual screening of a chemical library compiled by the EPA as part of the Tox21 program to identify potential THRβ-mediated EDCs using both QSAR models and docking. We concluded that the library is unlikely to have any EDC that would bind to the THRβ. Models developed in this study can be employed either to identify environmental chemicals interacting with the THR or, conversely, to eliminate the THR-mediated mechanism of action for chemicals of concern. - Highlights: • This is the largest curated dataset for ligand binding domain (LBD) of the THRβ. • We report the first QSAR model for antagonists of AF-2 domain of THRβ. • A combination of QSAR and docking enables prediction of both affinity and efficacy. • Models can be used to identify environmental chemicals interacting with THRβ. • Models can be used to eliminate the THRβ-mediated mechanism of action.« less

A novel approach using a minimal number of injections during the IVF/ICSI cycle: Luteal half-dose depot GnRH agonist following corifollitropin alfa versus the corifollitropin alfa with a GnRH-antagonist cycle.

PubMed

Haydardedeoğlu, Bülent; Kılıçdağ, Esra Bulgan

2016-01-01

Corifollitropin alfa is a good choice for assisted reproductive technology (ART) cycles because fewer injections are needed than with other agents. In this retrospective cohort, we analyzed luteal injected half-dose depot gonadotropin hormone-releasing hormone (GnRH) agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist. In this retrospective cohort, we analyzed luteal injected half-dose depot GnRH agonist cycles in women who received corifollitropin alfa and those who underwent a conventional corifollitropin alfa cycle with a GnRH antagonist at the Division of Reproductive Endocrinology and IVF Unit, Obstetrics and Gynecology Department, Başkent University School of Medicine, Adana, Turkey, from March 2014 to August 2015. The patient's baseline characteristics were similar between the two groups. Forty-five patients underwent the long protocol, in which a half-dose of depot GnRH agonist was administered on day 21 of the preceding cycle. Forty-nine patients underwent the GnRH-antagonist protocol. Corifollitropin alfa was administered on the menstrual cycle day 3. The mean ages of the two groups were similar (32.77±5.55 vs. 34.2±4.51 years ["for the long- and antagonist-protocol groups, respectively"]). The total number of retrieved oocytes, the fertilization rate, and the number of transferred embryos were similar between the two groups. The only significant difference between the two protocols was the number of injections during the controlled ovarian stimulation (COH) cycle, which included the depot-agonist injection in the long-protocol group (4.46±1.64 vs. 5.71±2.51, p=0.006). The clinical pregnancy and implantation rates were similar in the two protocols (16/45 [35.6%] vs. 16/49 [32.7%] for the intention to treat and 32.5±6.82% vs. 36.25±8.58%, respectively). Our results show that ART cycles could be performed with fewer injections using corifollitropin alfa and a half-dose of depot GnRH agonist.

Dual trigger of triptorelin and HCG optimizes clinical outcome for high ovarian responder in GnRH-antagonist protocols.

PubMed

Li, Saijiao; Zhou, Danni; Yin, Tailang; Xu, Wangming; Xie, Qingzhen; Cheng, Dan; Yang, Jing

2018-01-12

In this paper, a retrospective cohort study was conducted to the high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. The purpose of the study is to investigate whether dual triggering of final oocyte maturation with a combination of gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (HCG) can improve the clinical outcome compared with traditional dose (10000IU) HCG trigger and low-dose (8000IU) HCG trigger for high ovarian responders in GnRH-antagonist in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) cycles. Our study included 226 couples with high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. Standard dosage of HCG trigger (10000 IU of recombinant HCG) versus dual trigger (0.2 mg of triptorelin and 2000 IU of recombinant HCG) and low-dose HCG trigger (8000IU of recombinant HCG) were used for final oocyte maturation. Our main outcome measures were high quality embryo rate, the number of usable embryos, the risk of OHSS, duration of hospitalization and incidence rate of complications. Our evidence demonstrated that dual trigger is capable of preventing severe OHSS while still maintaining excellent high quality embryo rate in in high ovarian responders of GnRH-antagonist protocols.

Overview of elagolix for the treatment of endometriosis.

PubMed

Melis, Gian Benedetto; Neri, Manuela; Corda, Valentina; Malune, Maria Elena; Piras, Bruno; Pirarba, Silvia; Guerriero, Stefano; Orrù, Marisa; D'Alterio, Maurizio Nicola; Angioni, Stefano; Paoletti, Anna Maria

2016-05-01

Suppression of sex-steroid secretion is required in a variety of gynecological conditions. This can be achieved using gonadotropin releasing hormone (GnRH) agonists that bind pituitary gonadotropin receptors and antagonize the link-receptor of endogenous GnRH, inhibiting the mechanism of GnRH pulsatility. On the other hand, GnRH antagonists immediately reduce gonadal steroid levels, avoiding the initial stimulatory phase of the agonists. Potential benefits of GnRH antagonists over GnRH agonists include a rapid onset and reversibility of action. Older GnRH antagonists are synthetic peptides, obtained by modifications of certain amino acids in the native GnRH sequence. They require subcutaneous injections, implantation of long-acting depots. The peptide structure is responsible for histamine-related adverse events and the tendency to elicit hypersensitivity reactions. Research has worked towards the development of non-peptidic molecules exerting antagonist action on GnRH. They are available for oral administration and may have a more beneficial safety profile in comparison with peptide GnRH antagonists. This article focuses on the data of the literature about elagolix, a novel non-peptidic GnRHantagonist, in the treatment of endometriosis. Elagolix demonstrated efficacy in the management of endometriosis-associated pain and had an acceptable safety and tolerability profile. However, further studies are necessary to evaluate its non-inferiority in comparison with other endometriosis's treatments.

Environmental stress as a developmental cue: corticotropin-releasing hormone is a proximate mediator of adaptive phenotypic plasticity in amphibian metamorphosis.

PubMed

Denver, R J

1997-04-01

Environmentally induced phenotypic plasticity allows developing organisms to respond adaptively to changes in their habitat. Desert amphibians have evolved traits which allow successful development in unpredictable environments. Tadpoles of these species can accelerate metamorphosis as their pond dries, thus escaping mortality in the larval habitat. This developmental response can be replicated in the laboratory, which allows elucidation of the underlying physiological mechanisms. Here I demonstrate a link between a classical neurohormonal stress pathway (involving corticotropin-releasing hormone, CRH) and the developmental response to habitat desiccation. Injections of CRH-like peptides accelerated metamorphosis in western spadefoot toad tadpoles. Conversely, treatment with two CRH antagonists, the CRH receptor antagonist alpha-helical CRH(9-41) and anti-CRH serum, attenuated the developmental acceleration induced by habitat desiccation. Tadpoles subjected to habitat desiccation exhibited elevated hypothalamic CRH content at the time when they responded developmentally to the declining water level. CRH injections elevated whole-body thyroxine, triiodothyronine, and corticosterone content, the primary hormonal regulators of metamorphosis. In contrast, alpha-helical CRH(9-41) reduced thyroid activity. These results support a central role for CRH as a neurohormonal transducer of environmental stimuli into the endocrine response which modulates the rate of metamorphosis. Because in mammals, increased fetal/placental CRH production may initiate parturition, and CRH has been implicated in precipitating preterm birth arising from fetal stress, this neurohormonal pathway may represent a phylogenetically ancient developmental regulatory system that allows the organism to escape an unfavorable larval/fetal habitat.

Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice.

PubMed

Li, Yuesheng; Knapp, Joanne R; Kopchick, John J

2003-02-01

Growth hormone (GH) acts on adipose tissue by accelerating fat expenditure, preventing triglyceride accumulation, and facilitating lipid mobilization. To investigate whether GH is involved in the development and metabolism of interscapular brown adipose tissue (BAT), a site of nonshivering thermogenesis, we employed three lines of transgenic mice. Two of the lines are dwarf due to expression of a GH antagonist (GHA) or disruption of the GH receptor/binding-protein gene. A third mouse line is giant due to overexpression of a bovine GH (bGH) transgene. We have found that the body weights of those animals are proportional to their body lengths at 10 weeks of age. However, GHA dwarf mice tend to catch up with the nontransgenic (NT) littermates in body weight but not in body length at 52 weeks of age. The increase of body mass index (BMI) for GHA mice accelerates rapidly relative to controls as a function of age. We have also observed that BAT in both dwarf mouse lines but not in giant mice is enlarged in contrast to nontransgenic littermates. This enlargement occurs as a function of age. Northern analysis suggests that BAT can be a GH-responsive tissue because GHR/BP mRNAs were found there. Finally, the level of uncoupling protein-1 (UCP1) RNA was found to be higher in dwarf mice and lower in giant animals relative to controls, suggesting that GH-mediated signaling may negatively regulate UCP1 gene expression in BAT.

Lateral septum growth hormone secretagogue receptor affects food intake and motivation for sucrose reinforcement.

PubMed

Terrill, Sarah J; Wall, Kaylee D; Medina, Nelson D; Maske, Calyn B; Williams, Diana L

2018-03-28

The hormone ghrelin promotes eating and is widely considered to be a hunger signal. Ghrelin receptors, growth hormone secretagogue receptors (GHSRs), are found in a number of specific regions throughout the brain, including the lateral septum (LS), an area not traditionally associated with the control of feeding. Here we investigated whether GHSRs in the LS play a role in the control of food intake. We examined the feeding effects of ghrelin and the GHSR antagonists ([D-Lys3]-GHRP-6 and JMV 2959), at doses subthreshold for effect when delivered to the lateral ventricle. Intra-LS ghrelin significantly increased chow intake during the mid-light phase, suggesting that pharmacologic activation of LS GHSRs promotes feeding. Conversely, GHSR antagonist delivered to the LS shortly before dark onset significantly reduced chow intake. These data support the hypothesis that exogenous and endogenous stimulation of GHSRs in the LS influence feeding. Ghrelin is known to affect motivation for food, and the dorsal subdivision of LS (dLS) has been shown to play a role in motivation. Thus, we investigated the role of dLS GHSRs in motivation for food reward by examining operant responding for sucrose on a progressive ratio (PR) schedule. Intra-dLS ghrelin increased PR responding for sucrose, while blockade of LS GHSRs did not affect responding in either a fed or fasted state. Together these findings for the first time substantiate the LS as a site of action for ghrelin signaling in the control of food intake.

Ligand-based receptor tyrosine kinase partial agonists: New paradigm for cancer drug discovery?

PubMed

Riese, David J

2011-02-01

INTRODUCTION: Receptor tyrosine kinases (RTKs) are validated targets for oncology drug discovery and several RTK antagonists have been approved for the treatment of human malignancies. Nonetheless, the discovery and development of RTK antagonists has lagged behind the discovery and development of agents that target G-protein coupled receptors. In part, this is because it has been difficult to discover analogs of naturally-occurring RTK agonists that function as antagonists. AREAS COVERED: Here we describe ligands of ErbB receptors that function as partial agonists for these receptors, thereby enabling these ligands to antagonize the activity of full agonists for these receptors. We provide insights into the mechanisms by which these ligands function as antagonists. We discuss how information concerning these mechanisms can be translated into screens for novel small molecule- and antibody-based antagonists of ErbB receptors and how such antagonists hold great potential as targeted cancer chemotherapeutics. EXPERT OPINION: While there have been a number of important key findings into this field, the identification of the structural basis of ligand functional specificity is still of the greatest importance. While it is true that, with some notable exceptions, peptide hormones and growth factors have not proven to be good platforms for oncology drug discovery; addressing the fundamental issues of antagonistic partial agonists for receptor tyrosine kinases has the potential to steer oncology drug discovery in new directions. Mechanism based approaches are now emerging to enable the discovery of RTK partial agonists that may antagonize both agonist-dependent and -independent RTK signaling and may hold tremendous promise as targeted cancer chemotherapeutics.

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin-concentrating Hormone Receptor 1 Antagonist.

PubMed

Gennemark, P; Trägårdh, M; Lindén, D; Ploj, K; Johansson, A; Turnbull, A; Carlsson, B; Antonsson, M

2017-07-01

In this study, we present the translational modeling used in the discovery of AZD1979, a melanin-concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body-composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non-parametric input estimation (e.g., predicting energy intake from longitudinal body-weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose-prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Potential prostate cancer drug target: bioactivation of androstanediol by conversion to dihydrotestosterone.

PubMed

Mohler, James L; Titus, Mark A; Wilson, Elizabeth M

2011-09-15

High-affinity binding of dihydrotestosterone (DHT) to the androgen receptor (AR) initiates androgen-dependent gene activation, required for normal male sex development in utero, and contributes to prostate cancer development and progression in men. Under normal physiologic conditions, DHT is synthesized predominantly by 5α-reduction of testosterone, the major circulating androgen produced by the testis. During androgen deprivation therapy, intratumoral androgen production is sufficient for AR activation and prostate cancer growth, even though circulating testicular androgen levels are low. Recent studies indicate that the metabolism of 5α-androstane-3α, 17β-diol by 17β-hydroxysteroid dehydrogenase 6 in benign prostate and prostate cancer cells is a major biosynthetic pathway for intratumoral synthesis of DHT, which binds AR and initiates transactivation to promote prostate cancer growth during androgen deprivation therapy. Drugs that target the so-called backdoor pathway of DHT synthesis provide an opportunity to enhance clinical response to luteinizing-hormone-releasing hormone (LHRH) agonists or antagonists, AR antagonists, and inhibitors of 5α-reductase enzymes (finasteride or dutasteride), and other steroid metabolism enzyme inhibitors (ketoconazole or the recently available abiraterone acetate). ©2011 AACR.

Luteinizing hormone-releasing hormone (LHRH) and its analogs for contraception in women: a review.

PubMed

Thau, R B

1984-02-01

In animals, LHRH agonists have multiple sites of action including the pituitary, the gonads, and the reproductive tract. In humans, the major antifertility action of this class of peptides is believed to be mediated via the pituitary. Studies in women have indicated that potent LHRH agonists can block ovulation when administered once daily. In the volunteers who have used these agents no serious side effects were observed, although some women experienced irregular bleeding or amenorrhea. It is anticipated that formal clinical trials could be conducted in the near future to determine the efficacy of continuous LHRH agonist administration. Early attempts to use an LHRH agonist to produce luteal insufficiency, luteolysis, or interruption of pregnancy have either been unsuccessful or the results are still too preliminary to ascertain whether these approaches warrant further trials. LHRH antagonists are believed to act by inhibiting the action of LHRH on the pituitary. Although some of these peptides are known to be active in women, very large doses have been required. Recently several investigators have produced LHRH antagonists with increased potency. In the near future, it should be possible to determine whether these peptides should be considered as potential contraceptives in men or in women.

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer

PubMed Central

Singhal, Hari; Greene, Marianne E.; Tarulli, Gerard; Zarnke, Allison L.; Bourgo, Ryan J.; Laine, Muriel; Chang, Ya-Fang; Ma, Shihong; Dembo, Anna G.; Raj, Ganesh V.; Hickey, Theresa E.; Tilley, Wayne D.; Greene, Geoffrey L.

2016-01-01

The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored. PMID:27386569

Comparison of luteal estradiol patch and gonadotropin-releasing hormone antagonist suppression protocol before gonadotropin stimulation versus microdose gonadotropin-releasing hormone agonist protocol for patients with a history of poor in vitro fertilization outcomes.

PubMed

Weitzman, Vanessa N; Engmann, Lawrence; DiLuigi, Andrea; Maier, Donald; Nulsen, John; Benadiva, Claudio

2009-07-01

To compare IVF outcomes in poor-responder patients undergoing stimulation after luteal phase E(2) patch/GnRH antagonist (LPG) protocol versus microdose GnRH agonist protocol. Retrospective analysis. University-based IVF center. Forty-five women undergoing ovarian stimulation for IVF using the LPG protocol were compared with 76 women stimulated with the microdose GnRH agonist protocol from May 2005 to April 2006. Cancellation rate, number of oocytes retrieved, and clinical pregnancy rates. The mean number of oocytes (9.1 +/- 4.1 vs. 8.9 +/- 4.3) and mature oocytes (6.7 +/- 3.5 vs. 6.8 +/- 3.1) retrieved were similar, as were the fertilization rates (70.0% +/- 24.2% vs. 69.9% +/- 21.5%) and the number of embryos transferred (2.5 +/- 1.1 vs. 2.7 +/- 1.3). The cancellation rate was not significantly different between the groups (13/45, 28.9% vs. 23/76, 30.3%). Likewise, there were no significant differences among the implantation rate (15.0% vs. 12.5%), clinical pregnancy rate (43.3% vs. 45.1%), and ongoing pregnancy rate per transfer (33.3% vs. 26.0%) between both groups. This study demonstrates that the use of an E(2) patch and a GnRH antagonist during the preceding luteal phase in patients with a history of failed cycles can provide similar IVF outcomes when compared with the microdose GnRH agonist protocol.

The evolutionary origin and significance of Menopause

PubMed Central

Pollycove, Ricki; Naftolin, Frederick; Simon, James A.

2010-01-01

Contemporary human females have long life expectancy (81y US), especially relative to age at menopause (51y US). Menopause is a consequence of reproductive aging and follicular depletion (ovarian failure), yielding very low circulating estrogen* serum concentrations and biologically disadvantageous metabolic alterations. Stated in terms of antagonistic pleiotropy, the ongoing hypoestrogenic endocrine environment, beneficial during lactation, results in acceleration of several age-related health conditions following menopause (i.e. late postmenopausal osteoporosis, cardiovascular disease and cognitive decline). In contrast, the complex hypoestrogenic hormonal milieu present during postpartum lactation provides biologic advantages to both mother and newborn. The lactational hormonal milieu causes symptoms similar to those of the late perimenopause and early postmenopause, prompting theories for their biologic selective advantage. The precepts of evolutionary medicine encourage a reassessment of hormone therapy. Based on data presented, the authors propose additional opportunities for disease prevention and morbidity reduction in postmenopausal women. PMID:21252729

Effects of growth hormone over-expression on reproduction in the common carp Cyprinus carpio L.

PubMed

Cao, Mengxi; Chen, Ji; Peng, Wei; Wang, Yaping; Liao, Lanjie; Li, Yongming; Trudeau, Vance L; Zhu, Zuoyan; Hu, Wei

2014-01-01

To study the complex interaction between growth and reproduction we have established lines of transgenic common carp (Cyprinus carpio) carrying a grass carp (Ctenopharyngodon idellus) growth hormone (GH) transgene. The GH-transgenic fish showed delayed gonadal development compared with non-transgenic common carp. To gain a better understanding of the phenomenon, we studied body growth, gonad development, changes of reproduction related genes and hormones of GH-transgenic common carp for 2years. Over-expression of GH elevated peripheral gh transcription, serum GH levels, and inhibited endogenous GH expression in the pituitary. Hormone analyses indicated that GH-transgenic common carp had reduced pituitary and serum level of luteinizing hormone (LH). Among the tested genes, pituitary lhβ was inhibited in GH-transgenic fish. Further analyses in vitro showed that GH inhibited lhβ expression. Localization of ghr with LH indicates the possibility of direct regulation of GH on gonadotrophs. We also found that GH-transgenic common carp had reduced pituitary sensitivity to stimulation by co-treatments with a salmon gonadotropin-releasing hormone (GnRH) agonist and a dopamine antagonist. Together these results suggest that the main cause of delayed reproductive development in GH transgenic common carp is reduced LH production and release. Copyright © 2013 Elsevier Inc. All rights reserved.

Octopamine partially restores walking in hypokinetic cockroaches stung by the parasitoid wasp Ampulex compressa.

PubMed

Rosenberg, Lior Ann; Glusman, Jose Gustavo; Libersat, Frederic

2007-12-01

When stung by the parasitoid wasp Ampulex compressa, cockroaches Periplaneta americana enter a hypokinetic state that is characterized by little, if any, spontaneous locomotor activity. In the present study we investigate the effect of an octopamine receptor agonist and an antagonist on the locomotor behavior of stung and control cockroaches. We show that in cockroaches stung by a wasp the octopamine receptor agonist chlordimeform induces a significant increase in spontaneous walking. In good agreement, in control individuals an octopamine receptor antagonist significantly reduces walking activity. Adipokinetic hormone I (AKH-I) promotes spontaneous walking in controls but does not do so in stung individuals, which suggests that the venom effect is most probably not mediated by AKH-I. Dopamine receptor agonists or antagonists had no significant effect on the spontaneous walking of stung or control cockroaches, respectively. The effect of the octopamine receptor agonist was maximal when injected into the brain, suggesting that the wasp venom interferes with octopaminergic modulation of walking initiation in central structures of the cockroach brain.

Convergent Pathways for Steroid Hormone-and Neurotransmitter-Induced Rat Sexual Behavior

NASA Astrophysics Data System (ADS)

Mani, S. K.; Allen, J. M. C.; Clark, J. H.; Blaustein, J. D.; O'Malley, B. W.

1994-08-01

Estrogen and progesterone modulate gene expression in rodents by activation of intracellular receptors in the hypothalamus, which regulate neuronal networks that control female sexual behavior. However, the neurotransmitter dopamine has been shown to activate certain steroid receptors in a ligand-independent manner. A dopamine receptor stimulant and a D_1 receptor agonist, but not a D_2 receptor agonist, mimicked the effects of progesterone in facilitating sexual behavior in female rats. The facilitatory effect of the neurotransmitter was blocked by progesterone receptor antagonists, a D_1 receptor antagonist, or antisense oligonucleotides to the progesterone receptor. The results suggest that in rodents neurotransmitters may regulate in vivo gene expression and behavior by means of cross-talk with steroid receptors in the brain.

Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model.

PubMed

Kai, Zhen-Peng; Zhu, Jing-Jing; Deng, Xi-Le; Yang, Xin-Ling; Chen, Shan-Shan

2018-04-03

Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C -terminal amidated octapeptide Manse-AT (6-13). We identified three residues essential for bioactivity (Thr⁴, Arg6 and Phe⁸) by assaying alanine-replacement analogs of Manse-AT (6-13). Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse-ATR) was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10-13), we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10-13) validated our hypothesis. The IC 50 value of antagonist Manse-AT (10-13) is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10-13) was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents.

Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions

PubMed Central

Kleinberg, David L.; Wood, Teresa L.; Furth, Priscilla A.; Lee, Adrian V.

2009-01-01

Adult female mammary development starts at puberty and is controlled by tightly regulated cross-talk between a group of hormones and growth factors. Although estrogen is the initial driving force and is joined by luteal phase progesterone, both of these hormones require GH-induced IGF-I in the mammary gland in order to act. The same group of hormones, when experimentally perturbed, can lead to development of hyperplastic lesions and increase the chances, or be precursors, of mammary carcinoma. For example, systemic administration of GH or IGF-I causes mammary hyperplasia, and overproduction of IGF-I in transgenic animals can cause the development of usual or atypical hyperplasias and sometimes carcinoma. Although studies have clearly demonstrated the transforming potential of both GH and IGF-I receptor in cell culture and in animals, debate remains as to whether their main role is actually instructive or permissive in progression to cancer in vivo. Genetic imprinting has been shown to occur in precursor lesions as early as atypical hyperplasia in women. Thus, the concept of progression from normal development to cancer through precursor lesions sensitive to hormones and growth factors discussed above is gaining support in humans as well as in animal models. Indeed, elevation of estrogen receptor, GH, IGF-I, and IGF-I receptor during progression suggests a role for these pathways in this process. New agents targeting the GH/IGF-I axis may provide a novel means to block formation and progression of precursor lesions to overt carcinoma. A novel somatostatin analog has recently been shown to prevent mammary development in rats via targeted IGF-I action inhibition at the mammary gland. Similarly, pegvisomant, a GH antagonist, and other IGF-I antagonists such as IGF binding proteins 1 and 5 also block mammary gland development. It is, therefore, possible that inhibition of IGF-I action, or perhaps GH, in the mammary gland may eventually play a role in breast cancer chemoprevention by preventing actions of both estrogen and progesterone, especially in women at extremely high risk for developing breast cancer such as BRCA gene 1 or 2 mutations. PMID:19075184

Hormone suppression with GnRH antagonist promotes spermatogenic recovery from transplanted spermatogonial stem cells in irradiated cynomolgus monkeys.

PubMed

Shetty, G; Uthamanthil, R K; Zhou, W; Shao, S H; Weng, C C; Tailor, R C; Hermann, B P; Orwig, K E; Meistrich, M L

2013-11-01

Hormone suppression given before or after cytotoxic treatment stimulates the recovery of spermatogenesis from endogenous and transplanted spermatogonial stem cells (SSC) and restores fertility in rodents. To test whether the combination of hormone suppression and transplantation could enhance the recovery of spermatogenesis in primates, we irradiated (7 Gy) the testes of 12 adult cynomolgus monkeys and treated six of them with gonadotropin-releasing hormone antagonist (GnRH-ant) for 8 weeks. At the end of this treatment, we transfected cryopreserved testicular cells with green fluorescent protein-lentivirus and autologously transplanted them back into one of the testes. The only significant effect of GnRH-ant treatment on endogenous spermatogenesis was an increase in the percentage of tubules containing differentiated germ cells (tubule differentiation index; TDI) in the sham-transplanted testes of GnRH-ant-treated monkeys compared with radiation-only monkeys at 24 weeks after irradiation. Although transplantation alone after irradiation did not significantly increase the TDI, detection of lentiviral DNA in the spermatozoa of one radiation-only monkey indicated that some transplanted cells colonized the testis. However, the combination of transplantation and GnRH-ant clearly stimulated spermatogenic recovery as evidenced by several observations in the GnRH-ant-treated monkeys receiving transplantation: (i) significant increases (~20%) in the volume and weight of the testes compared with the contralateral sham-transplanted testes and/or to the transplanted testes of the radiation-only monkeys; (ii) increases in TDI compared to the transplanted testes of radiation-only monkeys at 24 weeks (9.6% vs. 2.9%; p = 0.05) and 44 weeks (16.5% vs. 6.1%, p = 0.055); (iii) detection of lentiviral sequences in the spermatozoa or testes of five of the GnRH-ant-treated monkeys and (iv) significantly higher sperm counts than in the radiation-only monkeys. Thus hormone suppression enhances spermatogenic recovery from transplanted SSC in primates and may be a useful tool in conjunction with spermatogonial transplantation to restore fertility in men after cancer treatment. © 2013 American Society of Andrology and European Academy of Andrology.

Hypothalamic regulation of body growth and appetite by ghrelin-derived peptides during balanced nutrition or undernutrition.

PubMed

Hassouna, Rim; Labarthe, Alexandra; Tolle, Virginie

2016-12-15

Among the gastrointestinal hormones that regulate food intake and energy homeostasis, ghrelin plays a unique role as the first one identified to increases appetite and stimulate GH secretion. This review highlights the latest mechanism by which ghrelin modulates body growth, appetite and energy metabolism by exploring pharmacological actions of the hormone and consequences of genetic or pharmacological blockade of the ghrelin/GHS-R (Growth Hormone Secretagogue Receptor) system on physiological responses in specific nutritional situations. Within the hypothalamus, novel mechanisms of action of this hormone involve its interaction with other ghrelin-derived peptides, such as desacyl ghrelin and obestatin, which are thought to act as functional ghrelin antagonists, and possible modulation of the GHS-R with other G-protein coupled receptors. During chronic undernutrition such as anorexia nervosa, variations of ghrelin-derived peptides may be an adaptative metabolic response to maintain normal glycemic control. Interestingly, some of ghrelin's metabolic actions are thought to be relayed through modulation of GH, an anabolic and hyperglycemic agent. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Conifer Diterpene Resin Acids Disrupt Juvenile Hormone-Mediated Endocrine Regulation in the Indian Meal Moth Plodia interpunctella.

PubMed

Oh, Hyun-Woo; Yun, Chan-Seok; Jeon, Jun Hyoung; Kim, Ji-Ae; Park, Doo-Sang; Ryu, Hyung Won; Oh, Sei-Ryang; Song, Hyuk-Hwan; Shin, Yunhee; Jung, Chan Sik; Shin, Sang Woon

2017-07-01

Diterpene resin acids (DRAs) are important components of oleoresin and greatly contribute to the defense strategies of conifers against herbivorous insects. In the present study, we determined that DRAs function as insect juvenile hormone (JH) antagonists that interfere with the juvenile hormone-mediated binding of the JH receptor Methoprene-tolerant (Met) and steroid receptor coactivator (SRC). Using a yeast two-hybrid system transformed with Met and SRC from the Indian meal moth Plodia interpunctella, we tested the interfering activity of 3704 plant extracts against JH III-mediated Met-SRC binding. Plant extracts from conifers, especially members of the Pinaceae, exhibited strong interfering activity, and four active interfering DRAs (7α-dehydroabietic acid, 7-oxodehydroabietic acid, dehydroabietic acid, and sandaracopimaric acid) were isolated from roots of the Japanese pine Pinus densiflora. The four isolated DRAs, along with abietic acid, disrupted the juvenile hormone-mediated binding of P. interpunctella Met and SRC, although only 7-oxodehydroabietic acid disrupted larval development. These results demonstrate that DRAs may play a defensive role against herbivorous insects via insect endocrine-disrupting activity.

Effects of long-term treatment with the luteinizing hormone-releasing hormone (LHRH) agonist Decapeptyl and the LHRH antagonist Cetrorelix on the levels of pituitary LHRH receptors and their mRNA expression in rats

PubMed Central

Horvath, Judit E.; Bajo, Ana M.; Schally, Andrew V.; Kovacs, Magdolna; Herbert, Francine; Groot, Kate

2002-01-01

The effects of depot formulations of the luteinizing hormone-releasing hormone (LHRH) agonist Decapeptyl (25 μg/day) for 30 days or LHRH antagonist Cetrorelix pamoate (100 μg/day) for 30 days and daily injections of 100 μg of Decapeptyl for 10 days on the expression of mRNA for pituitary LHRH receptor (LHRH-R) and the levels of LHRH-R protein were evaluated in rats. Serum sex steroid concentrations and the weights of the reproductive organs were greatly reduced in all groups treated with analogs, demonstrating an efficient blockade of the pituitary–gonadal axis. Decapeptyl microcapsules elevated serum LH in female rats, but decreased it in male rats. LHRH-R mRNA expression in female pituitaries was reduced to 41% and 56–65% on days 10 and 30, respectively, whereas LHRH-R protein was 64% of control on day 10 and returned to pretreatment levels on day 30. Decapeptyl microcapsules reduced LHRH-R mRNA expression in male pituitaries to 58% on day 30 but not LHRH-R protein. Daily injections of Decapeptyl caused a desensitization of LH responses in female rats, while raising LHRH-R mRNA expression in female rats by 23% and LHRH-R protein levels by 119%. Cetrorelix pamoate reduced serum LH in female rats and diminished LHRH-R mRNA to 30% and 26% and LHRH-R protein to 57% and 48% on days 10 and 30, respectively. Elevated LHRH-R protein levels of ovariectomized rats were reduced after 10-day treatment with Cetrorelix or 100 μg/day Decapeptyl. Thus, changes in the mRNA expression after treatment with Cetrorelix, but not always Decapeptyl, paralleled those of LHRH-R protein. The inhibitory effect of Cetrorelix on serum LH, pituitary LHRH-R mRNA, and LHRH-R protein was greater than that of Decapeptyl. PMID:12409615

Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

PubMed

Lowe, Jeovanna; Floyd, Kyle T; Rastogi, Neha; Schultz, Eric J; Chadwick, Jessica A; Swager, Sarah A; Zins, Jonathan G; Kadakia, Feni K; Smart, Suzanne; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E; Raman, Subha V; Janssen, Paul M L; Rafael-Fortney, Jill A

2016-01-01

Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

Vasopressin and a nonpeptide antidiuretic hormone receptor antagonist (OPC-31260).

PubMed

Burrell, L M; Phillips, P A; Stephenson, J M; Risvanis, J; Johnston, C I

1994-03-01

The development of nonpeptide orally active AVP analogues has provided a new tool with which to assess the physiological and pathophysiological role of vasopressin (AVP). We have previously characterised the nonpeptide vasopressin V1 receptor antagonist OPC-21268, and now report the in vitro characterisation of the nonpeptide V2 receptor antagonist OPC-31260 in the rat. OPC-31260 caused a concentration-dependent displacement of the selective AVP V2 receptor antagonist radioligand, [3H]desGly-NH2(9)[d(CH2)5, D-Ile2,Ile4]AVP from V2 receptors in rat kidney medulla membranes. The concentration of OPC-31260 that displaced 50% of specific AVP binding (IC50) was 20 +/- 2 nmol/l for renal V2 receptors. OPC-31260 also caused a concentration-dependent displacement of the selective AVP V1 receptor antagonist radioligand, [125I]-[d(CH2)5,sarcosine7]AVP from V1 receptors in both rat liver and kidney medulla membranes. The IC50 was 500 +/- 30 nmol/l for both renal and liver V1 receptors. After oral administration to rats, OPC-31260 was an effective inhibitor of AVP at renal V2 and liver V1 receptors in a time-dependent manner. In vitro binding kinetic studies showed that OPC-31260 was a competitive antagonist at both the renal V2 receptor and the hepatic V1 receptor. OPC-31260 is a nonpeptide, orally effective competitive inhibitor of AVP with a V2:V1 receptor selectivity ratio of 25:1 indicating relative V2 receptor selectivity.

Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB-649868, and alprazolam following insulin-induced hypoglycemia in humans.

PubMed

Patel, Ameera X; Miller, Sam R; Nathan, Pradeep J; Kanakaraj, Ponmani; Napolitano, Antonella; Lawrence, Philip; Koch, Annelize; Bullmore, Edward T

2014-10-01

The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress. Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans. Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p < 0.003), the peak electromyography (p < 0.0001) and galvanic skin response (GSR, p = 0.04) to acoustic startle, the resting GSR (p = 0.01), and increased appetite following ITT (p < 0.0005). SB-649868 pre-treatment produced no significant results. We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity.

Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination.

PubMed

Ren, Xiao-Min; Guo, Liang-Hong; Gao, Yu; Zhang, Bin-Tian; Wan, Bin

2013-05-01

Polybrominated diphenyl ethers (PBDEs) have been shown to disrupt thyroid hormone (TH) functions in experimental animals, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to TH receptors (TRs). However, previous data on TH receptor binding and TH activity of OH-PBDEs were very limited and sometimes inconsistent. In the present paper, we examined the binding potency of ten OH-PBDEs with different degrees of bromination to TR using a fluorescence competitive binding assay. The results showed that the ten OH-PBDEs bound to TR with potency that correlated to their bromination level. We further examined their effect on TR using a coactivator binding assay and GH3 cell proliferation assay. Different TR activities of OH-PBDEs were observed depending on their degree of bromination. Four low-brominated OH-PBDEs (2'-OH-BDE-28, 3'-OH-BDE-28, 5-OH-BDE-47, 6-OH-BDE-47) were found to be TR agonists, which recruited the coactivator peptide and enhanced GH3 cell proliferation. However, three high-brominated OH-PBDEs (3-OH-BDE-100, 3'-OH-BDE-154, 4-OH-BDE-188) were tested to be antagonists. Molecular docking was employed to simulate the interactions of OH-PBDEs with TR and identify the structural determinants for TR binding and activity. According to the docking results, low-brominated OH-PBDEs, which are weak binders but TR agonists, bind with TR at the inner side of its binding pocket, whereas high-brominated compounds, which are potent binders but TR antagonists, reside at the outer region. These results indicate that OH-PBDEs have different activities on TR (agonistic or antagonistic), possibly due to their different binding geometries with the receptor. Copyright © 2013 Elsevier Inc. All rights reserved.

Peptide YY3–36 and 5-Hydroxytryptamine Mediate Emesis Induction by Trichothecene Deoxynivalenol (Vomitoxin)

PubMed Central

Pestka, James J.

2013-01-01

Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3–36 (PYY3–36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15–30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3–36 (30–60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON’s emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3–36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3–36 and 5-HT play contributory roles in DON-induced emesis. PMID:23457120

Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix

PubMed Central

Struthers, R. Scott; Nicholls, Andrew J.; Grundy, John; Chen, Takung; Jimenez, Roland; Yen, Samuel S. C.; Bozigian, Haig P.

2009-01-01

Context: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. Objective: Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. Design: This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. Participants: Fifty-five healthy, regularly cycling premenopausal women participated. Interventions: Subjects were administered a single oral dose of 25–400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (±1) after onset of menses. Main Outcome Measures: Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. Results: Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50–200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 ± 3 to 68 ± 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. Conclusions: Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states. PMID:19033369

Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix.

PubMed

Struthers, R Scott; Nicholls, Andrew J; Grundy, John; Chen, Takung; Jimenez, Roland; Yen, Samuel S C; Bozigian, Haig P

2009-02-01

Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. Fifty-five healthy, regularly cycling premenopausal women participated. Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses. Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.

Copernicus Revisited: Overturning Ptolemy's View of the GPER Universe.

PubMed

Feldman, Ross D; Limbird, Lee E

2015-11-01

Whether aldosterone activates the G-protein-coupled estrogen receptor (GPER) has been questioned, recently, in the name of Copernicus. However, for G-protein-coupled receptors (GPCRs) multiple hormone activators are common. Further, studies in mineralocorticoid receptor (MR)-deficient systems, with pharmacological GPER-selective antagonists or regulation of GPER expression, consistently show that some aldosterone effects can be GPER mediated. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ghrelin receptor regulates adipose tissue inflammation in aging.

PubMed

Lin, Ligen; Lee, Jong Han; Buras, Eric D; Yu, Kaijiang; Wang, Ruitao; Smith, C Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

2016-01-01

Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands.

PubMed

Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Haskell-Luevano, Carrie

2017-01-26

The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.

Ghrelin receptor regulates adipose tissue inflammation in aging

PubMed Central

Buras, Eric D.; Yu, Kaijiang; Wang, Ruitao; Smith, C. Wayne; Wu, Huaizhu; Sheikh-Hamad, David; Sun, Yuxiang

2016-01-01

Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr−/− mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsr−/− mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsr−/− mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance. PMID:26837433

Energy conservation in stressed rats exposed to an oxytocin-injected cage mate.

PubMed

Agren, Greta; Lundeberg, Thomas

2002-08-07

In previous studies we found indications of stress reduction in saline-injected rats when exposed to an oxytocin (OT)-injected cage mate. Olfactory impairment and OT antagonist treatment abolished the effects. This suggested an olfactorily mediated oxytocinergic stress-inhibitory mechanism. To test this hypothesis bodyweight, tail skin temperatures, food-intake and plasma ACTH and corticosterone concentrations were analysed. Suppressed weight loss and decreased stress-hormone release was found in saline-injected rats exposed to an OT-injected cage mate, but not in OT antagonist-injected rats, supporting the hypothesis. Our results suggest that OT in a stressed animal can inhibit the olfactory stress cues emitted, and that the olfactory cues from the stressed animal can influence an OT in pathway in the odour recipient animals to reduce stress effects.

Live Birth after Rescue In vitro Maturation-intracytoplasmic Sperm Injection in Type 1 Diabetes, Polycystic Ovary Syndrome Patient Using Clomiphene-antagonist Protocol.

PubMed

Sankari, Samundi; Elanchezhian, M; Selvamani, Divya; Nagarajan, M; Gopikrishnan, D

2018-01-01

Infertility in patients with polycystic ovary syndrome (PCOS) associated with diabetes leads to challenging situations seeking alternative treatments. In vitro maturation (IVM) followed by intracytoplasmic sperm injection (ICSI) could overcome the challenges with promising pregnancies in such patients. In the treatment of a 32-year-old diabetic woman who also had PCOS, single immature oocyte was retrieved. Rescue IVM followed by ICSI yielded a grade 1 day 3 embryo which on transferring resulted in pregnancy and a healthy infant was delivered. Rescue IVM-ICSI could help in achieving pregnancy and live birth. Stimulation involving clomiphene and gonadotropin-releasing hormone antagonist is an effective and patient-friendly protocol for women with PCOS and diabetes and also for poor responders.

Cushing's syndrome: epidemiology and developments in disease management.

PubMed

Sharma, Susmeeta T; Nieman, Lynnette K; Feelders, Richard A

2015-01-01

Cushing's syndrome is a rare disorder resulting from prolonged exposure to excess glucocorticoids. Early diagnosis and treatment of Cushing's syndrome is associated with a decrease in morbidity and mortality. Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult. Surgery (resection of the pituitary or ectopic source of adrenocorticotropic hormone, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of Cushing's syndrome, but may not always lead to remission. Medical therapy (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for optimal control of hypercortisolemia and management of comorbidities.

Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women.

PubMed

Ng, Juki; Chwalisz, Kristof; Carter, David C; Klein, Cheri E

2017-05-01

Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women. Copyright © 2017 Endocrine Society

Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23.

PubMed

Velazquez, Hector A; Riccardi, Demian; Xiao, Zhousheng; Quarles, Leigh Darryl; Yates, Charless Ryan; Baudry, Jerome; Smith, Jeremy C

2018-02-01

Ensemble docking is now commonly used in early-stage in silico drug discovery and can be used to attack difficult problems such as finding lead compounds which can disrupt protein-protein interactions. We give an example of this methodology here, as applied to fibroblast growth factor 23 (FGF23), a protein hormone that is responsible for regulating phosphate homeostasis. The first small-molecule antagonists of FGF23 were recently discovered by combining ensemble docking with extensive experimental target validation data (Science Signaling, 9, 2016, ra113). Here, we provide a detailed account of how ensemble-based high-throughput virtual screening was used to identify the antagonist compounds discovered in reference (Science Signaling, 9, 2016, ra113). Moreover, we perform further calculations, redocking those antagonist compounds identified in reference (Science Signaling, 9, 2016, ra113) that performed well on drug-likeness filters, to predict possible binding regions. These predicted binding modes are rescored with the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) approach to calculate the most likely binding site. Our findings suggest that the antagonist compounds antagonize FGF23 through the disruption of protein-protein interactions between FGF23 and fibroblast growth factor receptor (FGFR). © 2017 John Wiley & Sons A/S.

Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI.

PubMed

Mohsen, Iman Abdel; El Din, Rasha Ezz

2013-02-01

To compare the IVF outcomes of letrozole/antagonist and microdose GnRH agonist flare up protocols in poor ovarian responders undergoing intracytoplasmic sperm injection. A randomized controlled trial was performed in patients with one or more previous failed IVF cycles in which four or less oocytes were retrieved when the gonadotrophin starting dose was at least 300 IU/day. Sixty patients were randomized by computer-generated list to receive either letrozole/antagonist (mild stimulation) n = 30 or GnRH-a protocol (microdose flare) n = 30. Both groups were similar with respect to background and hormonal characteristics (age, duration of infertility, BMI, FSH, LH and E2). The clinical pregnancy rate per cycle was similar in both groups (13.3 vs. 16.6%; OR = 0.769; 95% CI = 0.185, 3.198). The doses of used gonadotropins and the number of stimulation days were significantly lower in the letrozole/antagonist protocol. The peak E2 level on the day of hCG, the endometrial thickness, the retrieved oocytes, the number of fertilized oocytes, the number of transferred embryos and the cancellation rate were statistically similar in both groups. The letrozole/antagonist protocol is a cost-effective and patient-friendly protocol that may be used in poor ovarian responders for IVF/ICSI.

Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure.

PubMed

Barnes, Brian J; Howard, Patricia A

2005-01-01

To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

(D-Phe/sup 12/)bombesin analogues: a new class of bombesin receptor antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heinz-Erian, P.; Coy, D.H.; Tamura, M.

1987-03-01

Previous attempts to develop analogues of bombesin that function as specific receptor antagonists have been unsuccessful. Alteration of the histidine in luteinizing hormone releasing factor has resulted in analogues that function as competitive antagonists. In the present study the authors have used a similar strategy and altered the histidine in bombesin. (D-Phe/sup 12/)bombesin, (D-Phe/sup 12/,Leu/sup 14/)bombesin, and (Try/sup 4/, D-)je/sup 12/) bombesin did not stimulate amylase release from guinea pig pancreatic acini when present alone, but each analog inhibited bombesin-stimulated secretion. For each analog, detectable inhibition occurred at 1 ..mu..M and half-maximal inhibition at 4 ..mu..M. Each analog inhibited amylasemore » release by bombesin and other agonists that stimulate secretion by interacting with bombesin receptors. The analogues of bombesin did not alter stimulation by substance P or other agonists that interact with other receptors. The inhibition of the action of bombesin was competitive with Schild plots having slopes of 1.0. Each analog also inhibited binding of /sup 125/I-labeled (Try/sup 4/) bombesin but not /sup 125/I-labeled substance P. These results demonstrate that (D-Phe/sup 12/) analogues of bombesin function as bombesin receptor antagonists and are the only bombesin receptor antagonists that interact only with the bombesin receptor. Because of their specificity, these analogues may prove useful for defining the role of bombesin in various physiological or pathological processes.« less

Crosstalk among Jasmonate, Salicylate and Ethylene Signaling Pathways in Plant Disease and Immune Responses.

PubMed

Yang, You-Xin; Ahammed, Golam J; Wu, Caijun; Fan, Shu-ying; Zhou, Yan-Hong

2015-01-01

Phytohormone crosstalk is crucial for plant defenses against pathogens and insects in which salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) play key roles. These low molecular mass signals critically trigger and modulate plant resistance against biotrophic as well as necrotrophic pathogens through a complex signaling network that even involves participation of other hormones. Crosstalk among SA, JA and ET is mediated by different molecular players, considered as integral part of these crosscommunicating signal transduction pathways. Recent progress has revealed that the positive versus negative interactions among those pathways ultimately enable a plant to fine-tune its defense against specific aggressors. On the other hand, pathogens have evolved strategies to manipulate the signaling network to their favour in order to intensify virulence on host plant. Here we review recent advances and current knowledge on the role of classical primary defense hormones SA, JA and ET as well as their synergistic and antagonistic interaction in plant disease and immune responses. Crosstalk with other hormones such as abscisic acid, auxin, brassinosteroids, cytokinins and melatonin is also discussed mainly in plant disease resistance. In addition to our keen focus on hormonal crosstalk, this review also highlights potential implication of positive and negative regulatory interactions for developing an efficient disease management strategy through manipulation of hormone signaling in plant.

Modification of hormonal secretion in clinically silent pituitary adenomas.

PubMed

Daems, Tania; Verhelst, Johan; Michotte, Alex; Abrams, Pascale; De Ridder, Dirk; Abs, Roger

2009-01-01

Silent pituitary adenomas are a subtype of adenomas characterized by positive immunoreactivity for one or more hormones classically secreted by normal pituitary cells but without clinical expression, although in some occasions enhanced or changed secretory activity can develop over time. Silent corticotroph adenomas are the classical example of this phenomenon. A series of about 500 pituitary adenomas seen over a period of 20 years were screened for modification in hormonal secretion. Biochemical and immunohistochemical data were reviewed. Two cases were retrieved, one silent somatotroph adenoma and one thyrotroph adenoma, both without specific clinical features or biochemical abnormalities, which presented 20 years after initial surgery with evidence of acromegaly and hyperthyroidism, respectively. While the acromegaly was controlled by a combination of somatostatin analogs and growth hormone (GH) receptor antagonist therapy, neurosurgery was necessary to manage the thyrotroph adenoma. Immunohistochemical examination demonstrated an increase in the number of thyroid stimulating hormone (TSH)-immunoreactive cells compared to the first tissue. Apparently, the mechanisms responsible for the secretory modifications are different, being a change in secretory capacity in the silent somatotroph adenoma and a quantitative change in the silent thyrotroph adenoma. These two cases, one somatotroph and one thyrotroph adenoma, are an illustration that clinically silent pituitary adenomas may in rare circumstances evolve over time and become active, as previously demonstrated in silent corticotroph adenomas.

Effects of cetrorelix, a GnRH-receptor antagonist, on gonadal axis in women with functional hypothalamic amenorrhea.

PubMed

Berardelli, Rita; Gianotti, Laura; Karamouzis, Ioannis; Picu, Andreea; Giordano, Roberta; D'Angelo, Valentina; Zinnà, Domenico; Lanfranco, Fabio; Ghigo, Ezio; Arvat, Emanuela

2011-10-01

Gonadotropin Releasing Hormone (GnRH) antagonists (GnRHa) suppress gonadotropin and sex-steroid secretion. In normal women, acute GnRHa administration induces inhibitory effect on pituitary-gonadal axis, followed by Luteinizing Hormone (LH) rebound. Functional hypothalamic amenorrhea (HA) is characterised by impaired gonadotropin secretion and hypogonadism secondary to blunted GnRH pulsatility. We studied the effects of a GnRHa, cetrorelix (CTX 3.0 mg), in six women with HA (age 30.7 ± 3.2 years; BMI 21.5 ± 1.7 kg/m(2)) and six control subjects (CS, 28.2 ± 0.6 years; 22.6 ± 0.9 kg/m(2)) on LH, Follicle-Stimulating Hormone (FSH) and oestradiol levels over 4 h (08.00-12.00 am) before, +24 h and +96 h after CTX; LH, FSH, and oestradiol were also evaluated at +6, +8, +12, +48, +72 h after CTX. CS: CTX reduced (p < 0.05) LH, FSH, and oestradiol (nadir at +12 h, +24 h, and +24 h); LH rebounded at +96 h, FSH and oestradiol recovered at +48 h and +72 h. The 4-h evaluation showed LH and FSH reduction (p < 0.05) at +24 h, with LH rebound at +96 h. HA: CTX reduced (p < 0.05) LH, FSH, and oestradiol, (nadir at +24 h, +48 h, and +48 h, recovery at +48 h, +72 h, and +96 h). The 4-h evaluation showed gonadotropin reduction (p < 0.05) 24 h after CTX, without any rebound effect. One single CTX dose still modulates gonadotropin secretion in HA. Its 'paradoxical' stimulatory effect on gonadotropins needs to be verified after prolonged administration.

Pesticides in mixture disrupt metabolic regulation: in silico and in vivo analysis of cumulative toxicity of mancozeb and imidacloprid on body weight of mice.

PubMed

Bhaskar, Rakesh; Mohanty, Banalata

2014-09-01

Pesticides acting as endocrine disrupting chemicals disrupt the homeostasis of body metabolism. The present study elucidated that the low dose coexposure of thyroid disrupting dithiocarbamate fungicide mancozeb (MCZ) and neonicotinoid insecticide imidacloprid (IMI) during lactation increased the risk of body weight gain in mice later in life. Body weight gain has been linked to pesticide-induced hypothyroidism and hyperprolactinemia and alteration of lipid profiles. In vivo results were substantiated with in silico molecular docking (MD) analysis that predicted the binding affinity of pesticides with thyroid hormone receptors (TRα and TRβ) and peroxisome proliferator activated receptor gamma (PPARγ), the major nuclear receptors of peripheral fat metabolism. Binding potency of MCZ and IMI was compared with that of T3, and its antagonist ethylene thiourea (ETU) as well as PPARγ agonist (rosiglitazone) and antagonist (HL005). MD simulation predicted that both MCZ and IMI may compete with T3 for binding with TRs. Imidazole group of IMI formed hydrogen bonds with TRs like that of ETU. MCZ may compete with rosiglitazone and HL005 for PPARγ, but IMI showed no affinity. Thus while both MCZ and IMI could disrupt the TRs functioning, MCZ alone may affect PPARγ. Coexposure of pesticides decreased the plasma thyroid hormones and increased the cholesterol and triglyceride. Individual pesticide exposure in low dose might not exert the threshold response to affect the receptors signaling further to cause hormonal/metabolic impairment. Thus, cumulative response of the mixture of thyroid disrupting pesticides can disrupt metabolic regulation through several pathways and contribute to gain in body weight. Copyright © 2014 Elsevier Inc. All rights reserved.

The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis.

PubMed

Nahon, Jean-Louis

2006-08-01

A number of different neuropeptides exert powerful concerted controls on feeding behavior and energy balance, most of them being produced in hypothalamic neuronal networks under stimulation by anabolic and catabolic peripheral hormones such as ghrelin and leptin, respectively. These peptide-expressing neurons interconnect extensively to integrate the multiple opposing signals that mediate changes in energy expenditure. In the present review I have summarized our current knowledge about two key peptidic systems involved in regulating appetite and energy homeostasis, the melanocortin system (alpha-MSH, agouti and Agouti-related peptides, MC receptors and mahogany protein) and the melanin-concentrating hormone system (proMCH-derived peptides and MCH receptors) that contribute to satiety and feeding-initiation, respectively, with concurrent effects on energy expenditure. I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity).

Syntheses of precursors and reference compounds of the melanin-concentrating hormone receptor 1 (MCHR1) tracers [¹¹C]SNAP-7941 and [¹⁸F]FE@SNAP for positron emission tomography.

PubMed

Schirmer, Eva; Shanab, Karem; Datterl, Barbara; Neudorfer, Catharina; Mitterhauser, Markus; Wadsak, Wolfgang; Philippe, Cécile; Spreitzer, Helmut

2013-09-30

The MCH receptor has been revealed as a target of great interest in positron emission tomography imaging. The receptor's eponymous substrate melanin-concentrating hormone (MCH) is a cyclic peptide hormone, which is located predominantly in the hypothalamus with a major influence on energy and weight regulation as well as water balance and memory. Therefore, it is thought to play an important role in the pathophysiology of adiposity, which is nowadays a big issue worldwide. Based on the selective and high-affinity MCH receptor 1 antagonist SNAP-7941, a series of novel SNAP derivatives has been developed to provide different precursors and reference compounds for the radiosyntheses of the novel PET radiotracers [(11)C]SNAP-7941 and [(18)F]FE@SNAP. Positron emission tomography promotes a better understanding of physiologic parameters on a molecular level, thus giving a deeper insight into MCHR1 related processes as adiposity.

Androgens and the male reproductive tract: an overview of classical roles and current perspectives.

PubMed

Patrão, Marilia T C C; Silva, Erick J R; Avellar, Maria Christina W

2009-11-01

Androgens are steroid hormones that play key roles in the development and maintenance of male phenotype and reproductive function. These hormones also affect the function of several non-reproductive organs, such as bone and skeletal muscle. Endogenous androgens exert most of their effects by genomic mechanisms, which involve hormone binding to the androgen receptor (AR), a ligand-activated transcription factor, resulting in the modulation of gene expression. AR-induced non-genomic mechanisms have also been reported. A large number of steroidal and non-steroidal AR-ligands have been developed for therapeutic use, including the treatment of male hypogonadism (AR agonists) and prostate diseases (AR antagonists), among other pathological conditions. Here, the AR gene and protein structure, mechanism of action and AR gene homologous regulation were reviewed. The AR expression pattern, its in vivo regulation and physiological relevance in the developing and adult testis and epididymis, which are sites of sperm production and maturation, respectively, were also presented.

Bioassays for assessing jasmonate-dependent defenses triggered by pathogens, herbivorous insects, or beneficial rhizobacteria.

PubMed

Van Wees, Saskia C M; Van Pelt, Johan A; Bakker, Peter A H M; Pieterse, Corné M J

2013-01-01

Jasmonates, together with other plant hormones, are important orchestrators of the plant immune system. The different hormone-controlled signaling pathways cross-communicate in an antagonistic or a synergistic manner, providing the plant with a powerful capacity to finely regulate its immune response. Jasmonic acid (JA) signaling is required for plant resistance to harmful organisms, such as necrotrophic pathogens and herbivorous insects. Furthermore, JA signaling is essential in interactions of plants with beneficial microbes that induce systemic resistance to pathogens and insects. The role of JA signaling components in plant immunity can be studied by performing bioassays with different interacting organisms. Determination of the level of resistance and the induction of defense responses in plants with altered JA components, through mutation or ectopic expression, will unveil novel mechanisms of JA signaling. We provide detailed protocols of bioassays with the model plant Arabidopsis thaliana challenged with the pathogens Botrytis cinerea and Pseudomonas syringae, the insect herbivore Pieris rapae, and the beneficial microbe Pseudomonas fluorescens. In addition, we describe pharmacological assays to study the modulation of JA-regulated responses by exogenous application of combinations of hormones, because a simultaneous rise in hormone levels occurs during interaction of plants with other organisms.

Small and remarkable

PubMed Central

Campos, Marcelo Lattarulo; Carvalho, Rogério Falleiros; Benedito, Vagner Augusto

2010-01-01

Hormones are molecules involved in virtually every step of plant development and studies in this field have been shaping plant physiology for more than a century. The model plant Arabidopsis thaliana, long used as a tool to study plant hormones, lacks significant important developmental traits, such as fleshy climacteric fruit, compound leaf and multicellular trichomes, suggesting the necessity for alternative plant models. An attractive option often used is tomato, a species also of major economic importance, being ideal to bring together basic and applied plant sciences. The tomato Micro-Tom (MT) cultivar makes it possible to combine the direct benefits of studying a crop species with the fast life cycle and small size required for a suitable biological model. However, few obscure questions are constantly addressed to MT, creating a process herein called “MT mystification”. In this work we present evidence clarifying these questions and show the potential of MT, aiming to demystify it. To corroborate our ideas we showed that, by making use of MT, our laboratory demonstrated straightforwardly new hormonal functions and also characterized a novel antagonistic hormonal interaction between jasmonates and brassinosteroids in the formation of anti-herbivory traits in tomato. PMID:20037476

Corticotropin-releasing hormone and dopamine release in healthy individuals.

PubMed

Payer, Doris; Williams, Belinda; Mansouri, Esmaeil; Stevanovski, Suzanna; Nakajima, Shinichiro; Le Foll, Bernard; Kish, Stephen; Houle, Sylvain; Mizrahi, Romina; George, Susan R; George, Tony P; Boileau, Isabelle

2017-02-01

Corticotropin-releasing hormone (CRH) is a key component of the neuroendocrine response to stress. In animal models, CRH has been shown to modulate dopamine release, and this interaction is believed to contribute to stress-induced relapse in neuropsychiatric disorders. Here we investigated whether CRH administration induces dopamine release in humans, using positron emission tomography (PET). Eight healthy volunteers (5 female, 22-48 years old) completed two PET scans with the dopamine D 2/3 receptor radioligand [ 11 C]-(+)-PHNO: once after saline injection, and once after injection of corticorelin (synthetic human CRH). We also assessed subjective reports and measured plasma levels of endocrine hormones (adrenocorticotropic hormone and cortisol). Relative to saline, corticorelin administration decreased binding of the D 2/3 PET probe [ 11 C]-(+)-PHNO, suggesting dopamine release. Endocrine stress markers were also elevated, in line with activation of the hypothalamic-pituitary-adrenal axis, but we detected no changes in subjective ratings. Preliminary results from this proof-of-concept study suggests that CRH challenge in combination with [ 11 C]-(+)-PHNO PET may serve as an assay of dopamine release, presenting a potential platform for evaluating CRH/dopamine interactions in neuropsychiatric disorders and CRH antagonists as potential treatment avenues. Copyright © 2016 Elsevier Ltd. All rights reserved.

Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties.

PubMed

Janáky, T; Juhász, A; Rékási, Z; Serfözö, P; Pinski, J; Bokser, L; Srkalovic, G; Milovanovic, S; Redding, T W; Halmos, G

1992-11-01

Five hexapeptide and heptapeptide analogs of luteinizing hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhance target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were amidated with ethylamine and acylated on the N terminus. The receptor-binding affinity of one hexapeptide carrier AJ-41 (Ac-Ser-Tyr-D-Lys-Leu-Arg-Pro-NH-Et) to human breast cancer cell membranes was similar to that of [D-Trp6]LH-RH. Alkylating nitrogen mustards (melphalan, Ac-melphalan), anthraquinone derivatives including anticancer antibiotic doxorubicin, antimetabolite (methotrexate), and cisplatin-like platinum complex were linked to these peptides through their omega-amino group at position 6. The hybrid molecules showed no LH-RH agonistic activity in vitro and in vivo but had nontypical antagonistic effects on pituitary cells in vitro at the doses tested. These analogs showed a wide range of receptor-binding affinities to rat pituitaries and cell membranes of human breast cancer and rat Dunning prostate cancer. Several of these conjugates exerted some cytotoxic effects on MCF-7 breast cancer cell line.

Short-chain analogs of luteinizing hormone-releasing hormone containing cytotoxic moieties.

PubMed Central

Janáky, T; Juhász, A; Rékási, Z; Serfözö, P; Pinski, J; Bokser, L; Srkalovic, G; Milovanovic, S; Redding, T W; Halmos, G

1992-01-01

Five hexapeptide and heptapeptide analogs of luteinizing hormone-releasing hormone (LH-RH) were synthesized for use as carriers for cytotoxic compounds. These short analogs were expected to enhance target selectivity of the antineoplastic agents linked to them. Native LH-RH-(3-9) and LH-RH-(4-9) containing D-lysine and D-ornithine at position 6 were amidated with ethylamine and acylated on the N terminus. The receptor-binding affinity of one hexapeptide carrier AJ-41 (Ac-Ser-Tyr-D-Lys-Leu-Arg-Pro-NH-Et) to human breast cancer cell membranes was similar to that of [D-Trp6]LH-RH. Alkylating nitrogen mustards (melphalan, Ac-melphalan), anthraquinone derivatives including anticancer antibiotic doxorubicin, antimetabolite (methotrexate), and cisplatin-like platinum complex were linked to these peptides through their omega-amino group at position 6. The hybrid molecules showed no LH-RH agonistic activity in vitro and in vivo but had nontypical antagonistic effects on pituitary cells in vitro at the doses tested. These analogs showed a wide range of receptor-binding affinities to rat pituitaries and cell membranes of human breast cancer and rat Dunning prostate cancer. Several of these conjugates exerted some cytotoxic effects on MCF-7 breast cancer cell line. PMID:1332035

Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain.

PubMed

Ezzati, Mohammad; Carr, Bruce R

2015-01-01

Suppression of estrogen production and reduction of menstrual blood flow are the mainstays of medical treatment of endometriosis-related pain and have been traditionally achieved by methods such as combined hormonal contraception, progestins and GnRH analogs, all with comparable efficacies, though different side-effect profiles. Elagolix is the frontrunner among an emerging class of GnRH antagonists, which unlike their peptide predecessors has a nonpeptide structure resulting in its oral bioavailability. Phase I and II clinical trials have demonstrated safety of elagolix and its efficacy in partial and reversible suppression of ovarian estrogen production resulting in improvements in endometriosis-related pain. Phase III clinical trials are currently underway and elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

The prevention of ovarian hyperstimulation syndrome.

PubMed

Corbett, Shannon; Shmorgun, Doron; Claman, Paul

2014-11-01

To review the clinical aspects of ovarian hyperstimulation syndrome and provide recommendations on its prevention. Preventative measures, early recognition, and prompt systematic supportive care will help avoid poor outcomes. Establish guidelines to assist in the prevention of ovarian hyperstimulation syndrome, early recognition of the condition when it occurs, and provision of appropriate supportive measures in the correct setting. Published literature was retrieved through searches of Medline, Embase, and the Cochrane Library from 2011 to 2013 using appropriate controlled vocabulary ([OHSS] ovarian hyperstimulation syndrome and: agonist IVF, antagonist IVF, metformin, HCG, gonadotropin, coasting, freeze all, agonist trigger, progesterone) and key words (ovarian hyperstimulation syndrome, ovarian stimulation, gonadotropin, human chorionic gonadotropin, prevention). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to February 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Summary Statements 1. The particular follicle-stimulating hormone formulation used for ovarian stimulation does not affect the incidence of ovarian hyperstimulation syndrome. (I) 2. Coasting may reduce the incidence of severe ovarian hyperstimulation syndrome. (III) 3. Coasting for longer than 3 days reduces in vitro fertilization pregnancy rates. (II-2) 4. The use of either luteinizing hormone or human chorionic gonadotropin for final oocyte maturation does not influence the incidence of ovarian hyperstimulation syndrome. (I) 5. There is no clear published evidence that lowering the human chorionic gonadotropin dose will result in a decrease in the rate of ovarian hyperstimulation syndrome. (III) 6. Cabergoline starting from the day of human chorionic gonadotropin reduces the incidence of ovarian hyperstimulation syndrome in patients at higher risk and does not appear to lower in vitro fertilization pregnancy rates. (II-2) 7. Avoiding pregnancy by freezing all embryos will prevent severe prolonged ovarian hyperstimulation syndrome in patients at high risk. (II-2) 8. Pregnancy rates are not affected when using gonadotropin-releasing hormone (GnRH) agonists in GnRH antagonist protocols for final egg maturation when embryos are frozen by vitrification for later transfer. (II-2) Recommendations 1. The addition of metformin should be considered in patients with polycystic ovarian syndrome who are undergoing in vitro fertilization because it may reduce the incidence of ovarian hyperstimulation syndrome. (I-A) 2. Gonadotropin dosing should be carefully individualized, taking into account the patient's age, body mass, antral follicle count, and previous response to gonadotropins. (II-3B) 3. Cycle cancellation before administration of human chorionic gonadatropin is an effective strategy for the prevention of ovarian hyperstimulation syndrome, but the emotional and financial burden it imposes on patients should be considered before the cycle is cancelled. (III-C) 4. Gonadotropin-releasing hormone (GnRH) antagonist stimulation protocols are recommended in patients at high risk for ovarian hyperstimulation syndrome (OHSS). The risk of severe OHSS in patients on GnRH antagonist protocols who have a very robust ovarian stimulation response can be reduced by using a GnRH agonist as a substitute for human chorionic gonadotropin to trigger final oocyte maturation. (I-B) 5. A gonadotropin-releasing hormone (GnRH) antagonist protocol with a GnRH agonist trigger for final oocyte maturation is recommended for donor oocyte and fertility preservation cycles. (III-C) 6. Albumin or other plasma expanders at the time of egg retrieval are not recommended for the prevention of ovarian hyperstimulation syndrome. (I-E) 7. Elective single embryo transfer is recommended in patients at high risk for ovarian hyperstimulation syndrome. (III-C) 8. Progesterone, rather than human chorionic gonadotropin, should be used for luteal phase support. (I-A) 9. Outpatient culdocentesis should be considered for the prevention of disease progression in severe ovarian hyperstimulation syndrome. (II-2B).

The thyroid hormone triiodothyronine controls macrophage maturation and functions: protective role during inflammation.

PubMed

Perrotta, Cristiana; Buldorini, Marcella; Assi, Emma; Cazzato, Denise; De Palma, Clara; Clementi, Emilio; Cervia, Davide

2014-01-01

The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T3), in triggering the differentiation of bone marrow-derived monocytes into unpolarized macrophages. T3-induced macrophages displayed a classically activated (M1) signature. A T3-induced M1-priming effect was also observed on polarized macrophages because T3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo, circulating T3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T3 levels increased the recruited (potentially damaging) cells, whereas restoring T3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor β1 as the major player mediating T3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Cushing’s syndrome: epidemiology and developments in disease management

PubMed Central

Sharma, Susmeeta T; Nieman, Lynnette K; Feelders, Richard A

2015-01-01

Cushing’s syndrome is a rare disorder resulting from prolonged exposure to excess glucocorticoids. Early diagnosis and treatment of Cushing’s syndrome is associated with a decrease in morbidity and mortality. Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult. Surgery (resection of the pituitary or ectopic source of adrenocorticotropic hormone, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of Cushing’s syndrome, but may not always lead to remission. Medical therapy (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for optimal control of hypercortisolemia and management of comorbidities. PMID:25945066

Molecular aspects of melatonin (MLT)-mediated therapeutic effects.

PubMed

Tuli, Hardeep Singh; Kashyap, Dharambir; Sharma, Anil K; Sandhu, Sardul Singh

2015-08-15

Hormones are a class of molecules, which mediate their effects by regulating a variety of signalling pathways. Melatonin (N-acetyl-5-methoxytryptamine), a pineal gland hormone, is one among the categories of compounds having various therapeutic and pharmacological effects. Melatonin has many intracellular as well as extracellular targets including apoptosis, metastasis, angiogenesis and inflammatory pathways. Gene-profile studies have further established its antagonist effect on the various genes involved in the tumour progression, neurodegeneration and ageing. It has also been known to reduce the toxicity induced by chemotherapeutic agents in advanced stages of tumour. The present review extensively describes the molecular interactions of melatonin with various recognized cellular targets, which may lead the scientific community to propose novel therapeutic strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits

PubMed Central

Bielohuby, Maximilian; Zarkesh-Esfahani, Sayyed Hamid; Manolopoulou, Jenny; Wirthgen, Elisa; Walpurgis, Katja; Toghiany Khorasgani, Mohaddeseh; Aghili, Zahra Sadat; Wilkinson, Ian Robert; Hoeflich, Andreas; Thevis, Mario; Ross, Richard J.; Bidlingmaier, Martin

2014-01-01

The development of new growth hormone (GH) agonists and growth hormone antagonists (GHAs) requires animal models for pre-clinical testing. Ideally, the effects of treatment are monitored using the same pharmacodynamic marker that is later used in clinical practice. However, intact rodents are of limited value for this purpose because serum IGF-I, the most sensitive pharmacodynamic marker for the action of GH in humans, shows no response to treatment with recombinant human GH and there is little evidence for the effects of GHAs, except when administered at very high doses or when overexpressed. As an alternative, more suitable model, we explored pharmacodynamic markers of GH action in intact rabbits. We performed the first validation of an IGF-I assay for the analysis of rabbit serum and tested precision, sensitivity, linearity and recovery using an automated human IGF-I assay (IDS-iSYS). Furthermore, IGF-I was measured in rabbits of different strains, age groups and sexes, and we monitored IGF-I response to treatment with recombinant human GH or the GHA Pegvisomant. For a subset of samples, we used LC-MS/MS to measure IGF-I, and quantitative western ligand blot to analyze IGF-binding proteins (IGFBPs). Although recovery of recombinant rabbit IGF-I was only 50% in the human IGF-I assay, our results show that the sensitivity, precision (1.7–3.3% coefficient of variation) and linearity (90.4–105.6%) were excellent in rabbit samples. As expected, sex, age and genetic background were major determinants of IGF-I concentration in rabbits. IGF-I and IGFBP-2 levels increased after single and multiple injections of recombinant human GH (IGF-I: 286±22 versus 434±26 ng/ml; P<0.01) and were highly correlated (P<0.0001). Treatment with the GHA lowered IGF-I levels from the fourth injection onwards (P<0.01). In summary, we demonstrated that the IDS-iSYS IGF-I immunoassay can be used in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on sex, age and genetic background. Unlike in rodents, the IGF-I response to treatment with recombinant human GH or a GHA closely mimics the pharmacodynamics seen in humans, suggesting that rabbits are a suitable new model to test human GH agonists and antagonists. PMID:25239917

Cycle scheduling for in vitro fertilization with oral contraceptive pills versus oral estradiol valerate: a randomized, controlled trial

PubMed Central

2013-01-01

Background Both oral contraceptive pills (OCPs) and estradiol (E2) valerate have been used to schedule gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles and, consequently, laboratory activities. However, there are no studies comparing treatment outcomes directly between these two pretreatment methods. This randomized controlled trial was aimed at finding differences in ongoing pregnancy rates between GnRH antagonist IVF cycles scheduled with OCPs or E2 valerate. Methods Between January and May 2012, one hundred consecutive patients (nonobese, regularly cycling women 18–38 years with normal day 3 hormone levels and <3 previous IVF/ICSI attempts) undergoing IVF with the GnRH antagonist protocol were randomized to either the OCP or E2 pretreatment arms, with no restrictions such as blocking or stratification. Authors involved in data collection and analysis were blinded to group assignment. Fifty patients received OCP (30 μg ethinyl E2/150 μg levonorgestrel) for 12–16 days from day 1 or 2, and stimulation was started 5 days after stopping OCP. Similarly, 50 patients received 4 mg/day oral E2 valerate from day 20 for 5–12 days, until the day before starting stimulation. Results Pretreatment with OCP (mean±SD, 14.5±1.7 days) was significantly longer than with E2 (7.8±1.9 days). Stimulation and embryological characteristics were similar. Ongoing pregnancy rates (46.0% vs. 44.0%; risk difference, –2.0% [95% CI –21.2% to 17.3%]), as well as implantation (43.5% vs. 47.4%), clinical pregnancy (50.0% vs. 48.0%), clinical miscarriage (7.1% vs. 7.7%), and live birth (42.0% vs. 40.0%) rates were comparable between groups. Conclusions This is the first study to directly compare these two methods of cycle scheduling in GnRH antagonist cycles. Our results fail to show statistically significant differences in ongoing pregnancy rates between pretreatment with OCP and E2 for IVF with the GnRH antagonist protocol. Although the study is limited by its sample size, our results may contribute to a future meta-analysis. An interesting future direction would be to extend our study to women with decreased ovarian reserve, as these are the patients in whom an increase in oocyte yield—due to the hypothetical beneficial effect of steroid pretreatment on follicular synchronization—could more easily be demonstrated. Trial registration ClinicalTrials.gov http://NCT01501448. PMID:24074027

Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.

PubMed

Palm, Catrin; Pistrosch, Frank; Herbrig, Kay; Gross, Peter

2006-07-01

Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, vasopressin receptor antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia.

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.

PubMed

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.

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

PubMed Central

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

2015-01-01

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. PMID:26161425

A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

DTIC Science & Technology

2017-12-01

findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or...trial for patients with metastatic, castration resistant prostate cancer (CRPC). For patients with metastatic CRPC, there are few established...receptor ( AR ) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR

Study of the effects of the casein derived bitter tastant on the melanophores in milieu with the melatonin receptors.

PubMed

Mubashshir, Md; Ahmed, Fraz; Ovais, Mohd

2011-10-01

The present study was undertaken to ascertain whether the casein derived bitter tastant Cyclo (Leu-Trp) [CLT] has an affinity or not for the particular receptors of the pineal hormone, melatonin, on the melanophores of a major carp Labeo rohita (Ham.). The bitter tastant CLT, in the dose range of 3.34×10(-16) M to 3.34×10(-4) M, has induced an aggregatory effect but not in a dose dependent manner. Binding of CLT with the receptors may vary at different concentrations. Denervation of the melanophores has shown a complete inhibition of the CLT mediated aggregation. Prazosin has partially inhibited the aggregatory effect of CLT. Moreover, the bitter tastant's response is mediated through the α2 adrenoceptors only at particular dose ranges. The MT1 and MT2 melatonin receptor antagonist luzindole and the MT2 specific antagonist K185 have perfectly blocked the aggregatory effects of CLT. We have found that the CLT mediated aggregatory effect is dependent upon the release of neurotransmitters and the two subtypes of melatonin (MT) receptors (MT1 and MT2) possess a perfect affinity towards the bitter tastant CLT. Our study demands a need to further make a clinical research on the effects of bitter tastants on the physiology of the biological rhythm maintaining hormone melatonin.

Central peptidergic mechanisms controlling reproductive hormone secretion: novel methodology reveals a role for the natriuretic peptides.

PubMed

Samson, W K; Alexander, B D; Skala, K D; Huang, F L; Fulton, R J

1992-05-01

A variety of neural factors can influence reproductive hormone secretion by neuromodulatory actions within the hypothalamus or neuroendocrine actions within the anterior pituitary gland. Passive immunoneutralization and antagonist administration protocols have suggested physiological roles for a number of these factors; however, both experimental approaches have severe technical limitations. We have developed novel methodology utilizing cytotoxin cell targeting with neuropeptides linked to the toxic A chain of the plant cytotoxin ricin. With this methodology we can target and destroy in vivo or in vitro cells bearing receptors for that peptide. Ricin A chain conjugated to atrial natriuretic peptide (ANP), a neuropeptide known to pharmacologically inhibit luteinizing hormone-releasing hormone (LHRH) release, was injected into the cerebroventricular system of intact, cycling rats and ovariectomized rats. Cytotoxin conjugate treatment significantly lengthened the estrous cycle. In ovariectomized rats the luteinizing hormone surge induced by steroid priming was completely inhibited. LHRH content of the median eminences of these rats was not significantly altered. These data suggest that ANP binding to clearance receptors in the hypothalamus displaces the C-type natriuretic peptide (CNP) from the shared clearance receptor, making more CNP available to inhibit LHRH release. In the absence of cells bearing the clearance receptor all available CNP binds to the ANPR-B receptor and exerts its effect via an inhibitory interneuron, since LHRH fibers are spared by this treatment.

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

PubMed

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. Some cytotoxic analogues also significantly suppressed the growth of mammary and prostate cancers in vivo in animal models.

Analogues of luteinizing hormone-releasing hormone containing cytotoxic groups.

PubMed Central

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

1992-01-01

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. Some cytotoxic analogues also significantly suppressed the growth of mammary and prostate cancers in vivo in animal models. PMID:1310542

Evidence That GABA Mediates Dopaminergic and Serotonergic Pathways Associated with Locomotor Activity in Juvenile Chinook Salmon (Oncorhynchus tshawytscha)

USGS Publications Warehouse

Clements, S.; Schreck, C.B.

2004-01-01

The authors examined the control of locomotor activity in juvenile salmon (Oncorhynchus tshawytscha) by manipulating 3 neurotransmitter systems-gamma-amino-n-butyric acid (GABA), dopamine, and serotonin-as well as the neuropeptide corticotropin releasing hormone (CRH). Intracerebroventricular (ICV) injections of CRH and the GABAAagonist muscimol stimulated locomotor activity. The effect of muscimol was attenuated by administration of a dopamine receptor antagonist, haloperidol. Conversely, the administration of a dopamine uptake inhibitor (4???,4??? -difluoro-3-alpha-[diphenylmethoxy] tropane hydrochloride [DUI]) potentiated the effect of muscimol. They found no evidence that CRH-induced hyperactivity is mediated by dopaminergic systems following concurrent injections of haloperidol or DUI with CRH. Administration of muscimol either had no effect or attenuated the locomotor response to concurrent injections of CRH and fluoxetine, whereas the GABAA antagonist bicuculline methiodide potentiated the effect of CRH and fluoxetine.

Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats.

PubMed

Zhang, Qingsheng; He, Meng; Deng, Chao; Wang, Hongqin; Lian, Jiamei; Huang, Xu-Feng

2014-05-01

Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.

BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients

PubMed Central

Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A.; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

2016-01-01

Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile. PMID:26760770

Bone anabolics in osteoporosis: Actuality and perspectives

PubMed Central

Montagnani, Andrea

2014-01-01

Vertebral and nonvertebral fractures prevention is the main goal for osteoporosis therapy by inhibiting bone resorption and/or stimulating bone formation. Antiresorptive drugs decrease the activation frequency, thereby determining a secondary decrease in bone formation rate and a low bone turnover. Bisphosphonates are today’s mainstay among antiresorptive treatment of osteoporosis. Also, oral selective estrogen receptor modulators and recently denosumab have a negative effect on bone turnover. Agents active on bone formation are considered a better perspective in the treatment of severe osteoporosis. Recombinant-human parathyroid hormone (PTH) has showed to increase bone formation and significantly decrease vertebral fractures in severe patients, but with a modest effect on nonvertebral fractures. The study of Wnt signaling pathway, that induces prevalently an osteoblastic activity, opens large possibilities to antagonists of Wnt-inhibitors, such as sclerostin antibodies and dickkopf-1 antagonists, with potential effects not only on trabecular bone but also on cortical bone. PMID:25035827

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use

PubMed Central

Lensing, Anthonie W. A.; Middeldorp, Saskia; Levi, Marcel; Beyer-Westendorf, Jan; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A.; Cohen, Alexander T.; Trajanovic, Mila; Gebel, Martin; Lam, Phuong; Wells, Philip S.; Prins, Martin H.

2016-01-01

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an “unacceptable health risk” during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration. PMID:26696010

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.

PubMed

Martinelli, Ida; Lensing, Anthonie W A; Middeldorp, Saskia; Levi, Marcel; Beyer-Westendorf, Jan; van Bellen, Bonno; Bounameaux, Henri; Brighton, Timothy A; Cohen, Alexander T; Trajanovic, Mila; Gebel, Martin; Lam, Phuong; Wells, Philip S; Prins, Martin H

2016-03-17

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration. © 2016 by The American Society of Hematology.

Melanin-concentrating hormone: from fish skin to skinny mammals.

PubMed

Pissios, Pavlos; Maratos-Flier, Eleftheria

2003-07-01

In recent years, the key role of melanin-concentrating hormone (MCH) in regulating mammalian energy balance has been confirmed through several lines of evidence. When administered exogenously, MCH leads to a rapid and robust feeding response and chronic infusions result in the development of mild obesity. At the physiological level, it is known that MCH expression changes in states of altered energy balance, such as fasting and obesity. Genetic studies with mice have shown that ablation of either the gene for prepro-MCH or the gene encoding the MCH receptor leads to a lean phenotype. Finally, the administration of MCH antagonists appears to inhibit both feeding and the development of diet-induced obesity. The aim of this article is to review the recent data on MCH and MCH receptors in light of their emerging roles in energy homeostasis.

Definition of the Cellular Mechanisms which Distinguish Between Estrogen Receptor Agonists and Antagonists

DTIC Science & Technology

2001-07-01

hormones: 10-7 M 17p3- estradiol for ERa and ERI3, 10-7 M progesterone for PR-A and PR-B, 10-7 M dexamethasone for GR, 10-7 M 5ot-dihydrotestosterone...cyproterone acetate, d-Ald.: d-aldosterone, DHEA: dehydroepiandrosterone, DOC: 11-deoxycorticosterone, Dex: dexamethasone, MPA: medroxyprogesterone , OH-F...two receptors are not functionally equivalent and that tory activities by altering ER structure and indepen- each subtype plays a unique role in ER

Features of natural and gonadotropin-releasing hormone antagonist-induced corpus luteum regression and effects of in vivo human chorionic gonadotropin.

PubMed

Del Canto, Felipe; Sierralta, Walter; Kohen, Paulina; Muñoz, Alex; Strauss, Jerome F; Devoto, Luigi

2007-11-01

The natural process of luteolysis and luteal regression is induced by withdrawal of gonadotropin support. The objectives of this study were: 1) to compare the functional changes and apoptotic features of natural human luteal regression and induced luteal regression; 2) to define the ultrastructural characteristics of the corpus luteum at the time of natural luteal regression and induced luteal regression; and 3) to examine the effect of human chorionic gonadotropin (hCG) on the steroidogenic response and apoptotic markers within the regressing corpus luteum. Twenty-three women with normal menstrual cycles undergoing tubal ligation donated corpus luteum at specific stages in the luteal phase. Some women received a GnRH antagonist prior to collection of corpus luteum, others received an injection of hCG with or without prior treatment with a GnRH antagonist. Main outcome measures were plasma hormone levels and analysis of excised luteal tissue for markers of apoptosis, histology, and ultrastructure. The progesterone and estradiol levels, corpus luteum DNA, and protein contents in induced luteal regression resembled those of natural luteal regression. hCG treatment raised progesterone and estradiol in both natural luteal regression and induced luteal regression. The increase in apoptosis detected in induced luteal regression by cytochrome c in the cytosol, activated caspase-3, and nuclear DNA fragmentation, was similar to that observed in natural luteal regression. The antiapoptotic protein Bcl-2 was significantly lower during natural luteal regression. The proapoptotic proteins Bax and Bak were at a constant level. Apoptotic and nonapoptotic death of luteal cells was observed in natural luteal regression and induced luteal regression at the ultrastructural level. hCG prevented apoptotic cell death, but not autophagy. The low number of apoptotic cells disclosed and the frequent autophagocytic suggest that multiple mechanisms are involved in cell death at luteal regression. hCG restores steroidogenic function and restrains the apoptotic process, but not autophagy.

AN INDIVIDUALIZED APPROACH TO THE EVALUATION OF CUSHING SYNDROME.

PubMed

Sharma, Susmeeta T

2017-06-01

Cushing syndrome (CS) is caused by chronic exposure to excess glucocorticoids. Early recognition and treatment of hypercortisolemia can lead to decreased morbidity and mortality. The diagnosis of CS and thereafter, establishing the cause can often be difficult, especially in patients with mild and cyclic hypercortisolism. Surgical excision of the cause of excess glucocorticoids is the optimal treatment for CS. Medical therapy (steroidogenesis inhibitors, medications that decrease adrenocorticotropic hormone [ACTH] levels or glucocorticoid antagonists) and pituitary radiotherapy may be needed as adjunctive treatment modalities in patients with residual, recurrent or metastatic disease, in preparation for surgery, or when surgery is contraindicated. A multidisciplinary team approach, individualized treatment plan and long-term follow-up are important for optimal management of hypercortisolemia and the comorbidities associated with CS. ACTH = adrenocorticotropic hormone; BIPSS = bilateral inferior petrosal sinus sampling; CBG = corticosteroid-binding globulin; CD = Cushing disease; CRH = corticotropin-releasing hormone; CS = Cushing syndrome; Dex = dexamethasone; DST = dexamethasone suppression test; EAS = ectopic ACTH syndrome; FDA = U.S. Food & Drug Administration; HDDST = high-dose DST; IPS/P = inferior petrosal sinus to peripheral; MRI = magnetic resonance imaging; NET = neuroendocrine tumor; PET = positron emission tomography; UFC = urinary free cortisol.

Oocyte cryopreservation for fertility preservation in women with cancer.

PubMed

Domingo, Javier; Garcia-Velasco, Juan A

2016-12-01

It is necessary to clarify the fertility preservation-related points of concern that often frighten patients or physicians when it comes to deciding about oocyte cryopreservation for fertility preservation, which are often perceived as procedure limitations, are sometimes real and often theoretical and may make the prognosis worse. Letrozole added to gonadotrophins for controlled ovarian stimulation is safe when applied to hormone-sensitive cancer patients as it avoids associated high estradiol levels. This benefit is only for estrogens, but not for progesterone. Triggering ovulation with gonadotropin releasing hormone agonist bolus and adding the gonadotropin releasing hormone antagonist after oocyte retrieval help minimize its effect. A random start is currently widespread as neither results nor offspring are compromised, and it avoids waiting for menstruation and, therefore, delaying treatment. The cumulative live birth rate is conditioned by the number of available oocytes and patient's age. Assisted reproductive technologies may help cancer patients to achieve pregnancy with good obstetric outcomes and apparent oncological safety. Although counseling should be provided on an individual basis, fertility preservation in cancer patients and later pregnancy in survivors after adequate treatment and follow-up should not be discouraged.

Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations.

PubMed

Meczekalski, Blazej; Podfigurna-Stopa, Agnieszka; Warenik-Szymankiewicz, Alina; Genazzani, Andrea Riccardo

2008-01-01

Functional hypothalamic amenorrhea (FHA) is defined as a non-organic and reversible disorder in which the impairment of gonadotropin-releasing hormone (GnRH) pulsatile secretion plays a key role. There are main three types of FHA: stress-related amenorrhea, weight loss-related amenorrhea and exercise-related amenorrhea. The spectrum of GnRH-luteinizing hormone (LH) disturbances in FHA is very broad and includes lower mean frequency of LH pulses, complete absence of LH pulsatility, normal-appearing secretion pattern and higher mean frequency of LH pulses. Precise mechanisms underlying the pathophysiology of FHA are very complex and unclear. Numerous neuropeptides, neurotransmitters and neurosteroids play important roles in the physiological regulation of GnRH pulsatile secretion and there is evidence that different neuropeptides may be involved in the pathophysiology of FHA. Particular attention is paid to such substances as allopregnanolone, neuropeptide Y, corticotropin-releasing hormone, leptin, ghrelin and beta-endorphin. Some studies reveal significant changes in these mentioned substances in patients with FHA. There are also speculations about use some of these substances or their antagonists in the treatment of FHA.

McCune-Albright syndrome: growth hormone and prolactin hypersecretion.

PubMed

Christoforidis, Athanasios; Maniadaki, Ilianna; Stanhope, Richard

2006-05-01

McCune-Albright syndrome (MAS) has a special interest for endocrinologists as its pathogenesis results in hypersecretion of hormones in peripheral endocrine tissues. This can be expressed as precocious puberty, mainly in girls, primary hyperthyroidism, growth hormone (GH) and/or prolactin excess, hyperparathyroidism and hypercortisolism. The incidence of GH excess among patients with MAS has been assessed as up to 21%. The pathogenesis of GH hypersecretion in MAS is not completely understood, whereas it seems to be different from the aetiology of acromegaly/gigantism in non-MAS patients. The clinical expression of GH excess can be masked because of precocious puberty or craniofacial fibrous dysplasia, indicating the necessity for screening. Medical treatment is usually the only option in MAS patients with GH excess, as transsphenoidal surgery is usually restricted due to massive thickening of the skull base, whereas radiotherapy is contraindicated due to probable higher predisposition to sarcomatous transformation. The use of bromocriptine, cabergoline and octreotide, or the combination of these, has shown variable results, whereas pegvisomant, a GH receptor antagonist, is a new promising option, although not yet used in patients with MAS.

Inhibin at 90: From Discovery to Clinical Application, a Historical Review

PubMed Central

Makanji, Yogeshwar; Zhu, Jie; Mishra, Rama; Holmquist, Chris; Wong, Winifred P. S.; Schwartz, Neena B.; Mayo, Kelly E.

2014-01-01

When it was initially discovered in 1923, inhibin was characterized as a hypophysiotropic hormone that acts on pituitary cells to regulate pituitary hormone secretion. Ninety years later, what we know about inhibin stretches far beyond its well-established capacity to inhibit activin signaling and suppress pituitary FSH production. Inhibin is one of the major reproductive hormones involved in the regulation of folliculogenesis and steroidogenesis. Although the physiological role of inhibin as an activin antagonist in other organ systems is not as well defined as it is in the pituitary-gonadal axis, inhibin also modulates biological processes in other organs through paracrine, autocrine, and/or endocrine mechanisms. Inhibin and components of its signaling pathway are expressed in many organs. Diagnostically, inhibin is used for prenatal screening of Down syndrome as part of the quadruple test and as a biochemical marker in the assessment of ovarian reserve. In this review, we provide a comprehensive summary of our current understanding of the biological role of inhibin, its relationship with activin, its signaling mechanisms, and its potential value as a diagnostic marker for reproductive function and pregnancy-associated conditions. PMID:25051334

Insect growth regulators and insect control: a critical appraisal.

PubMed Central

Siddall, J B

1976-01-01

Insect growth regulators (IGRs) of the juvenile hormone type alter physiological processes essential to insect development and appear to act specifically on insects. Three natural juvenile hormones have been found in insects but not in other organisms. Future use of antagonists or inhibitors of hormone synthesis may be technically possible as an advantageous extension of pest control by IGRs. A documented survey of the properties, metabolism, toxicology, and uses of the most commercially advanced chemical, methoprene, shows it to be environmentally acceptable and toxicologically innocuous. Derivation of its current use patterns is discussed and limitations on these are noted. Residue levels and their measurement in the ppb region have allowed exemption from the requirement of tolerances in the EPA registered use of methoprene for mosquito control. Tolerances for foods accompany its fully approved use for control of manure breeding flies through a cattle feed supplement. The human health effects of using this chemical appear to be purely beneficial, but further advances through new IGR chemicals appear unlikely without major changes in regulatory and legislative policy. PMID:976222

Friends or foes: new insights in jasmonate and ethylene co-actions.

PubMed

Zhu, Ziqiang; Lee, Benjamin

2015-03-01

One strategy for sessile plants to adapt to their surrounding environment involves the modulation of their various internal phytohormone signaling and distributions when the plants sense environmental change. There are currently dozens of identified phytohormones in plant cells and they act in concert to regulate plant growth, development, metabolism and defense. It has been determined that phytohormones often act together to achieve certain physiological functions. Thus, the study of hormone-hormone interactions is becoming a competitive research field for deciphering the underlying regulatory mechanisms. Among phytohormones, jasmonate and ethylene present a fascinating case of synergism and antagonism. They are commonly recognized as defense hormones that act synergistically. Plants impaired in jasmonate and/or ethylene signaling are susceptible to infections by necrotrophic fungi, suggesting that these two hormones are both required for defense. Moreover, jasmonate and ethylene also act antagonistically, such as in the regulation of apical hook development and wounding responses. Here, we highlight the recent breakthroughs in the understanding of jasmonate-ethylene co-actions and point out the potential power of studying protein-protein interactions for systematically exploring signal cross-talk. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

[Steroid hormones and pancreas: a new paradigm].

PubMed

Morales-Miranda, Angélica; Robles-Díaz, Guillermo; Díaz-Sánchez, Vicente

2007-01-01

The relation between steroid hormones and pancreatic function has been poorly discussed and not very well understood. In general, there is a lack of recognition among the scientific community about the importance of steroids in pancreatic function (current paradigm). In the present article we present basic, as well as clinic and epidemiologic data that demonstrate steroid synthesis and steroid biotransformation by pancreatic tissue, how exocrine and endocrine functions are modulated by steroids, the gender specific frequency and behavior of some tumors and the use of synthetic steroids and steroid action antagonists as therapeutic agents. With the available information it is possible to establish that: 1. Pancreatic tissue synthesize and transform steroid hormones. 2. Pancreatic tissue respond to steroid hormones and express steroid specific receptor molecules. 3. Some endocrine functions such as insulin synthesis and release are modulated by steroids. 4. Tumor growth is modulated by steroids and anti-steroid drugs. This set of data creates a new paradigm for the holistic study of pancreas and opens new research fields. The application of this new paradigm might result in an increase in the knowledge of pancreatic physiology, in the design of new and better diagnostic methods and eventually in the design of more effective medical treatments for the pancreatic cancers.

The effects of kisspeptin in human reproductive function - therapeutic implications.

PubMed

Ratnasabapathy, Risheka; Dhillo, Waljit S

2013-03-01

Kisspeptin is a 54-amino acid peptide which is encoded by the KiSS-1 gene and activates the G protein-coupled receptor GPR54. Evidence suggests that this system is a key regulator of mammalian and human reproduction. Animal studies have shown that GPR54-deficient mice have abnormal sexual development. Central and peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis whilst pre-administration of a gonadotrophin releasing hormone (GnRH) antagonist abolishes this effect. In humans, inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism whilst activation of GPR54 signalling is associated with premature puberty. In healthy human volunteers, the acute intravenous administration of kisspeptin potently increases plasma luteinising hormone (LH) levels and significantly increases plasma follicle stimulating hormone (FSH) and testosterone without side effects in both males and in females particularly in the preovulatatory phase of the menstrual cycle. In infertility due to hypothalamic amenorrhoea acute administration of kisspeptin results in stimulation of reproductive hormones. The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans. Hence kisspeptin has potential as a novel tool for the manipulation of the HPG axis and treatment of infertility in humans. This review discusses the evidence highlighting kisspeptin's key role in human reproduction.

Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression

NASA Technical Reports Server (NTRS)

Lotinun, Sutada; Sibonga, Jean D.; Turner, Russell T.

2002-01-01

A mechanism explaining the differential skeletal effects of intermittent and continuous elevation of serum parathyroid hormone (PTH) remains elusive. Intermittent PTH increases bone formation and bone mass and is being investigated as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by osteomalacia, focal bone resorption, and peritrabecular bone marrow fibrosis. Intermittent and continuous PTH have similar effects on the number of osteoblasts and bone-forming activity. Many of the beneficial as well as detrimental effects of the hormone appear to be mediated by osteoblast-derived growth factors. This hypothesis was tested using cDNA microgene arrays to compare gene expression in tibia of rats treated with continuous and pulsatile administration of PTH. These treatments result in differential expression of many genes, including growth factors. One of the genes whose steady-state mRNA levels was increased by continuous but not pulsatile administration was platelet-derived growth factor-A (PDGF-A). Administration of a PDGF-A antagonist greatly reduced bone resorption, osteomalacia, and bone marrow fibrosis in a rat model for hyperparathyroidism, suggesting that PDGF-A is a causative agent for this disease. These findings suggest that profiling changes in gene expression can help identify the metabolic pathways responsible for the skeletal responses to the hormone.

Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate the CYP3A23 Hormone Response Element

PubMed Central

SCHUETZ, ERIN G.; BRIMER, CYNTHIA; SCHUETZ, JOHN D.

2013-01-01

The pregnenolone X receptor (PXR), a new member of the nuclear hormone receptor superfamily, was recently demonstrated to mediate glucocorticoid agonist and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate the CYP3A23 DR-3. Transient cotransfection of LLC-PK1 cells with (CYP3A23)2-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chlordane and the nonplanar polychlorinated biphenyls (PCBs) each induced the CYP3A23 DR-3 element, and this activation required PXR. Additionally, this study found that PXR is activated to induce (CYP3A23)2-tk-CAT by antihormones of several steroid classes including the antimineralocorticoid spironolactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs. PMID:9855641

Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial.

PubMed

Dunlop, Boadie W; Rothbaum, Barbara O; Binder, Elisabeth B; Duncan, Erica; Harvey, Philip D; Jovanovic, Tanja; Kelley, Mary E; Kinkead, Becky; Kutner, Michael; Iosifescu, Dan V; Mathew, Sanjay J; Neylan, Thomas C; Kilts, Clinton D; Nemeroff, Charles B; Mayberg, Helen S

2014-06-21

Pharmacologic treatment options for posttraumatic stress disorder (PTSD) are limited in number and effectiveness. Medications currently in use to treat PTSD were originally approved based on their efficacy in other disorders, such as major depression. Substantial research in PTSD suggests that increased activity of corticotropin releasing hormone (CRH)-containing circuits are involved in the pathophysiology of the disease. This Phase II trial aims to evaluate the efficacy of a CRH type 1 receptor (CRHR1) antagonist in the treatment of PTSD. Currently untreated adult women, ages 18 to 65 years, with a primary psychiatric diagnosis of PTSD of at least 3 months' duration, are being enrolled in a parallel-group, double-blind, placebo-controlled, randomized clinical trial evaluating the efficacy and safety of GSK561679, a novel CRHR1 receptor antagonist. GSK561679 (or matching placebo) is prescribed at a fixed dose of 350 mg nightly for six weeks. The primary trial hypothesis is that GSK561679 will reduce symptoms of PTSD, as measured by the Clinician-Administered PTSD Scale (CAPS), significantly more than placebo after six weeks of treatment. Putative biological markers of PTSD which may influence treatment response are measured prior to randomization and after five weeks' exposure to the study medication, including: fear conditioning and extinction using psychophysiological measures; variants of stress-related genes and gene expression profiles; and indices of HPA axis reactivity. In addition, the impact of PTSD and treatment on neuropsychological performance and functional capacity are assessed at baseline and after the fifth week of study medication. After completion of the six-week double blind treatment period, subjects enter a one-month follow-up period to monitor for sustained response and resolution of any adverse effects. Considerable preclinical and human research supports the hypothesis that alterations in central nervous system CRH neuronal activity are a potential mediator of PTSD symptoms. This study is the first to assess the efficacy of a specific antagonist of a CRH receptor in the treatment of PTSD. Furthermore, the biological and neuropsychological measures included in this trial will substantially inform our understanding of the mechanisms of PTSD. Clinicaltrials.gov Identifier: NCT01018992.Registered 6 November 2009. First patient randomized 14 January 2010.

Abscisic Acid Acts as a Blocker of the Bitter Taste G Protein-Coupled Receptor T2R4.

PubMed

Pydi, Sai P; Jaggupilli, Appalaraju; Nelson, Ken M; Abrams, Suzanne R; Bhullar, Rajinder P; Loewen, Michele C; Chelikani, Prashen

2015-04-28

Bitter taste receptors (T2Rs) belong to the G protein-coupled receptor superfamily. In humans, 25 T2Rs mediate bitter taste sensation. In addition to the oral cavity, T2Rs are expressed in many extraoral tissues, including the central nervous system, respiratory system, and reproductive system. To understand the mechanistic roles of the T2Rs in oral and extraoral tissues, novel blockers or antagonists are urgently needed. Recently, we elucidated the binding pocket of T2R4 for its agonist quinine, and an antagonist and inhibitory neurotransmitter, γ-aminobutyric acid. This structure-function information about T2R4 led us to screen the plant hormone abscisic acid (ABA), its precursor (xanthoxin), and catabolite phaseic acid for their ability to bind and activate or inhibit T2R4. Molecular docking studies followed by functional assays involving calcium imaging confirmed that ABA is an antagonist with an IC50 value of 34.4 ± 1.1 μM. However, ABA precursor xanthoxin acts as an agonist on T2R4. Interestingly, molecular model-guided site-directed mutagenesis suggests that the T2R4 residues involved in quinine binding are also predominantly involved in binding to the novel antagonist, ABA. The antagonist ability of ABA was tested using another T2R4 agonist, yohimbine. Our results suggest that ABA does not inhibit yohimbine-induced T2R4 activity. The discovery of natural bitter blockers has immense nutraceutical and physiological significance and will help in dissecting the T2R molecular pathways in various tissues.

Vasopressin and angiotensin II in reflex regulation of ACTH, glucocorticoids, and renin: effect of water deprivation

NASA Technical Reports Server (NTRS)

Brooks, V. L.; Keil, L. C.

1992-01-01

Angiotensin II (ANG II) and vasopressin participate in baroreflex regulation of adrenocorticotropic hormone (ACTH), glucocorticoid, and renin secretion. The purpose of this study was to determine whether this participation is enhanced in water-deprived dogs, with chronically elevated plasma ANG II and vasopressin levels, compared with water-replete dogs. The baroreflex was assessed by infusing increasing doses of nitroprusside (0.3, 0.6, 1.5, and 3.0 micrograms.kg-1.min-1) in both groups of animals. To quantitate the participation of ANG II and vasopressin, the dogs were untreated or pretreated with the competitive ANG II antagonist saralasin, a V1-vasopressin antagonist, or combined V1/V2-vasopressin antagonist, either alone or in combination. The findings were as follows. 1) Larger reflex increases in ANG II, vasopressin, and glucocorticoids, but not ACTH, were produced in water-deprived dogs compared with water-replete dogs. 2) ANG II blockade blunted the glucocorticoid and ACTH responses to hypotension in water-deprived dogs, but not water-replete dogs. In contrast, vasopressin blockade reduced the ACTH response only in water-replete dogs. 3) Vasopressin or combined vasopressin and ANG II blockade reduced the plasma level of glucocorticoids related either to the fall in arterial pressure or to the increase in plasma ACTH concentration in water-replete dogs, and this effect was enhanced in water-deprived dogs. 4) In both water-deprived and water-replete animals, saralasin and/or a V1-antagonist increased the renin response to hypotension, but a combined V1/V2-antagonist did not. These results reemphasize the importance of endogenous ANG II and vasopressin in the regulation of ACTH, glucocorticoid, and renin secretion.(ABSTRACT TRUNCATED AT 250 WORDS).

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

PubMed Central

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

2016-01-01

Background: 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. Methods: 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 χ2-test were used to compare the groups. The p<0.05 was considered to show a statistically significant result. Results: The mean total gonadotropin doses were 3814±891 IU in group 1 and 3539±877 IU in group 2 (p=0.02). The number of metaphase-II oocytes (3.6±2.4 vs. 2.8±1.9, p=0.005) and implantation rates (27.8% vs. 18.8%, p=0.04) in group 1 and group 2, respectively were significantly different. The fertilization rate in group 1 and group 2 was 73% vs. 68%, respectively (p=0.5) and clinical pregnancy rate was 19.8% vs. 14.4%, respectively (p=0.13). Conclusion: The GnRH agonist microdose 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. PMID:27478770

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

PubMed

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 p<0.05 was considered to show a statistically significant result. The mean total gonadotropin doses were 3814±891 IU in group 1 and 3539±877 IU in group 2 (p=0.02). The number of metaphase-II oocytes (3.6±2.4 vs. 2.8±1.9, p=0.005) and implantation rates (27.8% vs. 18.8%, p=0.04) in group 1 and group 2, respectively were significantly different. The fertilization rate in group 1 and group 2 was 73% vs. 68%, respectively (p=0.5) and clinical pregnancy rate was 19.8% vs. 14.4%, respectively (p=0.13). The GnRH agonist microdose 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.

Identification of Putative Steroid Receptor Antagonists in Bottled Water: Combining Bioassays and High-Resolution Mass Spectrometry

PubMed Central

Wagner, Martin; Schlüsener, Michael P.; Ternes, Thomas A.; Oehlmann, Jörg

2013-01-01

Endocrine disrupting chemicals (EDCs) are man-made compounds interfering with hormone signaling and thereby adversely affecting human health. Recent reports provide evidence for the presence of EDCs in commercially available bottled water, including steroid receptor agonists and antagonists. However, since these findings are based on biological data the causative chemicals remain unidentified and, therefore, inaccessible for toxicological evaluation. Thus, the aim of this study is to assess the antiestrogenic and antiandrogenic activity of bottled water and to identify the causative steroid receptor antagonists. We evaluated the antiestrogenic and antiandrogenic activity of 18 bottled water products in reporter gene assays for human estrogen receptor alpha and androgen receptor. Using nontarget high-resolution mass spectrometry (LTQ-Orbitrap Velos), we acquired corresponding analytical data. We combined the biological and chemical information to determine the exact mass of the tentative steroid receptor antagonist. Further MSn experiments elucidated the molecule’s structure and enabled its identification. We detected significant antiestrogenicity in 13 of 18 products. 16 samples were antiandrogenic inhibiting the androgen receptor by up to 90%. Nontarget chemical analysis revealed that out of 24520 candidates present in bottled water one was consistently correlated with the antagonistic activity. By combining experimental and in silico MSn data we identified this compound as di(2-ethylhexyl) fumarate (DEHF). We confirmed the identity and biological activity of DEHF and additional isomers of dioctyl fumarate and maleate using authentic standards. Since DEHF is antiestrogenic but not antiandrogenic we conclude that additional, yet unidentified EDCs must contribute to the antagonistic effect of bottled water. Applying a novel approach to combine biological and chemical analysis this is the first study to identify so far unknown EDCs in bottled water. Notably, dioctyl fumarates and maleates have been overlooked by science and regulation to date. This illustrates the need to identify novel toxicologically relevant compounds to establish a more holistic picture of the human exposome. PMID:24015248

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

PubMed

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 < 0.01) and the total dose of gonadotropin used (IU) (5,892.9 +/- 1,725.7 vs. 4,367.5 +/- 1,582.1, p < 0.05) were significantly lower in Group 2 when compared to Group 1. The numbers of retrieved oocyte-cumulus complexes (4.5 +/- 3.6 vs. 5.9 +/- 4.9, p < 0.05), metaphase II oocytes (3.6 +/- 3.1 vs. 4.9 +/- 4.2, p < 0.05), two pronucleated oocytes (2.6 +/- 2.3 vs. 4.0 +/- 3.4, p < 0.05), the number of available embryos at day 3 (2.6 +/- 2.2 vs. 4.2 +/- 3.2, p < 0.05) and the rate of embryos with > 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.

α1-Adrenergic receptor downregulates hepatic FGF21 production and circulating FGF21 levels in mice.

PubMed

Nonogaki, Katsunori; Kaji, Takao

2017-01-18

Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone and is suggested as a promising target for the treatment of metabolic diseases. FGF21 acts centrally to exert its effects on energy expenditure and body weight via the sympathetic nervous system in mice. Here we show that intraperitoneal injection of phentolamine (an α-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the saline controls in C57BL6J mice, whereas alprenolol (a β-adrenergic receptor antagonist, 6mg/kg) had no effect. In addition, intraperitoneal injection of prazosin (an α1-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the controls, whereas yohimbine (an α2-adrenergic receptor antagonist, 5mg/kg) had no effect. Moreover, the treatment with prazosin significantly increased the expression of hepatic FGF21, while having no effect on the expression of hepatic PPARα and PPARγ. After a 5-h fast, intraperitoneal injection of prazosin significantly increased plasma FGF21 levels and impaired glucose tolerance compared with controls. These findings suggest that α1-adrenergic receptor downregulates the expression of hepatic FGF21 and plasma FGF21 levels independently of feeding and hepatic PPARα and PPARγ expression in mice, and that the increases in circulating FGF21 levels might be related to impaired glucose tolerance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

V2 Vasopressin Receptor (V2R) Mutations in Partial Nephrogenic Diabetes Insipidus Highlight Protean Agonism of V2R Antagonists*

PubMed Central

Takahashi, Kazuhiro; Makita, Noriko; Manaka, Katsunori; Hisano, Masataka; Akioka, Yuko; Miura, Kenichiro; Takubo, Noriyuki; Iida, Atsuko; Ueda, Norishi; Hashimoto, Makiko; Fujita, Toshiro; Igarashi, Takashi; Sekine, Takashi; Iiri, Taroh

2012-01-01

Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI. PMID:22144672

Repeated doses of GnRH antagonist at midcycle in artificial frozen embryo transfer cycles may not affect pregnancy outcomes.

PubMed

Palmerola, Katherine L; Hsu, Jennifer Y; Grossman, Lisa C; Sauer, Mark V; Lobo, Roger A

2017-04-01

No significant differences in outcomes have been found between protocols of endometrial preparation for frozen embryo transfer (FET), though gonadotropin releasing hormone (GnRH) antagonists may have detrimental effects on the endometrium. We conducted a retrospective cohort noninferiority study at a single academic center of women receiving multiple doses of mid-cycle GnRH antagonist (GAnt) to those receiving GnRH agonist (GAg) to determine if there are detrimental effects of GnRH antagonists. 1047 FET cycles were identified, detailed data was available in 840 cycles: 610 GAg and 230 GAnt cycles. Patients undergoing GAnt cycles were older (40 ± 6.6 versus 37 ± 5.1 years, p < 0.0001), more often used donor oocyte (36% versus 18.6%, p < 0.0001), and more often exhibited diminished ovarian reserve (49.1% versus 36.2%, p = 0.0009). Clinical pregnancy rates (CPRs) per transfer and implantation rates (IRs) were similar for GAnt and GAg cycles. There was a trend for higher pregnancy and IRs with GAg cycles in younger women (CPR 38.8% versus 26.7%, p = 0.16; IR 36% versus 23.3%, p = 0.07). Stratifying by diagnosis, CPR and IR were similar in GAnt and GAg cycles. A GAnt protocol of endometrial preparation for FET is not inferior to a GAg protocol regardless of patient age, use of donor oocyte, or infertility diagnosis.

Corticosteroid signaling in frog metamorphosis.

PubMed

Kulkarni, Saurabh S; Buchholz, Daniel R

2014-07-01

Stress in fetal and larval life can impact later health and fitness in humans and wildlife. Long-term effects of early life stress are mediated by altered stress physiology induced during the process of relaying environmental effects on development. Amphibian metamorphosis has been an important model system to study the role of hormones in development in an environmental context. Thyroid hormone (TH) is necessary and sufficient to initiate the dramatic morphological and physiological changes of metamorphosis, but TH alone is insufficient to complete metamorphosis. Other hormones, importantly corticosteroid hormones (CSs), influence the timing and nature of post-embryonic development. Stressors or treatments with CSs delay or accelerate metamorphic change, depending on the developmental stage of treatment. Also, TH and CSs have synergistic, antagonistic, and independent effects on gene regulation. Importantly, the identity of the endogenous corticosteroid hormone or receptor underlying any gene induction or remodeling event has not been determined. Levels of both CSs, corticosterone and aldosterone, peak at metamorphic climax, and the corticosteroid receptors, glucocorticoid and mineralocorticoid receptors, have wide expression distribution among tadpole tissues. Conclusive experiments to identify the endogenous players have been elusive due to difficulties in experimental control of corticosteroid production and signaling. Current data are consistent with the hypothesis that the two CSs and their receptors serve largely overlapping functions in regulating metamorphosis and synergy with TH. Knowledge of the endogenous players is critical to understanding the basic mechanisms and significance of corticosteroid action in regulating post-embryonic development in environmental contexts. Copyright © 2014 Elsevier Inc. All rights reserved.

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

PubMed Central

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-01-01

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N epsilon-(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1,D-Phe(pCl)2, D-Pal(3)2, Arg5,D-Lys[DL-A2pr(Sal2Cu)]6,D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(DL-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 micrograms in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides. PMID:2548206

Highly potent metallopeptide analogues of luteinizing hormone-releasing hormone.

PubMed

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-08-01

Metal complexes related to the cytotoxic complexes cisplatin [cis-diamminedichloroplatinum(II)] and transbis(salicylaldoximato)copper(II) were incorporated into suitably modified luteinizing hormone-releasing hormone (LH-RH) analogues containing D-lysine at position 6. Some of the metallopeptides thus obtained proved to be highly active LH-RH agonists or antagonists. For instance, SB-40, a PtCl2-containing metallopeptide in which platinum is coordinated to an N epsilon-(DL-2,3-diaminopropionyl)-D-lysine residue [D-Lys(DL-A2pr] at position 6, showed 50 times higher LH-releasing potency than the native hormone. SB-95, [Ac-D-Nal(2)1,D-Phe(pCl)2, D-Pal(3)2, Arg5,D-Lys[DL-A2pr(Sal2Cu)]6,D-Ala10]LH-RH, where Nal(2) is 3-(2-naphthyl)alanine, Pal(3) is 3-(3-pyridyl)alanine, and copper(II) is coordinated to the salicylideneimino moieties resulting from condensation of salicylaldehyde with D-Lys(DL-A2pr)6, caused 100% inhibition of ovulation at a dose of 3 micrograms in rats. Most metallopeptide analogues of LH-RH showed high affinities for the membrane receptors of rat pituitary and human breast cancer cells. Some of these metallopeptides had cytotoxic activity against human breast cancer and prostate cancer cell lines in vitro (this will be the subject of a separate paper on cytotoxicity evaluation). Such cytostatic metallopeptides could be envisioned as targeted chemotherapeutic agents in cancers that contain receptors for LH-RH-like peptides.

Estradiol and corticosterone stimulate the proliferation of a GH cell line, MtT/S: Proliferation of growth hormone cells.

PubMed

Nogami, Haruo; Hiraoka, Yoshiki; Aiso, Sadakazu

2016-08-01

Estrogens are known as a potent growth-stimulator of the anterior pituitary cells such as prolactin cells and somatomammotroph cell lines, while glucocorticoids often inhibit cellular proliferation in the pituitary gland as well as in the extra-pituitary tissues. In this study, the involvement of these steroid hormones in the regulation of proliferation was examined in the MtT/S cells, secreting growth hormone (GH). Effects of estrogens and glucocorticoids were examined in MtT/S cells grown in the medium containing dextran-coated charcoal treated serum. The relative cell density after culture was estimated by the Cell Titer-Glo Luminescent Cell Viability Assay System, and the proliferation rate was determined by the BrdU incorporation method. The mRNA levels were determined by real-time PCR. Estradiol and the specific agonist for both estrogen receptor (ER) α and ERβ stimulated MtT/S growth at a dose dependent manner. The membrane impermeable estrogen, 17β-estradiol-bovine serum albumin conjugate also stimulated the MtT/S proliferation. The effects of all estrogens were inhibited by an estrogen receptor antagonist, ICI182780. Corticosterone stimulated the proliferation of MtT/S cells at doses lower than 10nM without stimulating GH gene transcription, whereas it did not change the proliferation rate at 1μM. The effects of corticosterone were inhibited by glucocorticoid receptor inhibitor, RU486, but not by the mineralocorticoid receptor antagonist, spironolactone. Both estrogens and glucocorticoids were found to stimulate the proliferation of MtT/S, increasing the mRNA expression of cyclins D1, D3, and E. The results suggest that estrogens and glucocorticoids may be involved in the mechanisms responsible for the proliferation of GH cells in the course of pituitary development, to maintain the population of GH cells in the adult pituitary gland, and also in the promotion of GH cell tumors. Copyright © 2016 Elsevier Ltd. All rights reserved.

The effects of stressful stimuli and hypothalamic-pituitary-adrenal axis activation are reversed by the melanin-concentrating hormone 1 receptor antagonist SNAP 94847 in rodents.

PubMed

Smith, Daniel G; Hegde, Laxminarayan G; Wolinsky, Toni D; Miller, Silke; Papp, Mariusz; Ping, Xiaoli; Edwards, Tanya; Gerald, Christophe P; Craig, Douglas A

2009-02-11

Melanin-concentrating hormone (MCH) is an orexigenic and dipsogenic neuropeptide that has been reported to mediate acute behavioral and neuroendocrine stress-related responses via MCH(1) receptor activation in rodents. The purpose of the present investigation was to use the MCH(1) receptor antagonist SNAP 94847 (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperidin-4-yl}-4-methyl-phenyl)-isobutyramide) to determine the effects of MCH(1) receptor blockade on MCH-evoked adrenocorticotropic hormone (ACTH) release, chronic mild stress-induced anhedonia, stress-induced hyperthermia and forced swim stress-induced immobility. The appropriate dose range for testing SNAP 94847 was determined by measuring MCH-evoked water drinking. The corresponding occupancy of MCH(1) receptors in rat striatum was also measured across a broad dose range. Orally administered (p.o.) SNAP 94847 (1-10 mg/kg) corresponds to 30-60% occupancy at MCH(1) receptors and significantly blocks water drinking induced by the intracerebroventricular (i.c.v.) injection of MCH. MCH (i.c.v.) significantly elevates plasma levels of ACTH in rats, and SNAP 94847 (2.5 mg/kg, p.o.) blocks MCH-evoked ACTH release. Using the chronic mild stress paradigm, we show that repeated daily exposure to environmental stressors for 5 weeks significantly suppresses sucrose intake in rats, and that SNAP 94847 (1 mg/kg, BID) for 1-5 weeks restores baseline sucrose intake. Moreover, a single administration of SNAP 94847 attenuates stress-induced hyperthermia and the behavioral effects of forced swim stress with minimal effective doses of 2.5 and 30 mg/kg (p.o.), respectively. The regulation of ACTH release and reversal of the effects of chronic and acute stress by SNAP 94847 are suggestive of a role for MCH(1) receptor blockade in the treatment of disorders characterized by high allostatic load.

Oral curcumin has anti-arthritic efficacy through somatostatin generation via cAMP/PKA and Ca(2+)/CaMKII signaling pathways in the small intestine.

PubMed

Yang, Yan; Wu, Xin; Wei, Zhifeng; Dou, Yannong; Zhao, Di; Wang, Ting; Bian, Difei; Tong, Bei; Xia, Ying; Xia, Yufeng; Dai, Yue

2015-01-01

Curcumin (CUR) has been proven to be clinically effective in rheumatoid arthritis (RA) therapy, but its low oral bioavailability eclipses existent evidence that attempts to explain the underlying mechanism. Small intestine, the only organ exposed to a relatively high concentration of CUR, is the main site that generates gut hormones which are involved in the pathogenesis of RA. This study aims at addressing the hypothesis that one or more gut hormones serve as an intermediary agent for the anti-arthritic action of CUR. The protein and mRNA levels of gut hormones in CUR-treated rats were analyzed by ELISA and RT-PCR. Somatostatin (SOM) depletor and receptor antagonist were used to verify the key role of SOM in CUR-mediated anti-arthritic effect. The mechanisms underlying CUR-induced upregulation of SOM levels were explored by cellular experiments and immunohistochemical staining. The data showed that oral administration of CUR (100 mg/kg) for consecutive two weeks in adjuvant-induced arthritis rats still exhibited an extremely low plasma exposure despite of a dramatic amelioration of arthritis symptoms. When injected intraperitoneally, CUR lost anti-arthritic effect in rats, suggesting that it functions in an intestine-dependent manner. CUR elevated SOM levels in intestines and sera, and SOM depletor and non-selective SOM receptor antagonist could abolish the inhibitory effect of CUR on arthritis. Immunohistochemical assay demonstrated that CUR markedly increased the number of SOM-positive cells in both duodenum and jejunum. In vitro experiments demonstrated that CUR could augment SOM secretion from intestinal endocrine cells, and this effect could be hampered by either MEK1/2 or Ca(2+)/calmodulin-dependent kinase II (CAMKII) inhibitor. In summary, oral administration of CUR exhibits anti-arthritic effect through augmenting SOM secretion from the endocrine cells in small intestines via cAMP/PKA and Ca(2+)/CaMKII signaling pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

PubMed

Farkas, Imre; Vastagh, Csaba; Sárvári, Miklós; Liposits, Zsolt

2013-01-01

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.

The antagonistic regulation of abscisic acid-inhibited root growth by brassinosteroids is partially mediated via direct suppression of ABSCISIC ACID INSENSITIVE 5 expression by BRASSINAZOLE RESISTANT 1.

PubMed

Yang, Xiaorui; Bai, Yang; Shang, Jianxiu; Xin, Ruijiao; Tang, Wenqiang

2016-09-01

Brassinosteroids (BRs) and abscisic acid (ABA) are plant hormones that antagonistically regulate many aspects of plant growth and development; however, the mechanisms that regulate the crosstalk of these two hormones are still not well understood. BRs regulate plant growth and development by activating BRASSINAZOLE RESISTANT 1 (BZR1) family transcription factors. Here we show that the crosstalk between BRs and ABA signalling is partially mediated by BZR1 regulated gene expression. bzr1-1D is a dominant mutant with enhanced BR signalling; our results showed that bzr1-1D mutant is less sensitive to ABA-inhibited primary root growth. By RNA sequencing, a subset of BZR1 regulated ABA-responsive root genes were identified. Of these genes, the expression of a major ABA signalling component ABA INSENSITIVE 5 (ABI5) was found to be suppressed by BR and by BZR1. Additional evidences showed that BZR1 could bind strongly with several G-box cis-elements in the promoter of ABI5, suppress the expression of ABI5 and make plants less sensitive to ABA. Our study demonstrated that ABI5 is a direct target gene of BZR1, and modulating the expression of ABI5 by BZR1 plays important roles in regulating the crosstalk between the BR and ABA signalling pathways. © 2016 John Wiley & Sons Ltd.

The acute and temporary modulation of PERIOD genes by hydrocortisone in healthy subjects.

PubMed

Yurtsever, Türkan; Schilling, Thomas M; Kölsch, Monika; Turner, Jonathan D; Meyer, Jobst; Schächinger, Hartmut; Schote, Andrea B

2016-01-01

The physiological stress system and the circadian clock system communicate with each other at different signaling levels. The steroid hormone cortisol, the end-effector of the hypothalamus-pituitary-adrenal axis, is released in response to stress and acts as a mediator in circadian rhythms. We determined the effect of escalating cortisol doses on the expression of PERIOD genes (PER1, PER2 and PER3) in healthy subjects and analyzed whether the glucocorticoid receptor (GR) is involved in the cortisol-mediated PERIOD gene expression. Forty participants (50% males and 50% females) were randomly assigned to groups receiving a saline placebo solution or 3 mg, 6 mg, 12 mg and 24 mg of hydrocortisone. Blood was drawn every 15 min to measure quantitative gene expression of PER1, PER2 and PER3. A potential role of the GR was determined by an ex vivo study stimulating whole blood with hydrocortisone and RU486 (a GR antagonist). As a result, moderate doses of hydrocortisone produced an acute and temporary induction of PER1 and PER3 mRNA levels, whereas PER2 was not responsive to the hormone administration. The cortisol-dependent induction of PER1 was blocked by the GR antagonist in whole blood after treatment with hydrocortisone and RU486 ex vivo. In conclusion, acute pharmacological stress modulated the expression of PER1 and PER3 in whole blood temporarily in our short-term sampling design, suggesting that these circadian genes mediate stable molecular mechanisms in the periphery.

Alpha 2-adrenoceptor blockade, pituitary-adrenal hormones, and agonistic interactions in rats.

PubMed

Haller, J; Barna, I; Kovács, J L

1994-08-01

The effects of adrenergic activation on aggressiveness and the aggression induced endocrine changes were tested in rats. Alpha 2 adrenoceptor blockers were used for enhancing activation of the adrenergic system, and changes in aggressiveness were tested in resident-intruder contests. Three experiments were conducted. In experiment 1, saline injected rats responded to the presence of an opponent by aggression and the increase in plasma ACTH and corticosterone. Intraperitoneal administration of 1 mg/kg CH-38083 (an alpha 2 adrenoceptor antagonist) produced a several fold increase in clinch fighting and mutual upright scores, and also further enhanced the plasma ACTH and corticosterone response. In experiment 2, the effect of three doses (0.5, 1 and 2 mg/kg) of three different alpha 2 adrenoceptor blockers CH-38083, idazoxan and yohimbine were tested. All the substances increased aggression at 0.5 and 1 mg/kg; at 2 mg/kg the effect of idazoxan and yohimbine disappeared, while with CH-38083 an additional increase was obtained. In yohimbine treated animals the enhancement of aggression was reduced already at 1 mg/kg. In experiment 3, indomethacin, a potent inhibitor of the catecholamine-induced ACTH release completely abolished the effects of the alpha 2 adrenoceptor antagonist CH-38083: the intensity of agonistic interactions, as well as ACTH and corticosterone plasma concentrations, returned to control levels. The possible role of catecholamines and the stress hormones in the activation of aggression is discussed.

5-Bromo-2'-deoxyuridine stimulates the pituitary-adrenal axis in the rat: an effect blocked partially by endothelin-receptor antagonists.

PubMed

Malendowicz, L K; Nussdorfer, G G

1996-01-01

The bolus intraperitoneal administration of 5-bromo-2'-deoxyuridine (BrdU), at a dose in the range of those currently used for in vivo cell-kinetic studies, was found to provoke a marked rise in the plasma concentrations of adrenocorticotrophic hormone (ACTH), corticosterone and aldosterone in rats. This secretagogue effect of BrdU was annulled by the chronic pretreatment of animals with dexamethasone. The prolonged administration of endothelin-1 (ET-1) raised the blood level of aldosterone (but not of ACTH or corticosterone), and did not alter the response to BrdU. The pretreatment of rats with BQ-123 or BQ-788, two specific antagonists of ET-1 receptor subtypes A and B, did not affect the plasma concentrations of ACTH, corticosterone and aldosterone, but did partially reverse the effects of BrdU. In view of these findings we concluded that BrdU activates the pituitary-adrenal axis in rats, with its main mode of action being pituitary ACTH release; and the suppressive actions of BQ-123 and BQ-788 are independent of their antagonism on ET-1 receptors, and may be due to their interference with the intra-cellular mechanism(s) mediating the secretagogue action of BrdU. This effect of BrdU may have particular relevance to in vivo studies using BrdU labelling to assess cell kinetics of tissues (e.g. lymphatic tissue) affected profoundly by adrenal steroid hormones.

Hypothalamic oxytocin mediates social buffering of the stress response

PubMed Central

Smith, Adam S.; Wang, Zuoxin

2013-01-01

Background While stressful life events can enhance the risk of mental disorders, positive social interactions can propagate good mental health and normal behavioral routines. Still, the neural systems that promote these benefits are undetermined. Oxytocin is a hormone involved in social behavior and stress; thus, we focus on the impact that social buffering has on the stress response and the governing effects of oxytocin. Methods Female prairie voles (Microtus ochrogaster) were exposed to 1 hr immobilization stress then recovered alone or with their male partner to characterize the effect of social contact on the behavioral, physiological, and neuroendocrine stress response. In addition, we treated immobilized females recovering alone with oxytocin, or vehicle, and females recovering with their male partner with a selective oxytocin receptor antagonist, or vehicle. Group sizes varied from 6 to 8 voles (n = 98 total). Results We found that 1 hr immobilization increased anxiety-like behaviors and circulating levels of corticosterone, a stress hormone, in females recovering alone, but not the females recovering with their male partner. This social buffering by the male partner on biobehavioral responses to stress was accompanied by increased oxytocin release in the paraventricular nucleus (PVN) of the hypothalamus. Intra-PVN oxytocin injections reduced behavioral and corticosterone responses to immobilization whereas injections of an oxytocin receptor antagonist blocked the effects of the social buffering. Conclusions Together, our data demonstrate that PVN oxytocin mediates the social buffering effects on the stress response, and thus may be a target for treatment of stress-related disorders. PMID:24183103

Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY.

PubMed

Flannery, Brenna M; Clark, Erica S; Pestka, James J

2012-12-01

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.

Role of Glucagon-Like Peptide-1 and Gastric Inhibitory Peptide in Anorexia Induction Following Oral Exposure to the Trichothecene Mycotoxin Deoxynivalenol (Vomitoxin).

PubMed

Jia, Hui; Wu, Wen-Da; Lu, Xi; Zhang, Jie; He, Cheng-Hua; Zhang, Hai-Bin

2017-09-01

Deoxynivalenol (DON), which is a Type B trichothecene mycotoxin produced by Fusarium, frequently contaminates cereal staples, such as wheat, barley and corn. DON threatens animal and human health by suppressing food intake and impairing growth. While anorexia induction in mice exposed to DON has been linked to the elevation of the satiety hormones cholecystokinin and peptide YY3-36 in plasma, the effects of DON on the release of other satiety hormones, such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have not been established. The purpose of this study was to determine the roles of GLP-1 and GIP in DON-induced anorexia. In a nocturnal mouse food consumption model, the elevation of plasma GLP-1 and GIP concentrations markedly corresponded to anorexia induction by DON. Pretreatment with the GLP-1 receptor antagonist Exendin9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexia. In contrast, the GIP receptor antagonist Pro3GIP induced a dose-dependent attenuation of both GIP- and DON-induced anorexia. Taken together, these results suggest that GLP-1 and GIP play instrumental roles in anorexia induction following oral exposure to DON, and the effect of GLP-1 is more potent and long-acting than that of GIP. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Stimulation of the young poor responder: comparison of the luteal estradiol/gonadotropin-releasing hormone antagonist priming protocol versus oral contraceptive microdose leuprolide.

PubMed

Shastri, Shefali M; Barbieri, Elizabeth; Kligman, Isaac; Schoyer, Katherine D; Davis, Owen K; Rosenwaks, Zev

2011-02-01

To evaluate in vitro fertilization (IVF) cycle outcomes in young poor responders treated with a luteal estradiol/gonadotropin-releasing hormone antagonist (E(2)/ANT) protocol versus an oral contraceptive pill microdose leuprolide protocol (OCP-MDL). Retrospective cohort. Academic practice. Poor responders: 186 women, aged <35 years undergoing IVF with either E(2)/ANT or OCP-MDL protocols. None. Clinical pregnancies, oocytes retrieved, cancellation rate. Patients in the E(2)/ANT group had a greater gonadotropin requirement (71.9 ± 22.2 vs. 57.6 ± 25.7) and lower E(2) level (1,178.6 ± 668 vs. 1,627 ± 889), yet achieved similar numbers of oocytes retrieved and fertilized, and a greater number of embryos transferred (2.3 ± 0.9 vs. 2.0 ± 1.1) with a better mean grade (2.14 ± .06 vs. 2.7 ± 1.8) compared with the OCP/MDL group. The E2/ANT group exhibited a trend toward improved implantation rates (30.5% vs. 21.1%) and ongoing pregnancy rates per started cycle: 44 out of 117 (37%) versus 17 out of 69 (25%). Poor responders aged <35 years may be treated with the aggressive E(2)/ANT protocol to improve cycle outcomes. Both protocols remain viable options for this group. Adequately powered, randomized clinical comparison appears justified. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Tipepidine, a non-narcotic antitussive, exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone-treated rats.

PubMed

Kawaura, Kazuaki; Ogata, Yukino; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

2016-04-01

We investigated whether tipepidine exerts an antidepressant-like effect in the forced swimming test in adrenocorticotropic hormone (ACTH)-treated rats, which is known as a treatment-resistant depression model, and we studied the pharmacological mechanisms of the effects of tipepidine. Male Wistar rats (5-7 weeks old) were used in this study. Tipepidine (20 and 40 mg/kg, i.p.) decreased the immobility time in the forced swimming test in ACTH-treated rats. The anti-immobility effect of tipepidine was blocked by a catecholamine-depleting agent, alpha-methyl-p-tyrosine (300 mg/kg, s.c.), but not by a serotonin-depleting agent, p-chlorophenylalanine. The anti-immobility effect of tipepidine was also blocked by a dopamine D1 receptor antagonist, SCH23390 (0.02 mg/kg, s.c.) and an adrenaline α2 receptor antagonist, yohimbine (2 mg/kg, i.p.). In microdialysis technique, tipepidine (40 mg/kg, i.p.) increased the extracellular dopamine level of the nucleus accumbens (NAc) in ACTH-treated rats. These results suggest that tipepidine exerts an antidepressant-like effect in the forced swimming test in ACTH-treated rats, and that the effect of tipepidine is mediated by the stimulation of dopamine D1 receptors and adrenaline α2 receptors. The results also suggest that an increase in the extracellular dopamine level in the NAc may be involved in the antidepressant-like effect of tipepidine in ACTH-treated rats. Copyright © 2016. Published by Elsevier B.V.

Effects of an oral vasopressin receptor antagonist (OPC-31260) in a dog with syndrome of inappropriate secretion of antidiuretic hormone.

PubMed

Fleeman, L M; Irwin, P J; Phillips, P A; West, J

2000-12-01

The syndrome of inappropriate secretion of antidiuretic hormone is a rare disorder in dogs characterised by hypo-osmolality and persistent arginine vasopressin production in the absence of hypovolaemia and/or hypotension. The study describes the efficacy and safety of the nonpeptide selective arginine vasopressin V2 receptor antagonist OPC-31260 in a dog with the naturally occurring syndrome. The detailed case history of a dog with spontaneous syndrome of inappropriate secretion of antidiuretic hormone that received long-term therapy with oral OPC-31260 is presented. Effects of the first dose of OPC-31260 and of a dose administered after a continuous dosing period of 12 days are reported. Packed cell volume, plasma sodium, total protein, arginine vasopressin, renin activity, atrial natriuretic peptide, urine specific gravity, urine output, heart rate and body weight were monitored for 2 h before, and for 4 h after, the first dose of OPC-31260. The same parameters plus plasma osmolality and urine osmolality were monitored when an identical dose was administered after 12 days of therapy. Oral administration of OPC-31260 at 3 mg/kg body weight resulted in marked aquaresis with increased urine output and decline in urine specific gravity within 1 h. Corresponding increases in concentrations of plasma sodium, plasma osmolality and plasma renin activity were recorded over a 4 h period. Arginine vasopressin concentration remained inappropriately elevated throughout the study. Results were similar when the trial procedure was repeated after a stabilisation period of 12 days. Long-term therapy with OPC-31260 at a dose of 3 mg/kg body weight orally every 12 h resulted in good control of clinical signs with no deleterious effects detected during a 3-year follow-up period. Despite sustained clinical benefits observed in this case, plasma sodium did not normalise with continued administration of the drug. Treatment of a dog with naturally occurring syndrome of inappropriate secretion of antidiuretic hormone with OPC-31260 at 3 mg/kg body weight orally every 12 h resulted in marked aquaresis and significant palliation of clinical signs with no discernible side-effects detected over a 3-year period. Thus, OPC-31260 appears to offer a feasible medical alternative to water restriction for treatment of dogs with syndrome of inappropriate secretion of antidiuretic hormone. Higher doses of OPC-31260 may be required to achieve and maintain normal plasma sodium in dogs with this syndrome.

The influence of hormonal and neuronal factors on rat heart adrenoceptors

PubMed Central

Kunos, George; Mucci, Lucia; O'Regan, Seana

1980-01-01

1 The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective α- and β-adrenoceptor antagonists. The numbers and affinities of α- and β-adrenoceptors were also determined by radioligand binding to ventricular membrane fragments. 2 Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria. 3 The decreased β- and increased α-receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (>2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days). 4 Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [3H]-dihydroalprenolol ([3H]-DHA) binding sites from 27.5 ± 2.7 to 45.5 ± 5.7 fmol/mg protein and decreased the density of [3H]-WB-4101 binding sites from 38.7 ± 3.1 to 18.7 ± 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of α1- and β-receptors remained the same. 5 Sympathetic denervation of thyroidectomized rats by 6-hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [3H]-DHA binding sites was higher and that of [3H]-WB-4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [3H]-DHA and [3H]-WB-4101 binding sites. 6 These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac α1- and β-adrenoceptors in altered thyroid states. These thyroid hormone-dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of α1- and β-adrenoceptors. Reciprocal regulation of cardiac α1- and β-adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter. PMID:7470752

Acute sex hormone suppression reduces skeletal muscle sympathetic nerve activity.

PubMed

Day, Danielle S; Gozansky, Wendolyn S; Bell, Christopher; Kohrt, Wendy M

2011-10-01

Comparisons of sympathetic nervous system activity (SNA) between young and older women have produced equivocal results, in part due to inadequate control for potential differences in sex hormone concentrations, age, and body composition. The aim of the present study was to determine the effect of a short-term reduction in sex hormones on tonic skeletal muscle sympathetic nerve activity (MSNA), an indirect measure of whole body SNA, using an experimental model of sex hormone deficiency in young women. We also assessed the independent effects of estradiol and progesterone add-back therapy on MSNA. MSNA was measured in 9 women (30±2 years; mean±SE) on three separate occasions: during the mid-luteal menstrual cycle phase, on the fifth day of gonadotropin-releasing hormone antagonist (GnRHant) administration, and after 5 days add-back of either estradiol (n=4) or progesterone (n=3) during continued GnRHant administration. In response to GnRHant, there were significant reductions in serum estradiol and progesterone (both p<0.01) and MSNA (25.0±1.9 vs. 19.2±2.4 bursts/min, p=0.04). Continued GnRHant plus add-back estradiol or progesterone resulted in a nonsignificant decrease (19.2±1.7 vs. 12.1±1.9 bursts/min, p=0.07) or increase (16.2±1.7 vs. 21.0±6.0 bursts/min, p=0.39), respectively, in MSNA when compared with GnRHant alone. The findings of this preliminary study suggest that short-term ovarian hormone suppression attenuates MSNA and that this may be related to the suppression of progesterone rather than estradiol.

Advances in pharmacotherapy for treating endometriosis.

PubMed

Tafi, Emanuela; Leone Roberti Maggiore, Umberto; Alessandri, Franco; Bogliolo, Stefano; Gardella, Barbara; Vellone, Valerio Gaetano; Grillo, Federica; Mastracci, Luca; Ferrero, Simone

2015-01-01

Endometriosis is an estrogen-dependent chronic disease requiring long-term therapy. Therefore, the choice of medical treatment should be based on efficacy, preference of patients, incidence and severity of adverse effects and cost. This review briefly summarizes the currently available medical treatment for endometriosis. The treatments most recently proposed for endometriosis will be described in detail, including gonadotropin-releasing hormone (GnRH) antagonists, aromatase inhibitors (AIs) and the flexible extended combined oral contraceptive. The oral contraceptive pill and progestogens allow for the treatment of the majority of patients with endometriosis. The flexible extended dosing regimen, containing drospirenone and ethinylestradiol, may be particularly useful in patients suffering severe dysmenorrhea and improving the adherence and compliance with treatment. GnRH agonists may be used in patients resistant to first-line therapy; up to now, limited data are available on the use of GnRH antagonist (such as elagolix) in patients with endometriosis. AIs should be regarded as experimental therapies and used only in patients with symptoms resistant to other therapies; however, the use of these drugs is limited by the possibility to administer the treatment for short-term periods only (6 months) and, similarly to GnRH antagonists, by the high incidence of adverse effects, requiring the use of add-back therapy.

Blastocyst transfer does not improve cycle outcome as compared to D3 transfer in antagonist cycles with an elevated progesterone level on the day of hCG.

PubMed

Demirel, Cem; Aydoğdu, Serkan; Özdemir, Arzu İlknur; Keskin, Gülşah; Baştu, Ercan; Buyru, Faruk

2017-09-01

To evaluate the association between progesterone elevation on the day of human chorionic gonadotropin (hCG) administration and clinical pregnancy rates of gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles with the transfer of embryos at different developmental stages (day-3 versus day-5 ETs). This is a retrospective analysis of fresh IVF/ICSI; 194 cycles out of 2676 conducted in a single center. A total of 2676 cycles were analyzed, of which 386 had no progesterone measurements available. Two hundred eighteen cycles had progesterone elevation (p>1.5 ng/mL) giving an overall incidence of 9.5%. Twenty-four cycles were excluded from further analysis. Of the remaining 194 cycles, 151 had day-3 transfers and 43 had blastocyst transfers. There was no statistically significant difference in pregnancy and clinical pregnancy rates per transfer between the D3-ET and D5-ET groups (46% vs. 49%, and 39% vs. 35%, respectively). The results of this study suggest that blastocyst transfer does not improve cycle outcomes compared with D3 transfer in GnRH antagonist cycles with an elevated progesterone level on the day of hCG.

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

PubMed

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).

Noradrenaline inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin 6 production in human whole blood.

PubMed Central

van der Poll, T; Jansen, J; Endert, E; Sauerwein, H P; van Deventer, S J

1994-01-01

Sepsis and lipopolysaccharide (LPS) trigger the systemic release of both cytokines and catecholamines. Cytokines are known to be capable of eliciting a stress hormone response in vivo. The present study sought insight into the effect of noradrenaline on LPS-induced release of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6) in human whole blood. Whole blood was incubated with LPS for 4 h at 37 degrees C in the presence and absence of noradrenaline and/or specific alpha and beta antagonists and agonists. Noradrenaline caused a dose-dependent inhibition of LPS-induced TNF and IL-6 production. This effect could be completely prevented by addition of the specific beta 1, antagonist metoprolol, while it was not affected by the alpha antagonist phentolamine. Specific beta-adrenergic stimulation by isoprenaline mimicked the inhibiting effect of noradrenaline on LPS-evoked cytokine production, whereas alpha-adrenergic stimulation by phenylephrine had no effect. Fluorescence-activated cell sorter analysis demonstrated that beta-adrenergic stimulation had no effect on LPS binding to and internalization into mononuclear cells or on the expression of CD14, the major receptor for LPS on mononuclear cells. In acute sepsis, enhanced release of noradrenaline may be part of a negative feedback mechanism meant to inhibit ongoing TNF and IL-6 production. PMID:8168970

Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study.

PubMed

Vuong, Thi Ngoc Lan; Ho, Manh Tuong; Ha, Tan Duc; Phung, Huy Tuan; Huynh, Gia Bao; Humaidan, Peter

2016-02-01

To determine the optimal GnRH agonist dose for triggering of oocyte maturation in oocyte donors. Single-center, randomized, parallel, investigator-blinded trial. IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam. One hundred sixty-five oocyte donors (aged 18-35 years, body mass index [BMI] <28 kg/m(2), antimüllerian hormone level >1.25 ng/mL, and antral follicle count ≥6). Ovulation trigger with 0.2, 0.3, or 0.4 mg triptorelin in a GnRH antagonist cycle. The primary end point was number of metaphase II oocytes. Secondary end points were fertilization and cleavage rates, number of embryos and top-quality embryos, steroid levels, ovarian volume, and ongoing pregnancy rate (PR) in recipients. There were no significant differences between the triptorelin 0.2, 0.3, and 0.4 mg trigger groups with respect to number of metaphase II oocytes (16.0 ± 8.5, 15.9 ± 7.8, and 14.7 ± 8.4, respectively), embryos (13.2 ± 7.8, 11.7 ± 6.9, 11.8 ± 7.0), and number of top-quality embryos (3.8 ± 2.9, 3.6 ± 3.0, 4.1 ± 3.0). Luteinizing hormone levels at 24 hours and 36 hours after trigger was significantly higher with triptorelin 0.4 mg versus 0.2 mg and 0.3 mg (9.8 ± 7.1 IU/L vs. 7.3 ± 4.1 IU/L and 7.2 ± 3.7 IU/L, respectively; 4.6 ± 3.2 IU/L vs. 3.2 ± 2.3 IU/L and 3.3 ± 2.1 IU/L, respectively. Progesterone level at oocyte pick-up +6 days was significantly higher in the 0.4-mg group (2.2 ± 3.7 ng/ml) versus 0.2 mg (1.1 ± 1.0 ng/ml) and 0.3 mg (1.2 ± 1.6 ng/ml). One patient developed early-onset severe ovarian hyperstimulation syndrome (OHSS). No significant differences between triptorelin doses of 0.2, 0.3, and 0.4 mg used for ovulation trigger in oocyte donors were seen with regard to the number of mature oocytes and top-quality embryos. NCT02208986. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Benvenga, S; Ruggeri, R M; Russo, A; Lapa, D; Campenni, A; Trimarchi, F

2001-08-01

Old studies in animals and unblinded studies in a few hyperthyroid patients suggested that L -carnitine is a periferal antagonist of thyroid hormone action at least in some tissues. This conclusion was substantiated by our recent observation that carnitine inhibits thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts. In the randomized, double-blind, placebo-controlled 6-month trial reported here, we assessed whether 2 or 4 g/d oral L-carnitine were able to both reverse and prevent/minimize nine hyperthyroidism- related symptoms. We also evaluated changes on nine thyroid hormone-sensitive biochemical parameters and on vertebral and hip mineral density (bone mineral density). Fifty women under a fixed TSH-suppressive dose of L -T(4) for all 6 months were randomly allocated to five groups of 10 subjects each. Group 0 associated placebo for 6 months; groups A2 and A4 started associating placebo (first bimester), substituted placebo with 2 or 4 g/d carnitine (second bimester), and then returned to the association with placebo. Groups B2 and B4 started associating 2 and 4 g/d carnitine for the first two bimesters, and then substituted carnitine with placebo (third bimester). Symptoms and biochemical parameters worsened in group 0. In group A, symptoms and biochemical parameters worsened during the first bimester, returned to baseline or increased minimally during the second bimester (except osteocalcin and urinary OH-proline), and worsened again in the third bimester. In group B, symptoms and biochemical parameters (except osteocalcin and urinary OH-proline) did not worsen or even improved over the first 4 months; they tended to worsen in the third bimester. In both the A and B groups, the two doses of carnitine were similarly effective. At the end of the trial, bone mineral density tended to increase in groups B and A (B > A). In conclusion, L-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a beneficial effect on bone mineralization. Because hyperthyroidism depletes the body deposits of carnitine and since carnitine has no toxicity, teratogenicity, contraindications and interactions with drugs, carnitine can be of clinical use.

Down-regulation of parathyroid hormone (PTH) receptors in cultured bone cells is associated with agonist-specific intracellular processing of PTH-receptor complexes.

PubMed

Teitelbaum, A P; Silve, C M; Nyiredy, K O; Arnaud, C D

1986-02-01

Exposure of cultured embryonic chicken bone cells to the PTH agonists bovine (b) PTH-(1-34) and [8Nle, 18Nle, 34Tyr]bPTH-(1-34)amide [bPTH-(1-34)A] reduces the subsequent cAMP response to the hormone and decreases the specific binding of 125I-labeled PTH to these cultures. To determine whether PTH receptor down-regulation in cultured bone cells is mediated by cellular internalization of PTH-receptor complexes, we measured the uptake of [125I]bPTH-(1-34) into an acid-resistant compartment. Uptake of radioactivity into this compartment was inhibited by incubating cells at 4 C with phenylarsineoxide and unlabeled bPTH-(1-34). Tracer uptake into the acid-resistant compartment at any time was directly proportional to total cell binding at 22 C. Thus, it is likely that PTH-receptor complexes are internalized by bone cells. This mechanism may explain the loss of cell surface receptors after PTH pretreatment. To determine whether internalized PTH-receptor complexes are reinserted into the plasma membrane, we measured PTH binding and PTH stimulation of cAMP production after cells were exposed to monensin, a known inhibitor of receptor recycling. Monensin (25 microM) had no effect on PTH receptor number or affinity and did not alter PTH-stimulated cAMP accumulation. However, monensin (25 microM) incubated with cells pretreated with various concentrations of bPTH-(1-34) for 1 h potentiated the effect of the hormone to reduce subsequent [125I]bPTH-(1-34) binding and PTH-stimulated cAMP accumulation by more than 2 orders of magnitude. Chloroquine also potentiated PTH-induced down-regulation of PTH receptors. By contrast, neither agent influenced PTH binding or PTH-stimulated cAMP production in cells pretreated with the antagonist bPTH-(3-34)A. Thus, monensin potentiated PTH receptor loss only in cells pretreated with PTH agonists, indicating that antagonist-occupied receptors may be processed differently from agonist-occupied receptors in bone cells. The data further suggest that the attenuation of PTH stimulation of cAMP production in treated bone cells may be, at least in part, due to receptor-mediated endocytosis of the hormone.

Male hormonal contraception: concept proven, product in sight?

PubMed

Matthiesson, Kati L; McLachlan, Robert I

2006-01-01

Current male hormonal contraceptive (MHC) regimens act at various levels within the hypothalamic pituitary testicular axis, principally to induce the withdrawal of the pituitary gonadotrophins and in turn intratesticular androgen production and spermatogenesis. Azoospermia or severe oligozoospermia result from the inhibition of spermatogonial maturation and sperm release (spermiation). All regimens include an androgen to maintain virilization, while in many the suppression of gonadotrophins/spermatogenesis is augmented by the addition of another anti-gonadotrophic agent (progestin, GnRH antagonist). The suppression of sperm concentration to 1 x 10(6)/ml appears to provide comparable contraceptive efficacy to female hormonal methods, but the confidence intervals around these estimates remain relatively large, reflecting the limited number of exposure years reported. Also, inconsistencies in the rapidity and depth of spermatogenic suppression, potential for secondary escape of sperm into the ejaculate and onset of fertility return not readily explainable by analysis of subject serum hormone levels, germ cell number or intratesticular steroidogenesis, are apparent. As such, a better understanding of the endocrine and genetic regulation of spermatogenesis is necessary and may allow for new treatment paradigms. The development of an effective, consumer-friendly male contraceptive remains challenging, as it requires strong translational cooperation not only between basic scientists and clinicians but also between public and private sectors. At present, a prototype MHC product using a long-acting injectable testosterone and depot progestin is well advanced.

Sex hormones in the cardiovascular system.

PubMed

dos Santos, Roger Lyrio; da Silva, Fabrício Bragança; Ribeiro, Rogério Faustino; Stefanon, Ivanita

2014-05-01

Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.

Central administration of orexin A suppresses basal and domperidone stimulated plasma prolactin.

PubMed

Russell, S H; Kim, M S; Small, C J; Abbott, C R; Morgan, D G; Taheri, S; Murphy, K G; Todd, J F; Ghatei, M A; Bloom, S R

2000-12-01

Orexin immunoreactive fibres are abundant in the hypothalamus suggesting a neuroendocrine regulatory role. Intracerebroventricular (ICV) administration of orexin A suppressed plasma prolactin in male rats by 71% at 20 min post-injection and 83% at 90 min post-injection (P < 0.005 vs saline at both time points). To investigate whether this effect was through the tuberoinfundibular dopaminergic (TIDA) system, a supra-maximal dose of domperidone, a dopamine receptor antagonist, was injected intraperitoneally (i.p.) prior to ICV injection of orexin A. ICV orexin A significantly suppressed domperidone (9 mg/kg)-stimulated plasma prolactin levels, by up to 40% (i.p. domperidone + ICV orexin A 3 nmol 34.5 +/- 7.4 ng/ml and i.p. domperidone + ICV orexin A 20 nmol 43.5 +/- 4.3 ng/ml, both P < 0.005 vs i.p. domperidone + ICV saline 57.9 +/- 2.7 ng/ml). Orexin A, 100 nM, significantly stimulated release of neurotensin, vasoactive intestinal polypeptide, somatostatin, corticotropin releasing factor and luteinizing hormone releasing hormone, but had no effect on release of dopamine, thyrotropin releasing hormone (TRH), vasopressin or melanin-concentrating hormone from hypothalamic explants in vitro. Orexin A did not alter basal or TRH stimulated prolactin release in dispersed pituitary cells harvested from male rats. The data suggest that ICV administration of orexin A suppresses plasma prolactin in part through a pathway independent of the dopaminergic system.

Therapy Insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease.

PubMed

Dooley, Mary Anne; Nair, Raj

2008-05-01

Cyclophosphamide remains a necessary treatment for severe rheumatic diseases, despite the continued search for alternative therapies with less gonadal toxicity. The risk of premature gonadal failure and sterility might lead young patients to delay treatment with cyclophosphamide. The patient's age at treatment and the cumulative dose received remain important risk factors for cyclophosphamide-induced gonadal failure in both males and females. Estrogen-containing oral contraceptives for females and testosterone for males are suggested to reduce the gonadal toxicity of cyclophosphamide, although few studies support these interventions. Owing to increased side effects, hormonal therapy is often avoided in patients with edema, hypertension, nephrotic syndrome or antiphospholipid antibodies. Agonists and antagonists of gonadotropin receptors are under study. Gonadotropin-receptor agonists might have beneficial effects in addition to suppression of sex-hormone production. The outcome of attempted cryopreservation of eggs, embryos or ovaries remains uncertain for women seeking to preserve their reproductive potential. Storing male gametes before chemotherapy is widely practiced and technically successful. As recovery of menses or production of testosterone does not predict individual fertility, identification of biomarkers of gonadal function and reserve, including serum levels of several hormones, ultrasonographic measurements of ovarian volume and antral follicle count, are necessary.

Investigational hormone receptor agonists as ongoing female contraception: a focus on selective progesterone receptor modulators in early clinical development.

PubMed

Nelson, Anita L

2015-01-01

As efforts are made to continue to increase the safety of contraceptive methods, those without estrogen have attracted new attention. Progestin-only options are available in many delivery systems, but most cause disturbed bleeding patterns. For gynecologic patients, selective progesterone receptor modulators (SPRMs) have been approved for medical abortion, for ovulation suppression in emergency contraception, and for the treatment of heavy menstrual bleeding due to leiomyoma. This article discusses the role of SPRMs in controlling fertility on an ongoing basis with particular emphasis on mifepristone and ulipristal acetate (UPA), since none of the other compounds has progressed out of early Phase I - II testing. It also discusses important information about the mechanisms of action and safety of these two SPRMs. Of all the investigational hormone agonist/antagonists, SPRMs have demonstrated the greatest potential as ongoing female contraceptives. They have the ability to suppress ovulation after initiation of the luteinizing hormone (LH) surge without affecting ovarian production of estrogen or inducing any significant metabolic changes. SPRMs may well be able to provide longer term contraception as oral agents, vaginal rings, and perhaps even intrauterine devices. UPA has the greatest promise. Current research needs to be expanded.

Neurohypophysial Hormones Regulate Amphibious Behaviour in the Mudskipper Goby.

PubMed

Sakamoto, Tatsuya; Nishiyama, Yudai; Ikeda, Aoi; Takahashi, Hideya; Hyodo, Susumu; Kagawa, Nao; Sakamoto, Hirotaka

2015-01-01

The neurohypophysial hormones, arginine vasotocin and isotocin, regulate both hydromineral balance and social behaviors in fish. In the amphibious mudskipper, Periophthalmus modestus, we previously found arginine-vasotocin-specific regulation of aggressive behavior, including migration of the submissive subordinate into water. This migration also implies the need for adaptation to dehydration. Here, we examined the effects of arginine vasotocin and isotocin administration on the amphibious behavior of individual mudskippers in vivo. The mudskippers remained in the water for an increased period of time after 1-8 h of intracerebroventricular (ICV) injection with 500 pg/g arginine vasotocin or isotocin. The 'frequency of migration' was decreased after ICV injection of arginine vasotocin or isotocin, reflecting a tendency to remain in the water. ICV injections of isotocin receptor antagonist with arginine vasotocin or isotocin inhibited all of these hormonal effects. In animals kept out of water, mRNA expression of brain arginine vasotocin and isotocin precursors increased 3- and 1.5-fold, respectively. Given the relatively wide distribution of arginine vasotocin fibres throughout the mudskipper brain, induction of arginine vasotocin and isotocin under terrestrial conditions may be involved also in the preference for an aquatic habitat as ligands for brain isotocin receptors.

Neurohypophysial Hormones Regulate Amphibious Behaviour in the Mudskipper Goby

PubMed Central

Sakamoto, Tatsuya; Nishiyama, Yudai; Ikeda, Aoi; Takahashi, Hideya; Hyodo, Susumu; Kagawa, Nao; Sakamoto, Hirotaka

2015-01-01

The neurohypophysial hormones, arginine vasotocin and isotocin, regulate both hydromineral balance and social behaviors in fish. In the amphibious mudskipper, Periophthalmus modestus, we previously found arginine-vasotocin-specific regulation of aggressive behavior, including migration of the submissive subordinate into water. This migration also implies the need for adaptation to dehydration. Here, we examined the effects of arginine vasotocin and isotocin administration on the amphibious behavior of individual mudskippers in vivo. The mudskippers remained in the water for an increased period of time after 1–8 h of intracerebroventricular (ICV) injection with 500 pg/g arginine vasotocin or isotocin. The ‘frequency of migration’ was decreased after ICV injection of arginine vasotocin or isotocin, reflecting a tendency to remain in the water. ICV injections of isotocin receptor antagonist with arginine vasotocin or isotocin inhibited all of these hormonal effects. In animals kept out of water, mRNA expression of brain arginine vasotocin and isotocin precursors increased 3- and 1.5-fold, respectively. Given the relatively wide distribution of arginine vasotocin fibres throughout the mudskipper brain, induction of arginine vasotocin and isotocin under terrestrial conditions may be involved also in the preference for an aquatic habitat as ligands for brain isotocin receptors. PMID:26230718

TR-DB: an open-access database of compounds affecting the ethylene-induced triple response in Arabidopsis.

PubMed

Hu, Yuming; Callebert, Pieter; Vandemoortel, Ilse; Nguyen, Long; Audenaert, Dominique; Verschraegen, Luc; Vandenbussche, Filip; Van Der Straeten, Dominique

2014-02-01

Small molecules which act as hormone agonists or antagonists represent useful tools in fundamental research and are widely applied in agriculture to control hormone effects. High-throughput screening of large chemical compound libraries has yielded new findings in plant biology, with possible future applications in agriculture and horticulture. To further understand ethylene biosynthesis/signaling and its crosstalk with other hormones, we screened a 12,000 compound chemical library based on an ethylene-related bioassay of dark-grown Arabidopsis thaliana (L.) Heynh. seedlings. From the initial screening, 1313 (∼11%) biologically active small molecules altering the phenotype triggered by the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC), were identified. Selection and sorting in classes were based on the angle of curvature of the apical hook, the length and width of the hypocotyl and the root. A MySQL-database was constructed (https://chaos.ugent.be/WE15/) including basic chemical information on the compounds, images illustrating the phenotypes, phenotype descriptions and classification. The research perspectives for different classes of hit compounds will be evaluated, and some general screening tips for customized high-throughput screening and pitfalls will be discussed. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Induction of calcium-dependent nitric oxide synthases by sex hormones.

PubMed

Weiner, C P; Lizasoain, I; Baylis, S A; Knowles, R G; Charles, I G; Moncada, S

1994-05-24

We have examined the effects of pregnancy and sex hormones on calcium-dependent and calcium-independent nitric oxide synthases (NOSs) in the guinea pig. Pregnancy (near term) caused a > 4-fold increase in the activity of calcium-dependent NOS in the uterine artery and at least a doubling in the heart, kidney, skeletal muscle, esophagus, and cerebellum. The increase in NOS activity in the cerebellum during pregnancy was inhibited by the estrogen-receptor antagonist tamoxifen. Treatment with estradiol (but not progesterone) also increased calcium-dependent NOS activity in the tissues examined from both females and males. Testosterone increased calcium-dependent NOS only in the cerebellum. No significant change in calcium-independent NOS activity was observed either during pregnancy or after the administration of any sex hormone. Both pregnancy and estradiol treatment increased the amount of mRNAs for NOS isozymes eNOS and nNOS in skeletal muscle, suggesting that the increases in NOS activity result from enzyme induction. Thus both eNOS and nNOS are subject to regulation by estrogen, an action that could explain some of the changes that occur during pregnancy and some gender differences in physiology and pathophysiology.

What goes on behind closed doors: physiological vs. pharmacological steroid hormone actions

PubMed Central

Simons, S. Stoney

2009-01-01

Summary Steroid hormone-activated receptor proteins are among the best understood class of factors for altering gene transcription in cells. Steroid receptors are of major importance in maintaining normal human physiology by responding to circulating concentrations of steroid in the nM range. Nonetheless, most studies of steroid receptor action have been conducted using the supra-physiological conditions of saturating concentrations (≥100 nM) of potent synthetic steroid agonists. Here we summarize the recent developments arising from experiments using two clinically relevant conditions: subsaturating concentrations of agonist (to mimic the circulating concentrations in mammals) and saturating concentrations of antagonists (which are employed in endocrine therapies to block the actions of endogenous steroids). These studies have revealed new facets of steroid hormone action that could not be uncovered by conventional experiments with saturating concentrations of agonist steroids, such as a plethora of factors/conditions for the differential control of gene expression by physiological levels of steroid, a rational approach for examining the gene-specific variations in partial agonist activity of antisteroids, and a dissociation of steroid potency and efficacy that implies the existence of separate, and possibly novel, mechanistic steps and cofactors. PMID:18623071

Bench-to-bedside review: The gut as an endocrine organ in the critically ill

PubMed Central

2010-01-01

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties. PMID:20887636

Screening of synthetic phage display scFv libraries yields competitive ligands of human leptin receptor.

PubMed

Molek, Peter; Vodnik, Miha; Strukelj, Borut; Bratkovič, Tomaž

2014-09-26

Initially considered the main endogenous anorexigenic factor, fat-derived leptin turned out to be a markedly pleiotropic hormone, influencing diverse physiological processes. Moreover, hyperleptinemia in obese individuals has been linked to the onset or progression of serious disorders, such as cancer, autoimmune diseases, and atherosclerosis, and antagonizing peripheral leptin's signalization has been shown to improve these conditions. To develop an antibody-based leptin antagonist we have devised a tailored panning procedure and screened two phage display libraries of single chain variable antibody fragments (scFvs) against recombinant leptin receptor. One of the scFvs was expressed in Escherichia coli and its interaction with leptin receptor was characterized in more detail. It was found to recognize a discontinuous epitope and to compete with leptin for receptor binding with IC50 and Kd values in the nanomolar range. The reported scFv represents a lead for development of leptin antagonists that may ultimately find use in therapy of various hyperleptinemia-related disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice.

PubMed

Zhou, Ming; Bakker, Eveline H M; Velzing, Els H; Berger, Stefan; Oitzl, Melly; Joëls, Marian; Krugers, Harm J

2010-11-01

Corticosteroid hormones are thought to promote optimal behavioral adaptation under fearful conditions, primarily via glucocorticoid receptors (GRs). Here, we examined - using pharmacological and genetic approaches in mice - if mineralocorticoid receptors (MRs) also play a role in fearful memory formation. As expected, administration of the GR-antagonist RU38486 prior to training in a fear conditioning paradigm impaired contextual memory when tested 24 (but not when tested 3) h after training. Tone-cue memory was enhanced by RU38486 when tested at 4 (but not 25) h after training. Interestingly, pre (but not post)-training administration of MR antagonist spironolactone impaired contextual memory, both at 3 and 24h after training. Similar effects were also found in forebrain-specific MR knockout mice. Spironolactone also impaired tone-cue memory, but only at 4h after training. These results reveal that - in addition to GRs - MRs also play a critical role in establishing fear memories, particularly in the early phase of memory formation. Copyright © 2010 Elsevier Inc. All rights reserved.

Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene-expression profiles in dystrophic skeletal muscles.

PubMed

Chadwick, Jessica A; Bhattacharya, Sayak; Lowe, Jeovanna; Weisleder, Noah; Rafael-Fortney, Jill A

2017-02-01

Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD. Copyright © 2017 the American Physiological Society.

Sex differences in acute hormonal and subjective response to naltrexone: the impact of menstrual cycle phase

PubMed Central

Roche, Daniel J.O.; King, Andrea C.

2015-01-01

Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n = 46 women) participated in two morning sessions in which they received 50 mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n = 23) or luteal phase of the MC. Serum cortisol, prolactin, and luteinizing hormone (LH), salivary cortisol, and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women. PMID:25459893

The effects of juvenile hormone on Lasius niger reproduction.

PubMed

Pamminger, T; Buttstedt, A; Norman, V; Schierhorn, A; Botías, C; Jones, J C; Basley, K; Hughes, W O H

2016-12-01

Reproduction has been shown to be costly for survival in a wide diversity of taxa. The resulting trade-off, termed the reproduction-survival trade-off, is thought to be one of the most fundamental forces of life-history evolution. In insects the pleiotropic effect of juvenile hormone (JH), antagonistically regulating reproduction and pathogen resistance, is suggested to underlie this phenomenon. In contrast to the majority of insects, reproductive individuals in many eusocial insects defy this trade-off and live both long and prosper. By remodelling the gonadotropic effects of JH in reproductive regulation, the queens of the long-lived black garden ant Lasius niger (living up to 27 years), have circumvented the reproduction-survival trade off enabling them to maximize both reproduction and pathogen resistance simultaneously. In this study we measure fertility, vitellogenin gene expression and protein levels after experimental manipulation of hormone levels. We use these measurements to investigate the mechanistic basis of endocrinological role remodelling in reproduction and determine how JH suppresses reproduction in this species, rather then stimulating it, like in the majority of insects. We find that JH likely inhibits three key aspects of reproduction both during vitellogenesis and oogenesis, including two previously unknown mechanisms. In addition, we document that juvenile hormone, as in the majority of insects, has retained some stimulatory function in regulating vitellogenin expression. We discuss the evolutionary consequences of this complex regulatory architecture of reproduction in L. niger, which might enable the evolution of similar reproductive phenotypes by alternate regulatory pathways, and the surprising flexibility regulatory role of juvenile hormone in this process. Copyright © 2016 Elsevier Ltd. All rights reserved.

A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear

PubMed Central

Meyer, Retsina M.; Burgos-Robles, Anthony; Liu, Elizabeth; Correia, Susana S.; Goosens, Ki A.

2014-01-01

Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is not a clear relationship between the levels of these hormones and stress-associated mental illnesses such as post-traumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin releasing factor (CRF) or corticosterone. Repeated intra-amygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was increased by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin and growth hormone in maladaptive changes following prolonged stress. PMID:24126924

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

PubMed

Stenbæk, D S; Toftager, M; Hjordt, L V; Jensen, P S; Holst, K K; Bryndorf, T; Holland, T; Bogstad, J; Pinborg, A; Hornnes, P; Frokjaer, V G

2015-01-01

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? 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. 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. A total of 83 women undergoing their first ART cycle were consecutively randomized 1:1 to GnRH antagonist (n = 42) or GnRH agonist (n = 41) protocol. The study population was a subgroup of a larger ongoing Danish clinical randomized trial and was established as an add-on in the period 2010-2012. Women in the GnRH antagonist protocol received daily injections with recombinant follicle-stimulating hormone, Puregon(®) and subcutaneous injections with GnRH antagonist, Orgalutran(®). Women in the GnRH agonist protocol received nasal administration of the GnRH agonist, Synarela(®) and subcutaneous injections with FSH, Puregon(®). The study design did not allow for a blinding procedure. All women self-reported the Profile of Mood States, the Perceived Stress Scale, the Symptom Checklist-92-Revised, and the Major Depression Inventory questionnaires, at baseline, at ART cycle day 35, on the day of oocyte pick-up, and on the day of hCG testing. Also, a series of Profile of Mood States were reported daily during pharmacological treatment to monitor mood fluctuations. The personality trait Neuroticism was assessed at baseline by the self-reported NEO-PI-R questionnaire. ART did not induce within- or between-protocol changes in any of the applied measures of mental distress. However, the GnRH antagonist protocol was associated with more pronounced median mood fluctuations during the stimulation phase (antagonist, 11.0 SD, [IQR = 21.1-6.1]; agonist, 8.9 SD, [IQR = 11.3-5.7], P = 0.025). This association became non-significant after applying a Bonferroni-Holm correction. Neuroticism was highly positively associated with increased levels of mental distress throughout treatment independent of protocols (all P-values <0.006), and cross-sectional analysis revealed that women with high or low Neuroticism scores at baseline showed a significant trend towards lower chances of a positive pregnancy test (P-value =0.028). Information on prognostic factors such as preceding length of infertility, number of retrieved oocytes and number of prior insemination treatments was not accounted for in the analyses. The stratification of protocols by age in the subgroups of women included in this study was suboptimal. Women with prior or current use of antidepressant medication were excluded from our study. Our results imply that mental distress emerging during ART treatment is not causally linked to hypogonadism per se or to the choice of protocol. Rather, our data highlight the potential importance of (i) rapid increases in ovarian steroids and (ii) addressing personality traits indexing negative emotionality, i.e. Neuroticism, in women undergoing ART treatment, to optimize both emotional adjustment and, possibly, the chances of obtaining pregnancy. The Danish Research Council for Independent Research and MSD, Denmark kindly supported the study. The authors declare no competing financial interests. EudraCT - 2008-005452-24. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Anorexia Induction by the Trichothecene Deoxynivalenol (Vomitoxin) Is Mediated by the Release of the Gut Satiety Hormone Peptide YY

PubMed Central

Pestka, James J.

2012-01-01

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin’s anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15–120min and lasted up to 120min (CCK) and 240min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression. PMID:22903826

Astressin B, a corticotropin-releasing hormone receptor antagonist, accelerates the return to normal luteal function after an inflammatory-like stress challenge in the rhesus monkey.

PubMed

Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas; Rivier, Jean; Ferin, Michel

2007-02-01

Endogenous release of CRH in stress has been associated with a dysfunctional reproductive endocrine axis. In the rhesus monkey, an inflammatory-like stress challenge in the luteal phase decreases luteal secretory function. Here, we tested the effectiveness of astressin B, a nonspecific CRH receptor antagonist, in constraining the deleterious impact of a 10-d lipopolysaccharide (LPS) challenge on the menstrual cycle. Two protocols were carried out in nine animals. In the first, the animals, after showing two normal consecutive control cycles, were injected daily for 10 days with LPS (75-125 mug/d) during the luteal phase of the cycle. The animals were followed through the two postchallenge cycles. The second protocol, carried out in the following year, was identical with protocol 1, except that the animals were treated with astressin B (0.45 mg/kg) 1 h before each daily LPS challenge during the luteal phase. Blood samples were obtained daily to document cyclic hormones levels. The LPS challenge significantly decreased luteal progesterone and LH release during the challenge cycle. Inhibition of luteal progesterone extended to the two successive postchallenge cycles. Astressin B treatment prevented luteal LH but not luteal progesterone decrease during the treatment cycle and restored normal progesterone secretion during the two posttreatment cycles. We conclude that the deleterious impact of a short-term inflammatory stress challenge on luteal function is far longer than the stress period itself. Systemic administration of astressin B accelerates the return to normal luteal function, presumably by restoring normal neuroendocrine regulation of gonadotropin secretion.

ORA59 and EIN3 interaction couples jasmonate-ethylene synergistic action to antagonistic salicylic acid regulation of PDF expression.

PubMed

He, Xiang; Jiang, Jishan; Wang, Chang-Quan; Dehesh, Katayoon

2017-04-01

Hormonal crosstalk is central for tailoring plant responses to the nature of challenges encountered. The role of antagonism between the two major defense hormones, salicylic acid (SA) and jasmonic acid (JA), and modulation of this interplay by ethylene (ET) in favor of JA signaling pathway in plant stress responses is well recognized, but the underlying mechanism is not fully understood. Here, we show the opposing function of two transcription factors, ethylene insensitive3 (EIN3) and EIN3-Like1 (EIL1), in SA-mediated suppression and JA-mediated activation of PLANT DEFENSIN1.2 (PDF1.2). This functional duality is mediated via their effect on protein, not transcript levels of the PDF1.2 transcriptional activator octadecanoid-responsive Arabidopsis59 (ORA59). Specifically, JA induces ORA59 protein levels independently of EIN3/EIL1, whereas SA reduces the protein levels dependently of EIN3/EIL1. Co-infiltration assays revealed nuclear co-localization of ORA59 and EIN3, and split-luciferase together with yeast-two-hybrid assays established their physical interaction. The functional ramification of the physical interaction is EIN3-dependent degradation of ORA59 by the 26S proteasome. These findings allude to SA-responsive reduction of ORA59 levels mediated by EIN3 binding to and targeting of ORA59 for degradation, thus nominating ORA59 pool as a coordination node for the antagonistic function of ET/JA and SA. © 2017 Institute of Botany, Chinese Academy of Sciences.

Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.

PubMed

Lerman, Tamara; Depenbusch, Marion; Schultze-Mosgau, Askan; von Otte, Soeren; Scheinhardt, Markus; Koenig, Inke; Kamischke, Axel; Macek, Milan; Schwennicke, Arne; Segerer, Sabine; Griesinger, Georg

2017-05-01

The incidence of low (<6 oocytes) and high (>18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre (n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women (n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P-value: 0.853, 0.769-0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P-value: 0.871, 0.787-0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response. Copyright © 2017. Published by Elsevier Ltd.

GHRH excess and blockade in X-LAG syndrome.

PubMed

Daly, Adrian F; Lysy, Philippe A; Desfilles, Céline; Rostomyan, Liliya; Mohamed, Amira; Caberg, Jean-Hubert; Raverot, Veronique; Castermans, Emilie; Marbaix, Etienne; Maiter, Dominique; Brunelle, Chloe; Trivellin, Giampaolo; Stratakis, Constantine A; Bours, Vincent; Raftopoulos, Christian; Beauloye, Veronique; Barlier, Anne; Beckers, Albert

2016-03-01

X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome. © 2016 Society for Endocrinology.

Hypothalamic oxytocin mediates social buffering of the stress response.

PubMed

Smith, Adam S; Wang, Zuoxin

2014-08-15

While stressful life events can enhance the risk of mental disorders, positive social interactions can propagate good mental health and normal behavioral routines. Still, the neural systems that promote these benefits are undetermined. Oxytocin is a hormone involved in social behavior and stress; thus, we focus on the impact that social buffering has on the stress response and the governing effects of oxytocin. Female prairie voles (Microtus ochrogaster) were exposed to 1 hour immobilization stress and then recovered alone or with their male partner to characterize the effect of social contact on the behavioral, physiological, and neuroendocrine stress response. In addition, we treated immobilized female voles recovering alone with oxytocin or vehicle and female voles recovering with their male partner with a selective oxytocin receptor antagonist or vehicle. Group sizes varied from 6 to 8 voles (N = 98 total). We found that 1 hour immobilization increased anxiety-like behaviors and circulating levels of corticosterone, a stress hormone, in female prairie voles recovering alone but not the female prairie voles recovering with their male partner. This social buffering by the male partner on biobehavioral responses to stress was accompanied by increased oxytocin release in the paraventricular nucleus of the hypothalamus. Intra-paraventricular nucleus oxytocin injections reduced behavioral and corticosterone responses to immobilization, whereas injections of an oxytocin receptor antagonist blocked the effects of the social buffering. Together, our data demonstrate that paraventricular nucleus oxytocin mediates the social buffering effects on the stress response and thus may be a target for treatment of stress-related disorders. Published by Society of Biological Psychiatry on behalf of Society of Biological Psychiatry.

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents

PubMed Central

Ye, Jianping; Hao, Zheng; Mumphrey, Michael B.; Townsend, R. Leigh; Patterson, Laurel M.; Stylopoulos, Nicholas; Münzberg, Heike; Morrison, Christopher D.; Drucker, Daniel J.

2014-01-01

Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9–39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification. PMID:24430883

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents.

PubMed

Ye, Jianping; Hao, Zheng; Mumphrey, Michael B; Townsend, R Leigh; Patterson, Laurel M; Stylopoulos, Nicholas; Münzberg, Heike; Morrison, Christopher D; Drucker, Daniel J; Berthoud, Hans-Rudolf

2014-03-01

Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.

ACTH releasing activity of KP-102 (GHRP-2) in rats is mediated mainly by release of CRF.

PubMed

Hirotani, Chiharu; Oki, Yutaka; Ukai, Kiyoharu; Okuno, Tadashi; Kurasaki, Shigeru; Ohyama, Tadashi; Doi, Naomi; Sasaki, Ken; Ase, Katsuhiko

2005-01-01

KP-102 (GHRP-2: pralmorelin) is a synthetic growth hormone releasing peptide (GHRP) that powerfully stimulates the release of GH by acting (i.v.) at both hypothalamic and pituitary sites. Intravenous (i.v.) administration of KP-102 also elicits slight but significant release of adrenocorticotropic hormone (ACTH) in both animals and humans, as is seen with other GHRPs. GHRPs are thought to stimulate the hypothalamic-pituitary-adrenal axis by releasing endogenous ACTH secretagogues such as arginine vasopressin (AVP) and/or corticotropin releasing factor (CRF), though neither AVP nor CRF has been shown clearly to be involved significantly in GHRP-evoked ACTH release. In the present study, we investigated the effects of KP-102 on ACTH release in conscious rats under improved experimental conditions that minimized the influence of stress. Administration of KP-102 i.v. increased plasma ACTH significantly, but did not stimulate ACTH release from rat primary pituitary cells. Administration of KP-102 together with either AVP or CRF elicited significantly greater increases in plasma ACTH levels than any of the agonists alone. Notably, the combination of KP-102 and AVP produced a much greater increase in ACTH than KP-102 plus CRF, indicating that KP-102 augments the effect of exogenous CRF only weakly. Conversely, a CRF antagonist markedly inhibited KP-102-induced ACTH release in conscious rats, whereas an AVP antagonist or anti-AVP antiserum did not. Taken together, these findings suggest that KP-102 acts via the hypothalamus to stimulate ACTH release in rats, and that these effects are mediated mainly by the release of CRF.

The non-peptide CRH1-antagonist CP-154,526 elicits a paradoxical route-dependent activation of the HPA axis.

PubMed

Zaretsky, Dmitry V; Zaretskaia, Maria V; Sarkar, Sumit; Rusyniak, Daniel E; DiMicco, Joseph A

2017-07-13

The corticotropin-releasing hormone (CRH) plays an important role in mediating physiological response to stress and is thought to be involved in the development of various psychiatric disorders. In this paper, we compare the differences between the effect of intraperitoneal (i.p.) and intraarterial (i.a.) administration of the non-peptide CRH 1 antagonist CP-154,526 (CP) (10 and 20mg/kg) on plasma adrenocorticotropic hormone levels (ACTH), heart rate, MAP, and c-Fos expression in the paraventricular nucleus of the hypothalamus. Intraperitoneal, but not i.a., injection of CP resulted in an increase in plasma ACTH (from 105±13 to 278±51pg/ml after 20mg/kg). This effect was accompanied by a dramatic increase in c-Fos expression in cells immunoreactive for CRH in the paraventricular nucleus of the hypothalamus. When the drug was administered i.p., CP-induced activation of the HPA appears to mask the inhibitory effect of CP on stress-induced ACTH secretion, an effect which was readily apparent when the drug was given i.a. Intraperitoneal administration of CP also increased the baseline MAP which may account for previous reports that treatment with this drug attenuated the increases associated with stress. CP given by either route had no effect on baseline heart rate or stress-induced tachycardia. Thus, in all studies in which CP 154,526 is given, the route of delivery must be given careful consideration. Copyright © 2017 Elsevier B.V. All rights reserved.

Blockage of neonatal leptin signaling induces changes in the hypothalamus associated with delayed pubertal onset and modifications in neuropeptide expression during adulthood in male rats.

PubMed

Mela, Virginia; Jimenez, Sara; Freire-Regatillo, Alejandra; Barrios, Vicente; Marco, Eva-María; Lopez-Rodriguez, Ana-Belén; Argente, Jesús; Viveros, María-Paz; Chowen, Julie A

2016-12-01

The neonatal leptin surge, occurring from postnatal day (PND) 5 to 13 and peaking at PND9 in rodents, is important for the development of neuroendocrine circuits involved in metabolic control and reproductive function. We previously demonstrated that treatment with a leptin antagonist from PND 5 to 9, coincident with peak leptin levels in the neonatal surge, modified trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus of peri-pubertal rats. The kisspeptin system and metabolic neuropeptide and hormone levels were also modified. Here our aim was to investigate if the timing of pubertal onset is altered by neonatal leptin antagonism and if the previously observed peripubertal modifications in hormones and neuropeptides persist into adulthood and affect male sexual behavior. To this end, male Wistar rats were treated with a pegylated super leptin antagonist (5mg/kg, s.c.) from PND 5 to 9 and killed at PND102-103. The appearance of external signs of pubertal onset was delayed. Hypothalamic kiss1 mRNA levels were decreased in adult animals, but sexual behavior was not significantly modified. Although there was no effect on body weight or food intake, circulating leptin, insulin and triglyceride levels were increased, while hypothalamic leptin receptor, POMC and AgRP mRNA levels were decreased. In conclusion, alteration of the neonatal leptin surge can modify the timing of pubertal onset and have long-term effects on hypothalamic expression of reproductive and metabolic neuropeptides. Copyright © 2016 Elsevier Inc. All rights reserved.

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET.

PubMed

Fouda, Usama M; Sayed, Ahmed M

2011-12-01

To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

Miraxanthin-V, Liriodenin and Chitranone are Hepcidin Antagonist In silico for Iron Deficiency Anemia

NASA Astrophysics Data System (ADS)

Yotriana, S.; Suselo, YH; Muthmainah; Indarto, D.

2018-03-01

Anemia is one of the greatest nutrition problem in the world that is commonly found in children, pregnant women and reproductive women. This disorder is predominantly caused by iron deficiency. Hepcidin, a hepatic hormone, regulates iron metabolism and high serum levels of this hormone are detected in patients with iron deficiency anemia (IDA). Anticalin is a sintetic compound which is able to interacts with hepcidin leading to inhibition of ferroportin-hepcidin binding complexes but its therapeutic effects are still under investigation. Indonesia has various herbal plants which are potentially developed to treat some human diseases. Therefore, the purpose of this study was to identify phytochemicals derived from Indonesian plants that is able to inhibit hepcidin-ferroportin interaction. A bioinformatics study with molecular docking method was used in this study. Three-dimensional structures of human hepcidin and anticalin were obtained from the Protein Data Bank (ID: 1M4F and 4QAE respectively). Because their molecular size was big, each molecule was cut into 2 parts of its binding sites. All phytochemicals structures were obtained from HerbalDB and PubChem NCBI database. Truncated anticalin/phytochemicals were molecularly docked with truncated hepcidin by using AutoDock Vina 1.1.2. and their interactions were visualized using PyMol 1.3. Truncated Anticalin had -4.6 and -4.2 kcal/mol binding affinity to truncated human hepcidin. Truncated anticalin 1 was bound to Cys13, Cys14, Arg16 and Ser17 residues in truncated hepcidin 1 while truncated anticalin 2 was at Cy23 and Lys24 residues in truncated hepcidin 2. Miraxanthine-V, Liriodenin and Chitranone had lower binding affinity (-4.8±0.77, -4.7±0.33 and -5.01±0.30 kcal/mol respectively) than that of anticalin and occupied binding sites as same as anticalin did. There are three phytochemicals that potentially become hepcidin antagonists in silico. In vitro assays are required for verification of the antagonist effect of these phytochemicals on iron metabolism.

Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

PubMed Central

Hassouna, Rim; Labarthe, Alexandra; Zizzari, Philippe; Videau, Catherine; Culler, Michael; Epelbaum, Jacques; Tolle, Virginie

2012-01-01

The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic applications, such as for cachexia and anorexia. PMID:23515849

MIBE acts as antagonist ligand of both estrogen receptor α and GPER in breast cancer cells

PubMed Central

2012-01-01

Introduction The multiple biological responses to estrogens are mainly mediated by the classical estrogen receptors ERα and ERβ, which act as ligand-activated transcription factors. ERα exerts a main role in the development of breast cancer; therefore, the ER antagonist tamoxifen has been widely used although its effectiveness is limited by de novo and acquired resistance. Recently, GPR30/GPER, a member of the seven-transmembrane G protein-coupled receptor family, has been implicated in mediating the effects of estrogens in various normal and cancer cells. In particular, GPER triggered gene expression and proliferative responses induced by estrogens and even ER antagonists in hormone-sensitive tumor cells. Likewise, additional ER ligands showed the ability to bind to GPER eliciting promiscuous and, in some cases, opposite actions through the two receptors. We synthesized a novel compound (ethyl 3-[5-(2-ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]but-2-enoate), referred to as MIBE, and investigated its properties elicited through ERα and GPER in breast cancer cells. Methods Molecular modeling, binding experiments and functional assays were performed in order to evaluate the biological action exerted by MIBE through ERα and GPER in MCF7 and SkBr3 breast cancer cells. Results MIBE displayed the ability to act as an antagonist ligand for ERα and GPER as it elicited inhibitory effects on gene transcription and growth effects by binding to both receptors in breast cancer cells. Moreover, GPER was required for epidermal growth factor receptor (EGFR) and ERK activation by EGF as ascertained by using MIBE and performing gene silencing experiments. Conclusions Our findings provide novel insights on the functional cross-talk between GPER and EGFR signaling. Furthermore, the exclusive antagonistic activity exerted by MIBE on ERα and GPER could represent an innovative pharmacological approach targeting breast carcinomas which express one or both receptors at the beginning and/or during tumor progression. Hence, the simultaneous inhibition of both ERα and GPER may guarantee major therapeutic benefits in respect to the use of a selective estrogen receptor antagonist. PMID:22251451

MIBE acts as antagonist ligand of both estrogen receptor α and GPER in breast cancer cells.

PubMed

Lappano, Rosamaria; Santolla, Maria Francesca; Pupo, Marco; Sinicropi, Maria Stefania; Caruso, Anna; Rosano, Camillo; Maggiolini, Marcello

2012-01-17

The multiple biological responses to estrogens are mainly mediated by the classical estrogen receptors ERα and ERβ, which act as ligand-activated transcription factors. ERα exerts a main role in the development of breast cancer; therefore, the ER antagonist tamoxifen has been widely used although its effectiveness is limited by de novo and acquired resistance. Recently, GPR30/GPER, a member of the seven-transmembrane G protein-coupled receptor family, has been implicated in mediating the effects of estrogens in various normal and cancer cells. In particular, GPER triggered gene expression and proliferative responses induced by estrogens and even ER antagonists in hormone-sensitive tumor cells. Likewise, additional ER ligands showed the ability to bind to GPER eliciting promiscuous and, in some cases, opposite actions through the two receptors. We synthesized a novel compound (ethyl 3-[5-(2-ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]but-2-enoate), referred to as MIBE, and investigated its properties elicited through ERα and GPER in breast cancer cells. Molecular modeling, binding experiments and functional assays were performed in order to evaluate the biological action exerted by MIBE through ERα and GPER in MCF7 and SkBr3 breast cancer cells. MIBE displayed the ability to act as an antagonist ligand for ERα and GPER as it elicited inhibitory effects on gene transcription and growth effects by binding to both receptors in breast cancer cells. Moreover, GPER was required for epidermal growth factor receptor (EGFR) and ERK activation by EGF as ascertained by using MIBE and performing gene silencing experiments. Our findings provide novel insights on the functional cross-talk between GPER and EGFR signaling. Furthermore, the exclusive antagonistic activity exerted by MIBE on ERα and GPER could represent an innovative pharmacological approach targeting breast carcinomas which express one or both receptors at the beginning and/or during tumor progression. Hence, the simultaneous inhibition of both ERα and GPER may guarantee major therapeutic benefits in respect to the use of a selective estrogen receptor antagonist.

Is the type of gonadotropin-releasing hormone suppression protocol for ovarian hyperstimulation associated with ectopic pregnancy in fresh autologous cycles for in vitro fertilization?

PubMed

Londra, Laura; Moreau, Caroline; Strobino, Donna; Bhasin, Aarti; Zhao, Yulian

2016-09-01

To evaluate the association between different ovarian hyperstimulation protocols and ectopic pregnancy (EP) in in vitro fertilization (IVF) cycles in fresh autologous embryo transfer cycles in the United States between 2008 and 2011 as reported to the Society of Assisted Reproductive Technology (SART). Historical cohort study. Not applicable. None. None. All autologous cycles that resulted in a clinical pregnancy after a fresh, intrauterine embryo transfer and described characteristics of cycles according to protocol were included: luteal GnRH agonist, GnRH agonist flare, or GnRH antagonist. Multivariate logistic regression was conducted to investigate the association between type of protocol and EP. Among 136,605 clinical pregnancies, 2,645 (1.94%) were EP. Ectopic pregnancy was more frequent with GnRH antagonist (2.4%) cycles than with GnRH agonist flare (2.1%) or luteal GnRH agonist (1.6%) cycles. After adjusting for maternal and treatment characteristics, the GnRH antagonist and the GnRH agonist flare protocols were associated with increased odds of EP (adjusted odds ratio [aOR] 1.52; 95% confidence interval [CI], 1.39-1.65; and aOR 1.25; 95% CI, 1.09-1.44, respectively) compared with luteal GnRH agonist. Analysis of differences in the factors related to EP in luteal GnRH agonist versus GnRH antagonist protocols indicated that diminished ovarian reserve was associated with an increased risk of EP in luteal GnRH agonist but not in GnRH antagonist cycles. The type of protocol used during ovarian hyperstimulation in fresh autologous cycles was associated with EP. This finding suggests a role for extrapituitary GnRH on the tubal and uterine environment during ovarian hyperstimulation treatment for IVF. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

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

PubMed

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 pregnancy rate when the oral hormonal programming pill (OHP) pretreatment was combined with a flexible protocol (RR 0.74, 95% CI 0.59-0.91) while without OHP, the RR was 0.84, 95% CI 0.71-1.0. Subgroup analysis for the fixed antagonist schedule demonstrated no evidence of a significant difference with or without OHP (RR 0.94, 95% CI 0.79-1.12 and RR 0.94, 95% CI 0.83-1.05, respectively). Antagonists resulted in significantly lower OHSS rates both in the general IVF patients and in women with PCOS (RR 0.63, 95% CI 0.50-0.81 and RR 0.53, 95% CI 0.30-0.95, respectively). No data on OHSS was available from trials in poor responders. In a general IVF population, GnRH antagonists are associated with lower ongoing pregnancy rates when compared to long protocol agonists, but also with lower OHSS rates. Within this population, antagonist treatment prevents one case of OHSS in 40 patients but results in one less ongoing pregnancy out of every 28 women treated. Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. In couples with PCOS and poor responders, GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and therefore could be considered as standard treatment. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Auxin crosstalk to plant immune networks: a plant-pathogen interaction perspective.

PubMed

Naseem, Muhammad; Srivastava, Mugdha; Tehseen, Muhammad; Ahmed, Nazeer

2015-01-01

The plant hormone auxin regulates a whole repertoire of plant growth and development. Many plant-associated microorganisms, by virtue of their auxin production capability, mediate phytostimulation effects on plants. Recent studies, however, demonstrate diverse mechanisms whereby plant pathogens manipulate auxin biosynthesis, signaling and transport pathways to promote host susceptibility. Auxin responses have been coupled to their antagonistic and synergistic interactions with salicylic acid and jasmonate mediated defenses, respectively. Here, we discuss that a better understanding of auxin crosstalk to plant immune networks would enable us to engineer crop plants with higher protection and low unintended yield losses.

Parathyroid hormone-related peptide and the hair cycle - is it the agonists or the antagonists that cause hair growth?

PubMed

Gensure, Robert C

2014-12-01

While the effects of PTHrP have been studied for almost 20 years, most of these studies have focused on effects on the termination of the anagen phase, giving an incomplete picture of the overall effect of PTHrP on the hair cycle. PTHrP was determined in several experimental models to promote transition of hair follicles from anagen to catagen phase, which by itself would suggest that PTHrP blockade might prolong the anagen phase and promote hair growth. However, clinical trials with topically applied PTHrP antagonists have been disappointing, leading to a reconsideration of this model. Additional studies performed in mouse models where hair follicles are damaged (alopecia areata, chemotherapy-induced alopecia) suggest that PTHrP has effects early in the hair cycle as well, promoting hair follicles' entry into anagen phase and initiates the hair cycle. While the mechanism of this has yet to be elucidated, it may involve activation of the Wnt pathway. Thus, the overall effect of PTHrP is to stimulate and accelerate the hair cycle, and in the more clinically relevant models of hair loss where hair follicles have been damaged or become quiescent, it is the agonists, not the antagonists, which would be expected to promote hair growth. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hormonal regulation of hepatic glycogenolysis in the carp, Cyprinus carpio

DOE Office of Scientific and Technical Information (OSTI.GOV)

Janssens, P.A.; Lowrey, P.

1987-04-01

Carp (Cyprinus carpio) liver maintained normal glycogen content and enzyme complement for several days in organ culture. Epinephrine-stimulated glycogenolysis, phosphorylase activation, and cyclic AMP (cAMP) accumulation in a concentration-dependent manner with EC/sub 50/s of 100, 100, and 500 nM, respectively. These actions were blocked by the ..beta..-adrenergic antagonist, propranolol, but not by the ..cap alpha..-adrenergic antagonist phentolamine. Glycogenolysis and tissue cAMP were uninfluenced by 10/sup -6/ M arginine vasotocin, arginine vasopressin, lysine vasotocin, lysine vasopressin, mesotocin, or oxytocin, but were slightly increased by 10/sup -5/ M isotocin and slightly decreased by 10/sup -6/ M angiotensin II. (/sup 125/I)-iodocyanopindolol (ICP), amore » ..beta..-adrenergic ligand, bound to isolated carp liver membranes with a K/sub D/ of 83 pM. Maximum binding of 45 fmol/mg protein was at 600 pM. Propranolol, isoprenaline, epinephrine, phenylephrine, norepinephrine, and phenoxybenzamine displaced ICP with K/sub D/s of 100 nM, 2, 20, 20, 60, and 200 ..mu..M, respectively. The ..cap alpha..-adrenergic antagonists, yohimbine and prazosin, showed no specific binding. These data provide evidence that catecholamines act via ..beta..-adrenergic receptors in carp liver and that ..cap alpha..-adrenergic receptors are not present. Vasoactive peptides play no significant role in regulation of carp liver glycogenolysis.« less

Interaction of ligands with the opiate receptors of brain membranes: Regulation by ions and nucleotides

PubMed Central

Blume, Arthur J.

1978-01-01

This study shows that nucleotides, as well as ions, regulate the opiate receptors of brain. GMP-P(NH)P and Na+ reduce the amount of steady-state specific [3H]dihydromorphine binding and increase the rate of dissociation of the ligand from the opiate receptor. In contrast, Mn2+ decreases the rate of ligand dissociation and antagonizes the ability of Na+ to increase dissociation. The effects of GMP-P(NH)P on steady-state binding and dissociation are not reversed by washing. Only GTP, GDP, ITP, and IMP-P(NH)P, in addition to GMP-P(NH)P, increase the rate of dihydromorphine dissociation. The site of nucleotide action appears to have high affinity: <1 μM GMP-P(NH)P produces half-maximal increases in ligand dissociation. GMP-P(NH)P- and Na+-directed increases in dissociation have also been found for the opiate agonists [3H]etorphine, [3H]Leu-enkephalin, and [3H]Met-enkephalin and the opiate antagonist [3H]naltrexone. Mn2+-directed decreases in dissociation have been found for the agonist [3H]-etorphine and the antagonist [3H]naltrexone. Although the plasma membrane receptors for a number of other neuro-transmitters and hormones are also regulated by guanine nucleotides, the opiate receptors appear unique because only they show nucleotide regulation of both agonist and antagonist binding. PMID:205867

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

PubMed Central

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

2013-01-01

Background: 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. Materials and Methods: 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. Results: 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). Conclusion: 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). PMID:24520450

Temperature variability is integrated by a spatially embedded decision-making center to break dormancy in Arabidopsis seeds.

PubMed

Topham, Alexander T; Taylor, Rachel E; Yan, Dawei; Nambara, Eiji; Johnston, Iain G; Bassel, George W

2017-06-20

Plants perceive and integrate information from the environment to time critical transitions in their life cycle. Some mechanisms underlying this quantitative signal processing have been described, whereas others await discovery. Seeds have evolved a mechanism to integrate environmental information by regulating the abundance of the antagonistically acting hormones abscisic acid (ABA) and gibberellin (GA). Here, we show that hormone metabolic interactions and their feedbacks are sufficient to create a bistable developmental fate switch in Arabidopsis seeds. A digital single-cell atlas mapping the distribution of hormone metabolic and response components revealed their enrichment within the embryonic radicle, identifying the presence of a decision-making center within dormant seeds. The responses to both GA and ABA were found to occur within distinct cell types, suggesting cross-talk occurs at the level of hormone transport between these signaling centers. We describe theoretically, and demonstrate experimentally, that this spatial separation within the decision-making center is required to process variable temperature inputs from the environment to promote the breaking of dormancy. In contrast to other noise-filtering systems, including human neurons, the functional role of this spatial embedding is to leverage variability in temperature to transduce a fate-switching signal within this biological system. Fluctuating inputs therefore act as an instructive signal for seeds, enhancing the accuracy with which plants are established in ecosystems, and distributed computation within the radicle underlies this signal integration mechanism.

Temperature variability is integrated by a spatially embedded decision-making center to break dormancy in Arabidopsis seeds

PubMed Central

Topham, Alexander T.; Taylor, Rachel E.; Yan, Dawei; Nambara, Eiji; Johnston, Iain G.

2017-01-01

Plants perceive and integrate information from the environment to time critical transitions in their life cycle. Some mechanisms underlying this quantitative signal processing have been described, whereas others await discovery. Seeds have evolved a mechanism to integrate environmental information by regulating the abundance of the antagonistically acting hormones abscisic acid (ABA) and gibberellin (GA). Here, we show that hormone metabolic interactions and their feedbacks are sufficient to create a bistable developmental fate switch in Arabidopsis seeds. A digital single-cell atlas mapping the distribution of hormone metabolic and response components revealed their enrichment within the embryonic radicle, identifying the presence of a decision-making center within dormant seeds. The responses to both GA and ABA were found to occur within distinct cell types, suggesting cross-talk occurs at the level of hormone transport between these signaling centers. We describe theoretically, and demonstrate experimentally, that this spatial separation within the decision-making center is required to process variable temperature inputs from the environment to promote the breaking of dormancy. In contrast to other noise-filtering systems, including human neurons, the functional role of this spatial embedding is to leverage variability in temperature to transduce a fate-switching signal within this biological system. Fluctuating inputs therefore act as an instructive signal for seeds, enhancing the accuracy with which plants are established in ecosystems, and distributed computation within the radicle underlies this signal integration mechanism. PMID:28584126

Mouse mammary tumor virus chromatin in human breast cancer cells is constitutively hypersensitive and exhibits steroid hormone-independent loading of transcription factors in vivo.

PubMed Central

Mymryk, J S; Berard, D; Hager, G L; Archer, T K

1995-01-01

We have stably introduced a reporter gene under the control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) into human T47D breast cancer cells to study the action of the progesterone receptor (PR) on transcription from a chromatin template. Unexpectedly, the chromatin organization of the MMTV LTR in these human breast cancer cells differed markedly from what we have observed previously. The region adjacent to the transcription start site (-221 to -75) was found to be constitutively hypersensitive to restriction enzyme cleavage in the absence of hormone. This region is normally encompassed within the second nucleosome of a phased array of six nucleosomes that is assembled when the MMTV LTR is stably maintained in mouse cells. Characteristically, in these rodent cells, the identical DNA sequences show increased restriction enzyme cleavage only in the presence of glucocorticoid. The increased access of restriction enzymes observed in the human PR+ cells was not observed in adjacent nucleosomes and was unaffected by treatment with the progesterone antagonist RU486. In addition, exonuclease III-dependent stops corresponding to the binding sites for nuclear factor 1 and the PR were observed before and after hormone treatment. These results indicate that MMTV chromatin replicated in these cells is organized into a constitutively open architecture and that this open chromatin state is accompanied by hormone-independent loading of a transcription factor complex that is normally excluded from uninduced chromatin. PMID:7799933

Mouse mammary tumor virus chromatin in human breast cancer cells is constitutively hypersensitive and exhibits steroid hormone-independent loading of transcription factors in vivo.

PubMed

Mymryk, J S; Berard, D; Hager, G L; Archer, T K

1995-01-01

We have stably introduced a reporter gene under the control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) into human T47D breast cancer cells to study the action of the progesterone receptor (PR) on transcription from a chromatin template. Unexpectedly, the chromatin organization of the MMTV LTR in these human breast cancer cells differed markedly from what we have observed previously. The region adjacent to the transcription start site (-221 to -75) was found to be constitutively hypersensitive to restriction enzyme cleavage in the absence of hormone. This region is normally encompassed within the second nucleosome of a phased array of six nucleosomes that is assembled when the MMTV LTR is stably maintained in mouse cells. Characteristically, in these rodent cells, the identical DNA sequences show increased restriction enzyme cleavage only in the presence of glucocorticoid. The increased access of restriction enzymes observed in the human PR+ cells was not observed in adjacent nucleosomes and was unaffected by treatment with the progesterone antagonist RU486. In addition, exonuclease III-dependent stops corresponding to the binding sites for nuclear factor 1 and the PR were observed before and after hormone treatment. These results indicate that MMTV chromatin replicated in these cells is organized into a constitutively open architecture and that this open chromatin state is accompanied by hormone-independent loading of a transcription factor complex that is normally excluded from uninduced chromatin.

Salicylic acid antagonizes abscisic acid inhibition of shoot growth and cell cycle progression in rice

NASA Astrophysics Data System (ADS)

Meguro, Ayano; Sato, Yutaka

2014-04-01

We analysed effects of abscisic acid (ABA, a negative regulatory hormone), alone and in combination with positive or neutral hormones, including salicylic acid (SA), on rice growth and expression of cell cycle-related genes. ABA significantly inhibited shoot growth and induced expression of OsKRP4, OsKRP5, and OsKRP6. A yeast two-hybrid assay showed that OsKRP4, OsKRP5, and OsKRP6 interacted with OsCDKA;1 and/or OsCDKA;2. When SA was simultaneously supplied with ABA, the antagonistic effect of SA completely blocked ABA inhibition. SA also blocked ABA inhibition of DNA replication and thymidine incorporation in the shoot apical meristem. These results suggest that ABA arrests cell cycle progression by inducing expression of OsKRP4, OsKRP5, and OsKRP6, which inhibit the G1/S transition, and that SA antagonizes ABA by blocking expression of OsKRP genes.

Effect of treatment at weaning with the serotonin antagonist mianserin on the brain serotonin and cerebrospinal fluid nocistatin level of adult female rats: a case of late imprinting.

PubMed

Csaba, G; Knippel, Barbara; Karabélyos, Cs; Inczefi-Gonda, Agnes; Hantos, Mónika; Tóthfalusi, L; Tekes, Kornélia

2004-07-09

Four weeks old (weanling) female rats were treated with the tricyclic antidepressant and histamine/serotonin receptor blocker mianserin for studying its faulty hormonal imprinting effect. Measurements were done four months later. Brain serotonin levels significantly decreased in four regions (hippocampus, hypothalamus, striatum and brainstem), without any change in the cortex. Sexual activity of the treated and control rats was similar. Cerebrospinal fluid nocistatin level was one magnitude higher in the treated rats, than in the controls. The density of uterine estrogen receptors was significantly reduced, while binding capacity of glucocorticoid receptors of liver and thymus remained at control level. The results call attention to the possibility of 1. a broad spectrum imprinting at the time of weaning by a receptor level acting non-hormone molecule 2. imprinting of the brain in a non-neonatal period of life and 3. a very durable (lifelong?) effect of the late imprinting with an antidepressant.

Evidence that shock-induced immune suppression is mediated by adrenal hormones and peripheral beta-adrenergic receptors.

PubMed

Cunnick, J E; Lysle, D T; Kucinski, B J; Rabin, B S

1990-07-01

Our previous work has demonstrated that presentations of mild foot-shock to Lewis rats induces a suppression of splenic and peripheral blood lymphocyte responses to nonspecific T-cell mitogens. The present study demonstrated that adrenalectomy prevented the shock-induced suppression of the mitogenic response of peripheral blood T-cells but did not attenuate the suppression of splenic T-cells. Conversely, the beta-adrenergic receptor antagonists, propranolol and nadolol, attenuated the shock-induced suppression of splenic T-cells in a dose-dependent manner but did not attenuate suppression of the blood mitogen response. These data indicate that distinct mechanisms mediate the shock-induced suppression of T-cell responsiveness to mitogens in the spleen and the peripheral blood. The results indicate that the peripheral release of catecholamines is responsible for splenic immune suppression and that adrenal hormones, which do not interact with beta-adrenergic receptors, are responsible for shock-induced suppression of blood mitogenic responses.

The role of growth hormone in lines of mice divergently selected on body weight.

PubMed

Hastings, I M; Bootland, L H; Hill, W G

1993-04-01

An understanding of the physiological and genetic changes which determine the response to selection is critical for both evolutionary theory and to assess the application of new molecular techniques to commercial animal breeding. We investigated an aspect of physiology, growth hormone (GH) metabolism, which might a priori have been expected to play a large part in the response of mouse lines selected for high or low body weight. Disruption of endogenous GH or addition of exogenous GH had similar proportionate effects on body weight in both lines of mice (although differences in body composition arose) suggesting that neither the production of GH nor receptor sensitivity to GH had been altered as a result of selection. This supports a 'pleiotropic model' of the response to selection: that many genes with diverse metabolic roles all contribute to the divergent phenotype. This result has significant commercial implications as it suggests that artificial selection, transgenic technology and environmental manipulation may be synergistic rather than antagonistic strategies.

Endocrine disrupting chemicals in the atmosphere: Their effects on humans and wildlife.

PubMed

Annamalai, Jayshree; Namasivayam, Vasudevan

2015-03-01

Endocrine disrupting chemicals (EDCs) are exogenous agents that interfere or disrupt the normal synthesis, secretion, transportation, binding and metabolism of natural hormones; eventually dysregulating homeostatic mechanisms, reproduction and development. They are emitted into the atmosphere during anthropogenic activities and physicochemical reactions in nature. Inhalation of these EDCs as particulate and gaseous vapors triggers their interaction with endocrine glands and exerts agonist or antagonists actions at hormone receptors. The endocrine disruption at nanogram levels of EDC's has gained concern in the last decade, due to infertility among men and women, early puberty, obesity, diabetes and cancer. Thus, the review explores the literature that addresses the major occurring EDCs in the atmosphere including phthalates, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), brominated flame retardants (BFRs), dioxins, alkylphenols (APs) and perfluorinated chemicals (PFCs). Sources, fate, half-life, mechanism, measured concentrations in air, bioaccumulation in tissues, laboratory exposures correlating to toxicological effects of these EDCs in humans and wildlife are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

How to personalize ovarian stimulation in clinical practice.

PubMed

Sighinolfi, Giovanna; Grisendi, Valentina; La Marca, Antonio

2017-09-01

Controlled ovarian stimulation (COS) in in vitro fertilization (IVF) cycles is the starting point from which couple's prognosis depends. Individualization in follicle-stimulating hormone (FSH) starting dose and protocol used is based on ovarian response prediction, which depends on ovarian reserve. Anti-Müllerian hormone levels and the antral follicle count are considered the most accurate and reliable markers of ovarian reserve. A literature search was performed for studies that addressed the ability of ovarian reserve markers to predict poor and high ovarian response in assisted reproductive technology cycles. According to the predicted response to ovarian stimulation (poor- normal- or high- response), it is possible to counsel couples before treatment about the prognosis, and also to individualize ovarian stimulation protocols, choosing among GnRH-agonists or antagonists for endogenous FSH suppression, and the FSH starting dose in order to decrease the risk of cycle cancellation and ovarian hyperstimulation syndrome. In this review we discuss how to choose the best COS therapy, based on ovarian reserve markers, in order to enhance chances in IVF.

[Perspectives on endocrine disruption].

PubMed

Olea, N; Fernández, M F; Araque, P; Olea-Serrano, F

2002-01-01

Two decades ago, reports of alterations in the reproductive function of some wild animal species and clear evidence of human and animal exposure to chemical substances with hormonal activity agonist and antagonist generated what is known now as the hypothesis of endocrine disruption. This is an emerging environmental health problem that has challenged some of the paradigms on which the control and regulation of the use of chemical compounds is based. The need to include in routine toxicology tests new research objectives that specifically refer to the development and growth of species and to the homeostasis and functionality of hormonal systems, has served to complicate both the evaluation of new compounds and the re-evaluation of existing ones. The repercussions on regulation and international trade have not taken long to be felt. On both sides of the Atlantic, screening systems for endocrine disrupters have been designed and established, and research programmes have been launched to characterise and quantify adverse effects on human and animal health and to develop preventive measures.

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

PubMed Central

Abizaid, Alfonso; Liu, Zhong-Wu; Andrews, Zane B.; Shanabrough, Marya; Borok, Erzsebet; Elsworth, John D.; Roth, Robert H.; Sleeman, Mark W.; Picciotto, Marina R.; Tschöp, Matthias H.; Gao, Xiao-Bing; Horvath, Tamas L.

2006-01-01

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding. PMID:17060947

Monitoring of hormonal drug effect in a single breast cancer cell using an estrogen responsive GFP reporter vector delivered by a nanoneedle.

PubMed

Han, Sung-Woong; Nakamura, Chikashi; Imai, Yosuke; Nakamura, Noriyuki; Miyake, Jun

2009-01-01

In this study, we have evaluated a sensor system for a hormonal drug effect in a single cell level using a novel low invasive single cell DNA delivery technology using a nanoneedle. An estrogen responsive GFP reporter vector (pEREGFP9) was constructed and its estrogenic response activity was confirmed in breast cancer cells (MCF-7) using lipofection as the means of transferring the vector to the cells. The pEREGFP9 vector was delivered to a single MCF-7 using a nanoneedle and the effect of ICI 182,780, which is an antagonist of estrogen, was observed using the GFP expression level. By ICI 182,780 treatment, the fluorescence intensity of the GFP was decreased by 30-50% within 24h. This technology is the very first trial of single cell diagnosis and we are looking forward to applying it to precious single cell diagnosis in medical fields.

Acromegaly pathogenesis and treatment

PubMed Central

Melmed, Shlomo

2009-01-01

Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly — a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder. PMID:19884662

Current and future medical treatments for patients with acromegaly.

PubMed

Maffezzoni, Filippo; Formenti, Anna Maria; Mazziotti, Gherardo; Frara, Stefano; Giustina, Andrea

2016-08-01

Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for acromegaly is targeted at decreasing GH and insulin-like growth hormone 1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant) and radiotherapy. However, despite all these treatments option, approximately 50% of patients are not adequately controlled. In this paper, the authors discuss: 1) efficacy and safety of current medical therapy 2) the efficacy and safety of the new multireceptor-targeted somatostatin ligand pasireotide 3) medical treatments currently under clinical investigation (oral octreotide, ITF2984, ATL1103), and 4) preliminary data on the use of new injectable and transdermal/transmucosal formulations of octreotide. This expert opinion supports the need for new therapeutic agents and modalities for patients with acromegaly.

Artificial reproduction of wild and cultured barbel (Barbus barbus, Cyprinidae) under controlled conditions.

PubMed

Targońska, Katarzyna; Kucharczyk, Dariusz; Zarski, Daniel; Cejko, Beata Irena; Krejszeff, Sławomir; Kupren, Krzysztof; Król, Radosław; Dryl, Katarzyna; Kowalski, Radosław Kajetan; Glogowski, Jan

2011-09-01

The aim of this work was to compare the effects of controlled reproduction of cultured and wild common barbel, Barbus barbus (L.). Preparations containing different GnRH analogues and dopamine receptor antagonists (Ovopel, Ovaprim) as well as human chorionic gonadotropin (hCG) (in the case of cultured fish) were applied and their influence on ovulation, spermiation and quality of gametes obtained was determined. No differences in the qualitative or quantitative parameters of semen were found between fish stimulated with different hormonal preparations and those not receiving hormonal stimulation. The high suitability of Ovaprim for ovulation induction in (cultured and wild) barbel was confirmed. The highest synchronisation of ovulation was obtained after the application of Ovopel (18 ± 3 h), but the best results of controlled reproduction (expressed as the percentage of ovulations and survival of embryos) were obtained by applying Ovaprim (83.2 ± 4.1). A significantly higher percentage of ovulation was obtained in cultured fish (80-90%) than in wild fish (< 25%).

Enclomiphene Citrate for the Treatment of Secondary Male Hypogonadism

PubMed Central

Rodriguez, Katherine M.; Pastuszak, Alexander W.; Lipshultz, Larry I.

2016-01-01

Introduction Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches. Areas Covered Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency. Expert Opinion Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option. PMID:27337642

Grape berry ripening delay induced by a pre-véraison NAA treatment is paralleled by a shift in the expression pattern of auxin- and ethylene-related genes.

PubMed

Ziliotto, Fiorenza; Corso, Massimiliano; Rizzini, Fabio Massimo; Rasori, Angela; Botton, Alessandro; Bonghi, Claudio

2012-10-09

Auxins act as repressors of ripening inception in grape (véraison), while ethylene and abscisic acid (ABA) play a positive role as inducers of the syndrome. Despite the increasing amount of information made available on this topic, the complex network of interactions among these hormones remains elusive. In order to shed light on these aspects, a holistic approach was adopted to evaluate, at the transcriptomic level, the crosstalk between hormones in grape berries, whose ripening progression was delayed by applying naphtalenacetic acid (NAA) one week before véraison. The NAA treatment caused significant changes in the transcription rate of about 1,500 genes, indicating that auxin delayed grape berry ripening also at the transcriptional level, along with the recovery of a steady state of its intracellular concentration. Hormone indices analysis carried out with the HORMONOMETER tool suggests that biologically active concentrations of auxins were achieved throughout a homeostatic recovery. This occurred within 7 days after the treatment, during which the physiological response was mainly unspecific and due to a likely pharmacological effect of NAA. This hypothesis is strongly supported by the up-regulation of genes involved in auxin conjugation (GH3-like) and action (IAA4- and IAA31-like). A strong antagonistic effect between auxin and ethylene was also observed, along with a substantial 'synergism' between auxins and ABA, although to a lesser extent. This study suggests that, in presence of altered levels of auxins, the crosstalk between hormones involves diverse mechanisms, acting at both the hormone response and biosynthesis levels, creating a complex response network.

A yeast bioassay for direct measurement of thyroid hormone disrupting effects in water without sample extraction, concentration, or sterilization.

PubMed

Li, Jian; Ren, Shujuan; Han, Shaolun; Li, Na

2014-04-01

The present study introduces an improved yeast bioassay for rapid yet sensitive evaluation of thyroid hormone disruption at the level of thyroid receptor (TR) in environmental water samples. This assay does not require water sample preparation and thus requires very little hands-on time. Based on different β-galactosidase substrates, two modified bioassays, a colorimetric bioassay and a chemiluminescent bioassay, were developed. The compounds tested included the known thyroid hormone 3,3',5-triiodo-l-thyronine (T3), the specific TR antagonist amiodarone hydrochloride (AH) and phthalate esters (PAEs), which potentially disrupt thyroid hormone signaling. The EC50 values for T3 were similar to those previously obtained using a 96-well plate bioassay. TR antagonism by AH was studied in the presence of 2.5 × 10(-7)M T3, and the concentration producing 20% of the maximum effect (RIC20) for AH was 3.1 × 10(-7)M and 7.8 × 10(-9)M for the colorimetric bioassay and chemiluminescent bioassay, respectively. None of the tested PAEs induced β-galactosidase expression, but diethylhexyl phthalate, benzyl butyl phthalate and dibutyl phthalate demonstrated TR antagonism. Furthermore, water samples collected from Guanting reservoir in Beijing were evaluated. Although TR agonism was not observed, antagonism was detected in all water samples and is expressed as AH equivalents. The toxicology equivalent quantity values obtained by the chemiluminescent bioassay ranged from 21.2 ± 1.6 to 313.9 ± 28.8 μg L(-1) AH, and similar values were obtained for the colorimetric bioassay. The present study shows that the modified yeast bioassay can be used as a valuable tool for quantification of thyroid hormone disrupting effects in environmental water samples. Copyright © 2013 Elsevier Ltd. All rights reserved.

Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

PubMed

Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David

2013-11-01

Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep. © 2013 International Society for Neurochemistry.

After-Ripening Induced Transcriptional Changes of Hormonal Genes in Wheat Seeds: The Cases of Brassinosteroids, Ethylene, Cytokinin and Salicylic Acid

PubMed Central

Yao, Zhen; Jordan, Mark C.; Park, Seokhoon; Ayele, Belay T.

2014-01-01

Maintenance and release of seed dormancy is regulated by plant hormones; their levels and seed sensitivity being the critical factors. This study reports transcriptional regulation of brassinosteroids (BR), ethylene (ET), cytokinin (CK) and salicylic acid (SA) related wheat genes by after-ripening, a period of dry storage that decays dormancy. Changes in the expression of hormonal genes due to seed after-ripening did not occur in the anhydrobiotic state but rather in the hydrated state. After-ripening induced dormancy decay appears to be associated with imbibition mediated increase in the synthesis and signalling of BR, via transcriptional activation of de-etiolated2, dwarf4 and brassinosteroid signaling kinase, and repression of brassinosteroid insensitive 2. Our analysis is also suggestive of the significance of increased ET production, as reflected by enhanced transcription of 1-aminocyclopropane-1-carboxylic acid oxidase in after-ripened seeds, and tight regulation of seed response to ET in regulating dormancy decay. Differential transcriptions of lonely guy, zeatin O-glucosyltransferases and cytokinin oxidases, and pseudo-response regulator between dormant and after-ripened seeds implicate CK in the regulation of seed dormancy in wheat. Our analysis also reflects the association of dormancy decay in wheat with seed SA level and NPR independent SA signaling that appear to be regulated transcriptionally by phenylalanine ammonia lyase, and whirly and suppressor of npr1 inducible1 genes, respectively. Co-expression clustering of the hormonal genes implies the significance of synergistic and antagonistic interaction between the different plant hormones in regulating wheat seed dormancy. These results contribute to further our understanding of the molecular features controlling seed dormancy in wheat. PMID:24498132

Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.

PubMed

Arai, Kiyoshi; Homma, Tsuyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiyoyuki; Aoki, Kazumasa; Ishikawa, Hirokazu; Mizuno, Makoto; Sada, Toshio

2015-08-15

The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5μM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Study of the interaction of 1,4-dihydropyridine derivatives with glucocorticoid hormone receptors from the rat liver.

PubMed

Vaitkuviene, Aida; Ulinskaite, Audrone; Meskys, Rolandas; Duburs, Gunars; Klusa, Vija; Liutkevicius, Evaldas

2006-01-01

Seventeen derivatives of 1,4-dihydropyridine (DHP) series were tested in vitro for their ability to inhibit [1,2,4-(3)H]-dexamethasone binding to glucocorticoid receptor from the rat liver cytosol. Depending on structural features and inhibiting activities, the compounds can be divided into three groups. The first group (nifedipine, foridone, J-6-163, OSI-4164 and OSI-7724) had the highest activity: they inhibited specific ligand-receptor binding by 70-80% at concentrations of 10(-5) M and 10(-4) M, with apparent IC(50)values of 1.5-6.0 muM. The second group (cerebrocrast, diethone, OSI-1211 and OSI-7265) was active at concentration of 10(-4) M, and their IC(50) values were 23-45 muM; compound OSI-5003 was almost inactive. Both groups are compounds with scarce water solubility, more or less lipophilic. The third group of compounds comprises ionogenic compounds (organic cations or anions with corresponding inorganic counterions): most of them are water-soluble (glutapyrone, carbatone, gammapyrone, OSI-2780, OSI-1580, OSI-2140) or liposome-forming (A-74). They lack the above-mentioned activity. Among the first two groups, compounds possessing more bulky substituents in positions 3 and 5 are less active. The aromatic ring in the position 4 is essential for the optimal activity. It seems that there is a bell-shaped dependence of activity upon lipophilicity. In general, the compounds of the first group are strong Ca-antagonists, while the second group includes moderate Ca-antagonists, but each group comprises also compounds which lack Ca antagonistic activity. All compounds of the third group lack Ca antagonistic properties.

"Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats".

PubMed

Valenza, Marta; Butelman, Eduardo R; Kreek, Mary Jeanne

2017-08-01

The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration. We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration. LY2444296 blocked U69,593-induced place aversion and -reduced motor activity as well as U69,593-induced release of serum CORT, confirming its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine-naïve rats. Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.

Editor's Highlight: Structure-Based Investigation on the Binding and Activation of Typical Pesticides With Thyroid Receptor.

PubMed

Xiang, Dandan; Han, Jian; Yao, Tingting; Wang, Qiangwei; Zhou, Bingsheng; Mohamed, Abou Donia; Zhu, Guonian

2017-12-01

A broad range of pesticides have been reported to interfere with the normal function of the thyroid endocrine system. However, the precise mechanism(s) of action has not yet been thoroughly elucidated. In this study, 21 pesticides were assessed for their binding interactions and the potential to disrupt thyroid homeostasis. In the GH3 luciferase reporter gene assays, 5 of the pesticides tested had agonistic effects in the order of procymidone > imidacloprid > mancozeb > fluroxypyr > atrazine. 11 pesticides inhibited luciferase activity of T3 to varying degrees, demonstrating their antagonistic activity. And there are 4 pesticides showed mixed effects when treated with different concentrations. Surface plasmon resonance (SPR) biosensor technique was used to directly measure the binding interactions of these pesticides to the human thyroid hormone receptor (hTR). 13 pesticides were observed to bind directly with TR, with a KD ranging from 4.80E-08 M to 9.44E-07 M. The association and disassociation of the hTR/pesticide complex revealed 2 distinctive binding modes between the agonists and antagonists. At the same time, a different binding mode was displayed by the pesticides showed mix agonist and antagonist activity. In addition, the molecular docking simulation analyses indicated that the interaction energy calculated by CDOCKER for the agonists and antagonists correlated well with the KD values measured by the surface plasmon resonance assay. These results help to explain the differences of the TR activities of these tested pesticides. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Antagonism of corticotropin-releasing factor CRF1 receptors blocks the enhanced response to cocaine after social stress.

PubMed

Ferrer-Pérez, Carmen; Reguilón, Marina D; Manzanedo, Carmen; Aguilar, M Asunción; Miñarro, José; Rodríguez-Arias, Marta

2018-03-15

Numerous studies have shown that social defeat stress induces an increase in the rewarding effects of cocaine. In this study we have investigated the role played by the main hypothalamic stress hormone, corticotropin-releasing factor (CRF), in the effects that repeated social defeat (RSD) induces in the conditioned rewarding effects and locomotor sensitization induced by cocaine. A total of 220 OF1 mice were divided into experimental groups according to the treatment received before each social defeat: saline, 5 or 10 mg/kg of the nonpeptidic corticotropin-releasing factor CRF 1 receptor antagonist CP-154,526, or 15 or 30 µg/kg of the peptidic corticotropin-releasing factor CRF 2 receptor antagonist Astressin 2 -B. Three weeks after the last defeat, conditioned place preference (CPP) induced by 1 mg/kg of cocaine was evaluated. Motor response to 10 mg/kg of cocaine was also studied after a sensitization induction. Blockade of corticotropin-releasing factor CRF 1 receptor reversed the increase in cocaine CPP induced by social defeat. Conversely, peripheral corticotropin-releasing factor CRF 2 receptor blockade produced similar effects to those observed in socially stressed animals. The effect of RSD on cocaine sensitization was again blocked by the corticotropin-releasing factor CRF 1 receptor antagonist, while peripheral CRF 2 receptor antagonist did not show effect. Acute administration of Astressin 2 -B induced an anxiogenic response. Our results confirm that CRF modulates the effects of social stress on reinforcement and sensitization induced by cocaine in contrasting ways. These findings highlight CRF receptors as potential therapeutic targets to be explored by research about stress-related addiction problems. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification of key residues involved in adrenomedullin binding to the AM1 receptor

PubMed Central

Watkins, HA; Au, M; Bobby, R; Archbold, JK; Abdul-Manan, N; Moore, JM; Middleditch, MJ; Williams, GM; Brimble, MA; Dingley, AJ; Hay, DL

2013-01-01

Background and Purpose Adrenomedullin (AM) is a peptide hormone whose receptors are members of the class B GPCR family. They comprise a heteromer between the GPCR, the calcitonin receptor-like receptor and one of the receptor activity-modifying proteins 1–3. AM plays a significant role in angiogenesis and its antagonist fragment AM22–52 can inhibit blood vessel and tumour growth. The mechanism by which AM interacts with its receptors is unknown. Experimental Approach We determined the AM22–52 binding epitope for the AM1 receptor extracellular domain using biophysical techniques, heteronuclear magnetic resonance spectroscopy and alanine scanning. Key Results Chemical shift perturbation experiments located the main binding epitope for AM22–52 at the AM1 receptor to the C-terminal 8 amino acids. Isothermal titration calorimetry of AM22–52 alanine-substituted peptides indicated that Y52, G51 and I47 are essential for AM1 receptor binding and that K46 and P49 and R44 have a smaller role to play. Characterization of these peptides at the full-length AM receptors was assessed in Cos7 cells by cAMP assay. This confirmed the essential role of Y52, G51 and I47 in binding to the AM1 receptor, with their substitution resulting in ≥100-fold reduction in antagonist potency compared with AM22–52. R44A, K46A, S48A and P49A AM22–52 decreased antagonist potency by approximately 10-fold. Conclusions and Implications This study localizes the main binding epitope of AM22–52 to its C-terminal amino acids and distinguishes essential residues involved in this binding. This will inform the development of improved AM receptor antagonists. PMID:23351143

Gender specific influence of endogenous glutamate release on stress-induced fear in rats.

PubMed

Jain, S K; Zelena, D

2011-01-01

Stress, fear and anxiety are among major public health concerns. The role of glutamate in these processes is becoming more recognized with promising new drug targets. The aim of this study was to establish the gender specificity of a possible treatment of fear by glutamate antagonists in correspondence with changes in stress-hormone release. Footshock-induced fear was used as an anxiogenic situation in rats. A combination of two ionotrop receptor antagonists such as MK-801 (dizocilpine; 0.2 mg/kg) for NMDA (N-methyl-D-aspartic acid) and GYKI 52466 (benzodiazepine derivative; 10 mg/kg) for AMPA/kainate receptors were used for 5 days following the hypothesis that they potentiate each other the main action, but at the same time the side effects may be minimized. Female rats tried to avoid the electrical stimulus more actively than males, as they spent more time with exploration and jumping and less time with freezing or rest. Ionotropic glutamate receptor antagonists have anxiolytic action. MK-801 was more effective in females, as it prevented the footshock-induced freezing per se, while in males it was effective only in combination with GyKI 52466. The locomotor side effect of MK-801 was not visible after repeated administration. The freezing behavior was positively correlated with the changes in prolactin but not with adrenocorticotropin levels. We proved the involvement of endogenous glutamate neurotransmission in stress-induced fear. Therapeutical usage may involve a combination of different receptor antagonists. Special attention should be paid to the gender, as females seem to be more sensitive, therefore they require smaller doses. During the treatment the prolactin levels should be monitored.

The acute and post-discontinuation effects of a glucocorticoid receptor (GR) antagonist probe on sleep and the HPA axis in chronic insomnia: a pilot study.

PubMed

Buckley, Theresa; Duggal, Vandana; Schatzberg, Alan F

2008-06-15

Hypothalamic-pituitary-adrenal axis (HPA) hyperactivity has been reported in patients with chronic insomnia without depression. Aglucocorticoid receptor (GR) antagonist may re-regulate HPA axis activity even after discontinuation and may have clinical benefit. Ten subjects with chronic insomnia participated in a placebo controlled double-blinded prospective 30-day pilot study of the acute and post-discontinuation effects of a 5-day course of 600 mg of the glucocorticoid antagonist, mifepristone. Sleep outcome measures were polysomnogram and Insomnia Severity Index. Hormonal outcome measures were mean overnight cortisol and ACTH (23:00-07:00). We predicted sleep would improve and that overnight cortisol and ACTH would decrease at 2 weeks post-treatment discontinuation. At 2 weeks post-discontinuation, Insomnia Severity Index (ISI) decreased by 4.0 points (effect size = 0.97). Polysomnogram findings were limited. Mean cortisol (0.84 microg/dL, effect size = 0.91) and ACTH (5.50 pg/mL, effect size = 0.96) were still mildly increased (23:00 to 07:00). Post hoc analysis revealed that, the ratio of cortisol/ ACTH decreased (-0.21, effect size = 1.15) as did mean cortisol from 18:00 to 23:00 (-0.47 microg/dL, effect size = 0.56). This is the first study of a GR antagonist in chronic insomnia. Sleep improvement manifests in terms of decreased ISI post-treatment discontinuation. The decrease in cortisol in the early evening (18:00 to 23:00) in combination with the decrease in cortisol/ ACTH ratio may be an indicator of the longer-term biological mode of action of the drug.

The clinical potential of ramosetron in the treatment of irritable bowel syndrome with diarrhea (IBS-D).

PubMed

Min, Yang Won; Rhee, Poong-Lyul

2015-05-01

Irritable bowel syndrome (IBS) is a highly prevalent functional bowel disorder. Serotonin (5-HT) is known to play a physiological and pathophysiological role in the regulation of gastrointestinal function. In experimental studies, 5-HT3 receptor antagonists have been reported to slow colon transit, to blunt gastrocolonic reflex, and to reduce rectal sensitivity. Alosetron and cilansetron, potent and selective 5-HT3 receptor antagonists, have proven efficacy in the treatment of IBS with diarrhea (IBS-D). However, alosetron was voluntarily withdrawn due to postmarketing reports of ischemic colitis and complications of constipation, and cilansetron was never marketed. Currently alosetron is available under a risk management program for women with severe IBS-D. Ramosetron is another potent and selective 5-HT3 receptor antagonist, which has been marketed in Japan, South Korea, and Taiwan. In animal studies, ramosetron reduced defecation induced by corticotrophin-releasing hormone and had inhibitory effects on colonic nociception. In two randomized controlled studies including 957 patients with IBS-D, ramosetron increased monthly responder rates of patient-reported global assessment of IBS symptom relief compared with placebo. Ramosetron was also as effective as mebeverine in male patients with IBS-D. In a recent randomized controlled trial with 343 male patients with IBS-D, ramosetron has proved effective in improving stool consistency, relieving abdominal pain/discomfort, and improving health-related quality of life. Regarding safety, ramosetron is associated with a lower incidence of constipation compared with other 5-HT3 receptor antagonists and has not been associated with ischemic colitis. Although further large prospective studies are needed to assess whether ramosetron is effective for female patients with IBS-D and to evaluate its long-term safety, ramosetron appears to be one of the most promising agents for patients with IBS-D.

Hypothalamic control of pituitary and adrenal hormones during hypothermia.

PubMed

Okuda, C; Miyazaki, M; Kuriyama, K

1986-01-01

In order to investigate neuroendocrinological mechanisms of hypothermia, we determined the changes in plasma concentrations of corticosterone (CS), prolactin (PRL), and thyrotropin (TSH), and their correlations with alterations in hypothalamic dopamine (DA) and thyrotropin releasing hormone (TRH), in rats restrained and immersed in a water bath at various temperatures. A graded decrease of body temperature induced a progressive increase in the plasma level of CS, whereas that of PRL showed a drastic decrease. The plasma level of TSH also showed an increase during mild hypothermia (about 35 degrees C), but this increase was not evident during profound hypothermia (below 24 degrees C). The changes in these hormones were readily reversed by rewarming animals. Although DA content in the hypothalamus was not affected, its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), showed an increase following the decrease of body temperature. Pretreatment of the animals with sulpiride, a D2-antagonist, prevented the hypothermia-induced inhibition of PRL release. Hypothalamic TRH was significantly decreased during mild hypothermia, and it returned to control levels after rewarming. These results suggest that the decrease in plasma PRL induced by hypothermia may be associated with the activation of hypothalamic DA neurons, whereas the increase in plasma TSH during mild hypothermia seems to be caused by the increased release of TRH in the hypothalamus.

Bisphenol A induces otolith malformations during vertebrate embryogenesis

PubMed Central

2011-01-01

Background The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models. Results We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype. Conclusions The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor. PMID:21269433

Bisphenol A induces otolith malformations during vertebrate embryogenesis.

PubMed

Gibert, Yann; Sassi-Messai, Sana; Fini, Jean-Baptiste; Bernard, Laure; Zalko, Daniel; Cravedi, Jean-Pierre; Balaguer, Patrick; Andersson-Lendahl, Monika; Demeneix, Barbara; Laudet, Vincent

2011-01-26

The plastic monomer and plasticizer bisphenol A (BPA), used for manufacturing polycarbonate plastic and epoxy resins, is produced at over 2.5 million metric tons per year. Concerns have been raised that BPA acts as an endocrine disruptor on both developmental and reproductive processes and a large body of evidence suggests that BPA interferes with estrogen and thyroid hormone signaling. Here, we investigated BPA effects during embryonic development using the zebrafish and Xenopus models. We report that BPA exposure leads to severe malformations of the otic vesicle. In zebrafish and in Xenopus embryos, exposure to BPA during the first developmental day resulted in dose-dependent defects in otolith formation. Defects included aggregation, multiplication and occasionally failure to form otoliths. As no effects on otolith development were seen with exposure to micromolar concentrations of thyroid hormone, 17-ß-estradiol or of the estrogen receptor antagonist ICI 182,780 we conclude that the effects of BPA are independent of estrogen receptors or thyroid-hormone receptors. Na+/K+ ATPases are crucial for otolith formation in zebrafish. Pharmacological inhibition of the major Na+/K+ ATPase with ouabain can rescue the BPA-induced otolith phenotype. The data suggest that the spectrum of BPA action is wider than previously expected and argue for a systematic survey of the developmental effects of this endocrine disruptor.

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

PubMed

Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H L; Wang, Jun; Mawji, Nasrin R; Sadar, Marianne D

2017-01-01

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.

Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer

PubMed Central

Myung, Jae-Kyung; Wang, Gang; Chiu, Helen H. L.; Wang, Jun; Mawji, Nasrin R.; Sadar, Marianne D.

2017-01-01

Androgen receptor (AR) is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD). Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA) and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD. PMID:28306720

Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge.

PubMed

Surkin, P N; Di Rosso, M E; Correa, F; Elverdin, J C; Genaro, A M; De Laurentiis, A; Fernández-Solari, J

2017-08-01

Immune challenge inhibits reproductive function and endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the eCB system mediates the inhibition of hormones that control reproduction as a result of immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on the hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated i.c.v. administration with a CB1 antagonist/inverse agonist (AM251) (500 ng/5 μL), followed by an i.p. injection of lipopolysaccharide (LPS) (5 mg/kg) 15 minutes later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 minutes post-LPS. The plasma concentration of tumour necrosis factor α and adenohypophyseal mRNA expression of Tnfα and Il1β increased 90 and 180 minutes post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 minutes post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotrophin-releasing hormone hypothalamic content and plasma levels of luteinising hormone and testosterone. These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 content, as well as by increased gonadotrophin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that, in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery by modulating the inflammatory process taking place after LPS administration. © 2017 British Society for Neuroendocrinology.

Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women.

PubMed

Brunt, Vienna E; Miner, Jennifer A; Kaplan, Paul F; Halliwill, John R; Strycker, Lisa A; Minson, Christopher T

2013-10-01

The individual effects of estrogen and progesterone on baroreflex function remain poorly understood. We sought to determine how estradiol (E2) and progesterone (P4) independently alter the carotid-cardiac and carotid-vasomotor baroreflexes in young women by using a hormone suppression and exogenous add-back design. Thirty-two young women were divided into two groups and studied under three conditions: 1) after 4 days of endogenous hormone suppression with a gonadotropin releasing hormone antagonist (control condition), 2) after continued suppression and 3 to 4 days of supplementation with either 200 mg/day oral progesterone (N = 16) or 0.1 to 0.2 mg/day transdermal 17β-estradiol (N = 16), and 3) after continued suppression and 3 to 4 days of supplementation with both hormones. Changes in heart rate (HR), mean arterial pressure (MAP), and femoral vascular conductance (FVC) were measured in response to 5 s of +50 mmHg external neck pressure to unload the carotid baroreceptors. Significant hormone effects on the change in HR, MAP, and FVC from baseline at the onset of neck pressure were determined using mixed model covariate analyses accounting for P4 and E2 plasma concentrations. Neither P4 (P = 0.95) nor E2 (P = 0.95) affected the HR response to neck pressure. Higher P4 concentrations were associated with an attenuated fall in FVC (P = 0.01), whereas higher E2 concentrations were associated with an augmented fall in FVC (P = 0.02). Higher E2 was also associated with an augmented rise in MAP (P = 0.01). We conclude that progesterone blunts whereas estradiol enhances carotid-vasomotor baroreflex sensitivity, perhaps explaining why no differences in sympathetic baroreflex sensitivity are commonly reported between low and high combined hormone phases of the menstrual cycle.

Short-term administration of progesterone and estradiol independently alter carotid-vasomotor, but not carotid-cardiac, baroreflex function in young women

PubMed Central

Brunt, Vienna E.; Miner, Jennifer A.; Kaplan, Paul F.; Halliwill, John R.; Strycker, Lisa A.

2013-01-01

The individual effects of estrogen and progesterone on baroreflex function remain poorly understood. We sought to determine how estradiol (E2) and progesterone (P4) independently alter the carotid-cardiac and carotid-vasomotor baroreflexes in young women by using a hormone suppression and exogenous add-back design. Thirty-two young women were divided into two groups and studied under three conditions: 1) after 4 days of endogenous hormone suppression with a gonadotropin releasing hormone antagonist (control condition), 2) after continued suppression and 3 to 4 days of supplementation with either 200 mg/day oral progesterone (N = 16) or 0.1 to 0.2 mg/day transdermal 17β-estradiol (N = 16), and 3) after continued suppression and 3 to 4 days of supplementation with both hormones. Changes in heart rate (HR), mean arterial pressure (MAP), and femoral vascular conductance (FVC) were measured in response to 5 s of +50 mmHg external neck pressure to unload the carotid baroreceptors. Significant hormone effects on the change in HR, MAP, and FVC from baseline at the onset of neck pressure were determined using mixed model covariate analyses accounting for P4 and E2 plasma concentrations. Neither P4 (P = 0.95) nor E2 (P = 0.95) affected the HR response to neck pressure. Higher P4 concentrations were associated with an attenuated fall in FVC (P = 0.01), whereas higher E2 concentrations were associated with an augmented fall in FVC (P = 0.02). Higher E2 was also associated with an augmented rise in MAP (P = 0.01). We conclude that progesterone blunts whereas estradiol enhances carotid-vasomotor baroreflex sensitivity, perhaps explaining why no differences in sympathetic baroreflex sensitivity are commonly reported between low and high combined hormone phases of the menstrual cycle. PMID:23873800

Regulation of alternative splicing of Slo K+ channels in adrenal and pituitary during the stress-hyporesponsive period of rat development.

PubMed

Lai, Guey-Jen; McCobb, David P

2006-08-01

Stress triggers release of ACTH from the pituitary, glucocorticoids from the adrenal cortex, and epinephrine from the adrenal medulla. Although functions differ, these hormone systems interact in many ways. Previous evidence indicates that pituitary and steroid hormones regulate alternative splicing of the Slo gene at the stress axis-regulated exon (STREX), with functional implications for the calcium-activated K+ channels prominent in adrenal medullary and pituitary cells. Here we examine the role of corticosterone in Slo splicing regulation in pituitary and adrenal tissues during the stress-hyporesponsive period of early rat postnatal life. The sharp drop in plasma corticosterone (CORT) that defines this period offers a unique opportunity to test CORT's role in Slo splicing. We report that in both adrenal and pituitary tissues, the percentage of Slo transcripts having STREX declines and recovers in parallel with CORT. Moreover, addition of 500 nm CORT to cultures of anterior pituitary cells from 13-, 21-, and 30-d postnatal animals increased the percentage of Slo transcripts with STREX, whereas 20 microm CORT reduced STREX representation. Applied to adrenal chromaffin cells, 20 microm CORT decreased STREX inclusion, whereas neither 500 nm nor 2 microm had any effect. The mineralocorticoid receptor antagonist RU28318 abolished the effect of 500 nm CORT on splicing in pituitary cells, whereas the glucocorticoid receptor antagonist RU38486 blocked the effect of 20 microm CORT on adrenal chromaffin cells. These results support the hypothesis that the abrupt, transient drop in CORT during the stress-hyporesponsive period drives the transient decline in STREX splice variant representation in pituitary, but not adrenal.

Treatment Outcome of Ovulation-inducing Agents in Patients with Anovulatory Infertility: A Prospective, Observational Study

PubMed Central

Prajapati, Kinjal; Desai, Mira; Shah, Samidh; Choudhary, Sumesh; Aggarwal, Rohina; Mishra, Vineet

2017-01-01

Objective: To compare different treatment regimens on pregnancy rate and outcome in patients with anovulatory infertility. Patients and Methods: A prospective observational study was conducted on patients with infertility due to anovulation. Patients treated with clomiphene citrate (CC) 50/100 mg/day from 2nd to 6th day of menstrual cycle (MC) (n = 38), short gonadotropin-releasing hormone (GnRH) agonist regimen (leuprolide [0.5 mg subcutaneous] + recombinant follicle-stimulating hormone [rFSH] [225 IU intramuscular [IM] from 2nd to 10th day of MC [n = 32]), long GnRH agonist regimen (leuprolide from 21st day followed by leuprolide + rFSH from 2nd to 10th day of MC [n = 19]), and antagonist regimen (human menopausal gonadotropin [hMG] [150 IU IM] from 2nd day followed by hMG + cetrorelix from 7th to 10th day of MC) (n = 6) were recruited and followed up for follicular size, endometrial thickness, and pregnancy test. Data were analyzed using appropriate statistical test andP < 0.05 was considered statistically significant. Results: A significant increase in follicular diameter and endometrial thickness was observed in patients treated with gonadotropin regimens as compared to CC alone (P < 0.0001). The highest number of positive pregnancy test with ultrasonographic evidence of gestational sac was observed with leuprolide + rFSH (long regimen) (10/19, 52.6%) followed by leuprolide + rFSH (short regimen) (13/32, 40.6%) while least in antagonist regimen (2/6, 33.3%) and CC (1/38, 2.63%). All regimens were well tolerated. Conclusion: Treatment outcome was better with long agonist regimen. PMID:29081619

Insulinotropic and antidiabetic effects of 17β-estradiol and the GPR30 agonist G-1 on human pancreatic islets.

PubMed

Kumar, Rajesh; Balhuizen, Alexander; Amisten, Stefan; Lundquist, Ingmar; Salehi, Albert

2011-07-01

We have recently shown that 17β-estradiol (E2) and the synthetic G protein-coupled receptor 30 (GPR30) ligand G-1 have antiapoptotic actions in mouse pancreatic islets, raising the prospect that they might exert beneficial effects also in human islets. The objective of the present study was to identify the expression of GPR30 in human islets and clarify the role of GPR30 in islet hormone secretion and β-cell survival. GPR30 expression was analyzed by confocal microscopy, Western blot, and quantitative PCR in islets from female and male donors. Hormone secretion, phosphatidylinositol hydrolysis, cAMP content, and caspase-3 activity in female islets were determined with conventional methods and apoptosis with the annexin-V method. Confocal microscopy revealed GPR30 expression in islet insulin, glucagon, and somatostatin cells. GPR30 mRNA and protein expression was markedly higher in female vs. male islets. An amplifying effect of G-1 or E2 on cAMP content and insulin secretion from isolated female islets was not influenced by the E2 genomic receptor (ERα and ERβ) antagonists ICI 182,780 and EM-652. Cytokine-induced (IL-1β plus TNFα plus interferon-γ) apoptosis in islets cultured for 24 h at 5 mmol/liter glucose was almost abolished by G-1 or E2 treatment and was not affected by the nuclear estrogen receptor antagonists. Concentration-response studies on female islets from healthy controls and type 2 diabetic subjects showed that both E2 and G-1 displayed important antidiabetic actions by improving glucose-stimulated insulin release while suppressing glucagon and somatostatin secretion. In view of these findings, we propose that small molecules activating GPR30 could be promising in the therapy of diabetes mellitus.

Cumulative and antagonistic effects of a mixture of the antiandrogens vinclozolin and iprodione in the pubertal male rat.

PubMed

Blystone, Chad R; Lambright, Christy S; Cardon, Mary C; Furr, Johnathan; Rider, Cynthia V; Hartig, Phillip C; Wilson, Vickie S; Gray, Leon E

2009-09-01

Vinclozolin and iprodione are dicarboximide fungicides that display antiandrogenic effects in the male rat, which suggests that a mixture would lead to cumulative effects on androgen-sensitive end points. Iprodione is a steroid synthesis inhibitor, but androgen receptor antagonist activity, which is displayed by vinclozolin, has not been fully evaluated. Here, we demonstrate that iprodione binds to the human androgen receptor (IC(50) = 86.0 microM), reduces androgen-dependent gene expression, and reduces androgen-sensitive tissue weights in castrated male rats (Hershberger assay). Since vinclozolin and iprodione affect common targets in the pubertal male rat, we tested the hypothesis that a mixture would have cumulative antiandrogenic effects. An iprodione dose, that does not significantly affect androgen-dependent morphological end points, was combined with vinclozolin doses (2 x 5 factorial design). Sprague-Dawley rats were dosed by gavage with vinclozolin at 0, 10, 30, 60, and 100 mg/kg/day with and without 50 mg iprodione/kg/day from postnatal day (PND) 23 to 55-57 (n = 8 per group). The age at puberty (preputial separation [PPS]), organ weights, serum hormones, and ex vivo testis steroid hormone production were measured. Vinclozolin delayed PPS, reduced androgen-sensitive organ weights, and increased serum testosterone. The addition of iprodione enhanced the vinclozolin inhibition of PPS (PND 47.5 vs.49.1; two-way ANOVA: iprodione main effect p = 0.0002). The dose response for several reproductive and nonreproductive organ weights was affected in a cumulative manner. In contrast, iprodione antagonized the vinclozolin-induced increase in serum testosterone. These results demonstrate that these fungicides interact on common targets in a tissue-specific manner when coadministered to the pubertal male rat.

Differential effects of centrally-administered oestrogen antagonist ICI-182,780 on oestrogen-sensitive functions in the hypothalamus.

PubMed

Steyn, F J; Anderson, G M; Grattan, D R

2007-01-01

Oestrogen actions within the hypothalamus are essential for a range of reproductive functions. In this study, we sought to develop a method for suppressing central oestrogen action without affecting peripheral oestrogenic effects. We administered the oestrogen receptor antagonist ICI-182,780 (ICI) via crystalline implants into the left lateral ventricle or the arcuate nucleus and measured the effectiveness of this drug on three endpoints known to be regulated by oestrogen: gonadotrophin-releasing hormone (GnRH) pulse frequency, progesterone receptor expression and the generation of a sustained prolactin surge during late pregnancy. To confirm that central ICI administration had no effect on peripheral actions of oestrogen, we monitored changes in uterine weight. Intracerebroventricular ICI treatment reversed the inhibitory effects of oestrogen on GnRH pulse frequency, as measured by plasma luteinising hormone pulse frequency. No effect on the oestrogenic induction of progesterone receptors within the arcuate nucleus or ventromedial hypothalamus was observed; however, a small yet significant reduction in progesterone receptor expression within dopaminergic neurones in the arcuate nucleus was observed. Intracerebroventricular or direct crystalline ICI administration to the arcuate nucleus did not change the serum prolactin level during late pregnancy. Central administration of ICI did not affect uterine weight, and thus did not have a peripheral effect. These data suggest that central administration of ICI can overcome some actions of oestrogen in the brain, such as GnRH pulse frequency, but does not affect other oestrogen mediated actions, including the induction of progesterone receptors or the antepartum prolactin surge. Thus, it appears that there is a differential sensitivity to the inhibition of central oestrogen actions by ICI.

Central proopiomelanocortin but not neuropeptide Y mediates sympathoexcitation and hypertension in fat fed conscious rabbits.

PubMed

Barzel, Benjamin; Lim, Kyungjoon; Davern, Pamela J; Burke, Sandra L; Armitage, James A; Head, Geoffrey A

2016-03-01

High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension. Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter. After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits. These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.

Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice.

PubMed

Ma, Xiaojun; Lin, Yuezhen; Lin, Ligen; Qin, Guijun; Pereira, Fred A; Haymond, Morey W; Butte, Nancy F; Sun, Yuxiang

2012-08-01

The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.

Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin

PubMed Central

Palm, Fredrik; Takahashi, Tomoko; Ikegami-Kawai, Mayumi; Friederich-Persson, Malou; Hansell, Peter

2017-01-01

The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10−10 and 10−8 M) increased HA 3-fold. On the contrary, at a high concentration (10−6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling. PMID:29236055

Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems.

PubMed

Mao, Yuqing; Li, Zhengyang; Chen, Kan; Yu, Huafang; Zhang, Shaoren; Jiang, Miao; Ma, Yuanhua; Liang, Chunli; Liu, Hongyan; Li, Huanqing; Hua, Qian; Zhou, Hao; Sun, Yonghong; Fan, Xiaoming

2017-01-01

Irritable bowel syndrome (IBS), defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. Maternal deprivation (MD) was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD) was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR) scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg) subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L) and naloxone (100 nmol/L) were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α) and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1) and µ and κ opioid receptors (MOR and KOR) in colon, dorsal root ganglion (DRG) and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analyses and immunofluorescence. Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG) and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS. © 2017 The Author(s). Published by S. Karger AG, Basel.

Role of Cholecystokinin in Anorexia Induction Following Oral Exposure to the 8-Ketotrichothecenes Deoxynivalenol, 15-Acetyldeoxynivalenol, 3-Acetyldeoxynivalenol, Fusarenon X, and Nivalenol

PubMed Central

Wu, Wenda; Zhou, Hui-Ren; He, Kaiyu; Pan, Xiao; Sugita-Konishi, Yoshiko; Watanabe, Maiko; Zhang, Haibin; Pestka, James J.

2014-01-01

Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY3–36 (PYY3–36), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY3–36 concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY3–36 was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY3–36 might play a lesser, congener-dependent role in this response. PMID:24385417

Role of cholecystokinin in anorexia induction following oral exposure to the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol.

PubMed

Wu, Wenda; Zhou, Hui-Ren; He, Kaiyu; Pan, Xiao; Sugita-Konishi, Yoshiko; Watanabe, Maiko; Zhang, Haibin; Pestka, James J

2014-04-01

Cereal grain contamination by trichothecene mycotoxins is known to negatively impact human and animal health with adverse effects on food intake and growth being of particular concern. The head blight fungus Fusarium graminearum elaborates five closely related 8-ketotrichothecene congeners: (1) deoxynivalenol (DON), (2) 3-acetyldeoxynivalenol (3-ADON), (3) 15-acetyldeoxynivalenol (15-ADON), (4) fusarenon X (FX), and (5) nivalenol (NIV). While anorexia induction in mice exposed intraperitoneally to DON has been linked to plasma elevation of the satiety hormones cholecystokinin (CCK) and peptide YY₃₋₃₆ (PYY₃₋₃₆), the effects of oral gavage of DON or of other 8-keotrichothecenes on release of these gut peptides have not been established. The purpose of this study was to (1) compare the anorectic responses to the aforementioned 8-ketotrichothecenes following oral gavage at a common dose (2.5 mg/kg bw) and (2) relate these effects to changes plasma CCK and PYY₃₋₃₆ concentrations. Elevation of plasma CCK markedly corresponded to anorexia induction by DON and all other 8-ketotrichothecenes tested. Furthermore, the CCK1 receptor antagonist SR 27897 and the CCK2 receptor antagonist L-365,260 dose-dependently attenuated both CCK- and DON-induced anorexia, which was consistent with this gut satiety hormone being an important mediator of 8-ketotrichothecene-induced food refusal. In contrast to CCK, PYY₃₋₃₆ was moderately elevated by oral gavage with DON and NIV but not by 3-ADON, 15-ADON, or FX. Taken together, the results suggest that CCK plays a major role in anorexia induction following oral exposure to 8-ketotrichothecenes, whereas PYY₃₋₃₆ might play a lesser, congener-dependent role in this response.

Corticotropin-releasing factor receptor-1 modulates biomarkers of DNA oxidation in Alzheimer’s disease mice

PubMed Central

Zhang, Cheng

2017-01-01

Increased production of hydroxyl radical is the main source of oxidative damage in mammalian DNA that accumulates in Alzheimer’s disease (AD). Reactive oxygen species (ROS) react with both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) to generate 8-hydroxy-2’-deoxyguanosine (8-OHdG), both of which can be measured in the urine. Knowledge of this pathway has positioned measurement of urine 8-OHdG as a reliable index of DNA oxidation and a potential biomarker target for tracking early cellular dysfunction in AD. Furthermore, epigenetic studies demonstrate decreased global DNA methylation levels (e.g. 5-methyl-2’-deoxycytidine, 5-mdC) in AD tissues. Moreover, stress hormones can activate neuronal oxidative stress which will stimulate the release of additional stress hormones and result in damages to hippocampal neurons in the AD brain. Our previous work suggests that treating AD transgenic mice the type-1 corticotropin-releasing factor receptor (CRFR1) antagonist, R121919, to reduce stress signaling, prevented onset of cognitive impairment, synaptic/dendritic loss and Aβ plaque accumulation. Therefore, to investigate whether levels of DNA oxidation can be impacted by the same therapeutic approach, urine levels of hydrogen peroxide, 8-OHdG, 5-mdC and total antioxidant capacity (TAC) were analyzed using an AD Tg mouse model. We found that Tg animals had an 80% increase in hydrogen peroxide levels compared to wild type (Wt) counterparts, an effect that could be dramatically reversed by the chronic administration with R121919. A significant decrease of 8-OHdG levels was observed in Tg mice treated with CRFR1 antagonist. Collectively our data suggest that the beneficial effects of CRFR1 antagonism seen in Tg mice may be mechanistically linked to the modulation of oxidative stress pathways. PMID:28750017

Anti-Mullerian hormone-tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF.

PubMed

Yates, A P; Rustamov, O; Roberts, S A; Lim, H Y N; Pemberton, P W; Smith, A; Nardo, L G

2011-09-01

Anti-Müllerian hormone (AMH) is increasingly used to quantify ovarian reserve, but it has not yet realized its full clinical potential in assisted reproduction technology. We investigated the possible benefits of using novel, stratified ovarian hyperstimulation protocols, tailored to individual AMH levels, compared with conventional stimulation. Retrospective data were collected from 769 women (first cycle of IVF, using fresh embryos), in a UK tertiary care unit: 346 women using conventional stimulation protocols; 423 women treated under new AMH-tailored protocols. Embryo transfer rates increased significantly (79-87%: P= 0.002) after the introduction of AMH-tailored stimulation protocols. Pregnancy rate per cycle started and live birth rate also increased significantly compared with conventionally treated women (17.9-27.7%, P= 0.002 and 15.9-23.9%, P = 0.007, respectively). Moreover, in the AMH group, the incidence of the ovarian hyperstimulation syndrome (OHSS) fell significantly (6.9-2.3%, P = 0.002) and failed fertilization fell from 7.8 to 4.5%. The cost of fertility drug treatment fell by 29% per patient and the overall cost of clinical management of OHSS fell by 43% in the AMH group. GnRH antagonist protocols, introduced as part of AMH-tailored treatment, may have contributed to the observed improvements: however, within the AMH-tailored group, the live birth rate was not significantly different between agonist and antagonist-treated groups. Although large, prospective, multicentre studies are indicated, we have clearly demonstrated that individualized, AMH-guided, controlled ovarian hyperstimulation protocols significantly improved positive clinical outcomes, reduced the incidence of complications and reduced the financial burden associated with assisted reproduction.

Estrogenic effects of herbal medicines from Costa Rica used for the management of menopausal symptoms.

PubMed

Doyle, Brian J; Frasor, Jonna; Bellows, Lauren E; Locklear, Tracie D; Perez, Alice; Gomez-Laurito, Jorge; Mahady, Gail B

2009-01-01

Outcomes from the Women's Health Initiative have demonstrated adverse effects associated with hormone therapy and have prioritized the need to develop new alternative treatments for the management of menopause and osteoporosis. To this end, we have been investigating natural herbal medicines used by Costa Rican women to manage menopausal symptoms. Seventeen plant species were collected and extracted in Costa Rica. To establish possible mechanisms of action and to determine their potential future use for menopause or osteoporosis, we investigated the estrogenic activities of the herbal extracts in an estrogen-reporter gene estrogen receptor (ER) beta-Chemically Activated Luciferase Expression assay in U2-OS cells and in reporter and endogenous gene assays in MCF-7 cells. Six of the plant extracts bound to the ERs. Four of the six extracts stimulated reporter gene expression in the ER-beta-Chemically Activated Luciferase Expression assay. All six extracts modulated expression of endogenous genes in MCF-7 cells, with four extracts acting as estrogen agonists and two extracts, Pimenta dioica and Smilax domingensis, acting as partial agonist/antagonists by enhancing estradiol-stimulated pS2 mRNA expression but reducing estradiol-stimulated PR and PTGES mRNA expression. Both P. dioica and S. domingensis induced a 2ERE-luciferase reporter gene in transient transfected MCF-7 cells, which was inhibited by the ER antagonist ICI 182,780. This work presents a plausible mechanism of action for many of the herbal medicines used by Costa Rican women to treat menopausal symptoms. However, it further suggests that studies of safety and efficacy are needed before these herbs should be used as alternative therapies to hormone therapy.

Effects of ANP receptor antagonists on ANP secretion from adult rat cultured atrial myocytes.

PubMed

Nachshon, S; Zamir, O; Matsuda, Y; Zamir, N

1995-03-01

Atrial natriuretic peptide (ANP) is a hormone-secreted predominantly by atrial myocytes. ANP exerts many of its actions via activation of the particulate guanylyl cyclase receptor ANPR-A and the formation of guanosine 3',5'-cyclic monophosphate (cGMP), which serves as a second messenger in the target cells. Using membrane-permeable cGMP analogues (8-bromo-cGMP and dibutyryl- cGMP), we first tested the hypothesis that ANP secretion by adult rat cultured atrial myocytes can be modulated through the second messenger cGMP. Second, we examined the effects of two competitive ANPR-A receptor antagonists, namely HS-142-1 and anantin, on cGMP formation and ANP secretion from cultured atrial myocytes. Cultured atrial myocytes secreted large quantities of immunoreactive (ir) ANP under basal conditions. We found that cGMP analogues inhibited basal irANP secretion from cultured atrial myocytes, whereas HS-142-1 and anantin had stimulating effects. HS-142-1 and anantin reduced cGMP formation in cultured atrial myocytes at basal conditions. These results suggest an autoregulatory mechanism of ANP secretion by atrial myocytes in an autocrine/paracrine fashion.

Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

PubMed

Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

2010-09-01

Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

GH Mediates Exercise-Dependent Activation of SVZ Neural Precursor Cells in Aged Mice

PubMed Central

Blackmore, Daniel G.; Vukovic, Jana; Waters, Michael J.; Bartlett, Perry F.

2012-01-01

Here we demonstrate, both in vivo and in vitro, that growth hormone (GH) mediates precursor cell activation in the subventricular zone (SVZ) of the aged (12-month-old) brain following exercise, and that GH signaling stimulates precursor activation to a similar extent to exercise. Our results reveal that both addition of GH in culture and direct intracerebroventricular infusion of GH stimulate neural precursor cells in the aged brain. In contrast, no increase in neurosphere numbers was observed in GH receptor null animals following exercise. Continuous infusion of a GH antagonist into the lateral ventricle of wild-type animals completely abolished the exercise-induced increase in neural precursor cell number. Given that the aged brain does not recover well after injury, we investigated the direct effect of exercise and GH on neural precursor cell activation following irradiation. This revealed that physical exercise as well as infusion of GH promoted repopulation of neural precursor cells in irradiated aged animals. Conversely, infusion of a GH antagonist during exercise prevented recovery of precursor cells in the SVZ following irradiation. PMID:23209615

Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala.

PubMed

Amat, J; Tamblyn, J P; Paul, E D; Bland, S T; Amat, P; Foster, A C; Watkins, L R; Maier, S F

2004-01-01

The intra dorsal raphe nucleus (DRN) administration of corticotropin releasing hormone (CRF) inhibits serotonergic (5-HT) activity in this structure, an effect blocked by antagonists selective for the type 1 CRF receptor (CRF1). The DRN has a high density of the type 2 receptor (CRF2), and so the present experiments explored the impact of CRF2 activation within the DRN on 5-HT function. The intra-DRN administration of the selective CRF2 agonist urocortin 2 (Ucn 2) dose dependently increased 5-HT efflux in the basolateral amygdala, a projection region of the DRN. Intra-DRN Ucn 2 also increased c-fos expression in labeled 5-HT neurons. Both of these effects of Ucn 2 were completely blocked by intra-DRN antisauvagine-30 (ASV-30), a relatively selective CRF2 antagonist. These data suggest that CRF1 and CRF2 activation within the DRN affect 5-HT neurons in opponent fashion. Implications of these results for understanding the behavioral effects of CRF and other CRF-like ligands are discussed.

Mineralocorticoids in the heart and vasculature: new insights for old hormones.

PubMed

Lother, Achim; Moser, Martin; Bode, Christoph; Feldman, Ross D; Hein, Lutz

2015-01-01

The mineralocorticoid aldosterone is a key regulator of water and electrolyte homeostasis. Numerous recent developments have advanced the field of mineralocorticoid pharmacology—namely, clinical trials have shown the beneficial effects of aldosterone antagonists in chronic heart failure and post-myocardial infarction treatment. Experimental studies using cell type-specific gene targeting of the mineralocorticoid receptor (MR) gene in mice have revealed the importance of extrarenal aldosterone signaling in cardiac myocytes, endothelial cells, vascular smooth cells, and macrophages. In addition, several molecular pathways involving signal transduction via the classical MR as well as the G protein-coupled receptor GPER mediate the diverse spectrum of effects of aldosterone on cells. This knowledge has initiated the development of new pharmacological ligands to specifically interfere with targets on different levels of aldosterone signaling. For example, aldosterone synthase inhibitors such as LCI699 and the novel nonsteroidal MR antagonist BAY 94-8862 have been tested in clinical trials. Interference with the interaction between MR and its coregulators seems to be a promising strategy toward the development of selective MR modulators.

Effect of intravenously-administered putative and potential antagonists of ethanol on sleep time in ethanol-narcotized mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hatch, R.C.; Jernigan, A.D.

Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly by a large dose of dl-amphetamine and by 4-aminopyridine. Significant increases were also produced by small and large doses of aminophylline and by yohimbine. MST was not altered significantly by small and medium doses of dl-amphetamine, a medium dose ofmore » aminophylline, or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST. 36 references, 1 table.« less

Detection of angiotensin II binding to single adrenal zona glomerulosa cells by confocal Raman microspectroscopy

NASA Astrophysics Data System (ADS)

McCoy, Michael J.; Habermann, Timothy J.; Hanke, Craig J.; Adar, Fran; Campbell, William B.; Nithipatikom, Kasem

1999-04-01

We developed a confocal Raman microspectroscopic technique to study ligand-receptor bindings in single cells using Raman-labeled ligands and surface-enhanced Raman scattering (SERS). The adrenal zona glomerulosa (ZG) cells were used as a model in this study. ZG cells have a high density of angiotensin II (AII) receptors on the cellular membrane. There are two identified subtypes of AII receptors,namely AT1 and AT2 receptors. AII is a peptidic hormone, which upon binding to its receptors, stimulates the release of aldosterone from ZG cells. The cellular localization of these receptors subtypes was detected in single ZG cells by using immunocomplexation of receptors with specific antibodies and confocal Raman microspectroscopy. In the binding study, we used biotin-labeled AII to bind to its receptors in ZG cells. Then, avidin and Raman-labeled AII. The binding was measure directly on the single ZG cells. The results showed that the binding was displaced with unlabeled AII and specific AII antagonists. This is a rapid and sensitive technique for detection of cellular ligand bindings as well as antagonists screening in drug discovery.

Trek2a regulates gnrh3 expression under control of melatonin receptor Mt1 and α2-adrenoceptor.

PubMed

Loganathan, Kavinash; Moriya, Shogo; Parhar, Ishwar S

2018-02-12

Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K + ) channel-related K + (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α 2 -adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α 2 -adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α 2 -adrenoceptor. Copyright © 2018 Elsevier Inc. All rights reserved.

Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant.

PubMed

Goldenberg, Naila; Racine, Michael S; Thomas, Pamela; Degnan, Bernard; Chandler, William; Barkan, Ariel

2008-08-01

Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a GH receptor antagonist, pegvisomant. This was a descriptive case series of up to 3.5 yr duration. The study was conducted at a university hospital. Patients included three children (one female, two males) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery, somatostatin analog, and dopamine agonist. The intervention was administration of pegvisomant. Plasma IGF-I and growth velocity were measured. In all three children, pegvisomant rapidly decreased plasma IGF-I concentrations. Growth velocity declined to subnormal or normal values. Statural growth fell into lower growth percentiles and acromegalic features resolved. Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog. Pegvisomant may be an effective modality for the therapy of pituitary gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular surveillance of tumor size is mandatory.

Abscisic Acid–Responsive Guard Cell Metabolomes of Arabidopsis Wild-Type and gpa1 G-Protein Mutants[C][W

PubMed Central

Jin, Xiaofen; Wang, Rui-Sheng; Zhu, Mengmeng; Jeon, Byeong Wook; Albert, Reka; Chen, Sixue; Assmann, Sarah M.

2013-01-01

Individual metabolites have been implicated in abscisic acid (ABA) signaling in guard cells, but a metabolite profile of this specialized cell type is lacking. We used liquid chromatography–multiple reaction monitoring mass spectrometry for targeted analysis of 85 signaling-related metabolites in Arabidopsis thaliana guard cell protoplasts over a time course of ABA treatment. The analysis utilized ∼350 million guard cell protoplasts from ∼30,000 plants of the Arabidopsis Columbia accession (Col) wild type and the heterotrimeric G-protein α subunit mutant, gpa1, which has ABA-hyposensitive stomata. These metabolomes revealed coordinated regulation of signaling metabolites in unrelated biochemical pathways. Metabolites clustered into different temporal modules in Col versus gpa1, with fewer metabolites showing ABA-altered profiles in gpa1. Ca2+-mobilizing agents sphingosine-1-phosphate and cyclic adenosine diphosphate ribose exhibited weaker ABA-stimulated increases in gpa1. Hormone metabolites were responsive to ABA, with generally greater responsiveness in Col than in gpa1. Most hormones also showed different ABA responses in guard cell versus mesophyll cell metabolomes. These findings suggest that ABA functions upstream to regulate other hormones, and are also consistent with G proteins modulating multiple hormonal signaling pathways. In particular, indole-3-acetic acid levels declined after ABA treatment in Col but not gpa1 guard cells. Consistent with this observation, the auxin antagonist α-(phenyl ethyl-2-one)-indole-3-acetic acid enhanced ABA-regulated stomatal movement and restored partial ABA sensitivity to gpa1. PMID:24368793

Alterations in neuropeptides in aging and disease. Pathophysiology and potential for clinical intervention.

PubMed

Leake, A; Ferrier, I N

1993-01-01

Marked specific and selective changes in the levels of some neuropeptides in age-related diseases, such as senile dementia of the Alzheimer (SDAT) or Lewy body (SDLT) types, Parkinson's disease, Huntington's disease and major depressive disorder, versus normal aging have been noted. However, the levels of most neuropeptides are normal. The only 2 peptides consistently altered in SDAT are somatostatin and corticotrophin-releasing hormone both of which are reduced. In Huntington's disease, the level of substance P in the basal ganglia is reduced suggesting a preferential vulnerability of spiny neurones in this disease. In Parkinson's disease, substance P is attenuated in the basal ganglia while somatostatin is reduced in the neocortex. These and other results suggest that substance P deficits are related to movement disorders while somatostatin deficits are related to cognitive impairment. SDLT is a type of dementia with features common to both SDAT and Parkinson's disease, although the changes in neuropeptides suggest that neurochemically the disease is more closely related to SDAT. In major depressive disorder, the level of corticotrophin-releasing hormone is reduced while there is a reciprocal increase in corticotrophin-releasing hormone receptors suggesting that the neurones remain functional. Potential clinical intervention has been limited by problems such as poor penetration of agents into the brain and the short half-lives of neuropeptide agonists and antagonists. However, some currently available agents may act, at least in part, through modulation of neuropeptide pathways, e.g. carbamazepine and alprazolam both modulate the corticotrophin-releasing hormone system in animals, and both have clinically proven antidepressant activity.

Physiological, Pharmacological, and Nutritional Regulation of Circulating Adiponectin Concentrations in Humans

PubMed Central

Swarbrick, Michael M.

2008-01-01

Abstract Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes. This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans. PMID:18510434

Thyroid hormone modulates food intake and glycemia via ghrelin secretion in Zucker fatty rats.

PubMed

Patel, K; Joharapurkar, A; Dhanesha, N; Patel, V; Kshirsagar, S; Raval, P; Raval, S; Jain, M R

2014-10-01

Hyperthyroidism is known to increase food intake and central administration of thyroid hormone shows acute orexigenic effects in rodents. We investigated whether T3 influences appetite and glucose homeostasis by modulating circulating ghrelin, an important orexigenic hormone, in Zucker fatty rats. The acute anorectic effects of T3 and ghrelin mimetic MK-0677 were studied in rats trained for fasting induced food intake. The serum concentration of T3, ghrelin, glucose, triglycerides, and liver glycogen were estimated. The involvement of sympathetic nervous system was evaluated by conducting similar experiments in vagotomized rats. T3 increased food intake and glucose in rats over 4 h, with increase in serum T3 and decrease in liver glycogen. T3 treatment was associated with increase in serum ghrelin. An additive effect on appetite and glucose was observed when T3 (oral) was administered with central (intracerebroventricular) administration of a ghrelin mimetic, MK-0677. Ghrelin antagonist, compound 8a, antagonized the hyperglycemic and hyperphagic effects of T3. In vagotomized rats, T3 did not show increase in appetite as well as glucose. Serum ghrelin levels were unchanged in these animals after T3 treatment. However, T3 showed increase in serum triglyceride levels indicating its peripheral lipolytic effect, in vagotomized as well as sham treated animals. To conclude, acute orexigenic and hyperglycemic effects of T3 are associated with ghrelin secretion and activity. This effect seems to be mediated via vagus nerves, and is independent of glucoregulatory hormones. © Georg Thieme Verlag KG Stuttgart · New York.

Enantioselective Synthesis of SNAP-7941

PubMed Central

Goss, Jennifer M.; Schaus, Scott E.

2009-01-01

An enantioselective synthesis of SNAP-7941, a potent melanin concentrating hormone receptor antagonist, was achieved using two organocatalytic methods. The first method utilized to synthesize the enantioenriched dihydropyrimidone core was the Cinchona alkaloid-catalyzed Mannich reaction of β-keto esters to acyl imines and the second was chiral phosphoric acid-catalyzed Biginelli reaction. Completion of the synthesis was accomplished via selective urea formation at the N3 position of the dihydropyrimidone with the 3-(4-phenylpiperidin-1-yl)propyl amine side chain fragment. The synthesis of SNAP-7921 highlights the utility of asymmetric organocatalytic methods in the construction of an important class of chiral heterocycles. PMID:18767801

Florigen and anti-florigen – a systemic mechanism for coordinating growth and termination in flowering plants

PubMed Central

Lifschitz, Eliezer; Ayre, Brian G.; Eshed, Yuval

2014-01-01

Genetic studies in Arabidopsis established FLOWERING LOCUS T (FT) as a key flower-promoting gene in photoperiodic systems. Grafting experiments established unequivocal one-to-one relations between SINGLE FLOWER TRUSS (SFT), a tomato homolog of FT, and the hypothetical florigen, in all flowering plants. Additional studies of SFT and SELF PRUNING (SP, homolog of TFL1), two antagonistic genes regulating the architecture of the sympodial shoot system, have suggested that transition to flowering in the day-neutral and perennial tomato is synonymous with “termination.” Dosage manipulation of its endogenous and mobile, graft-transmissible levels demonstrated that florigen regulates termination and transition to flowering in an SP-dependent manner and, by the same token, that high florigen levels induce growth arrest and termination in meristems across the tomato shoot system. It was thus proposed that growth balances, and consequently the patterning of the shoot systems in all plants, are mediated by endogenous, meristem-specific dynamic SFT/SP ratios and that shifts to termination by changing SFT/SP ratios are triggered by the imported florigen, the mobile form of SFT. Florigen is a universal plant growth hormone inherently checked by a complementary antagonistic systemic system. Thus, an examination of the endogenous functions of FT-like genes, or of the systemic roles of the mobile florigen in any plant species, that fails to pay careful attention to the balancing antagonistic systems, or to consider its functions in day-neutral or perennial plants, would be incomplete. PMID:25278944

Chapter 5: Allergic rhinitis.

PubMed

Uzzaman, Ashraf; Story, Rachel

2012-01-01

Rhinitis is a symptomatic inflammatory disorder of the nose with different causes such as allergic, nonallergic, infectious, hormonal, drug induced, and occupational and from conditions such as sarcoidosis and necrotizing antineutrophil cytoplasmic antibodies positive (Wegener's) granulomatosis. Allergic rhinitis affects up to 40% of the population and results in nasal (ocular, soft palate, and inner ear) itching, congestion, sneezing, and clear rhinorrhea. Allergic rhinitis causes extranasal untoward effects including decreased quality of life, decreased sleep quality, obstructive sleep apnea, absenteeism from work and school, and impaired performance at work and school termed "presenteeism." The nasal mucosa is extremely vascular and changes in blood supply can lead to obstruction. Parasympathetic stimulation promotes an increase in nasal cavity resistance and nasal gland secretion. Sympathetic stimulation leads to vasoconstriction and consequent decrease in nasal cavity resistance. The nasal mucosa also contains noradrenergic noncholinergic system, but the contribution to clinical symptoms of neuropeptides such as substance P remains unclear. Management of allergic rhinitis combines allergen avoidance measures with pharmacotherapy, allergen immunotherapy, and education. Medications used for the treatment of allergic rhinitis can be administered intranasally or orally and include oral and intranasal H(1)-receptor antagonists (antihistamines), intranasal and systemic corticosteroids, intranasal anticholinergic agents, and leukotriene receptor antagonists. For intermittent mild allergic rhinitis, an oral or intranasal antihistamine is recommended. In individuals with persistent moderate/severe allergic rhinitis, an intranasal corticosteroid is preferred. When used in combination, an intranasal H(1)-receptor antagonist and a nasal steroid provide greater symptomatic relief than monotherapy. Allergen immunotherapy is the only disease-modifying intervention available.

Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling

PubMed Central

2014-01-01

Background Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. Results In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Conclusions Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling. PMID:24898702

Molecular mechanism of 9-cis-retinoic acid inhibition of adipogenesis in 3T3-L1 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sagara, Chiaki; Takahashi, Katsuhiko; Kagechika, Hiroyuki

2013-03-29

Highlights: ► We examined the effects of 9-cis-RA on adipogenesis in mouse preadipocyte 3T3-L1. ► 9-cis-RA inhibited lipid accumulation in adipogenetically-induced 3T3-L1 cells. ► A RXR pan-antagonist suppressed the inhibitory effects of 9-cis-RA on adipogenesis. ► This antagonist had no effects on RXRα and PPARγ levels in 9-cis-RA-treated cells. ► 9-cis-RA-induced decrease in both RXRα and PPARγ was independent of RXR activation. -- Abstract: Retinoic acid (RA) signaling is mediated by specific nuclear hormone receptors. Here we examined the effects of 9-cis-RA on adipogenesis in mouse preadipocyte 3T3-L1 cells. 9-cis-RA inhibits the lipid accumulation of adipogenetically induced 3T3-L1 cells. Themore » complex of retinoid X receptor α (RXRα) with peroxisome proliferator-activated receptor γ (PPARγ) is a major transcription factor in the process of adipogenesis, and the levels of these molecules were decreased by 9-cis-RA treatment. A RXR pan-antagonist suppressed 9-cis-RA’s inhibitory effects on adipogenesis, but not on the intracellular levels of both RXRα and PPARγ. These results suggest that 9-cis-RA could inhibit adipogenesis by activating RXR, and decrease both RXR and PPARγs levels in a RXR activation-independent manner.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Navarro-Zaragoza, J.; Martínez-Laorden, E.; Mora, L.

Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic–pituitary–adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-inducedmore » increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts. - Highlights: • Morphine withdrawal caused an increase in myocardial sympathetic activity. • ERK regulates TH phosphorylation after naloxone-induced morphine withdrawal. • CRF1R is involved in cardiac adaptive changes during morphine dependence.« less

Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling.

PubMed

Xu, Enjun; Brosché, Mikael

2014-06-04

Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling.

Incretin hormone receptors are required for normal beta cell development and function in female mice.

PubMed

Omar, Bilal; Ahlkvist, Linda; Yamada, Yuchiro; Seino, Yutaka; Ahrén, Bo

2016-05-01

The incretin hormones, glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), potentiate insulin secretion and are responsible for the majority of insulin secretion that occurs after a meal. They may also, however, have a fundamental role in pancreatic beta cell development and function, independently of their role in potentiating insulin secretion after a meal. This has led to observations that a loss of GIP or GLP-1 action affects normal beta cell function, however each one of the incretin hormones may compensate when the action of the other is lost and therefore the overall impact of the incretin hormones on beta cell function is not known. We therefore utilized a mouse line deficient in both the GLP-1 and GIP receptor genes, the double incretin receptor knockout (DIRKO), to determine the consequences of a lifelong, complete lack of incretin hormone action on beta cell function, in vivo, in intact animals. We found that DIRKO mice displayed impaired glucose tolerance and insulin secretion in response to both oral glucose and mixed meal tolerance tests compared to wild-type mice. Assessment of beta cell function using the hyperglycemic clamp technique revealed an 80% decrease in first phase insulin response in DIRKO mice, but a normal second phase insulin secretion. A similar decline was seen when wild-type mice were given acute intravenous injection of glucose together with the GLP-1 receptor antagonist Ex9-39. Ex vivo assessments of the pancreas revealed significantly fewer islets in the pancreata of DIRKO mice despite no differences in total pancreatic mass. Insulin secretion from isolated islets of DIRKO mice was impaired to a similar extent to that seen during the hyperglycemic clamp. Insulin secretion in wild-type islets was impaired by acute treatment with Ex9-39 to a similar extent as the in vivo intravenous glucose tolerance tests. In conclusion, a loss of the action of both incretin hormones results in direct impairment of beta cell function both in vivo and in vitro in a process that appears to be independent of the intestinally secreted incretin hormones. We therefore conclude that the incretin hormones together significantly impact both beta-cell function and beta-cell development. Copyright © 2016. Published by Elsevier Inc.

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

PubMed

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 ganglia, the regions respectively responsible for neuroleptic and cataleptic effects; and as GnRH antagonist eliminated the effects of haloperidol without affecting GnRH-ir, it appears that GnRH released by haloperidol mediates its neuroleptic and cataleptic effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

TSH Receptor Signaling Abrogation by a Novel Small Molecule

PubMed Central

Latif, Rauf; Realubit, Ronald B.; Karan, Charles; Mezei, Mihaly; Davies, Terry F.

2016-01-01

Pathological activation of the thyroid-stimulating hormone receptor (TSHR) is caused by thyroid-stimulating antibodies in patients with Graves’ disease (GD) or by somatic and rare genomic mutations that enhance constitutive activation of the receptor influencing both G protein and non-G protein signaling. Potential selective small molecule antagonists represent novel therapeutic compounds for abrogation of such abnormal TSHR signaling. In this study, we describe the identification and in vitro characterization of a novel small molecule antagonist by high-throughput screening (HTS). The identification of the TSHR antagonist was performed using a transcription-based TSH-inhibition bioassay. TSHR-expressing CHO cells, which also expressed a luciferase-tagged CRE response element, were optimized using bovine TSH as the activator, in a 384 well plate format, which had a Z score of 0.3–0.6. Using this HTS assay, we screened a diverse library of ~80,000 compounds at a final concentration of 16.7 μM. The selection criteria for a positive hit were based on a mean signal threshold of ≥50% inhibition of control TSH stimulation. The screening resulted in 450 positive hits giving a hit ratio of 0.56%. A secondary confirmation screen against TSH and forskolin – a post receptor activator of adenylyl cyclase – confirmed one TSHR-specific candidate antagonist molecule (named VA-K-14). This lead molecule had an IC50 of 12.3 μM and a unique chemical structure. A parallel analysis for cell viability indicated that the lead inhibitor was non-cytotoxic at its effective concentrations. In silico docking studies performed using a TSHR transmembrane model showed the hydrophobic contact locations and the possible mode of inhibition of TSHR signaling. Furthermore, this molecule was capable of inhibiting TSHR stimulation by GD patient sera and monoclonal-stimulating TSHR antibodies. In conclusion, we report the identification of a novel small molecule TSHR inhibitor, which has the potential to be developed as a therapeutic antagonist for abrogation of TSHR signaling by TSHR autoantibodies in GD. PMID:27729899

Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor.

PubMed

Chaki, Shigeyuki; Hirota, Shiho; Funakoshi, Takeo; Suzuki, Yoshiko; Suetake, Sayoko; Okubo, Taketoshi; Ishii, Takaaki; Nakazato, Atsuro; Okuyama, Shigeru

2003-02-01

We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.

Evaluation of effects of an oral contraceptive containing ethinylestradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome.

PubMed

De Leo, Vincenzo; Morgante, Giuseppe; Piomboni, Paola; Musacchio, Maria Concetta; Petraglia, Felice; Cianci, Antonio

2007-07-01

To investigate whether the administration of an oral contraceptive containing the new antiandrogenic drospirenone is associated with reduced adrenal androgen synthesis in hyperandrogenic women with diagnosis of polycystic ovary syndrome. Drospirenone, an analogue of spironolactone and aldosterone antagonist, is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. Prospective study. Healthy volunteers in University Department of Obstetrics and Gynecology. Fifteen women ages 18 to 28 years with the diagnosis of polycystic ovary syndrome. Three months of contraceptive use (30 mcg ethinylestradiol, 3 mg drospirenone). An adrenocorticotropic hormone test was performed before and after the study. Adrenal production of cortisol was unchanged after therapy with oral contraceptives. An interesting observation was reduced basal concentrations of androgens such as androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone during therapy. The ratios of the areas of substrates to products before and after oral contraceptive administration were compared for differences in 17alpha-hydroxylase (17-hydroxyprogesterone/progesterone) and 17,20-lyase (androstenedione/17-hydroxyprogesterone); activities were significantly reduced, indicating a reduction in the activities of these enzymes. The present results show for the first time that oral contraceptives containing drospirenone affect adrenal steroidogenesis by reducing synthesis and release of androgens in response to adrenocorticotropic hormone, leaving adrenal production of cortisol unchanged.

Beta-endorphin and islet hormone release in type-2 diabetes mellitus the effects of normoglycemia, enkephalin, naloxone and somatostatin.

PubMed

Giugliano, D; Cozzolino, D; Salvatore, T; Ceriello, A; Giunta, R; Torella, R; D'Onofrio, F

1987-01-01

The present study was aimed at characterizing the effects of beta-endorphin on plasma glucose, insulin and glucagon plasma levels in subjects with type-2 diabetes mellitus. Infusion of 0.5 mg/h human beta-endorphin produced significant and simultaneous increments in both insulin and glucagon concentrations and decreased plasma glucose levels (-18 +/- 4 mg/dl, 60 min level, p less than 0.01). When the same diabetics were rendered euglycemic by an insulin infusion (1 mU/kg/min), beta-endorphin did not produce the expected decrease in plasma glucose concentrations nor raise plasma insulin levels; only the response of glucagon was preserved. Normal subjects were rendered hyperglycemic by an intravenous glucose infusion to match the plasma glucose levels of diabetic subjects. In this condition, beta-endorphin produced a significant increase of insulin concentrations, whereas glucagon remained suppressed. The intravenous administration of the long-acting met-enkephalin analogue DAMME (0.25 mg) blunted the hormonal responses to the subsequent beta-endorphin infusion in diabetic patients, although the inhibition was short-lived (30-40 min). Naloxone (5 mg), an opiate antagonist, did not produce any significant change in the insulin and glucagon responses to beta-endorphin, while somatostatin (0.25 mg/h) completely abolished the hormonal responses to the opioid.(ABSTRACT TRUNCATED AT 250 WORDS)

Benefits and limitations of drug studies in temperament research: biochemical responses as indicators of temperament.

PubMed

Netter, Petra

2018-04-19

This paper presents a discussion of principles and problems of neurotransmitter challenge tests using examples of experiments, most of which were performed in the author's laboratory. Drugs targeting synthesis, release, receptors or reuptake of dopamine, serotonin and noradrenergic transmitter (TM) systems were used for characterizing or discriminating certain temperament or personality traits and their sub-factors. Any personality or temperament trait is characterized by multiple TM responses, thus constellations of hormone responses to drugs acting on different TM systems or on different sources of TM activity were investigated within individuals in crossover designs. The major conclusions are: (i) intra-individual patterns of hormone responses to different TM-related drugs, or to agonists and antagonists, can help to discriminate subtypes of temperament dimensions, and (ii) the latency and shape of response curves may help specify processes of biological responses related to psychological dimensions and reveal common TM sensitivities in clusters of traits. TM sensitivity, defined by hormone responses, does not always correspond to accompanying behavioural indicators, but may provide more specific information on underlying mechanisms. Additional consideration of drug doses and experimental induction of stressors may serve to identify temperament-related susceptibilities to certain drugs. Limitations of the challenge approach and recommendations for future research are discussed.This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'. © 2018 The Author(s).

Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations.

PubMed

Hrabovszky, Zoltan; Hutson, John M

2002-11-01

Psychosexual development, gender assignment and surgical treatment in patients with intersex are controversial issues in the medical literature. Some groups are of the opinion that gender identity and sexual orientation are determined prenatally secondary to the fetal hormonal environment causing irreversible development of the nervous system. We reviewed the evidence in animal and human studies to determine the possible role of early postnatal androgen production in gender development. An extensive literature review was performed of data from animal experiments and human studies. RESULTS Many animal studies show that adding or removing hormonal stimulus in early postnatal life can profoundly alter gender behavior of the adult animal. Human case studies show that late intervention is unable to reverse gender orientation from male to female. Most studies have not permitted testing of whether early gender assignment and treatment as female with suppression/ablation of postnatal androgen production leads to improved concordance of the gender identity and sex of rearing. Animal studies support a role for postnatal androgens in brain/behavior development with human studies neither completely supportive nor antagonistic. Therefore, gender assignment in infants with intersex should be made with the possibility in mind that postnatal testicular hormones at ages 1 to 6 months may affect gender identity. A case-control study is required to test the hypothesis that postnatal androgen exposure may convert ambisexual brain functions to committed male behavior patterns.

Neuropeptide Y and sleep.

PubMed

Dyzma, Michal; Boudjeltia, Karim Z; Faraut, Brice; Kerkhofs, Myriam

2010-06-01

Neuropeptide Y (NPY), a 36-amino-acid peptide from the pancreatic polypeptide family, is one of the more abundant peptides in the central nervous system. It acts as a neurohormone and as a neuromodulator. NPY is widely distributed in the brain, particularly the hypothalamus, the amygdala, the locus coeruleus and the cerebral cortex. At least six NPY receptors subtypes have been identified. NPY is involved in the regulation of several physiological functions such as food intake, hormonal release, circadian rhythms, cardiovascular disease, thermoregulation, stress response, anxiety and sleep. Sleep promoting effects of NPY as well as wakefulness effects of NPY were found in animals, depending on the site of injection as well as on the functional state of the structure. In humans, NPY was found to have hypnotic properties, possibly acting as a physiological antagonist of corticotropin-releasing hormone (CRH). In conclusion, NPY participates in sleep regulation in humans, particularly in the timing of sleep onset and may as such play a role in the integration of sleep regulation, food intake and metabolism. Copyright 2009 Elsevier Ltd. All rights reserved.

Immunization against exon 1 decapeptides from the lutropin/choriogonadotropin receptor or the follitropin receptor as potential male contraceptive.

PubMed

Remy, J J; Couture, L; Rabesona, H; Haertle, T; Salesse, R

1996-11-01

Pituitary gonadotropin hormones lutropin (LH) and follitropin (FSH) control steroidogenesis and gametogenesis in male and female gonads through interaction with G protein-coupled receptors, LHR and FSHR. In the male, LH acts on leydig cells and is mostly responsible for the acquisition of puberty and the production of androgens while FSH, together with androgens, regulates spermatogenesis within Sertoli cells. We have engineered filamentous phages displaying mouse LHR and human FSHR decapeptides chosen in hormone binding regions. Peptides from both receptors displayed on phages belong either to the receptor specific exon 1 (amino acids 18-27) or to the homologous exon 4 (amino acids 98-107). Vaccination of prepubertal BALB/c male mice with hybrid phages using sub-cutaneous or intraperitoneal injections induced immunity against receptors. Anti-receptor immunization produced agonist or antagonist effects depending only on the circulating levels of the antibodies. Both anti-LHR and anti-FSHR vaccines induced efficient as well as reversible male contraception, through different mechanisms: targeting LH receptors inhibited or hyperstimulated Leydig cell testosterone production while targeting FSH receptors did not affect testosterone levels.

Reciprocal Inhibitory Interactions Between the Reward-Related Effects of Leptin and Cocaine.

PubMed

You, Zhi-Bing; Wang, Bin; Liu, Qing-Rong; Wu, Yan; Otvos, Laszlo; Wise, Roy A

2016-03-01

Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food- and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats. First, we report that cocaine and the expectancy of cocaine each depresses plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates the ability of cocaine to elevate dopamine levels in the nucleus accumbens, the ability of cocaine to establish a conditioned place preference, and the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus, whereas leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine.

Fish larval recruitment to reefs is a thyroid hormone-mediated metamorphosis sensitive to the pesticide chlorpyrifos

PubMed Central

Lambert, Anne; François, Loïc; Barth, Paul; Gillet, Benjamin; Hughes, Sandrine; Piganeau, Gwenaël; Leulier, Francois; Viriot, Laurent

2017-01-01

Larval recruitment, the transition of pelagic larvae into reef-associated juveniles, is a critical step for the resilience of marine fish populations but its molecular control is unknown. Here, we investigate whether thyroid-hormones (TH) and their receptors (TR) coordinate the larval recruitment of the coral-reef-fish Acanthurus triostegus. We demonstrate an increase of TH-levels and TR-expressions in pelagic-larvae, followed by a decrease in recruiting juveniles. We generalize these observations in four other coral reef-fish species. Treatments with TH or TR-antagonist, as well as relocation to the open-ocean, disturb A. triostegus larvae transformation and grazing activity. Likewise, chlorpyrifos, a pesticide often encountered in coral-reefs, impairs A. triostegus TH-levels, transformation, and grazing activity, hence diminishing this herbivore’s ability to control the spread of reef-algae. Larval recruitment therefore corresponds to a TH-controlled metamorphosis, sensitive to endocrine disruption. This provides a framework to understand how larval recruitment, critical to reef-ecosystems maintenance, is altered by anthropogenic stressors. PMID:29083300

Individualization of controlled ovarian stimulation in vitro fertilization using ovarian reserve markers.

PubMed

Grisendi, Valentina; La Marca, Antonio

2017-06-01

In assisted reproduction technologies (ART) the controlled ovarian stimulation (COS) therapy is the starting point from which a good oocytes retrieval depends. Treatment individualization is based on ovarian response prediction, which largely depends on a woman's ovarian reserve. Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are considered the most accurate and reliable markers of ovarian reserve. A literature search was carried out for studies that addressed the ability of AMH and AFC to predict poor and/or excessive ovarian response in IVF cycles. According to the predicted response to ovarian stimulation (poor- normal- or high-response) is today possible not only to personalize pre-treatment counseling with the couple, but also to individualize the ovarian stimulation protocol, choosing among GnRH-agonists or antagonists for endogenous follicle-stimulating hormone (FSH) suppression and formulating the FSH starting dose most adequate for the single patients. In this review we discuss how to choose the best COS therapy for the single patient, on the basis of the markers-guided ovarian response prediction.

Diagnosis and treatment of pituitary adenomas.

PubMed

Chanson, P; Salenave, S

2004-12-01

Pituitary tumors cause symptoms by secreting hormones (prolactin, PRL, responsible for amenorrhea-galactorrhea in women and decreased libido in men; growth hormone, GH, responsible for acromegaly; adrenocorticotropic hormone, ACTH, responsible for Cushing's syndrome; thyroid-stimulating hormone, TSH, responsible for hyperthyroidism), depressing the secretion of hormones (hypopituitarism), or by mass-related effects (headaches, visual field abnormalities...). All patients with pituitary tumors should be evaluated for gonadal, thyroid and adrenal function as well as PRL and GH secretion. Specific stimulation and suppression tests for pituitary hormones are performed in selected situations for detecting the type of hypersecretion or the response to treatment. Imaging procedures (mainly magnetic resonance imaging, MRI, nowadays) determine the presence, size and extent of the lesion. The classification of pituitary tumors is based on the staining properties of the cell cytoplasm viewed by light microscopy and immunocytochemistry revealing the secretory pattern of the adenoma. Treatment of pituitary adenomas consists of surgery (performed in more than 99% of cases via a transphenoidal route) and radiotherapy, generally fractionated or, in selected cases, using stereotactic techniques such as gamma-knife. The availability of medical treatment (dopamine, DA, agonists, somatostatin analogs, GH-receptor antagonists...) has profoundly modified the indications of radiotherapy, drugs being now generally used as a second-line treatment, after surgery (or even as first-line treatment). Based on the results of the different treatment modalities for each type of pituitary adenoma, recommendations will be proposed. They may be summarized as follows. For treatment of GH-secreting adenomas, trans-sphenoidal surgery is the first-line therapy except when the macroadenoma is giant or if surgery is contra-indicated; postoperative radiation therapy (fractionated, or by gamma-knife) is performed for partially resected tumors or when GH levels remain elevated (eventually after a trial of somatostatin analog). Somatostatin analogs, now available in slow release form, are proposed when surgery is contra-indicated, or has failed to normalize GH levels, or in waiting for the delayed effects of radiation therapy. If the probability of surgical cure is low (e.g. in patients with very large and/or invasive tumors), then somatostatin analogs may be reasonable primary therapeutic modality provided that the tumor does not threaten vision or neurological function. Pegvisomant, the new GH-receptor antagonist, is indicated in case of resistance to somatostatin analogs. Patients with PRL-secreting microadenomas may be treated either with trans-sphenoidal surgery or medically with DA agonists. In patients with macroadenomas, even in the presence of chiasmatic syndrome, DA agonists are now proposed as primary treatment. Indeed, effects on visual disturbances are often very rapid (within a few hours or days) and tumoral shrinkage is usually very significant. For patients with ACTH-secreting adenomas, primary therapy is generally trans-sphenoidal surgery by a skilled surgeon, whether or not a microadenoma is visible on MRI. Radiotherapy is reserved for patients who are subtotally resected or remain hyper-secretory after surgery. In waiting for the effects of radiotherapy, adrenal steroidogenesis inhibitors (mitotane, ketoconazole) may be indicated. If drugs are not available or not tolerated, bilateral adrenalectomy may be proposed. For patients with clinically non functioning adenomas (generally gonadotropin-secreting adenomas on immunocytochemistry), trans-sphenoidal surgery with or without postoperative radiation therapy is performed for almost all patients whether or not they have visual consequences of their tumor. Selected patients with small, incidentally discovered microadenomas may be carefully followed without immediate therapy.

Time- and dose-related effects of a gonadotropin-releasing hormone agonist and dopamine antagonist on reproduction in the Northern leopard frog (Lithobates pipiens).

PubMed

Vu, Maria; Weiler, Bradley; Trudeau, Vance L

2017-12-01

Gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone release to control ovulation and spermiation in vertebrates. Dopamine (DA) has a clear inhibitory role in the control of reproduction in numerous teleosts, and emerging evidence suggests that similar mechanisms may exist in amphibians. The interactions between GnRH and DA on spawning success and pituitary gene expression in the Northern leopard frog (Lithobates pipiens) were therefore investigated. Frogs were injected during the natural breeding season with a GnRH agonist [GnRH-A; (Des-Gly 10 , D-Ala 6 , Pro-NHEt 9 )-LHRH; 0.1μg/g and 0.4μg/g] alone and in combination with the dopamine receptor D2 antagonist metoclopramide (MET; 5μg/g and 10μg/g). Injected animals were allowed to breed in outdoor mesocosms. Time to amplexus and oviposition were assessed, and egg mass release, incidences of amplexus, egg mass weight, total egg numbers and fertilization rates were measured. To examine gene expression, female pituitaries were sampled at 12, 24 and 36h following injection of GnRH-A (0.4μg/g) alone and in combination with MET (10μg/g). The mRNA levels of the genes lhb, fshb, gpha, drd2 and gnrhr1 were measured using quantitative real-time PCR. Data were analyzed by a two-way ANOVA. Both GnRH-A doses increased amplexus, oviposition and fertilization alone. Co-injection of MET with GnRH-A did not further enhance spawning success. Injection of GnRH-A alone time-dependently increased expression of lhb, fshb, gpha and gnrhr1. The major effect of MET alone was to decrease expression of drd2. Importantly, the stimulatory effects of GnRH-A on lhb, gpha and gnrhr1 were potentiated by the co-injection of MET at 36h. At this time, expression of fshb was increased only in animals injected with both GnRH-A and MET. Spawning success was primarily driven by the actions of GnRH-A. The hypothesized inhibitory action of DA was supported by pituitary gene expression analysis. The results from this study provide a fundamental framework for future time- and dose-response investigations to improve current spawning methods in amphibians. Copyright © 2017. Published by Elsevier Inc.

Different critical perinatal periods and hypothalamic sites of oestradiol action in the defeminisation of luteinising hormone surge and lordosis capacity in the rat.

PubMed

Sakakibara, M; Deura, C; Minabe, S; Iwata, Y; Uenoyama, Y; Maeda, K-I; Tsukamura, H

2013-03-01

Female rats show a gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) surge in the presence of a preovulatory level of oestrogen, whereas males do not because of brain defeminisation during the developmental period by perinatal oestrogen converted from androgen. The present study aimed to identify the site(s) of oestrogen action and the critical period for defeminising the mechanism regulating the GnRH/LH surge. Animals given perinatal treatments, such as steroidal manipulations, brain local implantation of oestradiol (E(2) ) or administration of an NMDA antagonist, were examined for their ability to show an E(2) -induced LH surge at adulthood. Lordosis behaviour was examined to compare the mechanisms defeminising the GnRH/LH surge and sexual behaviour. A single s.c. oestradiol-benzoate administration on either the day before birth (E21), the day of birth (D0) or day 5 (D5) postpartum completely abolished the E(2) -induced LH surge at adulthood in female rats, although the same treatment did not inhibit lordosis. Perinatal castration on E21 or D0 partially rescued the E2-induced LH surge in genetically male rats, whereas castration from E21 to D5 totally rescued lordosis. Neonatal E(2) implantation in the anterior hypothalamus including the anteroventral periventricular nucleus (AVPV)/preoptic area (POA) abolished the E(2) -induced LH surge in female rats, whereas E(2) implantation in the mid and posterior hypothalamic regions had no inhibitory effect on the LH surge. Lordosis was not affected by neonatal E(2) implantation in any hypothalamic regions. In male rats, neonatal NMDA antagonist treatment rescued lordosis but not the LH surge. Taken together, these results suggest that an anterior hypothalamic region such as the AVPV/POA region is a perinatal site of oestrogen action where the GnRH/LH regulating system is defeminised to abolish the oestrogen-induced surge. The mechanism for defeminisation of the GnRH/LH surge system might be different from that of sexual behaviour, in terms of the site(s) of oestrogen action and critical period, as well as the neurotransmitter system involved. © 2012 British Society for Neuroendocrinology.

CONTRACEPTION TECHNOLOGY: PAST, PRESENT AND FUTURE

PubMed Central

Sitruk-Ware, Regine; Nath, Anita; Mishell, Daniel R.

2012-01-01

Steady progress in contraception research has been achieved over the past 50 years. Hormonal and non-hormonal modern contraceptives have improved women’s lives by reducing different health conditions that contributed to considerable morbidity. However the contraceptives available today are not suitable to all users and the need to expand contraceptive choices still exists. Novel products such as new implants, contraceptive vaginal rings, transdermal patches and newer combinations of oral contraceptives have recently been introduced in family planning programs and hormonal contraception is widely used for spacing and limiting births. Concerns over the adverse effects of hormonal contraceptives have led to research and development of new combinations with improved metabolic profile. Recent developments include use of natural compounds such as estradiol (E2) and estradiol valerate (E2V) with the hope to decrease thrombotic risk, in combination with newer progestins derived from the progesterone structure or from spirolactone, in order to avoid the androgenic effects. Progesterone antagonists and progesterone receptor modulators are highly effective in blocking ovulation and preventing follicular rupture and are undergoing investigations in the form of oral pills and in semi long-acting delivery systems. Future developments also include the combination of a contraceptive with an antiretroviral agent for dual contraception and protection against sexually transmitted diseases, to be used before intercourse or on demand, as well as for continuous use in dual-protection rings. Alhough clinical trials of male contraception have reflected promising results, limited involvement of industry in that area of research has decreased the likelihood of having a male method available in the current decade. Development of non-hormonal methods are still at an early stage of research, with the identification of specific targets within the reproductive system in ovaries and testes, as well as interactions between spermatozoa and ova. It is hoped that the introduction of new methods with additional health benefits would help women and couples with unmet needs to obtain access to a wider range of contraceptives with improved acceptability. PMID:22995540

Training reduces catabolic and inflammatory response to a single practice in female volleyball players.

PubMed

Eliakim, Alon; Portal, Shawn; Zadik, Zvi; Meckel, Yoav; Nemet, Dan

2013-11-01

We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Thirteen female, national team level, Israeli volleyball players (age 16.0 ± 1.4 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60 minutes of volleyball practice, before and after 7 weeks of training during the initial phase of the season. Training involved tactic and technical drills (20% of time), power and speed drills (25% of time), interval sessions (25% of time), endurance-type training (15% of time), and resistance training (15% of time). To achieve greater training responses, the study was performed during the early phase (first 7 weeks) of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, the catabolic hormone cortisol, the proinflammatory marker interleukin-6 (IL-6), and the anti-inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of vertical jump, anaerobic properties (peak and mean power by the Wingate Anaerobic Test), and predicted VO2max (by the 20-m shuttle run). Volleyball practice, both before and after the training intervention, was associated with a significant increase of serum lactate, GH, and IL-6. Training resulted in a significantly reduced cortisol response ([INCREMENT]cortisol: 4.2 ± 13.7 vs. -4.4 ± 12.3 ng · ml, before and after training, respectively; p < 0.02), and IL-6 response ([INCREMENT]IL-6: 1.3 ± 1.0 vs. 0.3 ± 0.4 pg · ml, before and after training, respectively; p < 0.01) to the same relative intensity volleyball practice. The results suggest that along with the improvement of power and anaerobic and aerobic characteristics, training reduces the catabolic and inflammatory response to exercise.

Hormonal Regulation and Distinct Functions of Semaphorin-3B and Semaphorin-3F in Ovarian Cancer

PubMed Central

Joseph, Doina; Ho, Shuk-Mei; Syed, Viqar

2009-01-01

Semaphorins comprise a family of molecules that influence neuronal growth and guidance. Class-3 semaphorins, semaphorin-3B (SEMA3B) and semaphorin-3F (SEMA3F) illustrate their effects by forming a complex with neuropilins (NP-1 or NP-2) and plexins. We examined the status and regulation of semaphorins and their receptors in human ovarian cancer cells. A significantly reduced expression of SEMA3B (83 kD), SEMA3F (90 kD), and plexin-A3 was observed in ovarian cancer (OVCA) cell lines when compared to normal human ovarian surface epithelial (HOSE) cells. The expression of NP-1, NP-2 and plexin-A1 was not altered in HOSE and OVCA cells. The decreased expression of SEMA3B, SEMA3F, and plexin-A3 was confirmed in stage 3 ovarian tumors. Treatment of OVCA cells with luteinizing hormone, follicle-stimulating hormone, and estrogen induced a significant upregulation of SEMA3B, whereas SEMA3F was upregulated only by estrogen. Co-treatment of cell lines with a hormone and its specific antagonist blocked the effect of the hormone. Ectopic expression of SEMA3B or SEMA3F reduced soft-agar colony formation, adhesion, and cell invasion of OVCA cell cultures. Forced expression of SEMA3B, but not SEMA3F, inhibited viability of OVCA cells. Overexpression of SEMA3B and SEMA3F reduced focal adhesion kinase (FAK) phosphorylation and matrix metalloproteinase (MMP)-2 and -9 expression in OVCA cells. Forced expression of SEMA3F, but not SEMA3B in OVCA cells, significantly inhibited endothelial cell tube formation. Collectively, our results suggest loss of SEMA3 expression could be a hallmark of cancer progression. Furthermore, gonadotropin- and/or estrogen-mediated maintenance of SEMA3 expression could control ovarian cancer angiogenesis and metastasis. PMID:20124444

Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

PubMed

Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

2016-07-22

It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iwamura, Yoshihiro; Mori, Mayumi; Nakashima, Katsuhiko

Highlights: Black-Right-Pointing-Pointer AIM induces lipolysis in a distinct manner from that of hormone-dependent lipolysis. Black-Right-Pointing-Pointer AIM ablates activity of peroxisome proliferator-activated receptor in adipocytes. Black-Right-Pointing-Pointer AIM reduces mRNA levels of lipid-droplet coating proteins leading to lipolysis. -- Abstract: Under fasting conditions, triacylglycerol in adipose tissue undergoes lipolysis to supply fatty acids as energy substrates. Such lipolysis is regulated by hormones, which activate lipases via stimulation of specific signalling cascades. We previously showed that macrophage-derived soluble protein, AIM induces obesity-associated lipolysis, triggering chronic inflammation in fat tissue which causes insulin resistance. However, the mechanism of how AIM mediates lipolysis remains unknown.more » Here we show that AIM induces lipolysis in a manner distinct from that of hormone-dependent lipolysis, without activation or augmentation of lipases. In vivo and in vitro, AIM did not enhance phosphorylation of hormone-sensitive lipase (HSL) in adipocytes, a hallmark of hormone-dependent lipolysis activation. Similarly, adipose tissue from obese AIM-deficient and wild-type mice showed comparable HSL phosphorylation. Consistent with the suppressive effect of AIM on fatty acid synthase activity, the amount of saturated and unsaturated fatty acids was reduced in adipocytes treated with AIM. This response ablated transcriptional activity of peroxisome proliferator-activated receptor (PPAR{gamma}), leading to diminished gene expression of lipid-droplet coating proteins including fat-specific protein 27 (FSP27) and Perilipin, which are indispensable for triacylglycerol storage in adipocytes. Accordingly, the lipolytic effect of AIM was overcome by a PPAR{gamma}-agonist or forced expression of FSP27, while it was synergized by a PPAR{gamma}-antagonist. Overall, distinct modes of lipolysis appear to take place in different physiological situations; one is a supportive response against nutritional deprivation achieved by enhancing lipase activity, and the other is a pathological consequence of obesity, causing subclinical inflammation and metabolic disorders, mediated by abolishing droplet-coating proteins.« less

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat.

PubMed

Miao, F J; Benowitz, N L; Heller, P H; Levine, J D

1997-01-01

1. In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. 2. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective beta 2-adrenoceptor blocker) (30 micrograms ml-1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg-1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 microgram kg-1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that beta 2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg-1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. 3. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg-1, s.c.), and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg-1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. 4. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg-1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. 5. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone.

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat

PubMed Central

Jia-Pei Miao, Frederick; Benowitz, Neal L; Heller, Philip H; Levine, Jon D

1997-01-01

In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective β2-adrenoceptor blocker) (30 μg ml−1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg−1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 μg kg−1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that β2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg−1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg−1, s.c.) and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg−1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg−1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone. PMID:9117123

The effects of estrogen receptors α- and β-specific agonists and antagonists on cell proliferation and energy metabolism in human bone cell line.

PubMed

Somjen, D; Katzburg, S; Sharon, O; Grafi-Cohen, M; Knoll, E; Stern, N

2011-02-01

In cultured human osteoblasts estradiol-17β (E2) modulated DNA synthesis, the specific activity of creatine kinase BB (CK), 12 and 15 lipoxygenase (LO) mRNA expression and formation of 12- and 15-hydroxyeicosatetraenoic acid (HETE). We now investigate the response of human bone cell line (SaOS2) to phytoestrogens and estrogen receptors (ER)-specific agonists and antagonists. Treatment of SaSO2 with E2, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN; ERβ-specific agonist), 4,4',4″-[4-propyl-(1H)-pyrazol-1,3,5-triyl] tris-phenol (PPT; ERα-specific agonist), biochainin A (BA), daidzein (D), genistein (G) and raloxifene (Ral) showed increased DNA synthesis and CK. Ral inhibited completely all stimulations except DPN and to some extent D. The ERα-specific antagonist methyl-piperidino-pyrazole (MPP) and the ERβ-specific antagonist 4-[2-phenyl-5,7-bis (tri-fluoro-methyl) pyrazolo [1,5-a]pyrimidin-3-yl] phenol (PTHPP) inhibited DNA synthesis, CK and reactive oxygen species (ROS) formation induced by estrogens according to their receptors affinity. The LO inhibitor baicaleine inhibited only E2, DPN and G's effects. E2 and Ral unlike all other compounds had no effect on ERα mRNA expression, while ERβ mRNA expression was stimulated by all compounds. All compounds modulated the expression of 12LO and 15LO mRNA, except E2, PPT and Ral for 12LO, and 12- and 15-HETE productions and stimulated ROS formation which was inhibited by NADPH oxidase inhibitors diphenyleneiodonium chloride (DPI) and N-acetyl cysteine and the estrogen inhibitor ICI. DPI did not affect hormonal-induced DNA and CK. In conclusion, we provide evidence for the separation of mediation via ERα and ERβ pathways in the effects of estrogenic compounds on osteoblasts, but the role of LO/HETE/ROS is unclear. Copyright © 2010 Wiley-Liss, Inc.

Paradoxical effects of oxytocin and vasopressin on basal prolactin secretion and the estrogen-induced prolactin surge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mai, Leemin; Pan, Jenntser

1990-01-01

The roles of oxytocin (OT) and vasopressin (AVP) on both basal and estrogen-induced prolactin (PRL) secretion were examined. Adult female Sprague-Dawley rats that were ovariectomized for 3 weeks and received estrogen treatment for 1 week were used. Intravenous administration of hormones and serial blood sampling were accomplished through indwelling intraatrial catheters which were implanted two days before. Plasma PRL levels were measured by radioimmunoassay. Oxytocin at a dose of 20 {mu}g/rat stimulated a moderate PRL release in the morning and lower doses were without effect. Vasopressin was most effective at a dose of 5 {mu}g/rat in stimulating PRL release, whilemore » consecutive injections of higher doses were less effective. In contrast, TRH, ranging from 1 to 8 {mu}g/rat, induced a dose-dependent increases in PRL secretion. Using the effective dosages determined from the morning studies, repeated injections of either OT, AVP or their specific antagonists MPOMeOVT were given hourly between 1300 to 1800h and blood samples were obtained hourly from 1100 to 1900h. It was found that either OT or AVP significantly reduced the afternoon PRL surge, while their antagonists were not as effective.« less

Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes.

PubMed

Di Marzo, Vincenzo; Piscitelli, Fabiana; Mechoulam, Raphael

2011-01-01

The cannabinoid receptors for Δ(9)-THC, and particularly, the CB(1) receptor, as well as its endogenous ligands, the endocannabinoids anandamide and 2-arachidonoylglycerol, are deeply involved in all aspects of the control of energy balance in mammals. While initially it was believed that this endocannabinoid signaling system would only facilitate energy intake, we now know that perhaps even more important functions of endocannabinoids and CB(1) receptors in this context are to enhance energy storage into the adipose tissue and reduce energy expenditure by influencing both lipid and glucose metabolism. Although normally well controlled by hormones and neuropeptides, both central and peripheral aspects of endocannabinoid regulation of energy balance can become dysregulated and contribute to obesity, dyslipidemia, and type 2 diabetes, thus raising the possibility that CB(1) antagonists might be used for the treatment of these metabolic disorders. On the other hand, evidence is emerging that some nonpsychotropic plant cannabinoids, such as cannabidiol, can be employed to retard β-cell damage in type 1 diabetes. These novel aspects of endocannabinoid research are reviewed in this chapter, with emphasis on the biological effects of plant cannabinoids and endocannabinoid receptor antagonists in diabetes.

The xenoestrogens, bisphenol A and para-nonylphenol, decrease the expression of the ABCG2 transporter protein in human term placental explant cultures.

PubMed

Sieppi, E; Vähäkangas, K; Rautio, A; Ietta, F; Paulesu, L; Myllynen, P

2016-07-05

Many endogenous and xenobiotic compounds are substrates and regulators of human placental ABC transporters. ABCG2 is protecting fetus against foreign chemicals. Environmental xenoestrogens, like bisphenol A (BPA) and p-nonylphenol (p-NP), mimic natural estrogens and can affect hormonal systems. Effects of BPA, p-NP, DES (diethylstilbestrol) and estradiol (E2), on ABCG2 expression were studied using human first trimester and term placental explants. Role of estrogen receptors (ER) in the effects of chemicals was studied by ER antagonist. Term placenta expressed less ABCG2 protein. In term placentas BPA (p < 0.05), p-NP (p < 0.01) and E2 (p < 0.05) decreased the ABCG2 protein expression after 48 h exposure while after 24 h exposure, only E2 decreased the expression (p < 0.05). The chemicals did not affect ABCG2 in first trimester placentas. The ER antagonist affected differently the responses of chemicals. In conclusion, environmental xenoestrogens downregulate placental ABCG2 protein expression depending on gestational age. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Treatment of Pituitary Gigantism with the Growth Hormone Receptor Antagonist Pegvisomant

PubMed Central

Goldenberg, Naila; Racine, Michael S.; Thomas, Pamela; Degnan, Bernard; Chandler, William; Barkan, Ariel

2008-01-01

Context: Treatment of pituitary gigantism is complex and the results are usually unsatisfactory. Objective: The objective of the study was to describe the results of therapy of three children with pituitary gigantism by a GH receptor antagonist, pegvisomant. Design: This was a descriptive case series of up to 3.5 yr duration. Setting: The study was conducted at a university hospital. Patients: Patients included three children (one female, two males) with pituitary gigantism whose GH hypersecretion was incompletely controlled by surgery, somatostatin analog, and dopamine agonist. Intervention: The intervention was administration of pegvisomant. Main Outcome Measures: Plasma IGF-I and growth velocity were measured. Results: In all three children, pegvisomant rapidly decreased plasma IGF-I concentrations. Growth velocity declined to subnormal or normal values. Statural growth fell into lower growth percentiles and acromegalic features resolved. Pituitary tumor size did not change in two children but increased in one boy despite concomitant therapy with a somatostatin analog. Conclusions: Pegvisomant may be an effective modality for the therapy of pituitary gigantism in children. Titration of the dose is necessary for optimal efficacy, and regular surveillance of tumor size is mandatory. PMID:18492755

Effect of the glucocorticoid receptor antagonist Org 34850 on fast and delayed feedback of corticosterone release.

PubMed

Spiga, Francesca; Harrison, Louise R; Wood, Susan A; MacSweeney, Cliona P; Thomson, Fiona J; Craighead, Mark; Grassie, Morag; Lightman, Stafford L

2008-02-01

We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and delayed inhibition of corticosterone secretion in response to the synthetic glucocorticoid methylprednisolone (MPL). Male rats were implanted with a catheter in the right jugular vein, for blood sampling and MPL administration, and with an s.c. cannula for Org 34850 administration. All experiments were conducted at the diurnal hormonal peak in the late afternoon. Rats were connected to an automated sampling system and blood samples were collected every 5 or 10 min. Org 34850 (10 mg/kg, s.c.) or vehicle (5% mulgofen in saline) was injected at 1630 h; 30 min later, rats received an injection of MPL (500 microg/rat, i.v.) or saline (0.1 ml/rat). We found that an acute administration of MPL rapidly decreased the basal corticosterone secretion and this effect was not prevented by acute pretreatment with Org 34850. However, blockade of GR with Org 34850 prevented delayed inhibition of MPL on corticosterone secretion measured between 4 and 12 h after MPL administration. Our data suggest an involvement of GR in modulating delayed, but not fast, inhibition induced by MPL on basal corticosterone secretion.

Environmental estrogens inhibit mRNA and functional expression of growth hormone receptors as well as growth hormone signaling pathways in vitro in rainbow trout (Oncorhynchus mykiss).

PubMed

Hanson, Andrea M; Ickstadt, Alicia T; Marquart, Dillon J; Kittilson, Jeffrey D; Sheridan, Mark A

2017-05-15

Fish in aquatic habitats are exposed to increasing concentrations and types of environmental contaminants, including environmental estrogens (EE). While there is growing evidence to support the observation that endocrine-disrupting compounds (EDCs) possess growth-inhibiting effects, the mechanisms by which these physiological effects occur are poorly understood. In this study, we examined the direct effects of EE, specifically 17β-estradiol (E2), β-sitosterol (βS), and 4-n-nonylphenol (NP), on GH sensitivity as assessed by mRNA expression and functional expression of growth hormone receptor in hepatocytes, gill filaments, and muscle in rainbow trout (Oncorhynchus mykiss). Additionally, we examined the effects of EE on signaling cascades related to growth hormone signal transduction (i.e., JAK-STAT, MAPK, and PI3K-Akt). Environmental estrogens directly suppressed the expression of GHRs in a tissue- and compound-related manner. The potency and efficacy varied with EE; effects were most pronounced with E2 in liver. EE treatment deactivated the JAK-STAT, MAPK, and PI3K-Akt pathways in liver a time-, EE- and concentration-dependent manner. Generally, E2 and NP were most effective in deactivating pathway elements; maximum suppression for each pathway was rapid, typically occurring at 10-30min. The observed effects occurred via an estrogen-dependent pathway, as indicated by treatment with an ER antagonist, ICI 182,780. These findings suggest that EEs suppress growth by reducing GH sensitivity in terms of reduced GHR synthesis and reduced surface GHR expression and by repressing GH signaling pathways. Copyright © 2016. Published by Elsevier Inc.

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

PubMed

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.

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

PubMed Central

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

2007-01-01

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% 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 αGsu and GnRHR but not the β-subunit gene promoters. We conclude that nucleocytoplasmic shuttling of FANCA is required for GnRH transduction of the αGSU and GnRHR gene promoters and propose that FANCA functions as a GnRH-induced signal transducer. PMID:16946016

Sex hormone influence on hepatitis in young male A/JCr mice infected with Helicobacter hepaticus.

PubMed

Theve, Elizabeth J; Feng, Yan; Taghizadeh, Koli; Cormier, Kathleen S; Bell, David R; Fox, James G; Rogers, Arlin B

2008-09-01

Hepatitis B virus (HBV), the leading cause of human hepatocellular carcinoma, is especially virulent in males infected at an early age. Likewise, the murine liver carcinogen Helicobacter hepaticus is most pathogenic in male mice infected before puberty. We used this model to investigate the influence of male sex hormone signaling on infectious hepatitis. Male A/JCr mice were infected with H. hepaticus or vehicle at 4 weeks and randomized into surgical and pharmacologic treatment groups. Interruption of androgen pathways was confirmed by hormone measurements, histopathology, and liver gene and Cyp4a protein expression. Castrated males and those receiving the competitive androgen receptor antagonist flutamide had significantly less severe hepatitis as determined by histologic activity index than intact controls at 4 months. Importantly, the powerful androgen receptor agonist dihydrotestosterone did not promote hepatitis. No effect on hepatitis was evident in males treated with the 5alpha-reductase inhibitor dutasteride, the peroxisome proliferator-activated receptor-alpha agonist bezafibrate, or the nonsteroidal anti-inflammatory drug flufenamic acid. Consistent with previous observations of hepatitis-associated liver-gender disruption, transcriptional alterations involved both feminine (cytochrome P450 4a14) and masculine (cytochrome P450 4a12 and trefoil factor 3) genes, as well gender-neutral (H19 fetal liver mRNA, lipocalin 2, and ubiquitin D) genes. Hepatitis was associated with increased unsaturated C(18) long-chain fatty acids (oleic acid and linoleic acid) relative to saturated stearic acid. Our results indicate that certain forms of androgen interruption can inhibit H. hepaticus-induced hepatitis in young male mice, whereas androgen receptor agonism does not worsen disease. This raises the possibility of targeted hormonal therapy in young male patients with childhood-acquired HBV.

Sex Hormone Influence on Hepatitis in Young Male A/JCr Mice Infected with Helicobacter hepaticus▿ †

PubMed Central

Theve, Elizabeth J.; Feng, Yan; Taghizadeh, Koli; Cormier, Kathleen S.; Bell, David R.; Fox, James G.; Rogers, Arlin B.

2008-01-01

Hepatitis B virus (HBV), the leading cause of human hepatocellular carcinoma, is especially virulent in males infected at an early age. Likewise, the murine liver carcinogen Helicobacter hepaticus is most pathogenic in male mice infected before puberty. We used this model to investigate the influence of male sex hormone signaling on infectious hepatitis. Male A/JCr mice were infected with H. hepaticus or vehicle at 4 weeks and randomized into surgical and pharmacologic treatment groups. Interruption of androgen pathways was confirmed by hormone measurements, histopathology, and liver gene and Cyp4a protein expression. Castrated males and those receiving the competitive androgen receptor antagonist flutamide had significantly less severe hepatitis as determined by histologic activity index than intact controls at 4 months. Importantly, the powerful androgen receptor agonist dihydrotestosterone did not promote hepatitis. No effect on hepatitis was evident in males treated with the 5α-reductase inhibitor dutasteride, the peroxisome proliferator-activated receptor-α agonist bezafibrate, or the nonsteroidal anti-inflammatory drug flufenamic acid. Consistent with previous observations of hepatitis-associated liver-gender disruption, transcriptional alterations involved both feminine (cytochrome P450 4a14) and masculine (cytochrome P450 4a12 and trefoil factor 3) genes, as well gender-neutral (H19 fetal liver mRNA, lipocalin 2, and ubiquitin D) genes. Hepatitis was associated with increased unsaturated C18 long-chain fatty acids (oleic acid and linoleic acid) relative to saturated stearic acid. Our results indicate that certain forms of androgen interruption can inhibit H. hepaticus-induced hepatitis in young male mice, whereas androgen receptor agonism does not worsen disease. This raises the possibility of targeted hormonal therapy in young male patients with childhood-acquired HBV. PMID:18559427

The tripeptide aldehyde, Boc-DPhe-Phe-Lysinal, is a novel Ca2+ channel inhibitor in pituitary cells.

PubMed

Makara, G B; Rappay, G; Garamvölgyi, V; Nagy, I; Dankó, S; Bajusz, S

1988-06-22

The effect of Boc-DPhe-Phe-Lysinal (Boc-DPPL) on the 45Ca2+ uptake of rat anterior pituitary monolayer cultures was investigated. The compound decreased the basal Ca2+ uptake at 3 x 10(-4) mol/l. The 45Ca2+ uptake stimulated by potassium-induced depolarization was more sensitive to Boc-DPPL inhibition, a slight decrease was seen with 3 x 10(-6) mol/l and there was a half maximal inhibition at 3 x 10(-5) mol/l. Boc-DPPL is known to inhibit pituitary hormone release in similar concentrations, an effect might also be due to its calcium antagonist property.

Comparison of Naloxone and Thyrotropin-Releasing Hormone in the Treatment of Experimental Spinal Injury: Endogenous Opioids and Experimental Spinal Injury.

DTIC Science & Technology

1983-09-30

BETHESDA ND A I FADEN 38 SEP 83 UNCLASSIFIED MPR-2509 FG 6/15 NL EIihlllIEllllI EIIhlEEE~llllE E/I/I/IEE/IlhI EIIIEEEEEEIIE = " W lo 111.2.0 1111IL25 LA 11_L...blood flow related to the release of endogenous opioi 1 ,,;. I LCV;0,,;’ ’ W i-’, ; . .- I:I, opiate receptor antagonist naloxone improve,; 1,ou- spinal...34iorl-one (TRH), which acts in part as a physiologic antaT-, iL endogenous opicii’ -;’’,tems, also significantly" i -rov s bloo (l Fo., .-,nd netir

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

PubMed Central

Gao, Wenqing; Kim, Juhyun; Dalton, James T.

2007-01-01

Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators. PMID:16841196

Assay of Vitamins and Amino Acids With Cultured Tissue Cells and Antimetabolites

PubMed Central

Savchuck, W. B.; Merriman, M. E.; Lockhart, W. L.

1964-01-01

A survey of growth responses of tissue-culture cells to vitamins and amino acids was undertaken to explore the potentialities of tissue culture in the assay of growth factors. An antagonist of the nutrient was included in each test system to improve its sensitivity. Addition of an antimetabolite was advantageous in the thiamine and phenylalanine assays. Tissue-culture assays of tryptophan and of phenylalanine supplemented with β-2-thienylalanine compared favorably with microbial assays, and may serve as confirmatory or supplementary test systems. The sensitivity of cultured tissue cells to minute amounts of a variety of physiologically active substances suggests their employment in hormone and toxic compound assays. Images FIG. 7 PMID:14199020

Structure-activity relationships of the melanocortin tetrapeptide Ac-His-DPhe-Arg-Trp-NH(2) at the mouse melanocortin receptors: part 2 modifications at the Phe position.

PubMed

Holder, Jerry Ryan; Bauzo, Rayna M; Xiang, Zhimin; Haskell-Luevano, Carrie

2002-07-04

The melanocortin pathway is an important participant in skin pigmentation, steroidogenesis, obesity, energy homeostasis and exocrine gland function. The centrally located melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intake aspects of energy homeostasis and are stimulated by melanocortin agonists such as alpha-melanocyte stimulation hormone (alpha-MSH). The melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," and it has been well-documented that inversion of chirality of the Phe to DPhe results in a dramatic increase in melanocortin receptor potency. Herein, we report a tetrapeptide library, based upon the template Ac-His-DPhe-Arg-Trp-NH(2), consisting of 26 members that have been modified at the DPhe(7) position (alpha-MSH numbering) and pharmacologically characterized for agonist and antagonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. The most notable results of this study include the identification of the tetrapeptide Ac-His-(pI)DPhe-Arg-Trp-NH(2) that is a full nanomolar agonist at the mMC1 and mMC5 receptors, a mMC3R partial agonist with potent antagonist activity (pA(2) = 7.25, K(i) = 56 nM) and, but unexpectedly, is a potent agonist at the mMC4R (EC(50) = 25 nM). This ligand possesses novel melanocortin receptor pharmacology, as compared to previously reported peptides, and is potentially useful for in vivo studies to differentiate MC3R vs MC4R physiological roles in animal models, such as primates, where "knockout" animals are not viable options. The DNal(2') substitution for DPhe resulted in a mMC3R partial agonist with antagonist activity (pA(2) = 6.5, K(i) = 295 nM) and a mMC4R (pA(2) = 7.8, K(i) = 17 nM) antagonist possessing 60- and 425-fold decreased potency, respectively, as compared with SHU9119 at these receptors. Examination of this DNal(2')-containing tetrapeptide at the F254S and F259S mutant mMC4Rs resulted in agonist activity of this mMC4R tetrapeptide antagonist, similar to that observed for the SHU9119 peptide, supporting our previously proposed hypothesis that the Phe 254 and 259 transmembrane six receptor residues are important for differentiating melanocortin sequence-based MC4R antagonists vs the agouti-related protein (AGRP) sequence-based antagonists.

The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPARγ in Xenopus tropicalis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Jingmin

2017-01-01

The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXRα (xRXRα) and PPARγ (xPPARγ) in vitro and in vivo. We found that UVI3003 activated xPPARγ either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPARγ in vitro; therefore, the activation of Xenopus PPARγ by UVI3003more » is novel. The ability of UVI3003 to activate xPPARγ explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPARγ leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions. - Highlights: • UVI3003 is a RXRs antagonist and shows teratogenicity to Xenopus embryos. • UVI3003 activated xPPARγ either in Cos7 cells or Xenopus embryos. • UVI3003 did not activate human or mouse PPARγ in Cos7 cells. • Activating PPARγ leads to teratogenic effects in Xenopus embryos.« less

A Unique Human Chorionic Gonadotropin Antagonist Suppresses Ovarian Hyperstimulation Syndrome in Rats

PubMed Central

Vardhana, Pratibhasri A.; Julius, Martin A.; Pollak, Susan V.; Lustbader, Evan G.; Trousdale, Rhonda K.; Lustbader, Joyce W.

2009-01-01

Ovarian hyperstimulation syndrome (OHSS) is a complication of in vitro fertilization associated with physiological changes after hCG administration to induce final oocyte maturation. It presents as widespread increases in vascular permeability and, in rare cases, results in cycle cancellation, multi-organ dysfunction, and pregnancy termination. These physiological changes are due primarily to activation of the vascular endothelial growth factor (VEGF) system in response to exogenous human chorionic gonadotropin (hCG). An hCG antagonist (hCG-Ant) could attenuate these effects by competitively binding to the LH/CG receptor, thereby blocking LH activity in vivo. We expressed a form of hCG that lacks three of its four N-linked glycosylation sites and tested its efficacy as an antagonist. The hCG-Ant binds the LH receptor with an affinity similar to native hCG and inhibits cAMP response in vitro. In a rat model for ovarian stimulation, hCG-Ant dramatically reduces ovulation and steroid hormone production. In a well-established rat OHSS model, vascular permeability and vascular endothelial growth factor (VEGF) expression are dramatically reduced after hCG-Ant treatment. Finally, hCG-Ant does not appear to alter blastocyst development when given after hCG in mice. These studies demonstrate that removing specific glycosylation sites on native hCG can produce an hCG-Ant that is capable of binding without activating the LH receptor and blocking the actions of hCG. Thus hCG-Ant will be investigated as a potential therapy for OHSS. PMID:19443574

Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress.

PubMed

Gastón, M S; Cid, M P; Salvatierra, N A

2017-03-01

Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABA A receptor competitive antagonist) but not by diazepam (a GABA A receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic-pituitary-adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABA A receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABA A receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABA A receptor. Copyright © 2016 Elsevier B.V. All rights reserved.

High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists

PubMed Central

Fung, Eileen; Sugianto, Priscilla; Hsu, Jason; Damoiseaux, Robert; Ganz, Tomas

2013-01-01

Anemia of inflammation (AI) is common in patients with infection, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be reversed, treatment options are limited to erythropoiesis-stimulating agents with or without intravenous iron therapy, modalities that are not always effective and can cause serious adverse effects. Hepcidin, the iron regulatory hormone, has been identified as a pathogenic factor in the development of AI. To explore new therapeutic options for AI and other iron-related disorders caused by hepcidin excess, we developed a cell-based screen to identify hepcidin antagonists. Of the 70,000 small molecules in the library, we identified 14 compounds that antagonized the hepcidin effect on ferroportin. One of these was fursultiamine, a Food and Drug Administration (FDA)–approved thiamine derivative. Fursultiamine directly interfered with hepcidin binding to its receptor, ferroportin, by blocking ferroportin C326 thiol residue essential for hepcidin binding. Consequently, fursultiamine prevented hepcidin-induced ferroportin ubiquitination, endocytosis, and degradation in vitro and allowed continuous cellular iron export despite the presence of hepcidin, with IC50 in the submicromolar range. Thiamine, the fursultiamine metabolite, and benfotiamine, another thiamine derivative, did not interfere with the effect of hepcidin on ferroportin. Other FDA-approved thiol-reactive compounds were at least 1000-fold less potent than fursultiamine in antagonizing hepcidin. In vivo, fursultiamine did not reproducibly antagonize the effect of hepcidin on serum iron, likely because of its rapid conversion to inactive metabolites. Fursultiamine is a unique antagonist of hepcidin in vitro that could serve as a template for the development of drug candidates that inhibit the hepcidin-ferroportin interaction. PMID:23292796

Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells.

PubMed

El-Bizri, Nesrine; Bkaily, Ghassan; Wang, Shimin; Jacques, Danielle; Regoli, Domenico; D'Orléans-Juste, Pedro; Sukarieh, Rami

2003-03-01

Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.

Synthetic antagonists of in vivo antidiuretic and vasopressor responses to arginine-vasopressin.

PubMed

Manning, M; Lammek, B; Kolodziejczyk, A M; Seto, J; Sawyer, W H

1981-06-01

Four analogues of [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid),4-valine,8-D-arginine]vasopressin [d-(CH2)5 VDAVP] and four analogues of its L-arginine isomer d(CH2)5 VAVP with O-methyl-, O-ethyl, O-isopropyl, and O-n-propyltyrosine substituents at position 2 were prepared by the solid-phase method using a slightly modified reoxidation procedure following deblocking with sodium in liquid ammonia to overcome losses due to insolubility. These analogues are the following: 1, d(CH2)5Tyr(Me)VDAVP;2, d(CH2)5Tyr(Et)VDAVP; 3, d(CH2)5Tyr(i-Pr)VDAVP; 4, d(CH2)5Tyr(n-Pr)VDAVP; 5, d(CH2)5Tyr(Me)VAVP; 6, d(CH2)5Tyr(Et)VAVP; 7, d(CH2)5Tyr(i-Pr)VAVP; 8, d(CH2)5Tyr(n-Pr)VAVP. These analogues were tested for agonistic and antagonistic activities in rat antidiuretic and rat vasopressor assay systems. All eight analogues cause a transient antidiuresis when injected intravenously and effectively antagonize antidiuretic responses to subsequent injections of arginine-vasopressin (AVP). They exhibit the following antiantidiuretic pA2 values: 1, 6.68 +/- 0.11; 2, 7.10 +/- 0.08; 3, 6.88 +/- 0.07; 4, 6.67 +/0 0.05; 5, 7.35 +/- 0.06; 6, 7.57 +/- 0.06; 7, 7.32 +/- 0.10; 8, 7.29 +/- 0.07. They are also highly effective antagonists of the vasopressor responses to AVP, with antivasopressor pA2 values in the range of 7.86 to 8.44. These findings indicate tht in this series O-ethyl substitution on the tyrosine at position 2 is optimal for antiantidiuretic potency and that L-arginine is far superior to D-arginine in this regard also. Thus, d(CH2)5Tyr(Et)VAVP with an antiantidiuretic pA2 of 7.57 +/- 0.06 is the most potent of these eight antidiuretic antagonists. These are the first known effective antagonists of in vivo antidiuretic responses to AVP. They are, thus, potentially useful pharmacological tools for studies on the roles of AVP in regulating water balance in normal and pathophysiological states in animals and in humans. They also serve as excellent lead compounds for the design of even more potent antagonists for potential therapeutic use for the treatment of hyponatremia secondary to inappropriate secretion of the antidiuretic hormone (SIADH or the Schwartz-Barter syndrome).

Bombesin-like peptides stimulate growth hormone secretion mediated by the gastrin-releasing peptide receptor in cattle.

PubMed

Zhao, Hongqiong; Matsuda, Seinosuke; Thanthan, Sint; Yannaing, Swe; Kuwayama, Hideto

2012-10-01

This study was designed to determine the effects of bombesin-like peptides (BLPs) on the secretion of growth hormone (GH) and to characterize the receptor subtypes mediating these effects in cattle. Four experiments were conducted: (1) six steers were randomly assigned to receive intravenous (IV) bolus injections of 0, 0.2, 1.0, 12.5 and 50.0 μg/kg neuromedin C (NMC); (2) seven pre-weaned calves were IV injected with 1.0 μg/kg NMC; (3) six steers were IV injected with 2.5μg/kg bovine gastrin-releasing peptide (GRP), 1.0 μg/kg NMC combined with 20.0 μg/kg [d-Lys(3)]-GHRP-6 (an antagonist for the GH secretagogue receptor type 1a [GHS-R1a]), 1.0 μg/kg NMC combined with 20.0 μg/kg N-acetyl-GRP(20-26)-OCH(2)CH(3) (N-GRP-EE, an antagonist for the GRP receptor), 20.0 μg/kg N-GRP-EE alone, 1.0 μg/kg neuromedin B (NMB); and (4) four rats were IV injected 1.0 μg/kg NMC. A serial blood sample was collected before and after injection. Plasma GH levels dose-dependently increased at 5 min after NMC injection and the minimal effective dose was 1.0 μg/kg. Plasma GH level was elevated by GRP, but not by NMB. The NMC-induced elevation of GH was completely blocked by N-GRP-EE. The administration of NMC elevated GH level in pre-weaned calves but not in rats. Ghrelin level was unaffected by any treatments; and [d-Lys(3)]-GHRP-6 did not block the NMC-induced elevation of GH. The results indicate BLP-induced elevation of GH levels is mediated by the GRP receptor but not through a ghrelin/GHS-R1a pathway in cattle. Copyright © 2012 Elsevier Inc. All rights reserved.

Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial

PubMed Central

Kåss, Anita; Hollan, Ivana; Fagerland, Morten Wang; Gulseth, Hans Christian; Torjesen, Peter Abusdal; Førre, Øystein Torleiv

2015-01-01

Objectives Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels. Methods We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1–2; 3mg days 3–5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed. Results The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0∙010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism ‘Good-responses’ (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1β, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups. Conclusions GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA. Trial Registration ClinicalTrials.gov NCT00667758 PMID:26460564

Effect of octopamine on the activity of juvenile-hormone esterase in the silkworm Bombyx mori and the red flour beetle Tribolium freemani.

PubMed

Hirashima, A; Suetsugu, E; Hirokado, S; Kuwano, E; Taniguchi, E; Eto, M

1999-12-01

This study focuses on the effect of octopamine (OA) on metamorphosis of the silkworm Bombyx mori and the red flour beetle Tribolium freemani Hinton. Titers of OA and juvenile-hormone esterase (JHE) were measured at various larval and pupal stadia of both insects. Effects of OA, OA agonists, and antagonists on metamorphosis and JHE activity were also examined. At day 2, peaks of OA and JHE activity were observed in third instars, and at day 3, a sharp peak of OA was observed, followed by a large peak of JHE activity at day 4 in last instars of B. mori. However, no peaks of OA and JHE activity were observed in fourth instars. A high titer of OA appeared at days 2-4, followed by a peak of JHE activity at day 7 and the second OA peak at day 9 after the start of assay of T. freemani. At pupation, a small peak of OA and the highest activity of JHE were observed. The effects of OA on JHE activity were examined in vitro, because the relationship could be responsible for triggering pupation in B. mori and T. freemani larvae. Exogeneous OA (0.1-10 mM) stimulated the JHE activity of final instars (day 2) of B. mori in vitro. Similarly, the presence of OA (10 mM) activated the JHE activity of newly ecdysed T. freemani pupae in vitro. OA antagonists chlorpromazine and gramine delayed the start of spinning and reduced the JHE activity of B. mori, when applied in diet at 10-100 ppm. Some OA agonists stimulated the pupation and JHE activity of T. freemani larvae reared under crowded conditions, when topically applied. Thus, OA may contribute to activation of the events preparatory to a pupal molt, i.e., the secretion of OA increases JHE activity followed by stimulation of pupation. Copyright 1999 Academic Press.

The reproductive-cell cycle theory of aging: an update.

PubMed

Atwood, Craig S; Bowen, Richard L

2011-01-01

The Reproductive-Cell Cycle Theory posits that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. Since reproduction is the most important function of an organism from the perspective of the survival of the species, if reproductive-cell cycle signaling factors determine the rate of growth, determine the rate of development, determine the rate of reproduction, and determine the rate of senescence, then by definition they determine the rate of aging and thus lifespan. The theory is able to explain: 1) the simultaneous regulation of the rate of aging and reproduction as evidenced by the fact that environmental conditions and experimental interventions known to extend longevity are associated with decreased reproductive-cell cycle signaling factors, thereby slowing aging and preserving fertility in a hostile reproductive environment; 2) two phenomena that are closely related to species lifespan-the rate of growth and development and the ultimate size of the animal; 3). the apparent paradox that size is directly proportional to lifespan and inversely proportional to fertility between species but vice versa within a species; 4). how differing rates of reproduction between species is associated with differences in their lifespan; 5). why we develop aging-related diseases; and 6). an evolutionarily credible reason for why and how aging occurs-these hormones act in an antagonistic pleiotrophic manner via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence (dyosis). In essence, the Reproductive-Cell Cycle Theory can explain aging in all sexually reproductive life forms. Published by Elsevier Inc.

RhHB1 mediates the antagonism of gibberellins to ABA and ethylene during rose (Rosa hybrida) petal senescence.

PubMed

Lü, Peitao; Zhang, Changqing; Liu, Jitao; Liu, Xiaowei; Jiang, Guimei; Jiang, Xinqiang; Khan, Muhammad Ali; Wang, Liangsheng; Hong, Bo; Gao, Junping

2014-05-01

Rose (Rosa hybrida) is one of the most important ornamental plants worldwide; however, senescence of its petals terminates the ornamental value of the flower, resulting in major economic loss. It is known that the hormones abscisic acid (ABA) and ethylene promote petal senescence, while gibberellins (GAs) delay the process. However, the molecular mechanisms underlying the antagonistic effects amongst plant hormones during petal senescence are still unclear. Here we isolated RhHB1, a homeodomain-leucine zipper I transcription factor gene, from rose flowers. Quantitative RT-PCR and GUS reporter analyses showed that RhHB1 was strongly expressed in senescing petals, and its expression was induced by ABA or ethylene in petals. ABA or ethylene treatment clearly accelerated rose petal senescence, while application of the gibberellin GA3 delayed the process. However, silencing of RhHB1 delayed the ABA- or ethylene-mediated senescence, and resulted in higher petal anthocyanin levels and lower expression of RhSAG12. Moreover, treatment with paclobutrazol, an inhibitor of GA biosynthesis, repressed these delays. In addition, silencing of RhHB1 blocked the ABA- or ethylene-induced reduction in expression of the GA20 oxidase encoded by RhGA20ox1, a gene in the GA biosynthetic pathway. Furthermore, RhHB1 directly binds to the RhGA20ox1 promoter, and silencing of RhGA20ox1 promoted petal senescence. Eight senescence-related genes showed substantial differences in expression in petals after treatment with GA3 or paclobutrazol. These results suggest that RhHB1 mediates the antagonistic effect of GAs on ABA and ethylene during rose petal senescence, and that the promotion of petal senescence by ABA or ethylene operates through an RhHB1-RhGA20ox1 regulatory checkpoint. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

Effects of gonadal hormones on the peripheral cannabinoid receptor 1 (CB1R) system under a myositis condition in rats.

PubMed

Niu, Katelyn Y; Zhang, Youping; Ro, Jin Y

2012-11-01

In this study, we assessed the effects of peripherally administered cannabinoids in an orofacial myositis model, and the role of sex hormones in cannabinoid receptor (CBR) expression in trigeminal ganglia (TG). Peripherally administered arachidonylcyclopropylamide (ACPA), a specific CB1R agonist, significantly attenuated complete Freund's adjuvant (CFA)-induced mechanical hypersensitivity in the masseter muscle in male rats. The ACPA effect was blocked by a local administration of AM251, a specific CB1R antagonist, but not by AM630, a specific CB2R antagonist. In female rats, a 30-fold higher dose of ACPA was required to produce a moderate reduction in mechanical hypersensitivity. CFA injected in masseter muscle significantly upregulated CB1R mRNA expression in TG in male, but not in female, rats. There was a close correlation between the CB1R mRNA levels in TG and the antihyperalgesic effect of ACPA. Interleukin (IL)-1β and IL-6, which are elevated in the muscle tissue following CFA treatment, induced a significant upregulation of CB1R mRNA expression in TG from male rats. The upregulation of CB1R was prevented in TG cultures from orchidectomized male rats, which was restored by the application of testosterone. The cytokines did not alter the CB1R mRNA level in TG from intact as well as ovariectomized female rats. Neither estradiol supplement nor estrogen receptor blockade had any effects on CB1R expression. These data indicate that testosterone, but not estradiol, is required for the regulation of CB1Rs in TG under inflammatory conditions, which provide explanations for the sex differences in the antihyperalgesic effects of peripherally administered cannabinoids. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Effect of the glucocorticoid receptor antagonist Org 34850 on basal and stress-induced corticosterone secretion.

PubMed

Spiga, F; Harrison, L R; Wood, S A; Atkinson, H C; MacSweeney, C P; Thomson, F; Craighead, M; Grassie, M; Lightman, S L

2007-11-01

The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.

A New Signaling Pathway for HCV Inhibition by Estrogen: GPR30 Activation Leads to Cleavage of Occludin by MMP-9.

PubMed

Ulitzky, Laura; Lafer, Manuel M; KuKuruga, Mark A; Silberstein, Erica; Cehan, Nicoleta; Taylor, Deborah R

2016-01-01

Poor outcome in response to hepatitis C virus, including higher viral load, hepatocellular carcinoma and cirrhosis, is more associated with men and postmenopausal women than with premenopausal women and women receiving hormone replacement therapy, suggesting that β-estradiol plays an innate role in preventing viral infection and liver disease. Consequently, most research in the field has concluded that estrogen affects HCV replication through viral interactions with estrogen receptor-α. Previously, estrogen-like antagonists, including Tamoxifen, were shown to reduce HCV RNA production and prevent viral entry, although the authors did not identify host factors involved. Estrogen can act alternatively through the membrane-bound G-protein-coupled estrogen receptor, GPR30. Here, human hepatoma Huh7.5 cells were infected with HCV J6/JFH-1 and treated with estrogen or Tamoxifen, resulting in a marked decrease in detectable virus. The effect was mimicked by G1, a GPR30-specific agonist, and was reversed by the GPR30-specific antagonist, G15. While previous studies have demonstrated that estrogen down-regulated occludin in cervical cancer cells, its action on liver cells was unknown. Occludin is a tight junction protein and HCV receptor and here we report that activation and cellular export of MMP-9 led to the cleavage of occludin upon estrogen treatment of liver cells. This is the first report of the cleavage of an HCV receptor in response to estrogen. We also identify the occludin cleavage site in extracellular Domain D; the motif required for HCV entry and spread. This pathway gives new insight into a novel innate antiviral pathway and the suboptimal environment that estrogen provides for the proliferation of the virus. It may also explain the disparate host-virus responses to HCV demonstrated by the two sexes. Moreover, these data suggest that hormone replacement therapy may have beneficial antiviral enhancement properties for HCV-infected postmenopausal women and show promise for new antiviral treatments for both men and women.

Prevention of Preharvest Sprouting through Hormone Engineering and Germination Recovery by Chemical Biology.

PubMed

Nonogaki, Mariko; Nonogaki, Hiroyuki

2017-01-01

Vivipary, germination of seeds on the maternal plant, is observed in nature and provides ecological advantages in certain wild species, such as mangroves. However, precocious seed germination in agricultural species, such as preharvest sprouting (PHS) in cereals, is a serious issue for food security. PHS reduces grain quality and causes economical losses to farmers. PHS can be prevented by translating the basic knowledge of hormone biology in seeds into technologies. Biosynthesis of abscisic acid (ABA), which is an essential hormone for seed dormancy, can be engineered to enhance dormancy and prevent PHS. Enhancing nine- cis -epoxycarotenoid dioxygenase (NCED), a rate-limiting enzyme of ABA biosynthesis, through a chemically induced gene expression system, has successfully been used to suppress germination of Arabidopsis seeds. The more advanced system NCED positive-feedback system, which amplifies ABA biosynthesis in a seed-specific manner without chemical induction, has also been developed. The proofs of concept established in the model species are now ready to be applied to crops. A potential problem is recovery of germination from hyperdormant crop grains. Hyperdormancy induced by the NCED systems can be reversed by inducing counteracting genes, such as NCED RNA interference or gibberellin (GA) biosynthesis genes. Alternatively, seed sensitivity to ABA can be modified to rescue germination using the knowledge of chemical biology. ABA antagonists, which were developed recently, have great potential to recover germination from the hyperdormant seeds. Combination of the dormancy-imposing and -releasing approaches will establish a comprehensive technology for PHS prevention and germination recovery.

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions.

PubMed

Cardoso, Rodolfo C; Puttabyatappa, Muraly; Padmanabhan, Vasantha

2015-01-01

The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS. © 2015 S. Karger AG, Basel.

Low dose transdermal oestradiol suppresses gonadotrophin secretion in breast-feeding women.

PubMed

Illingworth, P J; Seaton, J E; McKinlay, C; Reid-Thomas, V; McNeilly, A S

1995-07-01

The object of the study was to investigate the effect on gonadotrophin secretion of a small increase in oestradiol concentration. A total of 13 fully breast-feeding women (12 weeks post-partum) underwent serial blood sampling at 10 min intervals for 12 h on 2 different days; day 1 untreated and day 5 after 3 days of treatment with transcutaneous oestradiol (100 micrograms/day). On both days bolus gonadotrophin-releasing hormone (GnRH; 10 micrograms i.v.) was given after a 10 h baseline period. In six of the subjects, a naloxone infusion was administered during the second study day. Application of transdermal oestradiol raised the oestradiol concentration within the normal follicular phase range. The mean luteinizing hormone (LH) concentration on day 5 was found to be significantly lower than that on day 1 (P < 0.05). The LH response to GnRH was, however, significantly higher on day 5 than day 1 (P < 0.001). The mean follicle stimulating hormone (FSH) concentration on day 5 was also significantly lower than that on day 1 (P < 0.01), while the peak concentration after GnRH was unchanged. When the opioid antagonist naloxone was infused after oestradiol treatment, the subjects with low pre-study oestradiol concentrations exhibited no effect on LH concentration, while in the subjects with higher oestradiol concentrations the LH concentration was increased. It was concluded that the administration of small doses of oestradiol caused a significant fall in gonadotrophin concentration in breast-feeding women.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine disruptors affect larval zebrafish behavior: Testing potential mechanisms and comparisons of behavioral sensitivity to alternative biomarkers.

PubMed

Fraser, Thomas W K; Khezri, Abdolrahman; Lewandowska-Sabat, Anna M; Henry, Theodore; Ropstad, Erik

2017-12-01

Larval zebrafish (Danio rerio) are a tool for assessing endocrine disruption during early development. Here, we investigated the extent to which a simple light/dark behavioral test at five days post fertilization could compliment current methods within the field. We exposed fertilized embryos to hormones (17β-estradiol, testosterone, dihydrotestosterone, 11-ketotestosterone, thyroxine, triiodothyronine, progesterone, and hydrocortisone) and other relevant compounds (17α ethinylestradiol, bisphenol A, bisphenol S, nonylphenol, flutamide, nilutamide, linuron, drospirenone, potassium perchlorate, mifepristone, and fadrozole) to screen for behavioral effects between 96 and 118h post fertilization (hpf). With the exception of progesterone, all the hormones tested resulted in altered behaviors. However, some inconsistencies were observed regarding the age of the larvae at testing. For example, the xenoestrogens 17α- ethinylestradiol and nonylphenol had behavioral effects at 96hpf, but not at 118hpf. Furthermore, although thyroxine exposure had pronounced effects on behavior, the thyroid disruptor potassium perchlorate did not. Finally, we were unable to demonstrate a role of nuclear receptors following testosterone and 17α- ethinylestradiol exposure, as neither the androgen receptor antagonist flutamide nor the general estrogen receptor inhibitor fulvestrant (ICI) could rescue the observed behavioral effects, respectively. Similarly, molecular markers for androgen and estrogen disruption were upregulated at concentrations below which behavioral effects were observed. These results demonstrate hormones and endocrine disruptors can alter the behavior of larval zebrafish, but the mechanistic pathways remain unclear. Copyright © 2017 Elsevier B.V. All rights reserved.

In silico methods in the discovery of endocrine disrupting chemicals.

PubMed

Vuorinen, Anna; Odermatt, Alex; Schuster, Daniela

2013-09-01

The prevalence of sex hormone-dependent cancers, reproductive problems, obesity, and cardiovascular complications has risen especially in the Western world. It has been suggested, that the exposure to various endocrine disrupting chemicals (EDCs) contributes to the development and progression of these diseases. EDCs can interfere with various proteins: nuclear steroid hormone receptors, such as estrogen-, androgen-, glucocorticoid- and mineralocorticoid receptors (ER, AR, GR, MR), and enzymes that are involved in steroid hormone synthesis and metabolism, for example hydroxysteroid dehydrogenases (HSDs). Numerous chemicals are known as endocrine disruptors. However, the mechanism of action for most of these EDCs is still unknown. It is exhaustive and time consuming to test in vitro all chemicals - potential EDCs - used in industry, agriculture or as food preservatives against their effects on the endocrine system. Computational methods, such as virtual screening, quantitative structure activity relationships and docking, are already well recognized and used in drug development. The same methods could also aid the research on EDCs. So far, the computational methods in the search of EDCs have been retrospective. There are, however, some prospective studies reporting the use of in silico methods: five studies reporting the identification of previously unknown 17β-HSD3 inhibitors, MR agonists, and ER antagonists/agonists. This review provides an overview of case studies and in silico methods that are used in the search of EDCs. This article is part of a Special Issue entitled 'CSR 2013'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Reprint of "In silico methods in the discovery of endocrine disrupting chemicals".

PubMed

Vuorinen, Anna; Odermatt, Alex; Schuster, Daniela

2015-09-01

The prevalence of sex hormone-dependent cancers, reproductive problems, obesity, and cardiovascular complications has risen especially in the Western world. It has been suggested, that the exposure to various endocrine disrupting chemicals (EDCs) contributes to the development and progression of these diseases. EDCs can interfere with various proteins: nuclear steroid hormone receptors, such as estrogen-, androgen-, glucocorticoid- and mineralocorticoid receptors (ER, AR, GR, MR), and enzymes that are involved in steroid hormone synthesis and metabolism, for example hydroxysteroid dehydrogenases (HSDs). Numerous chemicals are known as endocrine disruptors. However, the mechanism of action for most of these EDCs is still unknown. It is exhaustive and time consuming to test in vitro all chemicals - potential EDCs - used in industry, agriculture or as food preservatives against their effects on the endocrine system. Computational methods, such as virtual screening, quantitative structure activity relationships and docking, are already well recognized and used in drug development. The same methods could also aid the research on EDCs. So far, the computational methods in the search of EDCs have been retrospective. There are, however, some prospective studies reporting the use of in silico methods: five studies reporting the identification of previously unknown 17β-HSD3 inhibitors, MR agonists, and ER antagonists/agonists. This review provides an overview of case studies and in silico methods that are used in the search of EDCs. This article is part of a Special Issue entitled 'CSR 2013'. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of in vitro and in vivo bioassays to measure thyroid hormone disrupting activity in water extracts.

PubMed

Leusch, Frederic D L; Aneck-Hahn, Natalie H; Cavanagh, Jo-Anne E; Du Pasquier, David; Hamers, Timo; Hebert, Armelle; Neale, Peta A; Scheurer, Marco; Simmons, Steven O; Schriks, Merijn

2018-01-01

Environmental chemicals can induce thyroid disruption through a number of mechanisms including altered thyroid hormone biosynthesis and transport, as well as activation and inhibition of the thyroid receptor. In the current study six in vitro bioassays indicative of different mechanisms of thyroid disruption and one whole animal in vivo assay were applied to 9 model compounds and 4 different water samples (treated wastewater, surface water, drinking water and ultra-pure lab water; both unspiked and spiked with model compounds) to determine their ability to detect thyroid active compounds. Most assays correctly identified and quantified the model compounds as agonists or antagonists, with the reporter gene assays being the most sensitive. However, the reporter gene assays did not detect significant thyroid activity in any of the water samples, suggesting that activation or inhibition of the thyroid hormone receptor is not a relevant mode of action for thyroid endocrine disruptors in water. The thyroperoxidase (TPO) inhibition assay and transthyretin (TTR) displacement assay (FITC) detected activity in the surface water and treated wastewater samples, but more work is required to assess if this activity is a true measure of thyroid activity or matrix interference. The whole animal Xenopus Embryonic Thyroid Assay (XETA) detected some activity in the unspiked surface water and treated wastewater extracts, but not in unspiked drinking water, and appears to be a suitable assay to detect thyroid activity in environmental waters. Copyright © 2017 Elsevier Ltd. All rights reserved.

The involvement of gonadotropin inhibitory hormone and kisspeptin in the metabolic regulation of reproduction.

PubMed

Wahab, F; Shahab, M; Behr, R

2015-05-01

Recently, kisspeptin (KP) and gonadotropin inhibitory hormone (GnIH), two counteracting neuropeptides, have been acknowledged as significant regulators of reproductive function. KP stimulates reproduction while GnIH inhibits it. These two neuropeptides seem to be pivotal for the modulation of reproductive activity in response to internal and external cues. It is well-documented that the current metabolic status of the body is closely linked to its reproductive output. However, how reproductive function is regulated by the body's energy status is less clear. Recent studies have suggested an active participation of hypothalamic KP and GnIH in the modulation of reproductive function according to available metabolic cues. Expression of KISS1, the KP encoding gene, is decreased while expression of RFRP (NPVF), the gene encoding GnIH, is increased in metabolic deficiency conditions. The lower levels of KP, as suggested by a decrease in KISS1 gene mRNA expression, during metabolic deficiency can be corrected by administration of exogenous KP, which leads to an increase in reproductive hormone levels. Likewise, administration of RF9, a GnIH receptor antagonist, can reverse the inhibitory effect of fasting on testosterone in monkeys. Together, it is likely that the integrated function of both these hypothalamic neuropeptides works as a reproductive output regulator in response to a change in metabolic status. In this review, we have summarized literature from nonprimate and primate studies that demonstrate the involvement of KP and GnIH in the metabolic regulation of reproduction. © 2015 The authors.

Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters.

PubMed

Kharlyngdoh, Joubert Banjop; Pradhan, Ajay; Asnake, Solomon; Walstad, Anders; Ivarsson, Per; Olsson, Per-Erik

2015-01-01

Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5α-reductases and β-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds. Copyright © 2014 Elsevier Ltd. All rights reserved.

Short-chain fatty acid sensing in rat duodenum.

PubMed

Akiba, Yasutada; Inoue, Takuya; Kaji, Izumi; Higashiyama, Masaaki; Narimatsu, Kazuyuki; Iwamoto, Ken-ichi; Watanabe, Masahiko; Guth, Paul H; Engel, Eli; Kuwahara, Atsukazu; Kaunitz, Jonathan D

2015-02-01

Luminal lipid in the duodenum modulates gastroduodenal functions via the release of gut hormones and mediators such as cholecystokinin and 5-HT. The effects of luminal short-chain fatty acids (SCFAs) in the foregut are unknown. Free fatty acid receptors (FFARs) for long-chain fatty acids (LCFAs) and SCFAs are expressed in enteroendocrine cells. SCFA receptors, termed FFA2 and FFA3, are expressed in duodenal enterochromaffin cells and L cells, respectively. Activation of LCFA receptor (FFA1) and presumed FFA3 stimulates duodenal HCO3(-) secretion via a glucagon-like peptide (GLP)-2 pathway, whereas FFA2 activation induces HCO3(-) secretion via muscarinic and 5-HT4 receptor activation. The presence of SCFA sensing in the duodenum with GLP-2 and 5-HT signals further supports the hypothesis that luminal SCFA in the foregut may contribute towards the generation of functional symptoms. Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short-chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO3(-) secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long-chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon-like peptide (GLP)-1, whereas FFA2 colocalised with 5-HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase-IV (DPPIV) inhibition, at the same time as increasing GLP-2 portal blood concentrations. Acetate-induced DBS was partially inhibited by monocarboxylate/HCO3(-) exchanger inhibition without affecting GLP-2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose-dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5-HT3 receptor antagonists, but was inhibited by atropine and a 5-HT4 antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP-2 release, enhanced by DPPIV inhibition and inhibited by a GLP-2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP-2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5-HT4 receptor activation. SCFA/HCO3(-) exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone release and possibly signal neural activation may be implicated in the pathogenesis of functional dyspepsia. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

The role of adrenal hormones in the response of glutamine synthetase to fasting in adult and old rats.

PubMed

Mezzarobba, V; Torrent, A; Leydier, I; Alles, S; Brajon, B; Mignon, M; Attaix, D; Meynial-Denis, D

2003-12-01

During fasting, skeletal muscle exports increased amounts of glutamine (Gln) while increasing the production of this amino acid by glutamine synthetase (GS) in order to maintain the intramuscular Gln pool. Glucocorticoid hormones are believed to be the principal mediators of GS induction during stress conditions. The aim of this study was to evaluate (1) the effect of fasting on GS activity and expression in skeletal muscle during aging and consequently, (2) the role of glucocorticoids in fasting-induced GS activity. Male Wistar rats (6-, 22-month old) were fasted for 5 days and both the activity and expression of GS were measured in tibialis anterior muscle. To better demonstrate the role of glucocorticoids in the response of GS to fasting, we suppressed their action by RU38486 administration (a potent glucocorticoid antagonist) and their production by adrenalectomy in fed and fasted rats. An increase in fasting-induced GS activity was observed in skeletal muscles from both adult and aged rats. Adrenalectomy, but surprisingly not RU38486, suppressed the fasting-induced increase in GS activity and expression. The data clearly show that the GS responsiveness to fasting was not modified by aging in skeletal muscle.

Effect of salinity changes on olfactory memory-related genes and hormones in adult chum salmon Oncorhynchus keta.

PubMed

Kim, Na Na; Choi, Young Jae; Lim, Sang-Gu; Jeong, Minhwan; Jin, Deuk-Hee; Choi, Cheol Young

2015-09-01

Studies of memory formation have recently concentrated on the possible role of N-methyl-d-aspartate receptors (NRs). We examined changes in the expression of three NRs (NR1, NR2B, and NR2C), olfactory receptor (OR), and adrenocorticotropic hormone (ACTH) in chum salmon Oncorhynchus keta using quantitative polymerase chain reaction (QPCR) during salinity change (seawater→50% seawater→freshwater). NRs were significantly detected in the diencephalon and telencephalon and OR was significantly detected in the olfactory epithelium. The expression of NRs, OR, and ACTH increased after the transition to freshwater. We also determined that treatment with MK-801, an antagonist of NRs, decreased NRs in telencephalon cells. In addition, a reduction in salinity was associated with increased levels of dopamine, ACTH, and cortisol (in vivo). Reductions in salinity evidently caused NRs and OR to increase the expression of cortisol and dopamine. We concluded that memory capacity and olfactory imprinting of salmon is related to the salinity of the environment during the migration to spawning sites. Furthermore, salinity affects the memory/imprinting and olfactory abilities, and cortisol and dopamine is also related with olfactory-related memories during migration. Copyright © 2015 Elsevier Inc. All rights reserved.

Evolutionary Conflict Between Maternal and Paternal Interests: Integration with Evolutionary Endocrinology.

PubMed

Mokkonen, Mikael; Koskela, Esa; Mappes, Tapio; Mills, Suzanne C

2016-08-01

Conflict between mates, as well as conflict between parents and offspring are due to divergent evolutionary interests of the interacting individuals. Hormone systems provide genetically based proximate mechanisms for mediating phenotypic adaptation and maladaptation characteristic of evolutionary conflict between individuals. Testosterone (T) is among the most commonly studied hormones in evolutionary biology, and as such, its role in shaping sexually dimorphic behaviors and physiology is relatively well understood, but its role in evolutionary conflict is not as clear. In this review, we outline the genomic conflicts arising within the family unit, and incorporate multiple lines of evidence from the bank vole (Myodes glareolus) system to outline how T impacts traits associated with reproduction and survival, resulting in a sexually antagonistic genetic trade-off in fitness. A major prediction arising from this work is that lower T is favored in females, whereas the optimal T level in males fluctuates in relation to social and ecological factors. We additionally discuss future directions to further integrate endocrinology into the study of sexual and parent-offspring conflicts. © The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

A Novel Role of Peripheral Corticotropin-Releasing Hormone (CRH) on Dermal Fibroblasts

PubMed Central

Rassouli, Olga; Liapakis, George; Lazaridis, Iakovos; Sakellaris, George; Gkountelias, Kostas; Gravanis, Achille; Margioris, Andrew N.

2011-01-01

Corticotropin-releasing hormone, or factor, (CRH or CRF) exerts important biological effects in multiple peripheral tissues via paracrine/autocrine actions. The aim of our study was to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing. We show expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh−/−) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF1 antagonist antalarmin recapitulated the findings in the Crh−/− cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6. In conclusion, our findings show an important role of fibroblast-expressed CRH in the proliferation, migration, and cytokine production of these cells, processes associated with the skin response to injury. Our data suggest that the immunomodulatory effects of CRH may include an important, albeit not explored yet, role in epidermal tissue remodeling and regeneration and maintenance of tissue homeostasis. PMID:21765902

[Prostate cancer and new hormonal treatments: mechanism of action and main clinical results].

PubMed

Neuzillet, Y; Flamand, V; Lebdai, S; Villers, A; Lebret, T

2013-10-01

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs. A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed. the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects. Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Pregnancy and acromegaly.

PubMed

Muhammad, Ammar; Neggers, Sebastian J; van der Lely, Aart J

2017-02-01

Acromegaly is a rare disorder in which, due to the high incidence of secondary hypogonadism, pregnancies are relatively rare. However, some women with acromegaly do get pregnant, which brings along questions about medication, complications and follow-up. This review tries to address these issues and provide the reader with practical information. This review summarizes published data. Acromegaly is a disorder that is characterized by changes in growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin concentrations and actions. All these hormones are important in pregnancy as well. In principle, the fetal-placental collaboration between mother and child more-or-less takes over the control over GH and IGF-1, not only in normal physiology but also to a certain extend in acromegaly. When medication for the high GH levels or actions is continued during pregnancy, both dopamine agonists, somatostatin analogs and GH receptor antagonists have been used and the available data suggest that there are no adverse consequences on mother or fetus to date. However, it is strongly advised to stop any medical intervention during pregnancy until more data are available on the safety of these compounds. Also, medical treatment is not needed as tumor size and disease activity are not reported to escape.

Investigational drugs for the treatment of endometriosis, an update on recent developments.

PubMed

Barra, Fabio; Scala, Carolina; Mais, Valerio; Guerriero, Stefano; Ferrero, Simone

2018-05-01

Endometriosis is a hormone-dependent benign chronic disease that requires a chronic medical therapy. Although currently available drugs are efficacious in treating endometriosis-related pain, some women experience partial or no improvement. Moreover, the recurrence of symptoms is expected after discontinuation of the therapies. Currently, new drugs are under intense clinical investigation for the treatment of endometriosis. Areas covered: This review aims to offer the reader a complete and updated overview on new investigational drugs and early molecular targets for the treatment of endometriosis. The authors describe the pre-clinical and clinical development of these agents. Expert opinion: Among the drugs under investigation, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis. Aromatase inhibitors (AIs) are efficacious in treating endometriosis related pain symptoms but they cause significant adverse effects that limit their long-term use. New targets have been identified to produce drugs for the treatment of endometriosis, but the majority of these new compounds have only been investigated in laboratory studies or early clinical trials. Thus, further clinical research is required in order to elucidate their efficacy and safety in human.

Kisspeptin as a promising oocyte maturation trigger for in vitro fertilisation in humans.

PubMed

Kasum, Miro; Franulić, Daniela; Čehić, Ermin; Orešković, Slavko; Lila, Albert; Ejubović, Emina

2017-08-01

The aim of this review is to analyse the effectiveness of exogenous kisspeptin administration as a novel alternative of triggering oocyte maturation, instead of currently used triggers such as human chorionic gonadotropin (hCG) or gonadotropin releasing hormone (GnRH) agonist, in women undergoing in vitro fertilisation (IVF) treatment. Kisspeptin has been considered a master regulator of two modes of GnRH and hence gonadotropin secretion, pulses and surges. Administration of kisspeptin-10 and kisspeptin-54 induces the luteinising hormone (LH) surge required for egg maturation and ovulation in animal investigations and LH release during the preovulatory phase of the menstrual cycle and hypothalamic amenorrhoea in humans. Exogenous kisspeptin-54 has been successfully administered as a promising method of triggering oocyte maturation, following ovarian stimulation with gonadotropins and GnRH antagonists in women undergoing IVF, due to its efficacy considering achieved pregnancy rates compared to hCG and GnRH agonists. Also, its safety in patients at high risk of developing ovarian hyperstimulation syndrome is noteworthy. Nevertheless, further studies would be desirable to establish the optimal trigger of egg maturation and to improve the reproductive outcome for women undergoing IVF treatment.

Cocaine Blocks Effects of Hunger Hormone, Ghrelin, Via Interaction with Neuronal Sigma-1 Receptors.

PubMed

Aguinaga, David; Medrano, Mireia; Cordomí, Arnau; Jiménez-Rosés, Mireia; Angelats, Edgar; Casanovas, Mireia; Vega-Quiroga, Ignacio; Canela, Enric I; Petrovic, Milos; Gysling, Katia; Pardo, Leonardo; Franco, Rafael; Navarro, Gemma

2018-06-07

Despite ancient knowledge on cocaine appetite-suppressant action, the molecular basis of such fact remains unknown. Addiction/eating disorders (e.g., binge eating, anorexia, bulimia) share a central control involving reward circuits. However, we here show that the sigma-1 receptor (σ 1 R) mediates cocaine anorectic effects by interacting in neurons with growth/hormone/secretagogue (ghrelin) receptors. Cocaine increases colocalization of σ 1 R and GHS-R1a at the cell surface. Moreover, in transfected HEK-293T and neuroblastoma SH-SY5Y cells, and in primary neuronal cultures, pretreatment with cocaine or a σ 1 R agonist inhibited ghrelin-mediated signaling, in a similar manner as the GHS-R1a antagonist YIL-781. Results were similar in G protein-dependent (cAMP accumulation and calcium release) and in partly dependent or independent (ERK1/2 phosphorylation and label-free) assays. We provide solid evidence for direct interaction between receptors and the functional consequences, as well as a reliable structural model of the macromolecular σ 1 R-GHS-R1a complex, which arises as a key piece in the puzzle of the events linking cocaine consumption and appetitive/consummatory behaviors.

Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma.

PubMed

Müssig, K; Gallwitz, B; Honegger, J; Strasburger, C J; Bidlingmaier, M; Machicao, F; Bornemann, A; Ranke, M B; Häring, H-U; Petersenn, S

2007-03-01

Gigantism is rare with the majority of cases caused by a growth hormone (GH)-secreting pituitary adenoma. Treatment options for GH-secreting pituitary adenomas have been widened with the availability of long-acting dopamine agonists, depot preparations of somatostatin analogues, and recently the GH receptor antagonist pegvisomant. A 23-year-old male patient presented with continuous increase in height during the past 6 years due to a GH-secreting giant pituitary adenoma. Because of major intracranial extension and failure of octreotide treatment to shrink the tumour, the tumour was partially resected by a trans-frontal surgical approach. At immunohistochemistry, the tumour showed a marked expression of GH and a sparsely focal expression of prolactin. Somatostatin receptors (sst) 1-5 were not detected. Tumour tissue weakly expressed dopamine receptor type 2. The Gs alpha subunit was intact. Conversion from somatostatin analogue to pegvisomant normalized insulin-like-growth-factor-I (IGF-I) levels and markedly improved glucose tolerance. Pegvisomant is a potent treatment option in patients with pituitary gigantism. In patients who do not respond to somatostatin analogues, knowledge of the SST receptor status may shorten the time to initiation of pegvisomant treatment.

Absence of luteal phase defect and spontaneous pregnancy in IVF patients despite GnRH-agonist trigger and "freeze all policy" without luteal phase support: a report of four cases.

PubMed

Gurbuz, Ali Sami; Deveer, Ruya; Ozcimen, Necati; Ozcimen, Emel Ebru; Lawrenz, Barbara; Banker, Manish; Garcia-Velasco, Juan Antonio; Fatemi, Human Mousavi

2016-01-01

Human chorionic gonadotropin (hCG) is commonly used for final oocyte maturation in "in vitro fertilization" (IVF)-treatment cycles, however, the main important risk is development of severe ovarian hyperstimulation syndrome (OHSS). OHSS can almost be avoided by using gonadotrophin-releasing-hormone agonist for final oocyte maturation in an antagonist protocol. However, primarily this approach lead to a very poor reproductive outcome, despite the use of a standard luteal phase support. The reason seems to be severe luteolysis. Obviously, luteolysis post-gonadotropin-releasing-hormone-agonist (post-GnRH-a) trigger is individual specific, and not all patients will develop a complete luteolysis, as expected previously. Luteolysis can been reverted by the administration of hCG. Unprotected intercourse around the time of ovulation induction and oocyte retrieval can lead to a spontaneous conception in IVF treatment and, endogenous hCG, produced by the trophoblast, will rescue the corpora lutea. Therefore, one should not rely on complete luteolysis after GnRH-a triggering and, especially patients for egg donation and pre-implantation-genetic diagnosis for single gene disorder, have to be counselled to avoid unprotected intercourse.

Regulation of aromatase expression in the anterior amygdala of the developing mouse brain depends on ERβ and sex chromosome complement.

PubMed

Cisternas, Carla Daniela; Cabrera Zapata, Lucas Ezequiel; Arevalo, María Angeles; Garcia-Segura, Luis Miguel; Cambiasso, María Julia

2017-07-13

During development sex differences in aromatase expression in limbic regions of mouse brain depend on sex chromosome factors. Genes on the sex chromosomes may affect the hormonal regulation of aromatase expression and this study was undertaken to explore that possibility. Male E15 anterior amygdala neuronal cultures expressed higher levels of aromatase (mRNA and protein) than female cultures. Furthermore, treatment with oestradiol (E2) or dihydrotestosterone (DHT) increased Cyp19a1 expression and aromatase protein levels only in female neuronal cultures. The effect of E2 on aromatase expression was not imitated by oestrogen receptor (ER) α agonist PPT or the GPER agonist G1, but it was fully reproduced by DPN, a specific ligand of ERβ. By contrast, the effect of DHT on aromatase expression was not blocked by the anti-androgen flutamide, but completely abrogated by the ERβ antagonist PHTPP. Experiments using the four core genotype model showed a sex chromosome effect in ERβ expression (XY > XX) and regulation by E2 or DHT (only XX respond) in amygdala neurons. In conclusion, sex chromosome complement governs the hormonal regulation of aromatase expression through activation of ERβ in developing mouse brain.

Pamidronic acid and cabergoline as effective long-term therapy in a 12-year-old girl with extended facial polyostotic fibrous dysplasia, prolactinoma and acromegaly in McCune-Albright syndrome: a case report

PubMed Central

2012-01-01

Introduction McCune-Albright syndrome is a complex inborn disorder due to early embryonal postzygotic somatic activating mutations in the GNAS1 gene. The phenotype is very heterogeneous and includes polyostotic fibrous dysplasia, typically involving the facial skull, numerous café-au-lait spots and autonomous hyperfunctions of several endocrine systems, leading to hyperthyroidism, hypercortisolism, precocious puberty and acromegaly. Case presentation Here, we describe a 12-year-old Caucasian girl with severe facial involvement of fibrous dysplasia, along with massive acromegaly due to growth hormone excess and precocious puberty, with a prolactinoma. Our patient was treated with a bisphosphonate and the prolactin antagonist, cabergoline, resulting in the inhibition of fibrous dysplasia and involution of both the prolactinoma and growth hormone excess. During a follow-up of more than two years, no severe side effects were noted. Conclusion Treatment with bisphosphonates in combination with cabergoline is a suitable option in patients with McCune-Albright syndrome, especially in order to circumvent surgical interventions in patients suffering from polyostotic fibrous dysplasia involving the skull base. PMID:22273876

Thyroid endocrine system disruption by pentachlorophenol: an in vitro and in vivo assay.

PubMed

Guo, Yongyong; Zhou, Bingsheng

2013-10-15

The present study aimed to evaluate the disruption caused to the thyroid endocrine system by pentachlorophenol (PCP) using in vitro and in vivo assays. In the in vitro assay, rat pituitary GH3 cells were exposed to 0, 0.1, 0.3, and 1.0 μM PCP. PCP exposure significantly downregulated basal and triiodothyronine (T3)-induced Dio 1 transcription, indicating the antagonistic activity of PCP in vitro. In the in vivo assay, zebrafish embryos were exposed to 0, 1, 3, and 10 μg/L of PCP until 14 days post-fertilization. PCP exposure resulted in decreased thyroxine (T4) levels, but elevated contents of whole-body T3. PCP exposure significantly upregulated the mRNA expression of genes along hypothalamic-pituitary-thyroid (HPT) axis, including those encoding thyroid-stimulating hormone, sodium/iodide symporter, thyroglobulin, Dio 1 and Dio 2, alpha and beta thyroid hormone receptor, and uridinediphosphate-glucuronosyl-transferase. PCP exposure did not influence the transcription of the transthyretin (TTR) gene. The results indicate that PCP potentially disrupts the thyroid endocrine system both in vitro and in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

Stress, catecholaminergic system and cancer.

PubMed

Krizanova, O; Babula, P; Pacak, K

2016-07-01

Stress as a modern civilization factor significantly affects our lives. While acute stress might have a positive effect on the organism, chronic stress is usually detrimental and might lead to serious health complications. It is known that stress induced by the physical environment (temperature-induced cold stress) can significantly impair the efficacy of cytotoxic chemotherapies and the anti-tumor immune response. On the other hand, epidemiological evidence has shown that patients taking drugs known as β-adrenergic antagonists ("β-blockers"), which are commonly prescribed to treat arrhythmia, hypertension, and anxiety, have significantly lower rates of several cancers. In this review, we summarize the current knowledge about catecholamines as important stress hormones in tumorigenesis and discuss the use of β-blockers as the potential therapeutic agents.

Cachexia.

PubMed

Graul, A I; Stringer, M; Sorbera, L

2016-09-01

Cachexia is a multiorgan, multifactorial and often irreversible wasting syndrome associated with cancer and other serious, chronic illnesses including AIDS, chronic heart failure, chronic kidney disease and chronic obstructive pulmonary disease. Treatment of the patient with cachexia is currently targeted to correcting the two underlying features of the condition: anorexia and metabolic disturbances. Greater understanding of the mechanisms behind cachexia and muscle wasting have led to new therapeutic possibilities, however. Several classes of drugs are under active development for cachexia including drugs acting on hormone receptors or cytokine receptors, myostatin/activin pathway antagonists, beta-adrenoceptor agonists and cannabinoids. This review will cover the pathophysiology, epidemiology, diagnosis, treatment, drug candidates under active development and targets for therapeutic intervention of cachexia. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

Fighting obesity with a sugar-based library: discovery of novel MCH-1R antagonists by a new computational-VAST approach for exploration of GPCR binding sites.

PubMed

Heifetz, Alexander; Barker, Oliver; Verquin, Geraldine; Wimmer, Norbert; Meutermans, Wim; Pal, Sandeep; Law, Richard J; Whittaker, Mark

2013-05-24

Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the MCH-1R binding site. X-ray crystallography and NMR, the major experimental sources of structural information, are very slow processes for membrane proteins and are not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of these methods to impact the drug discovery process for GPCR targets in "real-time", and hence, there is an urgent need for other practical and cost-efficient alternatives. We present here a conceptually pioneering approach that integrates GPCR modeling with design, synthesis, and screening of a diverse library of sugar-based compounds from the VAST technology (versatile assembly on stable templates) to provide structural insights on the MCH-1R binding site. This approach creates a cost-efficient new avenue for structure-based drug discovery (SBDD) against GPCR targets. In our work, a primary VAST hit was used to construct a high-quality MCH-1R model. Following model validation, a structure-based virtual screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R antagonists, including EOAI3367472 (IC50 = 131 nM) and EOAI3367474 (IC50 = 213 nM).

Ionotropic glutamate receptors mediate inducible defense in the water flea Daphnia pulex.

PubMed

Miyakawa, Hitoshi; Sato, Masanao; Colbourne, John K; Iguchi, Taisen

2015-01-01

Phenotypic plasticity is the ability held in many organisms to produce different phenotypes with a given genome in response to environmental stimuli, such as temperature, nutrition and various biological interactions. It seems likely that environmental signals induce a variety of mechanistic responses that influence ontogenetic processes. Inducible defenses, in which prey animals alter their morphology, behavior and/or other traits to help protect against direct or latent predation threats, are among the most striking examples of phenotypic plasticity. The freshwater microcrustacean Daphnia pulex forms tooth-like defensive structures, "neckteeth," in response to chemical cues or signals, referred to as "kairomones," in this case released from phantom midge larvae, a predator of D. pulex. To identify factors involved in the reception and/or transmission of a kairomone, we used microarray analysis to identify genes up-regulated following a short period of exposure to the midge kairomone. In addition to identifying differentially expressed genes of unknown function, we also found significant up-regulation of genes encoding ionotropic glutamate receptors, which are known to be involved in neurotransmission in many animal species. Specific antagonists of these receptors strongly inhibit the formation of neckteeth in D. pulex, although agonists did not induce neckteeth by themselves, indicating that ionotropic glutamate receptors are necessary but not sufficient for early steps of neckteeth formation in D. pulex. Moreover, using co-exposure of D. pulex to antagonists and juvenile hormone (JH), which physiologically mediates neckteeth formation, we found evidence suggesting that the inhibitory effect of antagonists is not due to direct inhibition of JH synthesis/secretion. Our findings not only provide a candidate molecule required for the inducible defense response in D. pulex, but also will contribute to the understanding of complex mechanisms underlying the recognition of environmental changes, which form the basis of phenotypic plasticity.

Kisspeptin and Neurokinin B Signaling Network Underlies the Pubertal Increase in GnRH Release in Female Rhesus Monkeys.

PubMed

Garcia, James P; Guerriero, Kathryn A; Keen, Kim L; Kenealy, Brian P; Seminara, Stephanie B; Terasawa, Ei

2017-10-01

Loss-of-function or inactivating mutations in the genes coding for kisspeptin and its receptor (KISS1R) or neurokinin B (NKB) and the NKB receptor (NK3R) in humans result in a delay in or the absence of puberty. However, precise mechanisms of kisspeptin and NKB signaling in the regulation of the pubertal increase in gonadotropin-releasing hormone (GnRH) release in primates are unknown. In this study, we conducted a series of experiments infusing agonists and antagonists of kisspeptin and NKB into the stalk-median eminence, where GnRH, kisspeptin, and NKB neuroterminal fibers are concentrated, and measuring GnRH release in prepubertal and pubertal female rhesus monkeys. Results indicate that (1) similar to those previously reported for GnRH stimulation by the KISS1R agonist (i.e., human kisspeptin-10), the NK3R agonist senktide stimulated GnRH release in a dose-responsive manner in both prepubertal and pubertal monkeys; (2) the senktide-induced GnRH release was blocked in the presence of the KISS1R antagonist peptide 234 in pubertal but not prepubertal monkeys; and (3) the kisspeptin-induced GnRH release was blocked in the presence of the NK3R antagonist SB222200 in the pubertal but not prepubertal monkeys. These results are interpreted to mean that although, in prepubertal female monkeys, kisspeptin and NKB signaling to GnRH release is independent, in pubertal female monkeys, a reciprocal signaling mechanism between kisspeptin and NKB neurons is established. We speculate that this cooperative mechanism by the kisspeptin and NKB network underlies the pubertal increase in GnRH release in female monkeys. Copyright © 2017 Endocrine Society.

Origin of Aberrant Blood Pressure and Sympathetic Regulation in Diet-Induced Obesity.

PubMed

Lim, Kyungjoon; Barzel, Benjamin; Burke, Sandra L; Armitage, James A; Head, Geoffrey A

2016-08-01

High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat; n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet-fed animals (4.2% fat; n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits (P<0.05) but not in control diet-fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits (P<0.05) but not in control diet-fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet-fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension. © 2016 American Heart Association, Inc.

Targeting of the Orphan Receptor GPR35 by Pamoic Acid: A Potent Activator of Extracellular Signal-Regulated Kinase and β-Arrestin2 with Antinociceptive ActivityS⃞

PubMed Central

Zhao, Pingwei; Sharir, Haleli; Kapur, Ankur; Cowan, Alan; Geller, Ellen B.; Adler, Martin W.; Seltzman, Herbert H.; Reggio, Patricia H.; Heynen-Genel, Susanne; Sauer, Michelle; Chung, Thomas D.Y.; Bai, Yushi; Chen, Wei; Caron, Marc G.; Barak, Larry S.

2010-01-01

Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drugs and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics oxantel pamoate and pyrantel pamoate; the psychoactive compounds hydroxyzine pamoate (Vistaril) and imipramine pamoate (Tofranil-PM); and the peptide hormones triptorelin pamoate (Trelstar) and octreotide pamoate (OncoLar). We have found that pamoic acid induces a Gi/o-linked, GPR35-mediated increase in the phosphorylation of extracellular signal-regulated kinase 1/2, recruitment of β-arrestin2 to GPR35, and internalization of GPR35. In mice, it attenuates visceral pain perception, indicating an antinociceptive effect, possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID2745687). Pamoic acid and potent antagonists such as CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35-associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent. PMID:20826425

Oxytocin reversed MK-801-induced social interaction and aggression deficits in zebrafish.

PubMed

Zimmermann, Fernanda Francine; Gaspary, Karina Vidarte; Siebel, Anna Maria; Bonan, Carla Denise

2016-09-15

Changes in social behavior occur in several neuropsychiatric disorders such as schizophrenia and autism. The interaction between individuals is an essential aspect and an adaptive response of several species, among them the zebrafish. Oxytocin is a neuroendocrine hormone associated with social behavior. The aim of the present study was to investigate the effects of MK-801, a non-competitive antagonist of glutamate NMDA receptors, on social interaction and aggression in zebrafish. We also examined the modulation of those effects by oxytocin, the oxytocin receptor agonist carbetocin and the oxytocin receptor antagonist L-368,899. Our results showed that MK-801 induced a decrease in the time spent in the segment closest to the conspecific school and in the time spent in the segment nearest to the mirror image, suggesting an effect on social behavior. The treatment with oxytocin after the exposure to MK-801 was able to reestablish the time spent in the segment closest to the conspecific school, as well as the time spent in the segment nearest to the mirror image. In addition, in support of the role of the oxytocin pathway in modulating those responses, we showed that the oxytocin receptor agonist carbetocin reestablished the social and aggressive behavioral deficits induced by MK-801. However, the oxytocin receptor antagonist L-368,899 was not able to reverse the behavioral changes induced by MK-801. This study supports the critical role for NMDA receptors and the oxytocinergic system in the regulation of social behavior and aggression which may be relevant for the mechanisms associated to autism and schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

17β-Estradiol Reverses Leptin-Inducing Ovarian Cancer Cell Migration by the PI3K/Akt Signaling Pathway.

PubMed

Hoffmann, Marta; Fiedor, Elżbieta; Ptak, Anna

2016-11-01

Accumulating evidence suggests that leptin is expressed at higher levels in obese women and stimulates cell migration in epithelial cancers. However, the biology of ovarian cancer is different from others, mainly due to the production of estrogens because of the involvement of ovarian tissue, which is the main source of estrogens; as a result, the levels are at least 100- to 1000-fold higher than normal circulating levels. Thus, ovarian cancer tissues are exposed to 17β-estradiol, which promotes ovarian cancer cell migration and may modulate the effect of other hormones. Therefore, this study investigated the effects of 17β-estradiol (1 nmol/L) with leptin (1-40 ng/mL) at physiological levels, on the migration of OVCAR-3 and SKOV-3 ovarian cancer cells, and the expression levels and activity of metalloproteinases (MMPs) 2 and 9. Here, we found that leptin stimulated ovarian cancer cell line migration, which is mediated via the expression and activity of MMP-9 in the OVCAR-3 but not in the SKOV-3 cells. After the administration of 17β-estradiol and leptin, we observed antagonistic effects of 17β-estradiol on leptin-induced OVCAR-3 cell migration and MMP-9 expression and activity. Moreover, the antagonistic effect of 17β-estradiol on leptin-induced cancer cell migration was reversed by pretreatment of the cells with the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor. Taken together, our results, for the first time, show that in ovarian cancer cells ObR + /ER + , 17β-estradiol has an antagonistic effect on leptin-induced cell migration as well as MMP-9 expression and activity, which is mediated by the PI3K pathway. © The Author(s) 2016.

Short-chain fatty acid sensing in rat duodenum

PubMed Central

Akiba, Yasutada; Inoue, Takuya; Kaji, Izumi; Higashiyama, Masaaki; Narimatsu, Kazuyuki; Iwamoto, Ken-ichi; Watanabe, Masahiko; Guth, Paul H; Engel, Eli; Kuwahara, Atsukazu; Kaunitz, Jonathan D

2015-01-01

Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short-chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO3− secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long-chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon-like peptide (GLP)-1, whereas FFA2 colocalised with 5-HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase-IV (DPPIV) inhibition, at the same time as increasing GLP-2 portal blood concentrations. Acetate-induced DBS was partially inhibited by monocarboxylate/HCO3− exchanger inhibition without affecting GLP-2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose-dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5-HT3 receptor antagonists, but was inhibited by atropine and a 5-HT4 antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP-2 release, enhanced by DPPIV inhibition and inhibited by a GLP-2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP-2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5-HT4 receptor activation. SCFA/HCO3− exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone release and possibly signal neural activation may be implicated in the pathogenesis of functional dyspepsia. PMID:25433076

The regulation of oxytocin and oxytocin receptor in human placenta according to gestational age.

PubMed

Kim, Seung-Chul; Lee, Jae-Eon; Kang, Seong Soo; Yang, Hoe-Saeng; Kim, Sun Suk; An, Beum-Soo

2017-10-01

Oxytocin (OXT) is a peptide hormone that plays a central role in the regulation of parturition and lactation. OXT signaling is mediated by OXT receptor (OXTR), which shows species- and tissue-specific expressions and gene regulation. In the present study, we examined the synthesis of OXT and OXTR in human placenta tissue according to gestational age. A total of 48 placentas were divided into early preterm, late preterm and term groups depending on gestational age, and expression of OXT and OXTR was evaluated. First, OXT and OXTR mRNA and protein were detected in normal placenta tissue via Q-PCR, Dot-blot and Western blot assay. Both OXT and OXTR levels in normal placenta increased gradually in the late stage of pregnancy, suggesting that local OXT may play a critical role in the function of the placenta. To determine the regulatory mechanism of OXT, placental BeWo cells were administrated estrogen (E2) or progesterone (P 4 ), and expression of OXT and OXTR was tested. The mRNA and protein levels of OXT and OXTR were upregulated by E2 but blocked by co-treatment with P 4 In order to confirm the estrogen receptor (ESR)-mediated signaling, we administrated ESR antagonists together with E2 to BeWo cells. As a result, both OXT and OXTR were significantly altered by ESR1 antagonist (MPP) while moderately regulated by ESR2 antagonist (PHTPP). These results suggest that OXT and OXTR are controlled mainly by E2 in the placenta via ESR1 and thus may play physiological functions in the human placenta during the late stage of pregnancy. © 2017 Society for Endocrinology.

Dopamine inhibits somatolactin gene expression in tilapia pituitary cells through the dopamine D2 receptors.

PubMed

Jiang, Quan; Lian, Anji; He, Qi

2016-07-01

Dopamine (DA) is an important neurotransmitter in the central nervous system of vertebrates and possesses key hypophysiotropic functions. Early studies have shown that DA has a potent inhibitory effect on somatolactin (SL) release in fish. However, the mechanisms responsible for DA inhibition of SL gene expression are largely unknown. To this end, tilapia DA type-1 (D1) and type-2 (D2) receptor transcripts were examined in the neurointermediate lobe (NIL) of the tilapia pituitary by real-time PCR. In tilapia, DA not only was effective in inhibiting SL mRNA levels in vivo and in vitro, but also could abolish pituitary adenylate cyclase-activating polypeptide (PACAP)- and salmon gonadotropin-releasing hormone (sGnRH)-stimulated SL gene expression at the pituitary level. In parallel studies, the specific D2 receptor agonists quinpirole and bromocriptine could mimic the DA-inhibited SL gene expression. Furthermore, the D2 receptor antagonists domperidone and (-)-sulpiride could abolish the SL response to DA or the D2 agonist quinpirole, whereas D1 receptor antagonists SCH23390 and SKF83566 were not effective in this respect. In primary cultures of tilapia NIL cells, D2 agonist quinpirole-inhibited cAMP production could be blocked by co-treatment with the D2 antagonist domperidone and the ability of forskolin to increase cAMP production was also inhibited by quinpirole. Using a pharmacological approach, the AC/cAMP pathway was shown to be involved in quinpirole-inhibited SL mRNA expression. These results provide evidence that DA can directly inhibit SL gene expression at the tilapia pituitary level via D2 receptor through the AC/cAMP-dependent mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

Acute stress-induced sensitization of the pituitary-adrenal response to heterotypic stressors: independence of glucocorticoid release and activation of CRH1 receptors.

PubMed

Belda, Xavier; Daviu, Núria; Nadal, Roser; Armario, Antonio

2012-09-01

A single exposure to some severe stressors causes sensitization of the hypothalamic-pituitary-adrenal (HPA) response to novel stressors. However, the putative factors involved in stress-induced sensitization are not known. In the present work we studied in adult male rats the possible role of glucocorticoids and CRH type 1 receptor (CRH-R1), using an inhibitor of glucocorticoid synthesis (metyrapone, MET), the glucocorticoid receptor (GR) antagonist RU38486 (mifepristone) and the non-peptide CRH-R1 antagonist R121919. In a first experiment we demonstrated with different doses of MET (40-150 mg/kg) that the highest dose acted as a pharmacological stressor greatly increasing ACTH release and altering the normal circadian pattern of HPA hormones, but no dose affected ACTH responsiveness to a novel environment as assessed 3 days after drug administration. In a second experiment, we found that MET, at a dose (75 mg/kg) that blocked the corticosterone response to immobilization (IMO), did not alter IMO-induced ACTH sensitization. Finally, neither the GR nor the CRH-R1 antagonists blocked IMO-induced ACTH sensitization on the day after IMO. Thus, a high dose of MET, in contrast to IMO, was unable to sensitize the HPA response to a novel environment despite the huge activation of the HPA axis caused by the drug. Neither a moderate dose of MET that markedly reduced corticosterone response to IMO, nor the blockade of GR or CRH-R1 receptors was able to alter stress-induced HPA sensitization. Therefore, stress-induced sensitization is not the mere consequence of a marked HPA activation and does not involve activation of glucocorticoid or CRH-R1 receptors. Copyright © 2012 Elsevier Inc. All rights reserved.

Effect of corticotropin-releasing factor receptor antagonist on psychologically suppressed masculine sexual behavior in rats.

PubMed

Miwa, Yoshiji; Nagase, Keiko; Oyama, Nobuyuki; Akino, Hironobu; Yokoyama, Osamu

2011-03-01

Corticotropin-releasing factor (CRF) coordinates various responses of the body to stress, and CRF receptors are important targets of treatment for stress-related disorders. To investigate the effect of a nonselective CRF receptor antagonist, astressin, on suppression of masculine sexual behavior by psychological stress in rats. First, we investigated the influence of psychological stress, induced 2 hours per day for three consecutive days, on sexual behavior. Then, rats were divided into 4 groups: a control group, an astressin administration group (A), a psychological stress loading group (PS), and a psychological stress loading and astressin administration group (PS + A). The rats were exposed to sham or psychological stress for three consecutive days. After the last stress loading, the rats were injected with vehicle or astressin, and their sexual behavior was observed. We also measured serum levels of adrenocorticotropic hormone (ACTH). The effects of astressin on sexual behavior and serum levels of ACTH in rats affected by psychological stress were determined. Sexual behavior was reduced after psychological stress loading. The PS rats had significantly longer mount, intromission, and ejaculation latencies and lower ejaculation frequency than did the control, A, and PS + A rats. The intromission latency and ejaculation frequency in the PS + A rats did not achieve the level observed in the controls. There was no significant difference in these parameters between the control and A rats. Serum ACTH levels were significantly lower in PS + A rats than in PS rats. Psychologically suppressed masculine sexual behavior could be partially recovered with astressin administration in rats. These data provide a rationale for the further study of CRF receptor antagonists as novel agents for treating psychological sexual disorders. © 2010 International Society for Sexual Medicine.

Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward.

PubMed

Skibicka, Karolina P; Shirazi, Rozita H; Hansson, Caroline; Dickson, Suzanne L

2012-03-01

Ghrelin, a stomach-derived hormone, is an orexigenic peptide that was recently shown to potently increase food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic system and food reward behavior remains unclear. Here we examined the contribution of neuropeptide Y (NPY) and opioids to ghrelin's effects on food motivation and intake. Both systems have well-established links to the mesolimbic ventral tegmental area (VTA) and reward/motivation control. NPY mediates the effect of ghrelin on food intake via activation of NPY-Y1 receptor (NPY-Y1R); their connection with respect to motivated behavior is unexplored. The role of opioids in any aspect of ghrelin's action on food-oriented behaviors is unknown. Rats were trained in a progressive ratio sucrose-induced operant schedule to measure food reward/motivation behavior. Chow intake was measured immediately after the operant test. In separate experiments, we explored the suppressive effects of a selective NPY-Y1R antagonist or opioid receptor antagonist naltrexone, injected either intracerebroventricularly or intra-VTA, on ghrelin-induced food reward behavior. The ventricular ghrelin-induced increase in sucrose-motivated behavior and chow intake were completely blocked by intracerebroventricular pretreatment with either an NPY-Y1R antagonist or naltrexone. The intra-VTA ghrelin-induced sucrose-motivated behavior was blocked only by intra-VTA naltrexone. In contrast, the intra-VTA ghrelin-stimulated chow intake was attenuated only by intra-VTA NPY-Y1 blockade. Finally, ghrelin infusion was associated with an elevated VTA μ-opioid receptor expression. Thus, we identify central NPY and opioid signaling as the necessary mediators of food intake and reward effects of ghrelin and localize these interactions to the mesolimbic VTA.

KATP channels in the nodose ganglia mediate the orexigenic actions of ghrelin

PubMed Central

Grabauskas, Gintautas; Wu, Xiaoyin; Lu, Yuanxu; Heldsinger, Andrea; Song, Il; Zhou, Shi-Yi; Owyang, Chung

2015-01-01

Abstract Ghrelin is the only known hunger signal derived from the peripheral tissues. Ghrelin overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. The mechanisms by which ghrelin reduces the sensory signals evoked by anorexigenic hormones, which act via the vagus nerve to stimulate feeding, are unknown. Patch clamp recordings of isolated rat vagal neurons show that ghrelin hyperpolarizes neurons by activating K+ conductance. Administering a KATP channel antagonist or silencing Kir6.2, a major subunit of the KATP channel, abolished ghrelin inhibition in vitro and in vivo. Patch clamp studies show that ghrelin inhibits currents evoked by leptin and CCK-8, which operate through independent ionic channels. The inhibitory actions of ghrelin were abolished by treating the vagal ganglia neurons with pertussis toxin, as well as phosphatidylinositol 3-kinase (PI3K) or extracellular signal-regulated kinase 1 and 2 (Erk1/2) small interfering RNA. In vivo gene silencing of PI3K and Erk1/2 in the nodose ganglia prevented ghrelin inhibition of leptin- or CCK-8-evoked vagal firing. Feeding experiments showed that silencing Kir6.2 in the vagal ganglia abolished the orexigenic actions of ghrelin. These data indicate that ghrelin modulates vagal ganglia neuron excitability by activating KATP conductance via the growth hormone secretagogue receptor subtype 1a–Gαi–PI3K–Erk1/2–KATP pathway. The resulting hyperpolarization renders the neurons less responsive to signals evoked by anorexigenic hormones. This provides a mechanism to explain the actions of ghrelin with respect to overcoming anorexigenic signals that act via the vagal afferent pathways. Key points Ghrelin, a hunger signalling peptide derived from the peripheral tissues, overcomes the satiety signals evoked by anorexigenic molecules, such as cholecystokinin (CCK) and leptin, to stimulate feeding. Using in vivo and in vitro electrophysiological techniques, we show that ghrelin hyperpolarizes neurons and inhibits currents evoked by leptin and CCK-8. Administering a KATP channel antagonist or silencing Kir6.2, a major subunit of the KATP channel, abolished ghrelin inhibition. The inhibitory actions of ghrelin were also abolished by treating the vagal ganglia neurons with pertussis toxin, as well as phosphatidylinositol 3-kinase (PI3K) or extracellular signal-regulated kinase 1 and 2 (Erk1/2) small interfering RNA. Feeding experiments showed that silencing Kir6.2 in the vagal ganglia abolished the orexigenic actions of ghrelin. These data indicate that ghrelin modulates vagal ganglia neuron excitability by activating KATP conductance via the growth hormone secretagogue receptor subtype 1a–Gαi–PI3K–Erk1/2–KATP pathway. This provides a mechanism to explain the actions of ghrelin with respect to overcoming anorexigenic signals that act via the vagal afferent pathways. PMID:26174421

The action of a synthetic derivative of Met5-enkephalin-Arg6-Phe7 on behavioral and endocrine responses.

PubMed

Csabafi, Krisztina; Jászberényi, Miklós; Bagosi, Zsolt; Tóth, Géza; Wollemann, Mária; Telegdy, Gyula

2011-08-01

The neuroendocrine and behavioral effects of Tyr-D-Ala-Gly-Phe-D-Nle-Arg-Phe (DADN), a more stable derivative of the endogenous opiate Met-enkephalin related peptide Met(5)-enkephalin-Arg(6)-Phe(7) were investigated in mice. The behavioral experiments consisted of monitoring the horizontal (square crossing) and vertical (rearing) locomotion in the open field system. To evaluate the effect of the heptapeptide on the hypothalamo-pituitary-adrenal (HPA) axis, the plasma corticosterone level was measured. DADN induced dose-dependent increases in locomotion and rearing 30 min after intracerebroventricular injection and also elicited marked activation of the hormonal stress response. To elucidate the receptors involved in the mediation of these actions, animals were pretreated with the nonselective opioid antagonist naloxone, the selective κ-receptor antagonist nor-binaltorphimine or the μ(1)-receptor blocker naloxonazine. Both the HPA activation and the behavioral responses were diminished by the preadministration of naloxone. Nor-binaltorphimine did not display a significant effect, while naloxonazine completely abolished the hyperactivity and the corticosterone elevation elicited by the analog. These findings suggest that μ-receptors predominate in the mediation of the neuroendocrine actions of DADN, while κ-receptors do not play a significant role. Copyright © 2011. Published by Elsevier Inc.

Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner.

PubMed

Perello, Mario; Sakata, Ichiro; Birnbaum, Shari; Chuang, Jen-Chieh; Osborne-Lawrence, Sherri; Rovinsky, Sherry A; Woloszyn, Jakub; Yanagisawa, Masashi; Lutter, Michael; Zigman, Jeffrey M

2010-05-01

Ghrelin is a potent orexigenic hormone that likely impacts eating via several mechanisms. Here, we hypothesized that ghrelin can regulate extra homeostatic, hedonic aspects of eating behavior. In the current study, we assessed the effects of different pharmacological, physiological, and genetic models of increased ghrelin and/or ghrelin-signaling blockade on two classic behavioral tests of reward behavior: conditioned place preference (CPP) and operant conditioning. Using both CPP and operant conditioning, we found that ghrelin enhanced the rewarding value of high-fat diet (HFD) when administered to ad lib-fed mice. Conversely, wild-type mice treated with ghrelin receptor antagonist and ghrelin receptor-null mice both failed to show CPP to HFD normally observed under calorie restriction. Interestingly, neither pharmacologic nor genetic blockade of ghrelin signaling inhibited the body weight homeostasis-related, compensatory hyperphagia associated with chronic calorie restriction. Also, ghrelin's effects on HFD reward were blocked in orexin-deficient mice and wild-type mice treated with an orexin 1 receptor antagonist. Our results demonstrate an obligatory role for ghrelin in certain rewarding aspects of eating that is separate from eating associated with body weight homeostasis and that requires the presence of intact orexin signaling. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Depression, Anxiety, and Anger in Patients with Polycystic Ovary Syndrome.

PubMed

Balikci, Adem; Erdem, Murat; Keskin, Uğur; Bozkurt Zincir, Selma; Gülsün, Murat; Özçelik, Fatih; Akgül, Emin Özgür; Akarsu, Süleyman; Öztosun, Muzaffer; Ergün, Ali

2014-12-01

Polycystic Ovary Syndrome (PCOS) is a syndrome of heterogeneous nature, affecting multiple systems, particularly the endocrine system. We propose to investigate the possible relationships among hormonal changes, levels of anxiety, depression, and anger in patients with PCOS. Forty-four female patients with PCOS and 44 body mass index (BMI )-matched healthy women participated in this study. We measured the sociodemographic features, some serum hormonal levels (insulin, gonadotropins, prolactin, dehydroepiandrosterone sulfate (DHEAS), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), 17 OH-progesterone, and total and free testosterone), and some other biochemical parameters of the participants. Also, all participants completed the Trait Anger-Anger Expression Scale (STAS), Beck Depression, and Beck Anxiety Inventories. We evaluated the psychiatric scale scores obtained from PCOS patients and control subjects. We used the independent-samples t-test for parametric data to evaluate normal distribution, and Mann-Whitney U-test was used for both abnormally distributed and nonparametric data. We used Pearson correlation analysis to evaluate the potential connection between the two groups' data. The mean ages of the patients with PCOS and control subjects who participated in this study were 27.3±5.6 and 27.4±6.1 years, respectively. The measures of BMI, insulin, luteinizing hormone (LH), DHEAS, and total testosterone serum levels in the patient group were significantly higher than in the control group (p<.05). There was a statistically significant positive correlation between Beck anxiety scores and serum DHEAS levels (Pearson r=.4366, P=.0001). We found significant differences between the two groups in terms of trait anger, anger control, outward and inward anger, anxiety level, and depression scores (P<.05). Anxiety symptoms indicate a stronger relationship compared to depression with DHEAS serum levels via the autonomic nervous system, considering the gamma-aminobutyric acid (GABA)-antagonistic effect of DHEAS. Obesity, hirsutism, and infertility may reduce self-confidence and create depressive symptoms in patients with PCOS. In addition, changes in hormonal levels may lead to anxiety directly. Possibly, depressive symptoms are a secondary reflection of these changes.

Depression, Anxiety, and Anger in Patients with Polycystic Ovary Syndrome

PubMed Central

BALIKCI, Adem; ERDEM, Murat; KESKIN, Uğur; BOZKURT ZINCIR, Selma; GÜLSÜN, Murat; ÖZÇELIK, Fatih; AKGÜL, Emin Özgür; AKARSU, Süleyman; ÖZTOSUN, Muzaffer; ERGÜN, Ali

2014-01-01

Introduction Polycystic Ovary Syndrome (PCOS) is a syndrome of heterogeneous nature, affecting multiple systems, particularly the endocrine system. We propose to investigate the possible relationships among hormonal changes, levels of anxiety, depression, and anger in patients with PCOS. Method Forty-four female patients with PCOS and 44 body mass index (BMI )-matched healthy women participated in this study. We measured the sociodemographic features, some serum hormonal levels (insulin, gonadotropins, prolactin, dehydroepiandrosterone sulfate (DHEAS), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), 17 OH-progesterone, and total and free testosterone), and some other biochemical parameters of the participants. Also, all participants completed the Trait Anger-Anger Expression Scale (STAS), Beck Depression, and Beck Anxiety Inventories. We evaluated the psychiatric scale scores obtained from PCOS patients and control subjects. We used the independent-samples t-test for parametric data to evaluate normal distribution, and Mann-Whitney U-test was used for both abnormally distributed and nonparametric data. We used Pearson correlation analysis to evaluate the potential connection between the two groups’ data. Results The mean ages of the patients with PCOS and control subjects who participated in this study were 27.3±5.6 and 27.4±6.1 years, respectively. The measures of BMI, insulin, luteinizing hormone (LH), DHEAS, and total testosterone serum levels in the patient group were significantly higher than in the control group (p<.05). There was a statistically significant positive correlation between Beck anxiety scores and serum DHEAS levels (Pearson r=.4366, P=.0001). We found significant differences between the two groups in terms of trait anger, anger control, outward and inward anger, anxiety level, and depression scores (P<.05). Conclusion Anxiety symptoms indicate a stronger relationship compared to depression with DHEAS serum levels via the autonomic nervous system, considering the gamma-aminobutyric acid (GABA)-antagonistic effect of DHEAS. Obesity, hirsutism, and infertility may reduce self-confidence and create depressive symptoms in patients with PCOS. In addition, changes in hormonal levels may lead to anxiety directly. Possibly, depressive symptoms are a secondary reflection of these changes. PMID:28360650

High Peak Estradiol/Mature Oocyte Ratio Predicts Lower Clinical Pregnancy, Ongoing Pregnancy, and Live Birth Rates in GnRH Antagonist Intracytoplasmic Sperm Injection Cycles.

PubMed

Sandoval, Juan S; Steward, Ryan G; Chen, Chen; Li, Yi-Ju; Price, Thomas M; Muasher, Suheil J

2016-01-01

To define the relationship between peak estradiol (E2)/mature oocyte ratio and pregnancy outcomes in gonadotropin-releasing hormone (GnRH) antagonist intracytoplasmic sperm injection (ICSI) cycles. Retrospective cohort study in the setting of an academic reproductive medicine practice. Records from 162 fresh, autologous, GnRH antagonist ICSI cycles performed between 2009 and 2012 .were analyzed. The main outcome measures were rates of clinical pregnancy (CPR), ongoing pregnancy (OPR), and live birth (LBR). For the primary analysis, 4 groups were created based on peak E2/mature oocyte ratio (group 1: <200, group 2: 200-300, group 3: 300-400, and group 4: >400 pg/mL/oocyte). After adjusting for age, basal FSH, and the number of mature oocytes, a significantly lower OPR was seen in group 4 as compared to group I (OR 0.15, 95% CI 0.03-0.86; p=0.032) and group 3 (OR 0.17, 95% CI 0.03-0.98; p=0.048), respectively. The adjusted LBR was also significantly lower in group 4 as compared to group 1 (OR 0.15, 95% CI 0.03-0.83; p=0.030). In a secondary analysis, 3 ranges of peak E2/ mature oocyte ratio (<200, 200-400, and >400 pg/ mL/oocyte) were compared between low, normal, and high responders (<6, 6-15, and >15 mature oocytes, respectively). Clinical pregnancy rate, OPR, and LBR were all lower in normal responders when the E2/oocyte ratio exceeded 400 pg/mL/oocyte as compared to <200 pg/mL/oocyte and 200-300 pg/mL/oocyte (CPR 1% vs. 16% and 32%, respectively, p=0.017; OPR 0 vs. 15% and 27%, respectively, p=0.011; and LBR 0 vs. 13% and 26%, respectively, p=0.018). Very elevated peak E2/mature oocyte ratio is associated with a lower CPR, OPR, and LBR in fresh, autologous, GnRH antagonist ICSI cycles.

Evidence Supporting a Role for Constitutive Ghrelin Receptor Signaling in Fasting-Induced Hyperphagia in Male Mice.

PubMed

Fernandez, Gimena; Cabral, Agustina; Andreoli, María F; Labarthe, Alexandra; M'Kadmi, Céline; Ramos, Jorge G; Marie, Jacky; Fehrentz, Jean-Alain; Epelbaum, Jacques; Tolle, Virginie; Perello, Mario

2018-02-01

Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone-releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance. Copyright © 2018 Endocrine Society.