10540-29-1NKANXQFJJICGDU-QPLCGJKRSA-NNKANXQFJJICGDU-QPLCGJKRSA-N
TamoxifenOHT
Ethanamine, 2-[4-[(1Z)-1,2-diphenyl-1-butenyl]phenoxy]-N,N-dimethyl-
(Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
Ethanamine, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-
Ethanamine, 2-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy]-N,N-dimethyl-
Ethylamine, 2-[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl-, (Z)-
Mammaton
Novaldex
Tamoxifen and its salts
tamoxifene
tamoxifeno
trans-Tamoxifen
Z-Tamoxifen
TAM
DTXSID103418784449-90-1GZUITABIAKMVPG-UHFFFAOYSA-NGZUITABIAKMVPG-UHFFFAOYSA-N
RaloxifeneRAL
Methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-
DTXSID3023550129453-61-8VWUXBMIQPBEWFH-WCCTWKNTSA-NVWUXBMIQPBEWFH-WCCTWKNTSA-N
Fulvestrant(7alpha,17beta)-7-{9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl}estra-1,3,5(10)-triene-3,17-diol
ICI 182,780
Faslodex
Estra-1,3,5(10)-triene-3,17-diol, 7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-, (7α,17β)-
DTXSID402236950-41-9PYTMYKVIJXPNBD-UHFFFAOYSA-NPYTMYKVIJXPNBD-UHFFFAOYSA-N
Clomiphene citrate (1:1)Clomiphene citrate
Clomid
Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
1-[p-(β-Diethylaminoethoxy)phenyl]-1,2-diphenyl-2-chloroethylene citrate
2-[4-(2-Chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethylethanamine 2-hydroxy-1,2,3-propanetricarboxylic acid (1:1)
2-[p-(2-Chloro-1,2-diphenylvinyl)phenoxy]triethylamine dihydrogen citrate
Chloramiphene
clomifen dihydrogen citrate
Clomifendihydrogencitrat
Clomifene citrate
Clomiphene dihydrogen citrate
Clomivid
Clomphid
Clostilbegit
Clostilbegyt
dihidrogenocitrato de clomifeno
dihydrogenocitrate de clomifen
Dyneric
Fertivet
Genozym
Ikaclomin
Ikaclomine
NSC 35770
Pergotime
Racemic clomiphene citrate
Serophene
Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate
Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate (1:1)
DTXSID8020337CHEBI:23965estradiolPR:000007204estrogen receptorD007987Gonadotropin Releasing HormoneCHEBI:81569Follicle stimulating hormoneCHEBI:81568Luteinizing hormoneCL:0002132stromal cell of ovaryUBERON:0004911epithelium of female gonadD000236AdenomaD016586Granular Cell TumorCHEBI:1646917beta-estradiolGO:0030284estrogen receptor activityGO:0046879hormone secretionGO:0046884follicle-stimulating hormone secretionGO:0032275luteinizing hormone secretionD006965hyperplasia2decreased1increasedTamoxifen2016-11-29T18:42:272016-11-29T18:42:27Raloxifene2016-11-29T18:42:272016-11-29T18:42:27Fulvestrant2016-11-29T18:42:272016-11-29T18:42:27Clomiphene citrate (1:1)2022-02-26T23:24:202022-02-26T23:24:20WCS_9606human10116rat10095mice10090CD-1 mouse10116 F344 rat9913cowDecreased, Ovarian E2Decreased, Ovarian E2TissueUBERON:0000992female gonad2016-11-29T18:41:282017-09-16T10:17:05Suppression, Estrogen receptor (ER) activitySuppression, Estrogen receptor (ER) activityMolecular<p><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Estrogen receptors are produced in all vertebrates and located in either the cell cytoplasm or nucleus</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Bondesson et al., 2015; Eick and Thornton, 2011)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. Estrogen receptors are localized either in cytoplasm, or on the cell surface.</span></span></p>
<p> </p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Site of action:</span></span></strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif""> Stressors (e.g., clomiphene) act on neuronal cell in the hypothalamus, where it inhibits hypothalamic Estrogen Receptors selectively.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Responses at the macromolecular level:</span></span></strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif""> Stressors activate the Estrogen Receptor α in the presence of lower level of estrogen and partially blocks the same for higher level of estrogen and works as antagonist for the Estrogen Receptor β</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Trost and Khera, 2014)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. Stressors appear to act in the brain's pituitary gland to secrete an increased amount of gonadotropins hormone (GnRH) in hypothalamus leading towards increased GnRH level in blood. </span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Estrogen Receptor α:</span></span></strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif""> ERα (Estrogen Receptor α or NR3A1 or ESR1) - A nuclear receptor and it is activated by the estrogen (sex hormone). Estrogen located at chromosome number 6 ( 6q25.1)</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Estrogen Receptor β:</span></span></strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif""> ERβ (Estrogen Receptor β or NR3A2 or ESR2) – This is also nuclear receptor and activated by the sex hormone estrogen which is located at chromosome number 14 (14q23.2). </span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">I ERβ has both N-terminal has DNA binding domain and C-terminal has ligand binding domain. This is localized to the nucleus, cytoplasm, and mitochondria. Selective estrogen receptor modulators (SERM) inhibits the ERβ. Drugs used as SERM are </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">clomiphene</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">, tamoxifen, raloxifene etc.</span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Biological compartments:</span></span></strong> <span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Estrogen receptors (ER) are present in the plasma membrane. Both ERα and ERβ have diverse functions depending on cells and organs. ERs have also been loacated in cytoplasmic organelles including mitochondria and the endoplasmic reticulum</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Levin, 2009)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. </span></span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">General role in biology:</span></span></strong><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif""> Estrogen receptors (both </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">) binds the estrogens to promote the t</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">he biological functions of estrogens. Depending upon a balance between ERα and ERβ activities in target organs, estrogen signaling is selectively stimulated or inhibited </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Welboren et al., 2009)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. ERβ has a high degree of sequence homology with the classical estrogen receptor. Interestingly, ERβ is detected in many tissues, including those previously assumed to be estrogen insensitive. In tissues where both ERs are expressed, such as the hypothalamus, uterus, mammary glands, and immune system, ERα promotes proliferation whereas ERβ has pro-apoptotic and pro-differentiating functions</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Morani et al., 2008)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. ERα is present mainly in ovary (thecal cells) where as ERβ is found mainly in ovary (granulosa cells)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Paterni et al., 2014)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. ERα and ERβ is identical approximately 97% in the DNA-binding domain and approximately 56% in the ligand-binding domain</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Dahlman-Wright et al., 2006)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. </span></span></span></span></p>
<p><em><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Radioreceptor assay/The estrogen receptor binding assay (using Rat Uterine Cytosol)</span></span></em><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">: This assay identifies chemicals that have the potential to interact with the estrogen receptor (ER) <em>in vitro</em>. Principle of this particular assay is based on the competitive protein-binding methods. A radiolabelled ligand and an unlabelled ligand are presented together to a specific receptor. The radioactivity measurement provides the quantitative estimation of the bound and unbound fraction of the ligand with the receptor. All cytosolic estrogen receptor subtypes that are expressed in the specific tissue, including ERα and ERβ are used for the determination of estrogen receptor binding. This assay is simple and rapid to perform when optimal conditions for binding are determined. Assay determines if a ligand/chemical can interact and displace the endogenous hormone 17β-estradiol </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Freyberger et al., 2010)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. </span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Neuronal cell in Hypothalamus</span></span></span></span></p>
UBERON:0001898hypothalamusCL:0000540neuronHighMixedHighNot Otherwise SpecifiedHighHighHigh<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Adashi, E. Y., Hsueh, A. J., & Yen, S. S. (1980). Alterations induced by clomiphene in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus of female rats. <em>J Endocrinol. </em>, 87(3), 383-92.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bharti, S., Misro, M., & Rai, U. (2013). Clomiphene citrate potentiates the adverse effects of estrogen on rat testis and down-regulates the expression of steroidogenic enzyme genes. <em>Fertility and sterility</em>, 99(1), 140-148. e5.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bondesson, M., Hao, R., Lin, C.-Y., Williams, C., & Gustafsson, J.-Å. (2015). Estrogen receptor signaling during vertebrate development. <em>Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms</em>, 1849(2), 142-151.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bussenot, I., Parinaud, J., Clamagirand, C., Vieitez, G., & Pontonnier, G. (1990). Effect of clomiphene cirate on oestrogen secretion by human granulosa cells in culture. <em>Human Reproduction</em>, 5(5), 533-536.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Dahlman-Wright, K., Cavailles, V., Fuqua, S. A., Jordan, V. C., Katzenellenbogen, J. A., Korach, K. S., et al. (2006). International union of pharmacology. LXIV. Estrogen receptors. <em>Pharmacological reviews</em>, 58(4), 773-781.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Dominguez, R., & Micevych, P. (2010). Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. <em>J Neurosci</em>, 30(38), 12589-96. doi:30/38/12589 [pii]</span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">10.1523/JNEUROSCI.1038-10.2010.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Eick, G. N., & Thornton, J. W. (2011). Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. <em>Molecular and cellular endocrinology</em>, 334(1-2), 31-38.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Freyberger, A., Wilson, V., Weimer, M., Tan, S., Tran, H. S., & Ahr, H. J. (2010). Assessment of a robust model protocol with accelerated throughput for a human recombinant full length estrogen receptor-alpha binding assay: protocol optimization and intralaboratory assay performance as initial steps towards validation. <em>Reprod Toxicol</em>, 30(1), 50-9. doi:S0890-6238(10)00003-1 [pii]</span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Kerin, J. F., Liu, J. H., Phillipou, G., & Yen, S. S. (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. <em>J Clin Endocrinol Metab. </em>, 61(2), 65-68.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Kettel, L. M., Roseff, S. J., Berga, S. L., Mortola, J. F., & Yen, S. S. (1993). Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome. <em>Fertil Steril. </em>, 59(3), 532-38.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Koch, Y., Dikstein, S., Superstine, E., & Sulman, F. G. (1971). THE EFFECT OF PROMETHAZINE AND CLOMIPHENE ON GONADOTROPHIN SECRETION IN THE RAT. <em>Journal of Endocrinology</em>, 49(1), 13-17. doi:10.1677/joe.0.0490013.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Kurosawa, T., Hiroi, H., Momoeda, M., Inoue, S., & Taketani, Y. (2010). Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors αand β. <em>Endocrine journal</em>, 57(6), 517-521.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Levin, E. R. (2009). Plasma membrane estrogen receptors. <em>Trends in Endocrinology & Metabolism</em>, 20(10), 477-482.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Morani, A., Warner, M., & Gustafsson, J. Å. (2008). Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. <em>Journal of internal medicine</em>, 264(2), 128-142.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Oride, A., Kanasaki, H., Tumurbaatar, T., Zolzaya, T., Okada, H., Hara, T., et al. (2020). Effects of the Fertility Drugs Clomiphene Citrate and Letrozole on Kiss-1 Expression in Hypothalamic Kiss-1-Expressing Cell Models. <em>Reproductive sciences (Thousand Oaks, Calif.)</em>, 27. doi:10.1007/s43032-020-00154-1.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Paterni, I., Granchi, C., Katzenellenbogen, J. A., & Minutolo, F. (2014). Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. <em>Steroids</em>, 90, 13-29.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Sutaria, U., Crooke, A., Bertrand, P., & Hodgson, C. (1980). Clomiphene citrate and human chorionic gonadotropin in the treatment of anovulatory infertility. <em>International Journal of Gynecology & Obstetrics</em>, 18(6), 435-437.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Taheripanah, R., Kabir-Salmani, M., Favayedi, M., Zamaniyan, M., Malih, N., & Taheripanah, A. (2020). Effects of clomiphene citrate plus estradiol or progesterone on endometrial ultrastructure: An RCT. <em>International Journal of Reproductive BioMedicine</em>, 18(3), 201.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Trost, L. W., & Khera, M. (2014). Alternative treatment modalities for the hypogonadal patient. <em>Current urology reports</em>, 15(7), 1-12.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Wahab, O. A., Princely, A. C., Oluwadamilare, A. A., Ore-Oluwapo, D. O., Blessing, A. O., & Alfred, E. F. (2019). Clomiphene citrate ameliorated lead acetate-induced reproductive toxicity in male Wistar rats. <em>JBRA assisted reproduction</em>, 23(4), 336-343. doi:10.5935/1518-0557.20190038.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Welboren, W.-J., Sweep, F. C., Span, P. N., & Stunnenberg, H. G. (2009). Genomic actions of estrogen receptor?: what are the targets and how are they regulated? <em>Endocrine-related cancer</em>, 16(4), 1073.</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"> </p>
2016-11-29T18:41:282022-02-28T23:08:11Increased, secretion of GnRH from hypothalamusIncreased, secretion of GnRH from hypothalamusCellularCL:0011111gonadotropin releasing neuron2016-11-29T18:41:292017-09-16T10:17:06Increased, secrection of FSH from anterior pituitaryIncreased, secrection of FSH from anterior pituitaryCellular2016-11-29T18:41:292016-12-03T16:37:52Increased, secretion of LH from anterior pituitaryIncreased, secretion of LH from anterior pituitaryCellular2016-11-29T18:41:292016-12-03T16:37:52Hyperplasia, ovarian stromal cellsHyperplasia, ovarian stromal cellsCellularCL:0002132stromal cell of ovary2016-11-29T18:41:292017-09-16T10:17:06Hyperplasia, ovarian epitheliumHyperplasia, ovarian epitheliumTissueUBERON:0004911epithelium of female gonad2016-11-29T18:41:292017-09-16T10:17:06Promotion, ovarian adenomasPromotion, ovarian adenomasTissue2016-11-29T18:41:292016-12-03T16:37:52Promotion, ovarian granular cell tumorsPromotion, ovarian granular cell tumorsCellular2016-11-29T18:41:292016-12-03T16:37:52Decrease, E2 blood concentrations at hypothalamusDecrease, E2 blood concentrations at hypothalamusTissueUBERON:0000178blood2016-11-29T18:41:292017-09-16T10:17:07fcecd37e-a0f7-4c40-bd4c-13008b58ac3253b896fe-0222-430b-b791-5c737c99e8da2016-11-29T18:41:362016-12-03T16:38:03cc254f56-80ac-4fb1-9ff0-0f6ecd3dcebe53b896fe-0222-430b-b791-5c737c99e8da2016-11-29T18:41:362016-12-03T16:38:0353b896fe-0222-430b-b791-5c737c99e8da60f04386-b177-4972-9835-99e541e419592016-11-29T18:41:362016-12-03T16:38:0360f04386-b177-4972-9835-99e541e419599f1091b2-8710-4724-af2f-bb36aaeef1792016-11-29T18:41:362016-12-03T16:38:0360f04386-b177-4972-9835-99e541e41959e330b5cb-ae9d-49a0-80ca-dddc592c9081<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">The release of gonadotrophin-releasing hormone (GnRH) stimulate the secretion of luteinising hormone (LH) </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Fields et al., 2009)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. GnRH causes the pituitary gland to secrete LH. Gonadotropin releasing hormone (GnRH) is the key regulator of the secretion of luteinising hormone </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Marques et al., 2018; Bowen et al., 1998; Tsutsumi and Webster, 2009)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. Metastin or kisspeptin in the control of gonadotropin-releasing hormone (GnRH) release and then it causes for pulsatile release of luteinizing hormone</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Ohkura et al., 2009)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. </span></span></span></span></p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Gonadotropin-releasing hormone (GnRH) is the master hormone for regulating the reproduction. GnRH pulses stimulate the synthesis and secretion of LH from the anterior pituitary</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Tsutsumi and Webster, 2009)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">.</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Nicol et al., reported that high GnRH dose enhances the secretion of LH </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Nicol et al., 2002)</span></span></span></span></li>
</ul>
<p><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH was isolated from porcine hypothalamus. It was structurally identified as a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly·NH2)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(AV et al., 971)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. During the childhood, GnRH levels are low but as </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri","sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">puberty </span></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">begins. GnRH levels start to rise and when the </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri","sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">testes </span></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">and </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri","sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">ovaries </span></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">are fully developed. GnRH regulates LH and these hormones to control the production of sex hormones in adult </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Marques et al., 2018)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. GnRH secretion have been described in pulsatile (in minutes) and surge modes. Pulsatile mode refers to episodic release of GnRH while the surge mode of GnRH secretion occurs in females during the pre-ovulatory phase </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Maeda et al., 2010)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">. Secretion of LH is also in pulsatile nature ( in hrs)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Bolt, 1971)</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">.</span></span></p>
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Compound class</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Species</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Study type</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Dose</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">KER findings</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Reference</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Cows</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">In-vivo</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH dose of 100 micro gram</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH dose increases LH secration</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Fields et al., 2009)</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Possums</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">In-vivo</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
<p> </p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH dose increases LH secration</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Crawford et al., 2009)</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bitches</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">In-vivo</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH dose of 06.-2.4 microgram/kg</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH dose increases LH secration</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Concannon et al., 2006)</span></span></span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH agonist (triptorelin acetate) dose </span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Humans</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">In-vivo</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH dose of 3.75 mg / person</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">GnRH agonist (triptorelin acetate) dose decrease LH seccretion</span></span></span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
<p><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Sonntag et al., 2005)</span></span></span></span></p>
</td>
</tr>
</tbody>
</table>
<p>Not Specified</p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Fields et al., studied the dose response of GnRH (100 micro gram) on cows and observed greater release of LH (25 %) aftrer 12-18 hours </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Fields et al., 2009)</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Crawford et al., used PCR techniques to study the effect of GnRH on LH in vivo on Possums. They reported the increase of LH quantitavely in absence of pulse of LH</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Crawford et al., 2009)</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Guillaume et al., studied the two GnRH antagonist Antarelix and Cetrorelix (0.01 mg/kg) on mare and observed that there is strong suppression of LH </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Guillaume et al., 2002)</span></span></span></span></li>
<li><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Washington et al., developed one mathematical model for the respose of LH under the pulsatile and continuous exposure of GnRH </span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Washington et al., 2004</span></span></span></span></li>
<li><span style="font-size:11.0pt"><span style="font-family:"Calibri","sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Shoemaker</span></span></span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif""> et al., developed a mathematical model on steroidogenesis in the fathead minnow. They quantified the relationship between GnRH and LH</span></span><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">(Shoemaker et al., 2010)</span></span></li>
</ul>
HighFemaleLowMaleHighAdult, reproductively matureHighHighHighLow<p>Adult</p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Adashi, E., Hsueh, A., & Yen, S. (1980). Alterations induced by clomiphene in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus of female rats. <em>Journal of Endocrinology</em>, 87(3), 383-392.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">AV, S., A, A., AJ, K., H, M., Y, B., TW, R., et al. (971). Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing. <em>Science</em>, 173(4001), 1036-38. doi:doi: 10.1126/science.173.4001.1036.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Berger, H., Nikolics, K., Szöke, B., & Mehlis, B. (1983). Proteolytic degradation of gonadotropin-releasing hormone (GnRH) by rat ovarian fractions in vitro. <em>Peptides</em>, 4(6), 821-825.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bharti, S., Misro, M., & Rai, U. (2013). Clomiphene citrate potentiates the adverse effects of estrogen on rat testis and down-regulates the expression of steroidogenic enzyme genes. <em>Fertility and sterility</em>, 99(1), 140-148. e5.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bolt, D. J. (1971). Changes in the concentration of luteinizing hormone in plasma of rams following administration of oestradiol, progesterone or testosterone. <em>J Reprod Fertil. </em>, 24(3), 435-38.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Botte, M., Lerrant, Y., Lozach, A., Berault, A., Counis, R., & Kottler, M. (1999). LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis. <em>Journal of Endocrinology</em>, 162(3), 409-415.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bowen, J. M., Dahl, G. E., Evans, N. P., Thrun, L. A., Wang, Y., Brown, M. B., et al. (1998). Importance of the gonadotropin-releasing hormone (GnRH) surge for induction of the preovulatory luteinizing hormone surge of the ewe: dose-response relationship and excess of GnRH. <em>Endocrinology</em>, 139(2), 588-595.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Bussenot, I., Parinaud, J., Clamagirand, C., Vieitez, G., & Pontonnier, G. (1990). Effect of clomiphene cirate on oestrogen secretion by human granulosa cells in culture. <em>Human Reproduction</em>, 5(5), 533-536.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Concannon, P. W., Temple, M., Montanez, A., & Newton, L. (2006). Effects of dose and duration of continuous GnRH-agonist treatment on induction of estrus in beagle dogs: competing and concurrent up-regulation and down-regulation of LH release. <em>Theriogenology</em>, 66(6-7), 1488-96. doi:S0093-691X(06)00095-1 [pii]</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">10.1016/j.theriogenology.2006.02.007.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Crawford, J. L., Heath, D. A., Haydon, L. J., Thomson, B. P., & Eckery, D. C. (2009). Gene expression and secretion of LH and FSH in relation to gene expression of GnRH receptors in the brushtail possum (Trichosurus vulpecula) demonstrates highly conserved mechanisms. <em>Reproduction</em>, 137(1), 129-40. doi:REP-08-0347 [pii]</span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">10.1530/REP-08-0347.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Fields, S. D., Perry, B. L., & Perry, G. A. (2009). Effects of GnRH treatment on initiation of pulses of LH, LH release, and subsequent concentrations of progesterone. <em>Domest Anim Endocrinol</em>, 37(4), 189-95. doi:S0739-7240(09)00038-1 [pii]</span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">10.1016/j.domaniend.2009.04.006.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Garrido-Gracia, J. C., Bellido, C., Aguilar, R., & Sanchez-Criado, J. E. (2006). Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion. <em>J Physiol Biochem</em>, 62(1), 35-42. doi:10.1007/BF03165804.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Guillaume, D., Bruneau, B., & Briant, C. (2002). Comparison of the effects of two GnRH antagonists on LH and FSH secretion, follicular growth and ovulation in the mare. <em>Reprod Nutr Dev</em>, 42(3), 251-64. doi:10.1051/rnd:2002023.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Kenealy, B., Keen, K., & Terasawa, E. (2011). Rapid action of estradiol in primate GnRH neurons: the role of estrogen receptor alpha and estrogen receptor beta. <em>Steroids</em>, 76(9), 861-866.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">KERIN, J. F., LIU, J. H., PHILLIPOU, G., & Yen, S. (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. <em>The Journal of Clinical Endocrinology & Metabolism</em>, 61(2), 265-268.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Kumar, A., & Pakrasi, P. L. (1995). Estrogenic and antiestrogenic properties of clomiphene citrate in laboratory mice. <em>Journal of Biosciences</em>, 20(5), 665-673.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Maeda, K., Ohkura, S., Uenoyama, Y., Wakabayashi, Y., Oka, Y., Tsukamura, H., et al. (2010). Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. <em>Brain Res. </em>, 10, 103-115.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Marques, P., Skorupskaite, K., George, J. T., & Anderson, R. A. (2018). Physiology of GNRH and gonadotropin secretion. <em>Endotext [Internet]</em>.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Nicol, L., McNeilly, J. R., Stridsberg, M., Crawford, J. L., & McNeilly, A. S. (2002). Influence of steroids and GnRH on biosynthesis and secretion of secretogranin II and chromogranin A in relation to LH release in LbetaT2 gonadotroph cells. <em>J Endocrinol</em>, 174(3), 473-83. doi:JOE04823 [pii]</span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">10.1677/joe.0.1740473.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Ohkura, S., Uenoyama, Y., Yamada, S., Homma, T., Takase, K., Inoue, N., et al. (2009). Physiological role of metastin/kisspeptin in regulating gonadotropin-releasing hormone (GnRH) secretion in female rats. <em>Peptides</em>, 30(1), 49-56.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Shoemaker, J. E., Gayen, K., Garcia-Reyero, Natà l., Perkins, E. J., Villeneuve, D. L., Liu, L., et al. (2010). Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. <em>BMC Systems Biology</em>, 4(1), 89. doi:10.1186/1752-0509-4-89.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Sonntag, B., Kiesel, L., Nieschlag, E., & Behre, H. M. (2005). Differences in serum LH and FSH levels using depot or daily GnRH agonists in controlled ovarian stimulation: influence on ovarian response and outcome of ART. <em>J Assist Reprod Genet</em>, 22(7-8), 277-83. doi:10.1007/s10815-005-5998-8.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Tsutsumi, R., & Webster, N. J. (2009). GnRH pulsatility, the pituitary response and reproductive dysfunction. <em>Endocrine journal</em>, 56(6), 729-737.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">Washington, T. M., Blum, J. J., Reed, M. C., & Conn, P. M. (2004). A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH. <em>Theor Biol Med Model</em>, 1, 9. doi:10.1186/1742-4682-1-9</span></span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,"sans-serif""><span style="font-size:12.0pt"><span style="font-family:"Segoe UI","sans-serif"">1742-4682-1-9 [pii].</span></span></span></span></p>
2016-11-29T18:41:362022-03-01T06:01:159f1091b2-8710-4724-af2f-bb36aaeef179796f35f4-3ff6-4998-9ca7-81dd0ba8e9d92016-11-29T18:41:362016-12-03T16:38:039f1091b2-8710-4724-af2f-bb36aaeef179848445a2-d5ca-4d33-a17c-865805c07d782016-11-29T18:41:362016-12-03T16:38:03e330b5cb-ae9d-49a0-80ca-dddc592c9081796f35f4-3ff6-4998-9ca7-81dd0ba8e9d92016-11-29T18:41:362016-12-03T16:38:03848445a2-d5ca-4d33-a17c-865805c07d78e47c6dc3-eae9-4c0f-9df8-388b9cd18b462016-11-29T18:41:362016-12-03T16:38:03796f35f4-3ff6-4998-9ca7-81dd0ba8e9d91af0ee92-ab6d-43e6-a13f-9c108e38a1662016-11-29T18:41:362016-12-03T16:38:03Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouseAntiestrogens and ovarian adenomas/granular cell tumors<p>Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)</p>
Under Development: Contributions and Comments WelcomeUnder Development1.29<p>This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.</p>
adjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighnon-adjacentNot SpecifiedHighnon-adjacentNot SpecifiedModeratenon-adjacentNot SpecifiedModeratenon-adjacentNot SpecifiedHighnon-adjacentNot SpecifiedHighnon-adjacentNot SpecifiedHighHighFemaleModerateHighNot SpecifiedNot SpecifiedNot Specified<p>1. Capen, C. C. (2004). Mechanisms of hormone-mediated carcinogenesis of the ovary. Toxicologic pathology 32 Suppl 2, 1-5.</p>
<p>2. Cohen, I. R., Sims, M. L., Robbins, M. R., Lakshmanan, M. C., Francis, P. C., and Long, G. G. (2000). The reversible effects of raloxifene on luteinizing hormone levels and ovarian morphology in mice. Reproductive toxicology 14(1), 37-44.</p>
<p>3. Long, G. G., Cohen, I. R., Gries, C. L., Young, J. K., Francis, P. C., and Capen, C. C. (2001). Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator. Toxicologic pathology 29(6), 719-26.</p>
2016-11-29T18:41:172023-04-29T16:02:58