25614-03-3 OZVBMTJYIDMWIL-AYFBDAFISA-N OZVBMTJYIDMWIL-AYFBDAFISA-N Bromocriptine Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'α)- 2-Bromoergocriptine 2-Bromoergocryptine 2-Bromo-α-ergocryptine 2-Bromo-α-ergokryptine Bromergocryptine Bromocriptin bromocriptina Bromocryptine Bromoergocryptine Ergocryptine, 2-bromo- Sandoz 15-754 α-Bromocryptine α-Bromoergocryptine DTXSID1022687 CHEBI:81580 CHEBI Prolactin CHEBI:17026 CHEBI progesterone CL:0002656 CL glandular cell of endometrium CL:0000150 CL glandular epithelial cell D000236 MESH Adenoma D002277 MESH Carcinoma PR:000007204 PR estrogen receptor GO:0001963 GO synaptic transmission, dopaminergic GO:0042701 GO progesterone secretion MP:0009092 MP endometrium hyperplasia D006965 MESH hyperplasia GO:0030284 GO estrogen receptor activity GO:0048018 GO receptor agonist activity 1 WIKI increased 2 WIKI decreased Bromocriptine 2016-11-29T18:42:27 2016-11-29T18:42:27 WikiUser_17 mammals WikiUser_19 ApacheUser rodentia WikiUser_28 Vertebrates 10116 NCBI Rattus norvegicus Increase, Dopaminergic activity Cellular CL:0000700 CL dopaminergic neuron AOPWiki 2016-11-29T18:41:26 2017-09-16T10:16:09 Decreased, Prolactin Tissue UBERON:0000178 UBERON blood AOPWiki 2016-11-29T18:41:26 2017-09-16T10:16:09 Decreased, Progesterone from corpus luteum Tissue <p>This key event is commonly measured using the E2/P4 ratio. </p> UBERON:0002512 UBERON corpus luteum AOPWiki 2016-11-29T18:41:26 2017-09-16T10:16:09 Increase, Hyperplasia (glandular epithelial cells of endometrium) Cellular <p style="text-align:justify">Endometrial hyperplasia is a proliferation of endometrial glands characterized by an increase in the gland-to-stroma ration when compared with normal proliferative endometrium.</p> <p>In 2014 the World Health Organization (WHO) updated their classification system to include two categories (Kurman 2014).</p> <ol> <li><strong>Hyperplasia without atypia</strong> &ndash; an overgrowth of endometrial cells that still appear relatively normal and are less likely to develop into cancer.</li> <li><strong>Atypical hyperplasia</strong> &ndash; an abnormal epithelial cell proliferation that is not extensive enough to be classified as carcinoma in situ.&nbsp; It is considered a non-cancerous, or benign, condition but is also a high-risk lesion for the later development of breast cancer</li> </ol> <p>OECD (2007), <em>Test No. 440: Uterotrophic Bioassay in Rodents: A short-term screening test for oestrogenic properties</em>, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris, <a href="https://doi.org/10.1787/9789264067417-en">https://doi.org/10.1787/9789264067417-en</a></p> <ul> <li>Hematoxylin and Eosin staining to visualize the cellular and architectural changes indicative of hyperplasia.</li> <li>Immunohistochemistry staining by using specific antibodies to identify abnormal or increased levels of certain proteins.</li> <li>Morphometry to conduct quantitaive analysis of tissue features.</li> </ul> <p><u>Taxonomic&nbsp;Applicability</u></p> <p>Endometrial hyperplasia is well established in human gynecology but has also been measured in:</p> <ul> <li>Dogs and Cats (Schlafer &amp; Foster 2016 and Potter et al., 1991)</li> <li>Chinchilla (Granson et al., 2011)</li> <li>Pigs (Wood et al., 2020)</li> <li>Wild canids (Asa et al., 2014)</li> </ul> <p>It plausibly applies to all mammals.&nbsp;</p> <p><u>Lifestage&nbsp;Applicability</u></p> <p>In humans, endometrial hyperplasia has been shown to occur from reproductive age (19-39) through peri and post-menopausal stages (Takai et al., 2016 and Reed et al., 2009), with incidence in younger women possibly related to symptomatic uterine conditions.</p> <p><u>Sex Applicability</u></p> <p>Endometrial hyperplasia is a female only condition, as it affects the endometrium, which the lining of the uterus.</p> UBERON:0001295 UBERON endometrium CL:0002656 CL glandular cell of endometrium High Female High Adult, reproductively mature High Adult High High <p>Asa, C. S., Bauman, K. L., Devery, S., Zordan, M., Camilo, G. R., Boutelle, S., &amp; Moresco, A. (2014). Factors associated with uterine endometrial hyperplasia and pyometra in wild canids: implications for fertility. Zoo Biology, 33(1), 8-19.</p> <p>Granson, H. J., Carr, A. P., Parker, D., &amp; Davies, J. L. (2011). Cystic endometrial hyperplasia and chronic endometritis in a chinchilla. Journal of the American Veterinary Medical Association, 239(2), 233-236.</p> <div>Kurman, R. J., Carcangiu, M. L., Herrington, C. S., &amp; Young, R. H. (2014). WHO classification of tumours of the female reproductive organs (IARC WHO classification of tumours). World Health Organization, 1-309.</div> <div>&nbsp;</div> <p>Potter, K., Hancock, D. H., &amp; Gallina, A. M. (1991). Clinical and pathologic features of endometrial hyperplasia, pyometra, and endometritis in cats: 79 cases (1980-1985). Journal of the American veterinary medical association, 198(8), 1427-1431.</p> <p>Reed, S. D., Newton, K. M., Clinton, W. L., Epplein, M., Garcia, R., Allison, K., ... &amp; Weiss, N. S. (2009). Incidence of endometrial hyperplasia. American journal of obstetrics and gynecology, 200(6), 678-e1.</p> <p>Schlafer, D. H., &amp; Foster, R. A. (2016). Female genital system. Jubb, Kennedy &amp; Palmer&#39;s Pathology of Domestic Animals: Volume 3, 358.</p> <p>Takai, I. U., Bukar, M., Mayun, A. A., Ugwa, E. A., Audu, B. M., &amp; Abdurrahman, A. (2016). Endometrial hyperplasia: A-2 decade retrospective analysis of histopathological pattern at a university teaching hospital in Northern Nigeria. Sub-Saharan African Journal of Medicine, 3(4), 171-175.</p> <p>Wood, P., Hall, J. L., McMillan, M., Constantino‐Casas, F., &amp; Hughes, K. (2020). Presence of cystic endometrial hyperplasia and uterine tumours in older pet pigs in the UK. Veterinary Record Case Reports, 8(1), e000924.</p> AOPWiki 2016-11-29T18:41:26 2025-09-18T15:31:48 Increase, Endometrial adenocarcinomas Tissue UBERON:0001295 UBERON endometrium AOPWiki 2016-11-29T18:41:26 2017-09-16T10:16:10 Agonism, Estrogen receptor Molecular <p>Site of action: The molecular site of action is the estrogen receptor (ER). ERs <a name="_Hlk162335835">are&nbsp;members of the steroid hormone receptor family which belongs to a group of nuclear receptors </a>that are transcriptionally activated by ligands leading to downstream activation of many cellular processes. ERs are composed of three principal domains &ndash; N-terminal domain (NTD), DNA binding domain (DBD), and the ligand binding domain (LBD). ER binds to specific DNA sequences known as estrogen response elements (EREs); EREs are generally short sequences located in the promoter region but can also exist in introns or exons (Klinge, 2001). ER-mediated gene transcription is initiated by binding of the DBD to an ERE with two distinct transcriptional activation domains, AF1 and AF2, located on the NTD and LBD respectively (Kumar et al., 2011).</p> <p>Responses at the macromolecular level: ER&rsquo;s bind to endogenous and exogenous compounds and are activated by endogenous ligands such as estrone (E1), estradiol (E2) and estriol (E3) (Ng et al., 2014). There are numerous compounds (e.g., natural or pharmaceutical estrogens, alkylphenols, organochlorine pesticides, phthalates, etc.) that can act as estrogen agonists or antagonists, and effectively mimic or block the natural effects of estrogens on the ER (Pillon et al., 2005; Schmieder et al., 2014).</p> <p>ER is part of a multi-protein complex consisting of HSP 90, HSP 70, and immunophilins (Stice &amp; Knowlton, 2008). In this multi-protein complex HSP 90 is the dominant protein and its binding to ER is essential for ER conformational binding of 17&beta;-estradiol (Segnitz &amp; Gehring, 1997). When binding on the LBD receptor occurs ER dissociates from HSP 90 and leads to receptor dimerization which can either be homodimers from the same isoform (ER&alpha;-Er&alpha;) or heterodimers containing one unit from both isoforms (ER&alpha;-Er&beta;) (Fliss et al., 2000). The translocation of these dimers into the nucleus modulates gene transcription (Aranda &amp; Pascual, 2001).</p> <ul> <li>OECD Test No. 455: Performance-based test guideline for stably transfected transactivation in vitro assays to detect estrogen receptor agonists and antagonists (OECD 2021).</li> <li>OECD Test No. 457: BG1Luc Estrogen Receptor Transactivation Test Method for Identifying Estrogen Receptor Agonists and Antagonists (OECD 2012).</li> <li>Standard Evaluation Procedure (SEP) for estrogen receptor transcriptional activation (Human Cell Line HeLa-9903) assay was developed by the U.S. Environmental Protection Agency (EPA).</li> <li>ER-based transactivation assays that have been used to detect ER agonists and antagonist using cell lines include T47D-Kbluc assay (Wehmas et al., 2011), the ER&alpha; CALUX assay (Van et al.); MELN assay (Berckmans et al., 2007); and the yeast estrogen screen (YES; (De Boever et al., 2001)). The T47D-Kbluc assay responds to both ER&alpha; and ER&szlig; agonists but support the assumption that ER&alpha; is inducing more reporter expression than ER&szlig;. Each of these assays have undergone some level of validation.</li> <li>Browne et al. (2015) integrated 18 ER ToxCast high-throughput screening (HTS) assays, measuring ER binding, dimerization, chromatin binding, transcriptional activation and ER-dependent cell proliferation, into the ToxCast ER pathway model. This mathematical model that in vitro assays to predict whether a chemical is an ER agonist or antagonist.</li> <li>OECD Test No. 440: Uterotrophic Bioassay in Rodents: A Short-Term Screenign Test for Oestrogenic Properties. OCED Publishing. 2018. has been used to detect in vivo estrogenic activity.</li> </ul> <p><a name="_Hlk165971069">Taxonomic applicability:</a> In mammals there are two ER subtypes, ER alpha (ER&alpha;) and ER beta (ER&beta;), which are located on chromosome 6 and 14 and encoded by two different genes (ESR1 and ESR2) <a name="_Hlk162433655"></a>(Ascenzi et al., 2006). ERs were conventionally identified as mammal specific, but most vertebrates contain functional ERs. However, although teleost fish have receptors homologous to mammilian ER&alpha;, ER&beta; is divided into ER&beta;1 and ER&beta;2 resulting in three distinct ERs (Asnake et al., 2019; Menuet et al., 2004; Menuet et al., 2002). The majority of invertebrates (i.e. mollusks) possess a gene that is the orthologue of the vertebrate ER but in many species it has been demonstrated to only have constitutive transcriptional activity, and is not activated by ligand binding (Balbi et al., 2019). However, ERs in annelids share functional characteristics with vertebrate ERs and its transcriptional activity can be disrupted by known endocrine-disrupting substances (Keay &amp; Thornton, 2009).</p> <p>This event would generally be viewed as relevant to vertebrates, but not invertebrates.</p> <p><a name="_Hlk165905099">Life stage:</a><a name="_Hlk165899451"> </a>This event is applicable to all life stages.</p> <p>Sex: This event is applicable to both sexes.</p> CL:0002371 CL somatic cell High Unspecific High Embryo High Fetal High Birth to < 1 month High Juvenile High Adult, reproductively mature High All life stages High High High <p>Aranda, A., &amp; Pascual, A. (2001). Nuclear hormone receptors and gene expression. Physiological reviews, 81(3), 1269-1304.</p> <p>Ascenzi, P., Bocedi, A., &amp; Marino, M. (2006). Structure&ndash;function relationship of estrogen receptor &alpha; and &beta;: Impact on human health. Molecular aspects of medicine, 27(4), 299-402.</p> <p>Asnake, S., Modig, C., &amp; Olsson, P.-E. (2019). Species differences in ligand interaction and activation of estrogen receptors in fish and human. The Journal of steroid biochemistry and molecular biology, 195, 105450.</p> <p>Balbi, T., Ciacci, C., &amp; Canesi, L. (2019). Estrogenic compounds as exogenous modulators of physiological functions in molluscs: Signaling pathways and biological responses. Comparative Biochemistry and Physiology Part C: Toxicology &amp; Pharmacology, 222, 135-144.</p> <p>Berckmans, P., Leppens, H., Vangenechten, C., &amp; Witters, H. (2007). Screening of endocrine disrupting chemicals with MELN cells, an ER-transactivation assay combined with cytotoxicity assessment. Toxicology in vitro, 21(7), 1262-1267.</p> <p>Browne, P., Judson, R. S., Casey, W. M., Kleinstreuer, N. C., &amp; Thomas, R. S. (2015). Screening Chemicals for Estrogen Receptor Bioactivity Using a Computational Model. Environmental Science &amp; Technology, 49(14), 8804-8814. <a href="https://doi.org/10.1021/acs.est.5b02641">https://doi.org/10.1021/acs.est.5b02641</a></p> <p>De Boever, P., Demar&eacute;, W., Vanderperren, E., Cooreman, K., Bossier, P., &amp; Verstraete, W. (2001). Optimization of a yeast estrogen screen and its applicability to study the release of estrogenic isoflavones from a soygerm powder. Environmental Health Perspectives, 109(7), 691-697.</p> <p>Fliss, A. E., Benzeno, S., Rao, J., &amp; Caplan, A. J. (2000). Control of estrogen receptor ligand binding by Hsp90. The Journal of steroid biochemistry and molecular biology, 72(5), 223-230.</p> <p>Keay, J., &amp; Thornton, J. W. (2009). Hormone-activated estrogen receptors in annelid invertebrates: implications for evolution and endocrine disruption. Endocrinology, 150(4), 1731-1738.</p> <p>Klinge, C. M. (2001). Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res, 29(14), 2905-2919. <a href="https://doi.org/10.1093/nar/29.14.2905">https://doi.org/10.1093/nar/29.14.2905</a></p> <p>Kumar, R., Zakharov, M. N., Khan, S. H., Miki, R., Jang, H., Toraldo, G., Singh, R., Bhasin, S., &amp; Jasuja, R. (2011). The dynamic structure of the estrogen receptor. Journal of amino acids, 2011.</p> <p>Menuet, A., Le Page, Y., Torres, O., Kern, L., Kah, O., &amp; Pakdel, F. (2004). Analysis of the estrogen regulation of the zebrafish estrogen receptor (ER) reveals distinct effects of ERalpha, ERbeta1 and ERbeta2. Journal of Molecular Endocrinology, 32(3), 975-986.</p> <p>Menuet, A., Pellegrini, E., Anglade, I., Blaise, O., Laudet, V., Kah, O., &amp; Pakdel, F. (2002). Molecular characterization of three estrogen receptor forms in zebrafish: binding characteristics, transactivation properties, and tissue distributions. Biology of reproduction, 66(6), 1881-1892.</p> <p>Ng, H. W., Perkins, R., Tong, W., &amp; Hong, H. (2014). Versatility or Promiscuity: The Estrogen Receptors, Control of Ligand Selectivity and an Update on Subtype Selective Ligands. International Journal of Environmental Research and Public Health, 11(9), 8709-8742. <a href="https://www.mdpi.com/1660-4601/11/9/8709">https://www.mdpi.com/1660-4601/11/9/8709</a></p> <p>Pillon, A., Boussioux, A.-M., Escande, A., A&iuml;t-A&iuml;ssa, S., Gomez, E., Fenet, H., Ruff, M., Moras, D., Vignon, F., &amp; Duchesne, M.-J. (2005). Binding of estrogenic compounds to recombinant estrogen receptor-&alpha;: application to environmental analysis. Environmental Health Perspectives, 113(3), 278-284.</p> <p>Schmieder, P. K., Kolanczyk, R. C., Hornung, M. W., Tapper, M. A., Denny, J. S., Sheedy, B. R., &amp; Aladjov, H. (2014). A rule-based expert system for chemical prioritization using effects-based chemical categories. SAR and QSAR in Environmental Research, 25(4), 253-287. <a href="https://doi.org/10.1080/1062936X.2014.898691">https://doi.org/10.1080/1062936X.2014.898691</a></p> <p>Segnitz, B., &amp; Gehring, U. (1997). The function of steroid hormone receptors is inhibited by the hsp90-specific compound geldanamycin. Journal of Biological Chemistry, 272(30), 18694-18701.</p> <p>Stice, J. P., &amp; Knowlton, A. A. (2008). Estrogen, NF&kappa;B, and the heat shock response. Molecular Medicine, 14, 517-527.</p> <p>Van, d., Winter, R., Weimer, M., Beckmanns, P., Suzuki, G., Gijsberg, L., Jonas, A., Van, d. W., Hilda, &amp; Aarts, J. Optimization and Prevalidation of the in Vitro ER CALUX Method to Test Estrogenic and Antiestrogenic Activity of Compounds.</p> <p>Wehmas, L. C., Cavallin, J. E., Durhan, E. J., Kahl, M. D., Martinovic, D., Mayasich, J., Tuominen, T., Villeneuve, D. L., &amp; Ankley, G. T. (2011). Screening complex effluents for estrogenic activity with the T47D‐KBluc cell bioassay: Assay optimization and comparison with in vivo responses in fish. Environmental toxicology and chemistry, 30(2), 439-445.</p> AOPWiki 2016-11-29T18:41:22 2025-09-11T15:13:57 AOPWiki 2016-11-29T18:41:35 2016-12-03T16:37:59 AOPWiki 2025-04-17T15:13:15 2025-04-17T15:13:15 AOPWiki 2025-04-17T15:13:28 2025-04-17T15:13:28 AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 AOPWiki 2016-11-29T18:41:35 2016-12-03T16:38:00 Dopaminergic activity- endometrial carcinoma Charles Wood <p>Cancer AOP group. 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> BY-SA 1.0 <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> adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified Not Specified Female Not Specified <p>Gunin, A. G., Emelianov, V., Tolmachev, A. S., &amp; Tolmacheva, A. (2002). Effect of prolactin and dopaminergic drugs on uterine response to chronic estrogen exposure. J Endocrinol, 172(1), 61-69.</p> <p>Harleman, J. H., Hargreaves, A., Andersson, H., &amp; Kirk, S. (2012). A review of the incidence and coincidence of uterine and mammary tumors in Wistar and Sprague-Dawley rats based on the RITA database and the role of prolactin. Toxicol Pathol, 40(6), 926-930. doi: 10.1177/0192623312444621</p> <p>O&#39;Connor, J. C., Plowchalk, D. R., Van Pelt, C. S., Davis, L. G., &amp; Cook, J. C. (2000). Role of prolactin in chloro-S-triazine rat mammary tumorigenesis. Drug Chem Toxicol, 23(4), 575-601. doi: 10.1081/DCT-100101972</p> AOPWiki 2016-11-29T18:41:16 2026-01-11T16:56:07