This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 1046

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Suppression, Estrogen receptor (ER) activity

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
neuron

Organ term

Organ term
hypothalamus

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
estrogen receptor activity	estrogen receptor	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Antiestrogens and ovarian adenomas/granular cell tumors	KeyEvent	Charles Wood (send email)	Under Development: Contributions and Comments Welcome
Hypothalamic estrogen receptors inhibition leading to ovarian cancer	MolecularInitiatingEvent	Kalyan Gayen (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
rat	Rattus norvegicus	High	NCBI
mice	Mus sp.	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Not Otherwise Specified	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Estrogen receptors are produced in all vertebrates and located in either the cell cytoplasm or nucleus(Bondesson et al., 2015; Eick and Thornton, 2011). Estrogen receptors are localized either in cytoplasm, or on the cell surface.

Site of action: Stressors (e.g., clomiphene) act on neuronal cell in the hypothalamus, where it inhibits hypothalamic Estrogen Receptors selectively.

Responses at the macromolecular level: 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(Trost and Khera, 2014). 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.

Estrogen Receptor α: 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)

Estrogen Receptor β: 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). 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 clomiphene, tamoxifen, raloxifene etc.

Biological compartments: 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(Levin, 2009).

General role in biology: Estrogen receptors (both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) binds the estrogens to promote the the biological functions of estrogens. Depending upon a balance between ERα and ERβ activities in target organs, estrogen signaling is selectively stimulated or inhibited (Welboren et al., 2009). 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(Morani et al., 2008). ERα is present mainly in ovary (thecal cells) where as ERβ is found mainly in ovary (granulosa cells)(Paterni et al., 2014). ERα and ERβ is identical approximately 97% in the DNA-binding domain and approximately 56% in the ligand-binding domain(Dahlman-Wright et al., 2006).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Radioreceptor assay/The estrogen receptor binding assay (using Rat Uterine Cytosol): This assay identifies chemicals that have the potential to interact with the estrogen receptor (ER) in vitro. 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 (Freyberger et al., 2010).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Neuronal cell in Hypothalamus

References

List of the literature that was cited for this KE description. More help

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. J Endocrinol. , 87(3), 383-92.

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. Fertility and sterility, 99(1), 140-148. e5.

Bondesson, M., Hao, R., Lin, C.-Y., Williams, C., & Gustafsson, J.-Å. (2015). Estrogen receptor signaling during vertebrate development. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1849(2), 142-151.

Bussenot, I., Parinaud, J., Clamagirand, C., Vieitez, G., & Pontonnier, G. (1990). Effect of clomiphene cirate on oestrogen secretion by human granulosa cells in culture. Human Reproduction, 5(5), 533-536.

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. Pharmacological reviews, 58(4), 773-781.

Dominguez, R., & Micevych, P. (2010). Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. J Neurosci, 30(38), 12589-96. doi:30/38/12589 [pii]10.1523/JNEUROSCI.1038-10.2010.

Eick, G. N., & Thornton, J. W. (2011). Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology, 334(1-2), 31-38.

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. Reprod Toxicol, 30(1), 50-9. doi:S0890-6238(10)00003-1 [pii].

Kerin, J. F., Liu, J. H., Phillipou, G., & Yen, S. S. (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab. , 61(2), 65-68.

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. Fertil Steril. , 59(3), 532-38.

Koch, Y., Dikstein, S., Superstine, E., & Sulman, F. G. (1971). THE EFFECT OF PROMETHAZINE AND CLOMIPHENE ON GONADOTROPHIN SECRETION IN THE RAT. Journal of Endocrinology, 49(1), 13-17. doi:10.1677/joe.0.0490013.

Kurosawa, T., Hiroi, H., Momoeda, M., Inoue, S., & Taketani, Y. (2010). Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors αand β. Endocrine journal, 57(6), 517-521.

Levin, E. R. (2009). Plasma membrane estrogen receptors. Trends in Endocrinology & Metabolism, 20(10), 477-482.

Morani, A., Warner, M., & Gustafsson, J. Å. (2008). Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. Journal of internal medicine, 264(2), 128-142.

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. Reproductive sciences (Thousand Oaks, Calif.), 27. doi:10.1007/s43032-020-00154-1.

Paterni, I., Granchi, C., Katzenellenbogen, J. A., & Minutolo, F. (2014). Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids, 90, 13-29.

Sutaria, U., Crooke, A., Bertrand, P., & Hodgson, C. (1980). Clomiphene citrate and human chorionic gonadotropin in the treatment of anovulatory infertility. International Journal of Gynecology & Obstetrics, 18(6), 435-437.

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. International Journal of Reproductive BioMedicine, 18(3), 201.

Trost, L. W., & Khera, M. (2014). Alternative treatment modalities for the hypogonadal patient. Current urology reports, 15(7), 1-12.

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. JBRA assisted reproduction, 23(4), 336-343. doi:10.5935/1518-0557.20190038.

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? Endocrine-related cancer, 16(4), 1073.