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Event: 2294

Key Event Title

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

Plasma estradiol, increased

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
Plasma E2, increased
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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
Cellular

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

Organ 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
Organ term
blood plasma

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
increased circulating estradiol level 17beta-estradiol increased

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
Aromatase induction leading to estrogen receptor alpha activation via increased estradiol KeyEvent Martina Panzarea (send email) Under development: Not open for comment. Do not cite
Activation, ERα leads to persistent vaginal cornification via increased kisspeptin KeyEvent John Frisch (send email) Under development: Not open for comment. Do not cite

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
mammals mammals Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult, reproductively mature Moderate
Juvenile Moderate

Sex Applicability

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

Increased plasma estradiol (E2) levels are generally due to increased secretion from organs, but can also be caused by birth control pills or hormone replacement therapy.  Estradiol is an 18-carbon steroid hormone (Zinn and Schell 2018).  In females, ovaries are a major source of estradiol, with production of E2 by the ovaries well-established by the two-cell, two gonadotropin model of steroid biosynthesis (for review see Drummond 2006; Kimura et al. 2007; Palermo 2007; Beevors et al. 2024). Luteinizing hormone stimulates steroid production in theca cells, with follicle-stimulating hormone stimulates steroid production in granulosa cells.

Table 1: List of steroid synthesis enzymes with identifier of enzyme (Uniprot, 2025).

Enzyme

Identifier

Steroidogenic acute regulatory protein, mitochondrial (STAR)

 

Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A)

EC:1.14.15.6

3 beta-hydroxysteroid dehydrogenase (3B-HSD)

EC:1.1.1.145

Steroid 17-alpha-hydroxylase (CYP17A1)

EC:1.14.14.19

17-beta-hydroxysteroid dehydrogenase (17B-HSD)

EC:1.1.1.105

Aromatase (CYP19A1)

EC:1.14.14.14

3-oxo-5-alpha-steroid 4-dehydrogenase 2 (SRD5A2)

EC:1.3.1.22

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

Estradiol can be measured via immunoassay, mass spectrometry or Western blotting (Rosner et al. 2013; studies that utilized this approach include Sashida and Johnson 1976; Spears et al. 1998; Li et al. 2008; Murray et al. 2008; Gan et al. 2024), and include commercially available ELISA kits (e.g. Neogen 402110 (non-species specific); ALPCO 11-ESTHU-E01 (human); Cayman Chemical 501890 (non-species specific)).  Mention of trade names or commercial products does not constitute endorsement or recommendation for use.  

Domain of Applicability

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

Life Stage: Adult, reproductively mature, juveniles.

Sex: Applies to both males and females as both sexes require signalling for hormone pathways.

Taxonomic: Primarily studied in laboratory rodents and humans.  Plausible for most mammals due to conserved hormone pathways regulating hypothalamus-pituitary-gonadal axis processes.  Plasma estradiol widespread among vertebrates, including mammals (Bondesson et al. 2015), birds (Hanlon et al. 2022), fish (Li et al. 2019), reptiles (Cruz-Cano et al. 2023), and amphibians (Bondesson et al. 2015).    

References

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

Beevors LI, Sundar S, Foster PA. 2024. Steroid metabolism and hormonal dynamics in normal and malignant ovaries. Essays in Biochemistry 68(4): 491-507.

Bondesson M, Hao R, Lin CY, Williams C, Gustafsson JA. 2015.  Estrogen receptor signaling during vertebrate development. Biochimica et Biophysica Acta 1849(2): 142-151. 

Cruz-Cano NB, Sanchez-Rivera UA, Alvarez-Rodriguez C, Cardenas-Leon M, Martinez-Torres M. 2023.  Sex steroid receptors in the ovarian follicles of the lizard Sceloporus torquatus. Zygote. 31(4): 386-392.

Drummond AE. 2006.  The role of steroids in follicular growth. Reproductive Biology and Endocrinology 4:16. 

Hanlon C, Ziezold CJ, Bedecarrats GY. 2022.  The Diverse Roles of 17β-Estradiol in Non-Gonadal Tissues and Its Consequential Impact on Reproduction in Laying and Broiler Breeder Hens. Frontiers in Physiology 13: 942790. 

Kimura S, Matsumoto T, Matsuyama R, Shiina H, Sato T, Takeyama K, Kato S. 2007. Androgen receptor function in folliculogenesis and its clinical implication in premature ovarian failure. Trends in Endocrinology and Metabolism 18(5): 183-189.

Li M, Sun L, Wang D. 2019.  Roles of estrogens in fish sexual plasticity and sex differentiation. General and Comparative Endocrinology 277: 9-16.

Murray AA, Swales AK, Smith RE, Molinek MD, Hillier SG, Spears N.  2008.  Follicular growth and oocyte competence in the in vitro cultured mouse follicle: effects of gonadotrophins and steroids. MHR-Basic Science of Reproductive Medicine 14(2): 75-83.

Palermo R. 2007. Differential actions of FSH and LH during folliculogenesis. Reproductive BioMedicine Online 15(3): 326-337.

Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME. 2013. Challenges to the measurement of estradiol: an endocrine society position statement. The Journal of Clinical Endocrinology and Metabolism. 98(4): 1376-1387.

Sashida T, Johnson DC. 1976.  Stimulation of the estrogen synthesizing system of the immature rat ovary by exogenous and endogenous gonadotropins. Steroids 27(4): 469-79. 

Spears N, Murray AA, Allison V, Boland NI, Gosden RG. 1998.  Role of gonadotrophins and ovarian steroids in the development of mouse follicles in vitro. Journal of Reproduction and Fertility 113(1): 19-26.

The UniProt Consortium.  UniProt: the Universal Protein Knowledgebase in 2025. https://www.uniprot.org/ (retrieved 2 November 2025).

Zinn S, Schnell M. 2018. Flexibility at the Fringes: Conformations of the Steroid Hormone β-Estradiol. ChemPhysChem 19(21): 2915-2920.

NOTE: Italics indicate edits from John Frisch January 2026.  A full list of updates can be found in the Change Log on the View History page.