API

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Relationship: 2583

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increased, estrogens leads to Increased, circulating estrogen levels

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Increased, estrogens
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased, circulating estrogen levels

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia adjacent High Moderate Cataia Ives (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 Do not cite Under Development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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mice Mus sp. High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High
Male High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult, reproductively mature High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Ovaries are the principle source of estrogen hormone in premenopausal women. This estrogen functions as a circulating hormone to act on different tissues. In postmenopausal women, estrogen is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. The monthly menstrual cycle in female is controlled through unique co-ordination between secreted hormones by the hypothalamus, the pituitary gland, and the ovary. Estrogen is synthesized from androgen, upon calalysis of aromatse enzyme present in the endoplasmic reticulam of the cells. Presence of aromatase enzyme is found majorly in the ovarian granulosa cells (premenopausal female), in the skin and adipose tissue (postmenopausal woman). Estrogen was synthesized in postmenopausal women due to the aromatization of steroids, found in the adipose and skin tissue.

Aromatase is a key enzyme for estrogen formation in human tissues. In men and postmenopausal women C19 steroids undergoes aromatization in different tissues (e.g. skin, adipose) to generate estrogen. In men, testicular steroidogenesis accounts for 15% of the circulating level of estrogen.

In women, the ovarian granulosa cells are important sites of estrogen formation for local use within the ovary as well as for endocrine signalling to the target tissues (e.g. uterus, skin, breast, brain, bone). In case of postmenopausal female, ovarian aromatase expression is stopped, but estrogen level is maintained in the plasma by the increased aromatase expression in other tissues (adipose and skin). Research had shown elevated circulating estradiol may persist at sufficient levels to cause postmenopausal uterine bleeding, endometrial hyperplasia, and even cancer.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Leung et al., had shown estradiol-17β (I mg) administration in the female rat for 3 days decrease the ovarian androgen levels (13 ± 2 pg/mg) compared to the control  (34 ± 7 pg/mg). Results of the study suggest estrogen levels controlled by the negative feedback loop of testosterone production (Leung et al., 1978).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Estrogen levels changes due to the following reasons.

  • High androgen levels caused by tumors
  • Androgen therapy
  • Elevations in estrogen due to aromatization
  • Obesity with increased tissue production of E1
  • Decreased estrogen clearance in liver disease
  • Estrogen producing tumors
  • Estrogen ingestion

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Judd et al, had measured the circulating estrogen level in the male and female lizards (Iguana iguana) (Judd et al., 1976).

Roberts et al., had estimated the circulating estrogen in the plasma collected from human volunteer (Roberts and Szego, 1946).

Truan et al., had shown the high circulating estrogen levels in the mice model  (Truan et al., 2010).