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Relationship: 3471

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

Plasma estradiol/progesterone ratio, increase leads to Increased E2 availability

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Plasma estradiol/progesterone ratio, increase
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased E2 availability

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
Decreased, GnRH pulsatility/release leading to estradiol availability, increased via impaired ovulation adjacent Travis Karschnik (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 Do not cite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 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
mammals mammals NCBI

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adults

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

In both rodents and human, estrogens produced from the developing follicles stimulate endometrial growth, and progesterone is responsible for converting the estrogen primed endometrium into a receptive state. In rodents, if pregnancy does not occur, diestrous (secretory phase in humans, cycle days 15–28) terminates with regression of the corpus luteum, and the endometrium is resorbed (menstruation in humans, cycle days 1–5). During proestrous (proliferative phase in humans, cycle days 6–14) follicles develop and start to produce estrogens that stimulate endometrial growth. During estrous (peri-ovulatory period in humans, cycle days 13–15) ovarian follicles mature. The magnitude of uterine growth stimulation is largely dependent upon the duration of bioavailable E2 and receptor interaction (Groothius et al., 2007).

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

The development of the KER is based on structured literature review of records. Description for KER is based on reviews and books on the topic. The method used are described in Annex B.1.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological relationship between these two KEs is considered strong. There is no doubt that a prolonged increased circulating E2/P4 ratio leads to an increase of E2 bioavailability in a variety of estrogenic-responsive organs, including uterus due to insufficient counterbalance by progesterone. However, compensatory mechanisms (e.g., intracrine networks) may differ across different tissues.  The degree to which E2/P4 ratio should increase to overwhelm these compensatory responses has not been established.

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

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
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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

References

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