API

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Relationship: 2580

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

Suppression, Estrogen receptor (ER) activity leads to Increased, secretion of GnRH from hypothalamus

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Suppression, Estrogen receptor (ER) activity
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased, secretion of GnRH from hypothalamus

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 Not Specified 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 Do not cite Under Development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 Low

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

Study on female human patient had shown Selective Estrogen Receptors Modulator (Clomiphene) act on the hypothalamic site and increase the hypothalamic GnRH secretion significantly (KERIN et al., 1985). Study on female rat had shown increased gonadotropin hormone secretion upon administration of very low dose (1-100 ng/kg) of clomiphene citrate. However, high dose (1µg/kg -2 mg/kg) of clomiphene citrate in female rat inhibit the gonadotropin hormone secretion (Koch et al., 1971).

Estradiol i.e. Estrogen receptor beta acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion (Hu et al., 2008). ESR2 control the GnRH release through the intracellular calcium ions release (Kenealy et al., 2011). Research had shown that nanomolar concentration of membrane-associated G protein-coupled estrogen receptor alter the patterns of Ca2+ release in GnRH neurone (Komatsuzaki and Kawato, 2007). Studies on mouse have shown several molecules such as, eastradiol, non-peptide neurotransmitters, gasotransmitters can modulate the GnRH neuron activity and GnRH secretion and control the reproductive functions (Spergel, 2019; Temple et al., 2004; Temple and Wray, 2005).

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

The release GnRH neurons depends on the concentration of the Selective Estrogen Receptors Modulator compound (Clomiphene). Scientific reports have shown the both stimulatory and inhibitory effects on the GnRH secretion exhibited by the estradiol depending on the concentration of clomiphene molecules and presence of types of receptors (Chu et al., 2009; Micevych and Kelly, 2012; Boyar, 1970).

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

GnRH secretion from the neurone can be modulated by prostaglandin, glutamate, ATP, carbon monoxide, nitric oxide, neurotransmitters (norepinephrine, epinephrine, GABA, histamine and acetylcholine) (Spergel, 2019).

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

Negative feedback action on GnRH secretion had shown in female guinea pig (Kelly et al., 1984).

Reduced firing of GnRH neurone was shown in adult female mice (Chu et al., 2009).

Alterations in the concentrations of oestrogen receptors in the hypothalamus was shown in rat (Adashi et al., 1980).

Negative Feedback of estrogen on GnRH secretion was studied in adult woman (Shaw et al., 2010).