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Relationship: 2525

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

Ovarian follicle pool, reduced leads to irregularities, ovarian cycle

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Ovarian follicle pool, reduced
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
irregularities, ovarian cycle

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
Inhibition of ALDH1A (RALDH) leading to impaired fertility via disrupted meiotic initiation of fetal oogonia of the ovary adjacent Moderate Low 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 Do not cite Under Development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, mouse, rat human, mouse, rat High NCBI

Sex Applicability

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

Reduced ovarian reserve, meaning the finite pool of primordial follicles containing the immature oocytes, is leading to ovarian cycle irregularities. Cycle irregularities include disturbances of the ovarian cycle like shorter cycle and prolonged estrus and/or ovulation problems like deferred ovulation and anovulation. This KER is considered canonical information.

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

As mentioned, several chemotherapy agents damage ovarian reserve and disrupt folliculogenesis. However, it has been shown that regular menses can resume upon treatment cessation (Jacobson et al, 2016). Therefore, in this case reduced ovarian reserve did not lead to permanent irregularities of ovarian cycle. In a systematic review and meta-analysis investigating the connection between the ovarian reserve and the length of the menstrual cycle, studies are mentioned where reduced ovarian reserve markers did not associate with irregular menstrual cycles (Younis et al, 2020). Several factors affect the impact of chemotherapy on ovarian health in humans, including the age at the treatment, size of ovarian reserve at treatment, and treatment regimen. However, late side effects of chemotherapy often include amenorrhea, premature ovarian insufficiency, and infertility.

Menstrual irregularities can be caused by factors other than reduced ovarian reserve. The most common factor affecting cyclicity is HPO axis dysregulation causing hypothalamic amenorrhea (Hannon et al, 2014). Another example is the contraceptive pill that decreases gonadotropin secretion by the pituitary gland, leading to inhibition of folliculogenesis and amenorrhea. Changes in hormone levels produced by the pituitary gland have also been connected to shorter and anovulatory cycles (Xu et al, 2010). Another factor affecting cyclicity is the thyroid gland function. Thyroid function disturbances, like hypo and hyperthyroidism have been connected to menstrual disturbances (Berga & Naftolin, 2012).

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

The size of the ovarian reserve at the time of stressor exposure is a factor that can affect the response-response relationship of this KER. Therefore, age can also be a modulating factor, as observed in the animal study mentioned in table 1, where even though all treated rats exhibited reduction in the ovarian reserve, irregular cycles were only observed in the adult ones but not the immature ones (Mayer et al, 2002). In addition, chemotherapy effects on fertility tend to be more severe with increasing age due to a smaller ovarian reserve (Jacobson et al, 2016).

Changes in hormones can affect menstrual/estrus cyclicity, without being connected to the size of the ovarian reserve. For instance, experiencing stress has been shown to affect the hypothalamus-pituitary-adrenal axis (HPA) activity. A high body mass index (BMI) has been shown to affect sex hormone-binding globulin (SHBG), free androgen index (FAI), testosterone, and insulin levels. Smoking, although it can also affect the reserve, can cause hypoestrogenism. Therefore, stress, obesity and smoking can affect menstrual cyclicity and influence the response-response relationship of this KER (Bae et al, 2018).

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