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Relationship: 2585


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, circulating estrogen levels leads to Hyperplasia, ovarian epithelium

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 non-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 Do not cite Under Development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

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

Hyperplasia of the ovarian epithelial cells characterized by aggregates of tubular like structures or cleft lines. In the mammalian ovary tissue presence of germ cells surrounded by the somatic cells is known as follicles. During the oestrous cycle early stage follicles either go through atresia or ovaluation to produce mature egg for fertilization. With the age ovaries run out of follicles and female undergo menopause. Repetitive rupture and repair of the epithelium tissue of the ovarian cells causes genetic aberrations causing the abnormal growth of these cells ultimately leads towards hyperplasia (Bajwa et al., 2016).

Yamagata et al., studied that the increased estrogen were reflected in such target tissues proliferation, hyperplasia, atypical hyperplasia of the endometrium were observed in patients with ovarian tumors (Yamagata et al., 1989). Goad et al., had shown that unopposed estrogen drives the endometrial hyperplasia leads towards the progression of endometrial cancer in the uterine epithelium (Goad et al., 2018). During the menstrual cycle, epithelium tissue of the ovary proliferate under the influence of higher estrogenic level, and the increased mitotic activity is likely to enhance the risk of the mutation in the cells (Harvey A. Risch, 1998b).

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 Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Nash et al., had shown 50% increase in the growth rate of the epithelial ovarian cancer cell line (PE04) with the treatment of 17β-estradiol in vitro cell culture study (Nash et al., 1989).

Meissner et al., had shown the endometrial hyperplasias and cancers by excessive estrogenic stimulation in the female rabbit (Meissner et al., 1957).

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

There are many kinds of ovarian tumors that are related with the estrogen or androgen levels. Granulosa cell tumor and thecoma are well-known estrogen-producing tumors. Metastatic ovarian tumors often have androgen-producing stroma and that mucinous cystadenoma produces estrogens. Many other ovarian tumors also can produce sexual hormones in their stroma (Tanaka et al., 2004).

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

Ho et al., had shown that steroid hormones, primarily estrogens and progesterone, are implicated in ovarian carcinogenesis and estrogens favor neoplastic transformation of the ovarian surface epithelium (Ho, 2003).

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

Not specified

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Vuong  et al., had shown estrogen replacement therapy in the primary culture of the mouse ovarian surface epithelium cells increases the risk of ovarian cancer.  Study had demonstrated that exogenous estradiol accelerates the onset of ovarian cancer in mouse models via the ESR1 pathway to result in the down-regulation of a tumour suppressor gene (Vuong et al., 2017).

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

Observed in months to years

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

Not specified

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

Increase in circulating estrogen level causing  increase in the ovarian stromal cells observed in adult female (human) also in rabbit and rodents.


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

Bajwa, P., Nagendra, P., Nielsen, S., Sahoo, S., Bielanowicz, A., Lombard, J., et al. (2016). Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium. Oncotarget, 7. doi:10.18632/oncotarget.8468.

Goad, J., Ko, Y.-A., Kumar, M., Jamaluddin, M. F. B., & Tanwar, P. S. (2018). Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling. Carcinogenesis, 39(9), 1105-1116.

Ho, S.-M. (2003). Estrogen, progesterone and epithelial ovarian cancer. Reproductive Biology and Endocrinology, 1(1), 1-8.

Meissner, W. A., Sommers, S. C., & Sherman, G. (1957). Endometrial hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by estrogen. Cancer, 10(3), 500-509. doi:<500::AID-CNCR2820100312>3.0.CO;2-V.

Mirabolghasemi, G., & Kamyab, Z. (2017). Changes of the uterine tissue in rats with polycystic ovary syndrome induced by estradiol valerate. International journal of fertility & sterility, 11(1), 47.

Nash, J. D., Ozols, R. F., Smyth, J. F., & Hamilton, T. C. (1989). Estrogen and anti-estrogen effects on the growth of human epithelial ovarian cancer in vitro. Obstetrics and gynecology, 73(6), 1009-1016.

Nephew, K. P., Long, X., Osborne, E., Burke, K. A., Ahluwalia, A., & Bigsby, R. M. (2000). Effect of estradiol on estrogen receptor expression in rat uterine cell types. Biology of Reproduction, 62(1), 168-177.

Risch, H. A. (1998a). Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. Journal of the National Cancer Institute, 90(23), 1774-1786.

Risch, H. A. (1998b). Hormonal Etiology of Epithelial Ovarian Cancer, With a Hypothesis Concerning the Role of Androgens and Progesterone. JNCI: Journal of the National Cancer Institute, 90(23), 1774-1786. doi:10.1093/jnci/90.23.1774.

Tanaka, Y. O., Tsunoda, H., Kitagawa, Y., Ueno, T., Yoshikawa, H., & Saida, Y. (2004). Functioning Ovarian Tumors: Direct and Indirect Findings at MR Imaging. RadioGraphics, 24(suppl_1), S147-S166. doi:10.1148/rg.24si045501.

Vuong, N. H., Salah Salah, O., & Vanderhyden, B. C. (2017). 17β-Estradiol sensitizes ovarian surface epithelium to transformation by suppressing Disabled-2 expression. Scientific Reports, 7(1), 16702. doi:10.1038/s41598-017-16219-2.

Yamagata, S., Yamamoto, K., Tsuchida, S., Kawamura, N., Matsumoto, Y., Ueki, S., et al. (1989). Estrogen production in epithelial tumors of the ovary--clinical and endocrinological study in postmenopausal women. Nihon Sanka Fujinka Gakkai zasshi, 41(11), 1761-1768.