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Relationship: 2584


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 stromal cells

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

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

Ovarian tumor termed as hyperplasia is characterized as enlarged ovary with increased numbers of corpora lutea and tertiary follicles. In some cases cystic/incompletely lutenised corpora lutea may also be observed. Ovarian tumors may contain Leydig cells and originate within the specific ovarian stroma cells (Sternberg and Roth, 1973). Studies on the female rats have shown increased hormonal levels (e.g. estradiol 17-β, progesterone, prolactin) in the plasma are causing the tumor formation in the ovarian granulosa cell (Long et al., 2001).

High levels of circulating estrogen in the plasma can produce tumors in the ovarian granulosa cells. Magnetic resonance (MR) imaging was used for the detection of the ovarian tumors directly (Tanaka et al., 2004). Eriksson et al., had shown the estrogen levels (1 pg/mL ±0.048) in men samples using gas chromatography - mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry(Eriksson et al., 2018). In another study the serum estradiol concentration ranges was determined (~20 - 80 pg/mL) in females during the early to mid-follicular phases of the menstrual cycle and before puberty (~ 20 pg/mL) (Carmina et al., 2019). Barr Fritcher et al., had found that the expression of estrogen receptor (ER) is proportional with age and diagnosed with atypical hyperplasia (Barr Fritcher et al., 2011).

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

Barr Fritcher et al., had studied the expression of estrogen receptors (ER) over 246 women with atypical hyperplasia and found that  87 (35%) had atypical ductal hyperplasia (ADH), 141 (57%) had atypical lobular hyperplasia (ALH), and 18 (7%) had both type of hyperplasia and also found the increasing ER expression in atypical hyperplasia with increasing age(Barr Fritcher et al., 2011).

In a diiferent study Shaaban et al., had shown the positive correlation between ER-α and cellular proliferation causing hyperplasia  with an increased risk of subsequent breast cancer development (Shaaban et al., 2002).

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

Estradiol is the most biologically active estrogen, primarily secreted by ovarian granulosa cells and the conversion of  estradiol to estrone occur with the action of 17β-hydroxysteroid dehydrogenase enzyme(Melmed et al., 2015).

Samavat, H. and M.S. Kurzer, found that in postmenopausal women endogenous estrogens are associated with breast cancer. But for premenopausal women this relationship has not been firmly established but it may possible during the menstrual cycle due to the large variations in hormone levels (Samavat and Kurzer, 2015).

Hankinson, S.E. and A.H. Eliassen, found that a positive association has been observed to the women with high levels of estrogen consistently with approximate two fold increases in invasive breast cancer risk(Hankinson and Eliassen, 2007).

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

Zhao et al., had shown serum estrogen concentration decreased to naormal level after three days of the removal of ovarian tumor (Zhiyi Zhao et al., 2019).

Montgomery et al., had reviewed the works on endometrial and mentioned that unopposed estrogen in woman taking the hormone replace therapy increase the risk of endometrial hyperplasia (Montgomery et al., 2004).

Travis et al., had suggested that circulating oestrogens have strong corelation with the increased risk of breast cancer in postmenopausal women (Travis and Key, 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

Regulation of gonadotropin secretion, Dysregulation of ovarian function,  Insulin-resistant hyperinsulinism, Modulation of androgen action (Rosenfield and Ehrmann, 2016).

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

Not specified

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

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

Wood, et al., had found that circulating estrogen level positively correlated with uterine width and stromal cell proliferation and negatively correlated with glandular epithelial proliferation and stromal compartments in the rodents (Wood et al., 2007).

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 rodents.


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

Barr Fritcher, E. G., Degnim, A. C., Hartmann, L. C., Radisky, D. C., Boughey, J. C., Anderson, S. S., et al. (2011). Estrogen receptor expression in atypical hyperplasia: lack of association with breast cancer. Cancer prevention research, 4(3), 435-444.

Carmina, E., Stanczyk, F. Z., & Lobo, R. A. (2019). Evaluation of hormonal status. Yen and Jaffe's Reproductive Endocrinology (pp. 887-915. e4). Elsevier.

Eriksson, A. L., Perry, J. R., Coviello, A. D., Delgado, G. E., Ferrucci, L., Hoffman, A. R., et al. (2018). Genetic determinants of circulating estrogen levels and evidence of a causal effect of estradiol on bone density in men. The Journal of Clinical Endocrinology & Metabolism, 103(3), 991-1004.

Hankinson, S. E., & Eliassen, A. H. (2007). Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk. The Journal of steroid biochemistry and molecular biology, 106(1-5), 24-30.

Long, G. G., Cohen, I. R., Gries, C. L., Young, J. K., Francis, P. C., & Capen, C. C. (2001). Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator. Toxicol Pathol, 29(6), 719-26. doi:10.1080/019262301753386031.

Melmed, S., Polonsky, K. S., Larsen, P. R., & Kronenberg, H. M. (2015). Williams Textbook of Endocrinology E-Book. Elsevier Health Sciences.

Montgomery, B. E., Daum, G. S., & Dunton, C. J. (2004). Endometrial hyperplasia: a review. Obstetrical & gynecological survey, 59(5), 368-378.

Nilsson, M. E., Vandenput, L., Tivesten, Å., Norlén, A.-K., Lagerquist, M. K., Windahl, S. H., et al. (2015). Measurement of a comprehensive sex steroid profile in rodent serum by high-sensitive gas chromatography-tandem mass spectrometry. Endocrinology, 156(7), 2492-2502.

Rosenfield, R. L., & Ehrmann, D. A. (2016). The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Endocrine reviews, 37(5), 467-520. doi:10.1210/er.2015-1104.

Samavat, H., & Kurzer, M. S. (2015). Estrogen metabolism and breast cancer. Cancer letters, 356(2), 231-243.

Schrader, E. A., Paterniti, T. A., & Ahmad, S. (2021). Lifestyle, nutrition, and risk of gynecologic cancers. Overcoming Drug Resistance in Gynecologic Cancers (pp. 23-48). Elsevier.

Schweikert, H. (2003). Estrogen in the male: nature, sources and biological effects. Encyclopedia of Hormones. Elsevier Inc. San Diego, California, S, 584, 587-589.

Shaaban, A. M., Sloane, J. P., West, C. R., & Foster, C. S. (2002). Breast cancer risk in usual ductal hyperplasia is defined by estrogen receptor-α and Ki-67 expression. The American journal of pathology, 160(2), 597-604.

Sternberg, W. H., & Roth, L. M. (1973). Ovarian stromal tumors containing Leydig cells. I. Stromal-Leydig cell tumor and non-neoplastic transformation of ovarian stroma to Leydig cells. Cancer, 32(4), 940-51. doi:10.1002/1097-0142(197310)32:4<940::aid-cncr2820320428>;2-5.

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, 147-166.

Travis, R. C., & Key, T. J. (2003). Oestrogen exposure and breast cancer risk. Breast Cancer Research, 5(5), 1-9.

Wood, G. A., Fata, J. E., Watson, K. L., & Khokha, R. (2007). Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus. Reproduction, 133(5), 1035-1044.

Zhao, H., Zhou, L., Shangguan, A. J., & Bulun, S. E. (2016). Aromatase expression and regulation in breast and endometrial cancer. Journal of molecular endocrinology, 57(1), R19.

Zhao, Z., Yan, L., Lv, H., Liu, H., & Rong, F. (2019). Sclerosing stromal tumor of the ovary in a postmenopausal woman with estrogen excess: A case report. Medicine, 98(47).