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Increased, circulating estrogen levels leads to Hyperplasia, ovarian epithelium
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Hypothalamic estrogen receptors inhibition leading to ovarian cancer||non-adjacent||High||Not Specified||Kalyan Gayen (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
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 Supporting this KER
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).
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
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).
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).
Observed in months to years
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Increase in circulating estrogen level causing increase in the ovarian stromal cells observed in adult female (human) also in rabbit and rodents.
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:https://doi.org/10.1002/1097-0142(195705/06)10:3<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). 17Î²-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.