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Increased, circulating estrogen levels leads to Hyperplasia, ovarian stromal cells
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 Do not cite||Under Development|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
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
Evidence Supporting this KER
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).
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
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
Regulation of gonadotropin secretion, Dysregulation of ovarian function, Insulin-resistant hyperinsulinism, Modulation of androgen action (Rosenfield and Ehrmann, 2016).
Observed in months
Known Feedforward/Feedback loops influencing this KER
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
Increase in circulating estrogen level causing increase in the ovarian stromal cells observed in adult female (human) also in rodents.
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>3.0.co;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).