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Reduction, Plasma 17beta-estradiol concentrations leads to irregularities, ovarian cycle
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female||adjacent||High||Elise Grignard (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
The development and the function of the female reproductive tract depends upon hormone concentrations and balance. Changes in this fine-tuned hormonal machinery may result in reproductive system dysfunction (e.g. menstrual cycle irregularities, impaired fertility, endometriosis, polycystic ovarian syndrome). Ovarian estrogen is the major component of negative and positive feedback for pituitary release of gonadotrophic hormones; therefore abnormal alterations in the estradiol levels result in irregularities of the ovarian cycle.
Evidence Supporting this KER
Estrogens are crucial for female and male fertility, as proved by the severe reproductive defects observed when their synthesis (Simpson, 2004), (Schomberg et al., 1999) are blocked. As a secreted hormone, estradiol modulates the structure and function of female reproductive tissues, such as the uterus and oviduct. Estradiol is also one of the principal determinants of pituitary neuron functioning and is critical in enabling these cells to exhibit fluctuating patterns of biosynthetic and secretory activity and to generate the preovulatory surge of luteinising hormone (LH) (Hillier, 1985). Estradiol also contributes to cyclical variations in sexual female behaviour. Suppression of estradiol levels results in increased serum follicle stimulating hormone (FSH) levels and an absence of LH surges necessary for ovulation (Everett, 1961), (Davis, Maronpot, & Heindel, 1994) and changes the length of the cycle (Eldridge et al., 1994).
Uncertainties and Inconsistencies
The impact on the ovarian cycle may result from defect in hypothalamic-pituitary-gonadal (HPG) axis signalling, other than by alteration of estradiol level. Table 1 shows some chemicals which impact on other hormones and cause irregularities of ovarian cycle.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
See Table 1.
Davis, B J, R R Maronpot, and J J Heindel. 1994. “Di-(2-Ethylhexyl) Phthalate Suppresses Estradiol and Ovulation in Cycling Rats.” Toxicology and Applied Pharmacology 128 (2) (October): 216–23. doi:10.1006/taap.1994.1200.
Eldridge, J C, D G Fleenor-Heyser, P C Extrom, L T Wetzel, C B Breckenridge, J H Gillis, L G Luempert, and J T Stevens. 1994. “Short-Term Effects of Chlorotriazines on Estrus in Female Sprague-Dawley and Fischer 344 Rats.” Journal of Toxicology and Environmental Health 43 (2) (October): 155–67. doi:10.1080/15287399409531912.
Everett, J. W. 1961. “The Mammalian Female Reproductive Cycle and Its Controlling Mechanisms.” Sex and Internal Secretions I. Herreros, Maria a, Antonio Gonzalez-Bulnes, Silvia Iñigo-Nuñez, Ignacio Contreras-Solis, Jose M Ros, and Teresa Encinas. 2013. “Toxicokinetics of di(2-Ethylhexyl) Phthalate (DEHP) and Its Effects on Luteal Function in Sheep.” Reproductive Biology 13 (1) (March): 66–74. doi:10.1016/j.repbio.2013.01.177.
Hillier, S G. 1985. “Sex Steroid Metabolism and Follicular Development in the Ovary.” Oxford Reviews of Reproductive Biology 7 (January): 168–222.
Hirosawa, Narumi, Kazuyuki Yano, Yuko Suzuki, and Yasushi Sakamoto. 2006. “Endocrine Disrupting Effect of Di-(2-Ethylhexyl)phthalate on Female Rats and Proteome Analyses of Their Pituitaries.” Proteomics 6 (3) (February): 958–71. doi:10.1002/pmic.200401344.
Laskey, J.W., and E. Berman. 1993. “Steroidogenic Assessment Using Ovary Culture in Cycling Rats: Effects of Bis (2-Diethylhexyl) Phthalate on Ovarian Steroid Production.” Reproductive Toxicology 7 (1) (January): 25–33. doi:10.1016/0890-6238(93)90006-S. Laws, S. C. 2000. “Estrogenic Activity of Octylphenol, Nonylphenol, Bisphenol A and Methoxychlor in Rats.” Toxicological Sciences 54 (1) (March 1): 154–167. doi:10.1093/toxsci/54.1.154.
Li, X, D C Johnson, and K K Rozman. 1995. “Effects of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) on Estrous Cyclicity and Ovulation in Female Sprague-Dawley Rats.” Toxicology Letters 78 (3) (August): 219–22.
Schilling, K., Deckardt. K., Gembardt, Chr., and Hildebrand, B. 1999. “Di-2-Ethylhexyl Phthalate – Two-Generation Reproduction Toxicity Range-Finding Study in Wistar Rats. Continuos Dietary Administration.”
Schomberg, D W, J F Couse, A Mukherjee, D B Lubahn, M Sar, K E Mayo, and K S Korach. 1999. “Targeted Disruption of the Estrogen Receptor-Alpha Gene in Female Mice: Characterization of Ovarian Responses and Phenotype in the Adult.” Endocrinology 140 (6) (June): 2733–44. doi:10.1210/endo.140.6.6823.
Simpson, Evan R. 2004. “Models of Aromatase Insufficiency.” Seminars in Reproductive Medicine 22 (1) (February): 25–30. doi:10.1055/s-2004-823024.
Takai, Ryo, Shuji Hayashi, Junpei Kiyokawa, Yoshika Iwata, Saori Matsuo, Masami Suzuki, Keiji Mizoguchi, Shuichi Chiba, and Toshiaki Deki. 2009. “Collaborative Work on Evaluation of Ovarian Toxicity. 10) Two- or Four-Week Repeated Dose Studies and Fertility Study of Di-(2-Ethylhexyl) Phthalate (DEHP) in Female Rats.” The Journal of Toxicological Sciences 34 Suppl 1 (I) (January): SP111–9.