This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2583

Title

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, estrogens leads to Increased, circulating estrogen levels

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increased, estrogens

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, circulating estrogen levels

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	adjacent	High	Moderate	Kalyan Gayen (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 Do not cite	Under Development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
Male	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

Ovaries are the principle source of estrogen hormone in premenopausal women. This estrogen functions as a circulating hormone to act on different tissues. In postmenopausal women, estrogen is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. The monthly menstrual cycle in female is controlled through unique co-ordination between secreted hormones by the hypothalamus, the pituitary gland, and the ovary. Estrogen is synthesized from androgen, upon calalysis of aromatse enzyme present in the endoplasmic reticulam of the cells. Presence of aromatase enzyme is found majorly in the ovarian granulosa cells (premenopausal female), in the skin and adipose tissue (postmenopausal woman). Estrogen was synthesized in postmenopausal women due to the aromatization of steroids, found in the adipose and skin tissue.

Aromatase is a key enzyme for estrogen formation in human tissues. In men and postmenopausal women C19 steroids undergoes aromatization in different tissues (e.g. skin, adipose) to generate estrogen. In men, testicular steroidogenesis accounts for 15% of the circulating level of estrogen.

In women, the ovarian granulosa cells are important sites of estrogen formation for local use within the ovary as well as for endocrine signalling to the target tissues (e.g. uterus, skin, breast, brain, bone). In case of postmenopausal female, ovarian aromatase expression is stopped, but estrogen level is maintained in the plasma by the increased aromatase expression in other tissues (adipose and skin). Research had shown elevated circulating estradiol may persist at sufficient levels to cause postmenopausal uterine bleeding, endometrial hyperplasia, and even cancer.

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

Steger et al., had shown the age related changes in steroid productions in the ovaries of rat model. In this work researchers had shown the elevated serum estrone and estradiol level in the rats (mid–aged) (Steger and Peluso, 1982).

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

Estrogens in humans are classified as estrone (E1) and estradiol (E2). E2 is synthesized majorly in ovaries and testes by aromatization of testosterone. Small amounts of estrogens are produced in the adrenal glands and some peripheral tissues (e.g. skin, fat tissues). E2 and E1 are interchangeable, and both can be deactivated via hydroxylation. E2 has 1.25 to 5 times higher biological potency of E1. E2 circulates at 1.5 to 4 times more concentration of E1 in premenopausal women. E2 levels in men and postmenopausal women are much lower than in nonpregnant women. E2 levels in premenopausal women fluctuate during the menstrual cycle. An E2 level is lowest during the early follicular phase, then rise gradually until 2 to 3 days before ovulation. In the ovulatory phase E2 levels again declined.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Compound class	Species	Study type	Dose	KER findings	Reference
Circulating estrogen	lizards (Iguana iguana)	Assay of plasma protein	-	Estrogens mean concentrations were higher in the females compared to males. Estradiol (258 ± 46 pg/ml), Estrone (205 ± 147 pg/ml) – In Females. Estradiol, 79 ± 42 pglml, Estrone, 37 ± 2 pglml – In Male	(Judd et al., 1976)
Circulating estrogen	Human Plasma	Assay of plasma protein fractions	-	1.5 to 2.0 µg of estriol (1.8 µg – in average) per 100 ml. of original plasma.	(Roberts and Szego, 1946)
Circulating estrogen	Mice	Ovariectomized athymic mice (BALB/c nu/nu, 4–5 wk old)	A 100-µL cell suspension (4 x10⁶MCF-7 cells)	High circulating estrogen (E2) concentration (E2 pellet (0.36 mg/ 60-day release) simulating premenopause	(Truan et al., 2010)

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

Leung et al., had shown estradiol-17β (I mg) administration in the female rat for 3 days decrease the ovarian androgen levels (13 ± 2 pg/mg) compared to the control (34 ± 7 pg/mg). Results of the study suggest estrogen levels controlled by the negative feedback loop of testosterone production (Leung et al., 1978).

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

Estrogen levels changes due to the following reasons.

High androgen levels caused by tumors
Androgen therapy
Elevations in estrogen due to aromatization
Obesity with increased tissue production of E1
Decreased estrogen clearance in liver disease
Estrogen producing tumors
Estrogen ingestion

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Estrone concentrations in human

Males: 10-60 pg/mL, Females: Premenopausal: 17-200 pg/mL, Postmenopausal: 7-40 pg/mL

Estradiol concentrations in human

Males: 10-40 pg/mL, Females: Premenopausal: 15-350 pg/mL, Postmenopausal: <10 pg/mL (Cummings et al., 1998; Elmlinger et al., 2002)

Response-response Relationship

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

Leung et al., had shown estradiol-17β (I mg) administration in the female rat for 3 days decrease the ovarian androgen levels (13 ± 2 pg/mg) compared to the control (34 ± 7 pg/mg) (Leung et al., 1978).

Time-scale

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

Elevation of the circulating estrogen can be observed in days

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

Judd et al, had measured the circulating estrogen level in the male and female lizards (Iguana iguana) (Judd et al., 1976).

Roberts et al., had estimated the circulating estrogen in the plasma collected from human volunteer (Roberts and Szego, 1946).

Truan et al., had shown the high circulating estrogen levels in the mice model (Truan et al., 2010).

References

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

Cummings, S. R., Browner, W. S., Bauer, D., Stone, K., Ensrud, K., Jamal, S., et al. (1998). Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med, 339(11), 733-8. doi:10.1056/NEJM199809103391104.

Elmlinger, M. W., Kuhnel, W., & Ranke, M. B. (2002). Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults. Clin Chem Lab Med, 40(11), 1151-60. doi:10.1515/CCLM.2002.202.

Judd, H. L., Laughlin, G. A., Bacon, J. P., & Benirschke, K. (1976). Circulating androgen and estrogen concentrations in lizards (Iguana iguana). Gen Comp Endocrinol, 30(3), 391-5. doi:0016-6480(76)90091-5 [pii]10.1016/0016-6480(76)90091-5.

Leung, P. C., Goff, A. K., Kennedy, T. G., & Armstrong, D. T. (1978). An intraovarian inhibitory action of estrogen on androgen production in vivo. Biol Reprod, 19(3), 641-7. doi:10.1095/biolreprod19.3.641.

Roberts, S., & Szego, C. M. (1946). The nature of circulating estrogen; lipoprotein-bound estrogen in human plasma. Endocrinology, 39, 183-7. doi:10.1210/endo-39-3-183.

Roy, E. J., & Wilson, M. A. (1981). Diurnal rhythm of cytoplasmic estrogen receptors in the rat brain in the absence of circulating estrogens. Science, 213(4515), 1525-7. doi:10.1126/science.7197053.

Steger, R. W., & Peluso, J. J. (1982). Effects of age on hormone levels and in vitro steroidogenesis by rat ovary and adrenal. Exp Aging Res, 8(3-4), 203-8. doi:10.1080/03610738208260367.

Truan, J. S., Chen, J. M., & Thompson, L. U. (2010). Flaxseed oil reduces the growth of human breast tumors (MCF-7) at high levels of circulating estrogen. Mol Nutr Food Res, 54(10), 1414-21. doi:10.1002/mnfr.200900521.

Wu, S., Zhu, Y., Zhang, J., Hu, X., & Yi, Y. (2020). [Effect of circulating estrogen level on the outcome of free fat grafting in nude mice]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 34(2), 220-225. doi:10.7507/1002-1892.201903011.