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: 3532

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

Inhibition, Aromatase leads to Reduction, Plasma 17beta-estradiol concentrations

Upstream event

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

Inhibition, Aromatase

Downstream event

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

Reduction, Plasma 17beta-estradiol concentrations

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
mammals	mammals	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Mixed	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	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

Aromatase (CYP19A1, estrogen synthetase) is an enzyme responsible for synthesis of estrogens from androgens, e.g. testosterone into 17-beta-estradiol (E2) and androstenedione into estrone. Estrone can be further converted to E2 by the enzyme 17-beta-hydroxysteroid dehydrogenase (17-beta-HSD). Decreased levels or activity of aromatase lead to decreased levels of E2 (Bondesson, 2015; Blakemore, 2016; Wang, 2019; Ghosh, 2023).

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

The KER describes a generally recognized and understood process, i.e. canonical knowledge. The aim of the literature search was therefore to identify review articles and book chapters that summarise the canonical knowledge. PubMed was searched using key words related to steroidogenesis. The search was restricted to reviews from the last 10 years.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

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

Aromatase (CYP19A1, estrogen synthetase) is the rate limiting enzyme synthesising E2. Aromatase is also synthesizing estrone from androstenedione that is further converted to E2 by the enzyme 17-beta-HSD. E2 is mainly produced in ovary and placenta and transported in the blood to other organs. In humans, E2 is locally synthesized also in testis, brain, adipose tissue, blood vessels and bone. Since aromatase is the only enzyme responsible for synthesis of E2, decreased levels or activity of aromatase will result in decreased levels of E2 (Bondesson, 2015; Blakemore, 2016; Wang, 2019; Ghosh, 2023).

Mouse knockout studies of the aromatase gene show that estrogen production is abolished in the mice (Simpson, 2004).

A few clinical cases of mutations in the aromatase gene that results in a nonfunctional enzyme have been reported. All such patients with a mutation have nondetectable estrogen levels (Simpson, 2004; Jones, 2006; Stumper, 2023).

The role of aromatase in synthesis of 17-beta-estradiol is a well-studied and generally recognized process and the biological plausibility of the KER therefore is high.

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

Aromatase inhibitors such as the steroidal exemestane and the non-steroidal letrozole and anastrozole are used in treatment of hormone dependent breast cancer. The inhibitors block estrogen synthesis and result in reduced estrogen levels in the patients (Wang, 2019; Shoombuatong; Ghosh, 2023; Generali, 2023).

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

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

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

Response-response Relationship

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

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

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

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

Taxonomic applicability.

Aromatase enzyme and E2 are present in mammals and also in most vertebrates (Bondesson, 2015). However, this KER is focused on mammals.

Life stage applicability

Aromatase enzyme and E2 are present from fetal period throughout life (Bondesson, 2015).

Sex applicability

Aromatase enzyme and E2 are present both in females and males (Blakemore, 2016).

References

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

Blakemore, J. and Naftolin F. 2016. ‘Aromatase: Contributions to Physiology and Disease in Women and Men.’ Physiology (Bethesda, Md.) 31 (4): 258–69. https://doi.org/10.1152/physiol.00054.2015.

Bondesson, M, Hao R., Lin, C.-Y., Williams, C. and Gustafsson, J.-Å. 2015. ‘Estrogen Receptor Signaling during Vertebrate Development’. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1849 (2): 142–51. https://doi.org/10.1016/j.bbagrm.2014.06.005.

Generali, D., Berardi, R., Caruso, M., Cazzaniga, M., Garrone, O., Minchella, I., Paris, I., Pinto, C. and De Placido, S. 2023. ‘Aromatase Inhibitors: The Journey from the State of the Art to Clinical Open Questions.’ Frontiers in Oncology 13: 1249160. https://doi.org/10.3389/fonc.2023.1249160.

Ghosh, D. 2023. ‘Structures and Functions of Human Placental Aromatase and Steroid Sulfatase, Two Key Enzymes in Estrogen Biosynthesis.’ Steroids 196 (August): 109249. https://doi.org/10.1016/j.steroids.2023.109249.

Jones, M. E.E., Boon, W-C., Proietto, J., and Simpson, E.R.. 2006. ‘Of Mice and Men: The Evolving Phenotype of Aromatase Deficiency’. Trends in Endocrinology & Metabolism 17 (2): 55–64. https://doi.org/10.1016/j.tem.2006.01.004.

Shoombuatong, W., Schaduangrat N, and Nantasenamat C. 2018. ‘Towards Understanding Aromatase Inhibitory Activity via QSAR Modeling.’ EXCLI Journal 17: 688–708. https://doi.org/10.17179/excli2018-1417.

Simpson, E. R. 2004. ‘Models of Aromatase Insufﬁciency’. SEMINARS IN REPRODUCTIVE MEDICINE 22 (1).

Stumper, N. A., Wientgen H., Al-Hashimi, L., Müller, H.-W., Ohrndorf, S., Gaber, T. , Siggelkow, H. and Paula Hoff. 2023. ‘Aromatase Mutation in Men as a Rare Cause of Osteoporosis: A Case Report and Review of the Literature.’ Clinical and Experimental Rheumatology 41 (7): 1434–42. https://doi.org/10.55563/clinexprheumatol/gj7xal.

Wang, Y., Pan P, Li X, Zhu Q, Huang T, and Ge RS. 2019. ‘Food Components and Environmental Chemicals of Inhibiting Human Placental Aromatase.’ Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association 128 (June): 46–53. https://doi.org/10.1016/j.fct.2019.03.043.