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Relationship: 3521

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

Decreased, Progesterone levels leads to Reduction, androstenedione

Upstream event

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

Decreased, Progesterone levels

Downstream event

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

Reduction, androstenedione

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

This key event relationship links a decrease in progesterone to a reduction in androstenedione.

CYP17A1 is responsible for the conversion of progesterone to 17-OH-progesterone which can then be converted into the weak androgen androstenedione by the same enzyme. Progesterone can be converted to 17-OH-progesterone by CYP17A1 or converted by CYP21 to form corticosterone. When CYP17A1 is dominant over CYP21, which depends on tissue specific gene expression, synthesis of 17OH-progesterone takes place. (Bhatt et al., 2017; V et al., 2018; WL, 2017). Therefore, since progesterone is one of the possible precursors of androstenedione, if levels of progesterone decrease, then androstenedione levels may decrease as well.

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

It is well established that the synthesis and presence of progesterone plays a role for levels of androstenedione.

The pathway in which progesterone is converted to androstenedione is known as the Δ4 pathway. This pathway is present and active in mice, rats, and guinea pigs but minor in humans (Bhatt et al., 2017). Androstenedione can also be formed through the Δ5 pathway, which converts pregnenolone, into its hydroxylated form, and ultimately into DHEA and androstenedione. This pathway is dominant in humans and primates (Flück et al., 2003; Miller & Auchus, 2011). Furthermore, the Δ4 pathway was recently observed in human fetal Leydig cells during GW8-9 to produce mainly progesterone but also androgens in the testis. This is temporary as they switch to Δ5 pathway after this to produce higher levels of androgens as Leydig cells mature (Bhatt et al., 2017; Savchuk et al., 2019).

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

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

Progesterone is a precursor to other steroid hormones as well, like corticoids (T et al., 2015; Taraborrelli, 2015). The levels of the hormones can also depend on the enzyme activity of CYP17A1 (FK & RJ, 2015; M et al., 2017; Sherbet et al., 2003). Therefore, the reduction of progesterone levels doesn’t always translate to an effect on androstenedione levels.

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

Androstenedione itself can increase progesterone synthesis (Goyeneche et al., 2002; López-García et al., 2008)

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

This KER can be applicable to vertebrates as these processes are well conserved, but we have decided to focus on mammals (Bremer & Miller, 2014; Flück et al., 2003; Taraborrelli, 2015).

Life stage applicability

It is also applicable during development and adulthood (Bremer & Miller, 2014; Taraborrelli, 2015).

Sex applicability

This KER is applicable in both sexes as it is observed in Leydig cells and in ovaries (Bremer & Miller, 2014; Miller & Auchus, 2011; Taraborrelli, 2015).

References

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

Bhatt, M. R., Khatri, Y., Rodgers, R. J., & Martin, L. L. (2017). Role of cytochrome b5 in the modulation of the enzymatic activities of cytochrome P450 17α-hydroxylase/17,20-lyase (P450 17A1). The Journal of Steroid Biochemistry and Molecular Biology, 170, 2–18. https://doi.org/10.1016/j.jsbmb.2016.02.033..

Bremer, A. A., & Miller, W. L. (2014). Regulation of Steroidogenesis. In Cellular Endocrinology in Health and Disease (pp. 207–227). Elsevier. https://doi.org/10.1016/B978-0-12-408134-5.00013-5

FK, Y., & RJ, A. (2015). The diverse chemistry of cytochrome P450 17A1 (P450c17, CYP17A1). The Journal of Steroid Biochemistry and Molecular Biology, 151, 52–65. https://doi.org/10.1016/j.jsbmb.2014.11.026

Flück, C. E., Miller, W. L., & Auchus, R. J. (2003). The 17, 20-Lyase Activity of Cytochrome P450c17 from Human Fetal Testis Favors the Δ 5 Steroidogenic Pathway. The Journal of Clinical Endocrinology & Metabolism, 88(8), 3762–3766. https://doi.org/10.1210/jc.2003-030143

Goyeneche, A. A., Calvo, V., Gibori, G., & Telleria, C. M. (2002). Androstenedione Interferes in Luteal Regression by Inhibiting Apoptosis and Stimulating Progesterone Production1. Biology of Reproduction, 66(5), 1540–1547. https://doi.org/10.1095/biolreprod66.5.1540

López-García, C., López-Contreras, A. J., Cremades, A., Castells, M. T., Marín, F., Schreiber, F., & Peñafiel, R. (2008). Molecular and Morphological Changes in Placenta and Embryo Development Associated with the Inhibition of Polyamine Synthesis during Midpregnancy in Mice. Endocrinology, 149(10), 5012–5023. https://doi.org/10.1210/en.2008-0084

M, K. S., J, J., Z, T., P, K., L, L., & J, H. (2017). The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition. General Physiology and Biophysics, 36(5), 487–499. https://doi.org/10.4149/gpb_2017024

Miller, W. L., & Auchus, R. J. (2011). The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders. Endocrine Reviews, 32(1), 81–151. https://doi.org/10.1210/er.2010-0013

Savchuk, I., Morvan, M. L., Antignac, J. P., Kurek, M., Le Bizec, B., Söder, O., & Svechnikov, K. (2019). Ontogenesis of human fetal testicular steroidogenesis at early gestational age. Steroids, 141, 96–103. https://doi.org/10.1016/j.steroids.2018.12.001

Sherbet, D. P., Tiosano, D., Kwist, K. M., Hochberg, Z., & Auchus, R. J. (2003). CYP17 Mutation E305G Causes Isolated 17,20-Lyase Deficiency by Selectively Altering Substrate Binding. Journal of Biological Chemistry, 278(49), 48563–48569. https://doi.org/10.1074/jbc.M307586200

T, M., S, I., S, K., A, U., & K, M. (2015). Transcriptional regulation of genes related to progesterone production. Endocrine Journal, 62(9), 757–763. https://doi.org/10.1507/endocrj.EJ15-0260

Taraborrelli, S. (2015). Physiology, production and action of progesterone. Acta Obstetricia et Gynecologica Scandinavica, 94, 8–16. https://doi.org/10.1111/aogs.12771

V, S., DM, S., & BJ, C. (2018). Current knowledge on the acute regulation of steroidogenesis. Biology of Reproduction, 99(1), 13–26. https://doi.org/10.1093/biolre/ioy102

WL, M. (2017). Steroidogenesis: Unanswered Questions. Trends in Endocrinology and Metabolism: TEM, 28(11), 771–793. https://doi.org/10.1016/j.tem.2017.09.002