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Event: 1693

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Decreased, Progesterone levels

Short name

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Biological Context

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Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Luteinizing hormone receptor antagonism	KeyEvent	Young Jun Kim (send email)	Under Development: Contributions and Comments Welcome

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI

Life Stages

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

Life stage	Evidence
All life stages	High

Sex Applicability

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

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Steroidogenesis starts with transport of cholesterol into the mitochondria. Cholesterol is converted to pregnenolone which can subsequently be converted to progesterone. The enzymatic step between pregnenolone and progesterone is catalysed by the 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD enzyme). Progesterone can then either be converted into deoxycorticosterone to synthesize mineralocorticoids, or into its metabolite 17α-hydroxyprogesterone which may be converted into glucocorticoids or into androgens and subsequently, depending on circumstances, into estrogens (Bremer & Miller, 2014; S et al., 2021; WL, 2017).

Other than being a precursor to several other downstream hormones, progesterone fulfills its role through the binding to its receptor, PGR. Mammalian progesterone receptors, which are nuclear receptors, are found in two main isoforms, PRA and PRB. Membrane bound progesterone receptors are also present in mammals (Brinton et al., 2008).

Progesterone signalling is known to be critical for maintenance of pregnancy, and its correct signalling is needed to prevent certain diseases linked to the uterus such as endometriosis or endometrial cancer (Wetendorf & DeMayo, 2014). Like many steroid hormones, progesterone can be found bound or free. During the menstrual cycle for example, the majority of progesterone is bound to albumin (Westphal, 1986).

All these processes affect progesterone levels. Progesterone decrease can be due to disruption of upstream and downstream enzyme activity, but may also be affected by precursor levels. Progesterone decrease can therefore impact fertility, brain function and overall health.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

There is no validated OECD test guideline for progesterone measurements.

The cells used for validated H295R steroidogenesis assay (OECD TG456) (NCI-H295R) can be used to measure effects on progesterone levels, though not validated for this purpose (Haggard et al., 2018; Karmaus et al., 2016). Other cell lines are also capable of producing progesterone and can hence be used to test the effect of chemicals on progesterone levels. These cell lines include for instance the mouse Leydig tumor cell line MA-10 or ovarian granulosa cell lines (ASCOLI, 1981; Havelock et al., 2004).

Progesterone can be detected by using high throughput LC-MS/MS (Andersson et al., 2018; Evangelista et al., 2024; Stanislaus et al., 2012). Classically, progesterone has been detected using immunoassays such as ELISA or RIA. Considerations for steroid hormone measurements have been extensively discussed and analysed (Andersson et al., 2018; Stanislaus et al., 2012).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic applicability.

Progesterone is conserved throughout vertebrates. Its role is highly conserved in mammals (Batth et al., 2020; Miller & Auchus, 2011).

Life stage applicability

Progesterone is expressed throughout all life stages from development to adulthood (Taraborrelli, 2015).

Sex applicability

Progesterone expression is important in both females and males. Progesterone is largely synthesized in the ovary, by the corpus luteum after ovulation and in the placenta during pregnancy. It is essential for brain function and female fertility. Progesterone is also synthesized in the adrenal cortex, adipose tissue, and Leydig cells (Taraborrelli, 2015).

References

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

Andersson, N., Arena, M., Auteri, D., Barmaz, S., Grignard, E., Kienzler, A., Lepper, P., Lostia, A. M., Munn, S., Parra Morte, J. M., Pellizzato, F., Tarazona, J., Terron, A., & Van der Linden, S. (2018). Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA Journal, 16(6). https://doi.org/10.2903/j.efsa.2018.5311

Ascoli, M. (1981). Characterization of Several Clonal Lines of Cultured Ley dig Tumor Cells: Gonadotropin Receptors and Steroidogenic Responses*. Endocrinology, 108(1), 88–95. https://doi.org/10.1210/endo-108-1-88

Batth, R., Nicolle, C., Cuciurean, I. S., & Simonsen, H. T. (2020). Biosynthesis and Industrial Production of Androsteroids. Plants, 9(9), 1144. https://doi.org/10.3390/plants9091144

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

Brinton, R. D., Thompson, R. F., Foy, M. R., Baudry, M., Wang, J., Finch, C. E., Morgan, T. E., Pike, C. J., Mack, W. J., Stanczyk, F. Z., & Nilsen, J. (2008). Progesterone receptors: Form and function in brain. Frontiers in Neuroendocrinology, 29(2), 313–339. https://doi.org/10.1016/j.yfrne.2008.02.001

Evangelista, S., Vazakidou, P., Koekkoek, J., Heinzelmann, M. T., Lichtensteiger, W., Schlumpf, M., Tresguerres, J. A. F., Linillos-Pradillo, B., van Duursen, M. B. M., Lamoree, M. H., & Leonards, P. E. G. (2024). High throughput LC-MS/MS method for steroid hormone analysis in rat liver and plasma – unraveling methodological challenges. Talanta, 266, 124981. https://doi.org/10.1016/j.talanta.2023.124981

Haggard, D. E., Karmaus, A. L., Martin, M. T., Judson, R. S., Setzer, R. W., & Paul Friedman, K. (2018). High-Throughput H295R Steroidogenesis Assay: Utility as an Alternative and a Statistical Approach to Characterize Effects on Steroidogenesis. Toxicological Sciences, 162(2), 509–534. https://doi.org/10.1093/toxsci/kfx274

Havelock, J. C., Rainey, W. E., & Carr, B. R. (2004). Ovarian granulosa cell lines. Molecular and Cellular Endocrinology, 228(1–2), 67–78. https://doi.org/10.1016/j.mce.2004.04.018

Karmaus, A. L., Toole, C. M., Filer, D. L., Lewis, K. C., & Martin, M. T. (2016). High-Throughput Screening of Chemical Effects on Steroidogenesis Using H295R Human Adrenocortical Carcinoma Cells. Toxicological Sciences, 150(2), 323–332. https://doi.org/10.1093/toxsci/kfw002

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

S, C.-P., T, L., P, L., C, D.-L., A, D., PA, F., & S, M.-G. (2021). Six Decades of Research on Human Fetal Gonadal Steroids. International Journal of Molecular Sciences, 22(13). https://doi.org/10.3390/ijms22136681

Stanislaus, D., Andersson, H., Chapin, R., Creasy, D., Ferguson, D., Gilbert, M., Rosol, T. J., Boyce, R. W., & Wood, C. E. (2012). Society of Toxicologic Pathology Position Paper: Review Series: Assessment of Circulating Hormones in Nonclinical Toxicity Studies: General Concepts and Considerations. Toxicologic Pathology, 40(6), 943–950. https://doi.org/10.1177/0192623312444622

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

Westphal, U. (1986). Steroid-Protein Interactions II (Vol. 27). Springer Berlin Heidelberg. https://doi.org/10.1007/978-3-642-82486-9

Wetendorf, M., & DeMayo, F. J. (2014). Progesterone receptor signaling in the initiation of pregnancy and preservation of a healthy uterus. The International Journal of Developmental Biology, 58(2-3–4), 95–106. https://doi.org/10.1387/ijdb.140069mw

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