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Event: 1693
Key Event Title
Decreased, Progesterone levels
Short name
Biological Context
Level of Biological Organization |
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Tissue |
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
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
Term | Scientific Term | Evidence | Link |
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Vertebrates | Vertebrates | High | NCBI |
Life Stages
Life stage | Evidence |
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All life stages | High |
Sex Applicability
Term | Evidence |
---|---|
Mixed | High |
Key Event Description
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
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
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
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