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Relationship: 2581


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, secretion of LH from anterior pituitary leads to Increased, Steroidogenic acute regulatory protein (StAR)

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 Cataia Ives (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 Do not cite Under Development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 Moderate NCBI
mice Mus sp. Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High
Male Low

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

The activity of StAR protein in theca cells is control by LH (Murayama et al., 2012). Subsequently, StAR protein regulates cholesterol transportation to the mitochondria and therefore, the production of steroid hormones is regulated by StAR protein (Clark and Stocco, 1995).

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
  • Murayama et al. studied the in vitro LH pulse dose in Bovine ovaries and  reported LH dose  enhances the activity of StAR protein (Murayama et al., 2012).
  • Johnson and Bridgham performed in vitro studied in granulosa cells from prehierarchal and preovulatory hen follicles to examine the regulation of steroidogenic acute regulatory protein (StAR) by LH. They reported the treatment with LH rapidly increased StAR mRNA and protein (Johnson and Bridgham, 2001).
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

In mammalian species (e.g., rat,rabbit, human), LH stimulates the StAR protein to increase the cholesterol transport in to the inner mitochondrial membrane. Cholesterol is the precursor of sex hormones. Therefore, LH regulate the steroidogenic function of theca cells (Murayama et al., 2012; Johnson and Bridgham, 2001; Rekawiecki et al., 2005).

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

No uncertainties and inconsistencies are observed

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

Not specified

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

Not specified

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

Time scale for the response between LH to StAR protein in hours (3-20 h) (Johnson and Bridgham, 2001; Martinat et al., 2005; Rekawiecki et al., 2005).

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



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

Clark, B. J., & Stocco, D. M. (1995). Expression of the steroidogenic acute regulatory (StAR) protein: a novel LH-induced mitochondrial protein required for the acute regulation of steroidogenesis in mouse Leydig tumor cells. Endocr Res, 21(1-2), 243-57. doi:10.3109/07435809509030440.

Eacker, S. M., Agrawal, N., Qian, K., Dichek, H. L., Gong, E. Y., Lee, K., et al. (2008). Hormonal regulation of testicular steroid and cholesterol homeostasis. Mol Endocrinol, 22(3), 623-35.

Johnson, A. L., & Bridgham, J. T. (2001). Regulation of steroidogenic acute regulatory protein and luteinizing hormone receptor messenger ribonucleic acid in hen granulosa cells. Endocrinology, 142(7), 3116-24.

Liu, T., Wimalasena, J., Bowen, R. L., & Atwood, C. S. (2007). Luteinizing hormone receptor mediates neuronal pregnenolone production via up-regulation of steroidogenic acute regulatory protein expression. J Neurochem. , 100(5), 1329-39.

Martinat, N., Crepieux, P., Reiter, E., & Guillou, F. (2005). Extracellular signal-regulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression. Reprod Nutr Dev, 45(1), 101-8. doi:10.1051/rnd:2005007.

Murayama, C., Miyazaki, H., Miyamoto, A., & Shimizu, T. (2012). Luteinizing hormone (LH) regulates production of androstenedione and progesterone via control of histone acetylation of StAR and CYP17 promoters in ovarian theca cells. Mol Cell Endocrinol, 350(1), 1-9. doi:S0303-7207(11)00677-0 [pii]10.1016/j.mce.2011.11.014.

Rekawiecki, R., Nowik, M., & Kotwica, J. (2005). Stimulatory effect of LH, PGE2 and progesterone on StAR protein, cytochrome P450 cholesterol side chain cleavage and 3beta hydroxysteroid dehydrogenase gene expression in bovine luteal cells. Prostaglandins Other Lipid Mediat, 78(1-4), 169-84. doi:S1098-8823(05)00080-8 [pii]10.1016/j.prostaglandins.2005.06.009.

Tsang, B. K., Armstrong, D. T., & Whitfield, J. F. (1980). Steroid biosynthesis by isolated human ovarian follicular cells in vitro. J Clin Endocrinol Metab. , 51(6), 1407-11.

Tsuchiya, M., Inoue, K., Matsuda, H., Nakamura, K., Mizutani, T., Miyamoto, K., et al. (2003). Expression of steroidogenic acute regulatory protein (StAR) and LH receptor in MA-10 cells. Life Sciences, 73(22), 2855-2863. doi: