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Relationship: 1089


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 GnRH from hypothalamus leads to Increased, secretion of LH from anterior pituitary

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
Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse adjacent High Charles Wood (send email) Under Development: Contributions and Comments Welcome
Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia adjacent High Moderate Kalyan Gayen (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 Do not cite Under Development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 High NCBI
mice Mus sp. High NCBI
cow Bos taurus Low 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 release of gonadotrophin-releasing hormone (GnRH) stimulate the secretion of  luteinising hormone (LH) (Fields et al., 2009). GnRH causes the pituitary gland to secrete LH. Gonadotropin releasing hormone (GnRH) is the key regulator of the secretion of luteinising hormone (Marques et al., 2018; Bowen et al., 1998; Tsutsumi and Webster, 2009). Metastin or kisspeptin in the control of gonadotropin-releasing hormone (GnRH) release and then it causes for pulsatile release of luteinizing hormone(Ohkura et al., 2009).

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
  • Gonadotropin-releasing hormone (GnRH) is the master hormone for regulating the reproduction. GnRH pulses stimulate the synthesis and secretion of LH from the anterior pituitary(Tsutsumi and Webster, 2009).
  • Nicol et al., reported that high GnRH dose enhances the secretion of LH (Nicol et al., 2002)
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

GnRH was isolated from porcine hypothalamus. It was structurally identified as a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly·NH2)(AV et al., 971). During the childhood, GnRH levels are low but as puberty begins. GnRH levels start to rise and when the testes and ovaries are fully developed. GnRH regulates  LH and these hormones to control the production of sex hormones in adult (Marques et al., 2018). GnRH secretion have been described in pulsatile (in minutes) and surge modes. Pulsatile mode refers to episodic release of GnRH while the surge mode of GnRH secretion occurs in females during the pre-ovulatory phase (Maeda et al., 2010). Secretion of LH is also in pulsatile nature ( in hrs)(Bolt, 1971).

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

Not Specified

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
  • Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion (Garrido-Gracia et al., 2006)
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
  • Generally time scale is in hours (6-18) between GnRH and LH response (Fields et al., 2009).
  • GnRH is degraded by proteolysis within a few minutes(Kenealy et al., 2011).
  • It has very low activity during childhood, and is activated at puberty or adolescence and in reproductive years, pulse activity is critical for successful reproductive function(Berger et al., 1983).
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

Adashi, E., Hsueh, A., & Yen, S. (1980). Alterations induced by clomiphene in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus of female rats. Journal of Endocrinology, 87(3), 383-392.

AV, S., A, A., AJ, K., H, M., Y, B., TW, R., et al. (971). Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing. Science, 173(4001), 1036-38. doi:doi: 10.1126/science.173.4001.1036.

Berger, H., Nikolics, K., Szöke, B., & Mehlis, B. (1983). Proteolytic degradation of gonadotropin-releasing hormone (GnRH) by rat ovarian fractions in vitro. Peptides, 4(6), 821-825.

Bharti, S., Misro, M., & Rai, U. (2013). Clomiphene citrate potentiates the adverse effects of estrogen on rat testis and down-regulates the expression of steroidogenic enzyme genes. Fertility and sterility, 99(1), 140-148. e5.

Bolt, D. J. (1971). Changes in the concentration of luteinizing hormone in plasma of rams following administration of oestradiol, progesterone or testosterone. J Reprod Fertil. , 24(3), 435-38.

Botte, M., Lerrant, Y., Lozach, A., Berault, A., Counis, R., & Kottler, M. (1999). LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis. Journal of Endocrinology, 162(3), 409-415.

Bowen, J. M., Dahl, G. E., Evans, N. P., Thrun, L. A., Wang, Y., Brown, M. B., et al. (1998). Importance of the gonadotropin-releasing hormone (GnRH) surge for induction of the preovulatory luteinizing hormone surge of the ewe: dose-response relationship and excess of GnRH. Endocrinology, 139(2), 588-595.

Bussenot, I., Parinaud, J., Clamagirand, C., Vieitez, G., & Pontonnier, G. (1990). Effect of clomiphene cirate on oestrogen secretion by human granulosa cells in culture. Human Reproduction, 5(5), 533-536.

Concannon, P. W., Temple, M., Montanez, A., & Newton, L. (2006). Effects of dose and duration of continuous GnRH-agonist treatment on induction of estrus in beagle dogs: competing and concurrent up-regulation and down-regulation of LH release. Theriogenology, 66(6-7), 1488-96. doi:S0093-691X(06)00095-1 [pii]


Crawford, J. L., Heath, D. A., Haydon, L. J., Thomson, B. P., & Eckery, D. C. (2009). Gene expression and secretion of LH and FSH in relation to gene expression of GnRH receptors in the brushtail possum (Trichosurus vulpecula) demonstrates highly conserved mechanisms. Reproduction, 137(1), 129-40. doi:REP-08-0347 [pii]10.1530/REP-08-0347.

Fields, S. D., Perry, B. L., & Perry, G. A. (2009). Effects of GnRH treatment on initiation of pulses of LH, LH release, and subsequent concentrations of progesterone. Domest Anim Endocrinol, 37(4), 189-95. doi:S0739-7240(09)00038-1 [pii]10.1016/j.domaniend.2009.04.006.

Garrido-Gracia, J. C., Bellido, C., Aguilar, R., & Sanchez-Criado, J. E. (2006). Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion. J Physiol Biochem, 62(1), 35-42. doi:10.1007/BF03165804.

Guillaume, D., Bruneau, B., & Briant, C. (2002). Comparison of the effects of two GnRH antagonists on LH and FSH secretion, follicular growth and ovulation in the mare. Reprod Nutr Dev, 42(3), 251-64. doi:10.1051/rnd:2002023.

Kenealy, B., Keen, K., & Terasawa, E. (2011). Rapid action of estradiol in primate GnRH neurons: the role of estrogen receptor alpha and estrogen receptor beta. Steroids, 76(9), 861-866.

KERIN, J. F., LIU, J. H., PHILLIPOU, G., & Yen, S. (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. The Journal of Clinical Endocrinology & Metabolism, 61(2), 265-268.

Kumar, A., & Pakrasi, P. L. (1995). Estrogenic and antiestrogenic properties of clomiphene citrate in laboratory mice. Journal of Biosciences, 20(5), 665-673.

Maeda, K., Ohkura, S., Uenoyama, Y., Wakabayashi, Y., Oka, Y., Tsukamura, H., et al. (2010). Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res. , 10, 103-115.

Marques, P., Skorupskaite, K., George, J. T., & Anderson, R. A. (2018). Physiology of GNRH and gonadotropin secretion. Endotext [Internet].

Nicol, L., McNeilly, J. R., Stridsberg, M., Crawford, J. L., & McNeilly, A. S. (2002). Influence of steroids and GnRH on biosynthesis and secretion of secretogranin II and chromogranin A in relation to LH release in LbetaT2 gonadotroph cells. J Endocrinol, 174(3), 473-83. doi:JOE04823 [pii]10.1677/joe.0.1740473.

Ohkura, S., Uenoyama, Y., Yamada, S., Homma, T., Takase, K., Inoue, N., et al. (2009). Physiological role of metastin/kisspeptin in regulating gonadotropin-releasing hormone (GnRH) secretion in female rats. Peptides, 30(1), 49-56.

Shoemaker, J. E., Gayen, K., Garcia-Reyero, Natàl., Perkins, E. J., Villeneuve, D. L., Liu, L., et al. (2010). Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. BMC Systems Biology, 4(1), 89. doi:10.1186/1752-0509-4-89.

Sonntag, B., Kiesel, L., Nieschlag, E., & Behre, H. M. (2005). Differences in serum LH and FSH levels using depot or daily GnRH agonists in controlled ovarian stimulation: influence on ovarian response and outcome of ART. J Assist Reprod Genet, 22(7-8), 277-83. doi:10.1007/s10815-005-5998-8.

Tsutsumi, R., & Webster, N. J. (2009). GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocrine journal, 56(6), 729-737.

Washington, T. M., Blum, J. J., Reed, M. C., & Conn, P. M. (2004). A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH. Theor Biol Med Model, 1, 9. doi:10.1186/1742-4682-1-91742-4682-1-9 [pii].