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Relationship: 2580


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

Suppression, Estrogen receptor (ER) activity leads to Increased, secretion of GnRH from hypothalamus

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 Not Specified 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 Do not cite Under Development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 High NCBI
mice Mus sp. High 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

Study on female human patient had shown Selective Estrogen Receptors Modulator (Clomiphene) act on the hypothalamic site and increase the hypothalamic GnRH secretion significantly (KERIN et al., 1985). Study on female rat had shown increased gonadotropin hormone secretion upon administration of very low dose (1-100 ng/kg) of clomiphene citrate. However, high dose (1µg/kg -2 mg/kg) of clomiphene citrate in female rat inhibit the gonadotropin hormone secretion (Koch et al., 1971).

Estradiol i.e. Estrogen receptor beta acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion (Hu et al., 2008). ESR2 control the GnRH release through the intracellular calcium ions release (Kenealy et al., 2011). Research had shown that nanomolar concentration of membrane-associated G protein-coupled estrogen receptor alter the patterns of Ca2+ release in GnRH neurone (Komatsuzaki and Kawato, 2007). Studies on mouse have shown several molecules such as, eastradiol, non-peptide neurotransmitters, gasotransmitters can modulate the GnRH neuron activity and GnRH secretion and control the reproductive functions (Spergel, 2019; Temple et al., 2004; Temple and Wray, 2005).

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

Koch et al., had shown the ~107% increase in GnRH secretion after administration of clomiphene citrate (1-100 ng/kg) in adult female rat (Koch et al., 1971).

Boyer et al., had also shown the increasing GnRH secretion after administration of clomiphene citrate (1.0 mg/kg/day)in immature female rats (Boyar, 1970).

Roy et al., had shown that 17β-estradiol at 1 nm concentration over a 48 h time period down regulate (~55%) the expression of GnRH mRNA in GnRH-secreting, hypothalamic cell line (GT1–7) (Roy et al., 1999).

Chu et al., had shown using whole cell electrophysiology of the brain slice in adult female mice 10 picomolar concentration of estradiol reduce the firing of GnRH neurone (Chu et al., 2009).

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

Molecular mechanism for the enhancement of GnRH by suppression of Estrogen receptor activity is poorly known.

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

The release GnRH neurons depends on the concentration of the Selective Estrogen Receptors Modulator compound (Clomiphene). Scientific reports have shown the both stimulatory and inhibitory effects on the GnRH secretion exhibited by the estradiol depending on the concentration of clomiphene molecules and presence of types of receptors (Chu et al., 2009; Micevych and Kelly, 2012; Boyar, 1970).

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

GnRH secretion from the neurone can be modulated by prostaglandin, glutamate, ATP, carbon monoxide, nitric oxide, neurotransmitters (norepinephrine, epinephrine, GABA, histamine and acetylcholine) (Spergel, 2019).

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

Neural activity and elevated hormone release are observed for hours in in vivo study (Chu et al., 2009).

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

Negative feedback action on GnRH secretion had shown in female guinea pig (Kelly et al., 1984).

Reduced firing of GnRH neurone was shown in adult female mice (Chu et al., 2009).

Alterations in the concentrations of oestrogen receptors in the hypothalamus was shown in rat (Adashi et al., 1980).

Negative Feedback of estrogen on GnRH secretion was studied in adult woman (Shaw et al., 2010).


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.

Baez-Jurado, E., Rincon-Benavides, M. A., Hidalgo-Lanussa, O., Guio-Vega, G., Ashraf, G. M., Sahebkar, A., et al. (2018). Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells. Front Neuroendocrinol, 52, 44-64. doi:S0091-3022(18)30094-3 [pii]10.1016/j.yfrne.2018.09.001.

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.

Boyar, R. M. (1970). Effects of clomiphene citrate on pituitary FSH, FSH-RF, and release of LH in immature and mature rats. Endocrinology, 86(3), 629-33. doi:10.1210/endo-86-3-629.

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.

Chu, Z., Andrade, J., Shupnik, M. A., & Moenter, S. M. (2009). Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype. J Neurosci, 29(17), 5616-27. doi:29/17/5616 [pii]10.1523/JNEUROSCI.0352-09.2009.

Cosman, F. (2003). Selective estrogen-receptor modulators. Clin Geriatr Med, 19(2), 371-9. doi:S0749-0690(02)00114-3 [pii]10.1016/s0749-0690(02)00114-3.

Couse, J. F., & Korach, K. S. (1999). Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev, 20(3), 358-417. doi:10.1210/edrv.20.3.0370.

Goerzen, J., Corenblum, B., & Taylor, P. J. (1985). Potentiation of GnRH response by clomiphene citrate. J Reprod Med, 30(10), 749-52.

Haskell, S. G. (2003). Selective estrogen receptor modulators. South Med J, 96(5), 469-76. doi:10.1097/01.SMJ.0000051146.93190.4A.

Hu, L., Gustofson, R. L., Feng, H., Ki Leung, P., Mores, N., Krsmanovic, L. Z., et al. (2008). Converse regulatory functions of estrogen receptor-α and-β subtypes expressed in hypothalamic gonadotropin-releasing hormone neurons. Molecular Endocrinology, 22(10), 2250-2259.

Kelly, M. J., Ronnekleiv, O. K., & Eskay, R. L. (1984). Identification of estrogen-responsive LHRH neurons in the guinea pig hypothalamus. Brain Res Bull, 12(4), 399-407. doi:0361-9230(84)90112-6 [pii]10.1016/0361-9230(84)90112-6.

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.

Koch, Y., Dikstein, S., Superstine, E., & Sulman, F. G. (1971). The effect of promethazine and clomiphene on gonadotrophin secretion in the rat. J Endocrinol, 49(1), 13-7. doi:10.1677/joe.0.0490013.

Komatsuzaki, Y., & Kawato, S. (2007). Rapid Effect of Progesterone on the Intracellular Ca2+ Oscillation of Immortalized Hypothalamic GT1-7 Cells. bioimages, 15, 1-7.

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

Micevych, P. E., & Kelly, M. J. (2012). Membrane estrogen receptor regulation of hypothalamic function. Neuroendocrinology, 96(2), 103-10. doi:000338400 [pii]10.1159/000338400.

Ng, Y., Wolfe, A., Novaira, H. J., & Radovick, S. (2009). Estrogen regulation of gene expression in GnRH neurons. Molecular and cellular endocrinology, 303(1-2), 25-33.

Petersen, S. L., McCrone, S., Keller, M., & Shores, S. (1995). Effects of estrogen and progesterone on luteinizing hormone-releasing hormone messenger ribonucleic acid levels: consideration of temporal and neuroanatomical variables. Endocrinology, 136(8), 3604-10. doi:10.1210/endo.136.8.7628399.

Roy, D., Angelini, N. L., & Belsham, D. D. (1999). Estrogen directly represses gonadotropin-releasing hormone (GnRH) gene expression in estrogen receptor-α (ERα)-and ERβ-expressing GT1–7 GnRH neurons. Endocrinology, 140(11), 5045-5053.

Shaw, N. D., Histed, S. N., Srouji, S. S., Yang, J., Lee, H., & Hall, J. E. (2010). Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab, 95(4), 1955-61. doi:jc.2009-2108 [pii]10.1210/jc.2009-2108.

Spergel, D. J. (2019). Modulation of Gonadotropin-Releasing Hormone Neuron Activity and Secretion in Mice by Non-peptide Neurotransmitters, Gasotransmitters, and Gliotransmitters. Front Endocrinol (Lausanne), 10, 329. doi:10.3389/fendo.2019.00329.

Tan, S. L., Farhi, J., Homburg, R., & Jacobs, H. S. (1996). Induction of ovulation in clomiphene-resistant polycystic ovary syndrome with pulsatile GnRH. Obstet Gynecol, 88(2), 221-6. doi:0029-7844(96)00190-1 [pii]10.1016/0029-7844(96)00190-1.

Temple, J. L., Laing, E., Sunder, A., & Wray, S. (2004). Direct action of estradiol on gonadotropin-releasing hormone-1 neuronal activity via a transcription-dependent mechanism. J Neurosci, 24(28), 6326-33. doi:10.1523/JNEUROSCI.1006-04.200424/28/6326 [pii].

Temple, J. L., & Wray, S. (2005). Bovine serum albumin-estrogen compounds differentially alter gonadotropin-releasing hormone-1 neuronal activity. Endocrinology, 146(2), 558-63. doi:en.2004-1117 [pii]10.1210/en.2004-1117.

Zhang, Z., Bartsch, J. W., Benzel, J., Lei, T., Nimsky, C., & Voellger, B. (2009). Selective estrogen receptor modulators decrease invasiveness in pituitary adenoma cell lines AtT-20 and TtT/GF by affecting expression of MMP-14 and ADAM12. FEBS Open Bio, 10(11), 2489-2498. doi:10.1002/2211-5463.12999.

Zoeller, R. T., & Young, W. S., 3rd (1988). Changes in cellular levels of messenger ribonucleic acid encoding gonadotropin-releasing hormone in the anterior hypothalamus of female rats during the estrous cycle. Endocrinology, 123(3), 1688-9. doi:10.1210/endo-123-3-1688.