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Relationship: 2580
Title
Suppression, Estrogen receptor (ER) activity leads to Increased, secretion of GnRH from hypothalamus
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite | Under Development |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
Sex Applicability
Sex | Evidence |
---|---|
Female | High |
Male | Low |
Life Stage Applicability
Term | Evidence |
---|---|
Adult, reproductively mature | High |
Key Event Relationship Description
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
Evidence Supporting this KER
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
Molecular mechanism for the enhancement of GnRH by suppression of Estrogen receptor activity is poorly known.
Empirical Evidence
Compound class |
Species |
Study type |
Dose |
KER findings |
Reference |
Clomiphene citrate |
Adult Rat (female) |
Quantification of GnRH |
(1-100 ng/kg, 21-48 days) |
GnRH – 37.0± 3.6 µg/mg (Control) GnRH – 76.7±5.8 µg/mg (Clomiphene treated) |
(Koch et al., 1971) |
Clomiphene citrate |
Immature female rats (female) |
Quantification of pituitary concentra- tion of FSH (ovarian weight augmenta- tion method) |
1.0 mg/kg/day for 20 days |
FSH-RF – 32.0 (22.3- 41.7) µg/mg (Control) FSH-RF – 122.0 (29.2- 215.8) µg/mg (Clomiphene treated) |
(Boyar, 1970) |
17β-estradiol |
Hypothalamic cell line of transgenic mice (GT1–7) |
Expression of GnRH mRNA |
1 nm |
~55% down regulation of the expression of GnRH mRNA. |
(Roy et al., 1999) |
Uncertainties and Inconsistencies
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
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).
Quantitative Understanding of the Linkage
Not Specified
Response-response Relationship
Not Specified
Time-scale
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
Not Specified
Domain of Applicability
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).
References
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.
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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.
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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.
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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.
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