AOP-Wiki

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<div id="title">
<h2>AOP ID and Title:</h2>
<div class="title">AOP 440: Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</div>
Short Title: Hypothalamic estrogen receptors inhibition leading to ovarian cancer
</div>
<h2>Graphical Representation</h2>
<img src="https://aopwiki.org/system/dragonfly/production/2023/01/27/6lme0ftqfj_AOP440_coach_feedback_2023.01.26_.png" height="500" width="700" alt=""/>
<div id="authors">
<h2>Authors</h2>
Kalyan Gayen, Department of Chemical Engineering, National Institute of Technology Agartala, India
Tridib Kumar Bhowmick, Department of Bioengineering, National Institute of Technology Agartala, India
</div>
<div id="status">
<h2>Status</h2>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Author status</th>
<th scope="col">OECD status</th>
<th scope="col">OECD project</th>
<th scope="col">SAAOP status</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Under development: Not open for comment. Do not cite</td>
<td>Under Development</td>
<td>1.104</td>
<td>Included in OECD Work Plan</td>
</tr>
</tbody>
</table>
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</div>
<div id="coaches">
<h2>Coaches</h2>
<ul>
<li class="contributor" id="coach_63">
Rex FitzGerald
</li>
</ul>
</div>
<div id="abstract">
<h2>Abstract</h2>
Malfunctioning of sex hormones (e.g., estradiol, estrone and progesterone) may result in ovarian cancer (Fooladi et al. 2020, Meehan and Sadar 2003). Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, etc. are the causes of ovarian cancer (Samtani, Sharma and Garg 2018). Some stressors molecules (e.g., clomiphene citrate, Tamoxifen, Toremifene) act on neuronal cell in the hypothalamus (molecular initiating event, MIE), where they inhibit hypothalamic Estrogen Receptors selectively and these chemicals increase the risk of ovarian cancer (McLemore et al. 2009). These stressors molecules stimulate the releasing of gonadotropin-releasing hormone (GnRH) from hypothalamic region of brain by the suppression of hypothalamic Estrogen Receptors. Subsequently, secretion of luteinizing hormone (LH) from pituitary becomes high(Cassidenti et al. 1992, Mungenast and Thalhammer 2014a, Tomao et al. 2014). This hormone regulates the synthesis of sex hormones (e.g., estrogens) at cellular level (Shoemaker et al. 2010a, Tomao et al. 2014). These sex hormones are primarily produced in the gonads through a series of enzyme-mediated reactions from cholesterol (precursor) and control through complex signalling pathway along hypothalamus – pituitary –  gonadal (HPG) axis (Shoemaker et al. 2010a, Perkins et al. 2019). High estrogen level increases the risk of ovarian cancer via ovarian epithelial cell hyperplasia (McLemore et al. 2009, Tomao et al. 2014).
</div>
~~<div id="background">~~
~~<h3>Background</h3>~~
Development and progression of certain types of cancer disease (e.g. ovarian cancer, breast cancer, prostate cancer etc.) is related with the hormonal levels in human. Lack of proper diagnosis at early stage of the disease increase the mortality rate of the cancer. Among many types of cancer ovarian cancer has the high mortality rate (~50%) due to the lack of proper diagnosis at early stage of the disease progression. Circulating levels of the steroidal sex hormones in conjunction with the gene expression is related with the progression of this disease. Some important sex hormones which are related with many cancer diseases include oestrogen, progesterone and testosterone. Oestrogen hormone mainly involved in female sex organ development, controlling of menstruation cycle etc. Progesterone also involved in controlling menstrual cycle, maintaining pregnancy and spermatogenesis. Testosterone hormone regulates sexual development, bone mass development, red blood cell production in male.
<h2>AOP Development Strategy</h2>
<div id="context">
<h3>Context</h3>
Development and progression of certain types of cancer disease (e.g. ovarian cancer, breast cancer, prostate cancer etc.) is related with the hormonal levels in human. Lack of proper diagnosis at early stage of the disease increase the mortality rate of the cancer. Among many types of cancer ovarian cancer has the high mortality rate (~50%) due to the lack of proper diagnosis at early stage of the disease progression. Circulating levels of the steroidal sex hormones in conjunction with the gene expression is related with the progression of this disease. Some important sex hormones which are related with many cancer diseases include oestrogen, progesterone and testosterone. Oestrogen hormone mainly involved in female sex organ development, controlling of menstruation cycle etc. Progesterone also involved in controlling menstrual cycle, maintaining pregnancy and spermatogenesis. Testosterone hormone regulates sexual development, bone mass development, red blood cell production in male.
~~</div>~~
</div>
<div id="development_strategy">
<h3>Strategy</h3>
In females, sexual hormone balance protects the ovaries from the tumor development. A number of researches revealed that molecular level perturbation leading towards sex hormone imbalance plays important role in the development of the ovarian cancer. Specifically, high level of estrogens (estradiol, estrone and progesterone) enhances the risk of ovarian cancer via ovarian epithelial cell hyperplasia. Estrones are regulated in hypothalamus and activity of estrogen receptors plays crucial role. Research reports reveled that suppression of the activity of estrogen receptors, leads to high level of estrogens in blood circulation via hypothalamus – pituitary – gonadal (HPG) axis. Therefore, suppression of the activity of estrogen receptors is considered as molecular initiating event (MIE). This MIE regulates several Key Events (Kes) along HPG axis for high level of estrogens in circulating blood that increases the risk of ovarian cancer via ovarian epithelial cell hyperplasia.
</div>
<div id="aop_summary">
<h2>Summary of the AOP</h2>
<h3>Events</h3>
<h3>Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sequence</th>
<th scope="col">Type</th>
<th scope="col">Event ID</th>
<th scope="col">Title</th>
<th scope="col">Short name</th>
</tr>
</thead>
<tbody>
<tr>
<td></td>
<td>MIE</td>
<td>1046</td>
<td><a href="/events/1046">Suppression, Estrogen receptor (ER) activity</a></td>
<td>Suppression, Estrogen receptor (ER) activity</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td></td>
<td>KE</td>
<td>1047</td>
<td><a href="/events/1047">Increased, secretion of GnRH from hypothalamus</a></td>
<td>Increased, secretion of GnRH from hypothalamus</td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1050</td>
<td><a href="/events/1050">Increased, secretion of LH from anterior pituitary</a></td>
<td>Increased, secretion of LH from anterior pituitary</td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1972</td>
<td><a href="/events/1972">Increased, Steroidogenic acute regulatory protein (StAR) </a></td>
<td>Increased, Steroidogenic acute regulatory protein (StAR) </td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1973</td>
<td><a href="/events/1973">Increased, estrogens </a></td>
<td>Increased, estrogens </td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1076</td>
<td><a href="/events/1076">Increased, circulating estrogen levels</a></td>
<td>Increased, circulating estrogen levels</td>
</tr>
<tr>
<td></td>
<td>KE</td>
<td>1052</td>
<td><a href="/events/1052">Hyperplasia, ovarian epithelium</a></td>
<td>Hyperplasia, ovarian epithelium</td>
</tr>
<tr><td></td><td></td><td></td><td></td><td></td></tr>
<tr>
<td></td>
<td>AO</td>
<td>1053</td>
<td><a href="/events/1053">Promotion, ovarian adenomas</a></td>
<td>Promotion, ovarian adenomas</td>
</tr>
<tr>
<td></td>
<td>AO</td>
<td>2092</td>
<td><a href="/events/2092">Promotion, Ovarian Cancer </a></td>
<td>Promotion, Ovarian Cancer </td>
</tr>
</tbody>
</table>
</div>
<h3>Key Event Relationships</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Upstream Event</th>
<th scope="col">Relationship Type</th>
<th scope="col">Downstream Event</th>
<th scope="col">Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/relationships/2580">Suppression, Estrogen receptor (ER) activity</a></td>
<td>adjacent</td>
<td>Increased, secretion of GnRH from hypothalamus</td>
<td>High</td>
<td>Not Specified</td>
</tr>
<tr>
<td><a href="/relationships/1089">Increased, secretion of GnRH from hypothalamus</a></td>
<td>adjacent</td>
<td>Increased, secretion of LH from anterior pituitary</td>
<td>High</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/2581">Increased, secretion of LH from anterior pituitary</a></td>
<td>adjacent</td>
<td>Increased, Steroidogenic acute regulatory protein (StAR) </td>
<td>High</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/2582">Increased, Steroidogenic acute regulatory protein (StAR) </a></td>
<td>adjacent</td>
<td>Increased, estrogens </td>
<td>High</td>
<td>Moderate</td>
</tr>
<tr>
<td><a href="/relationships/2583">Increased, estrogens </a></td>
<td>adjacent</td>
<td>Increased, circulating estrogen levels</td>
<td>High</td>
<td>Moderate</td>
</tr>
<tr>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr>
<td><a href="/relationships/2585">Increased, circulating estrogen levels</a></td>
<td>non-adjacent</td>
<td>Hyperplasia, ovarian epithelium</td>
<td>High</td>
<td>Not Specified</td>
</tr>
<tr>
<td><a href="/relationships/1093">Hyperplasia, ovarian epithelium</a></td>
<td>non-adjacent</td>
<td>Promotion, ovarian adenomas</td>
<td>High</td>
<td>Not Specified</td>
</tr>
<tr>
<td><a href="/relationships/2829">Promotion, ovarian adenomas</a></td>
<td>non-adjacent</td>
<td>Promotion, Ovarian Cancer </td>
<td>Moderate</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
<h3>Stressors</h3>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Name</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Tamoxifen</td>
<td>Moderate</td>
</tr>
<tr>
<td>Raloxifene</td>
<td>Moderate</td>
</tr>
<tr>
<td>Clomiphene citrate (1:1)</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div id="overall_assessment">
<h2>Overall Assessment of the AOP</h2>
Suppression, Estrogen receptor (ER) activity [Evidence- Strong]: There are number of reports available related to  suppression of Estrogen receptor activity (ER) (Baez-Jurado et al., 2018; Cosman, 2003; Haskell, 2003; Ng et al., 2009; Kang et al., 2001; Roy et al., 1999; Marques P, 2018; Mungenast and Thalhammer, 2014b; Ghasemnejad-Berenji et al., 2020; J. H. Liu, 2020; Oride et al., 2020; Zhang et al., 2020; John F. Kerin et al., 1985b; The Practice Committee of the American Society for Reproductive Medicine, 2013; Moskovic et al., 2012 ; Bryan J. Herzog, 2020). Stressors act on neuronal cell in the hypothalamus, where it inhibits hypothalamic Estrogen Receptors selectively. A number of compounds or molecules (e.g. Clomiphene citrate, Tamoxifen, Toremifene etc.) are detected which show the modulation activity of estrogen receptor in brain leading to high GnRH pulses (Haskell, 2003; Cosman, 2003).
Increased, secretion of GnRH from hypothalamus[Evidence- Strong]: A number of evidencesare found by the researchesthat the increased secretion of gonadotropin-releasing hormone (GnRH)(Shander and Goldman, 1978; Tsourdi et al., 2009). Studies had shown that of inhibition of Estrogen receptor activity (ER) enhances the secretion of GnRH in human (Adashi et al., 1980; Bussenot et al., 1990; JOHN F KERIN et al., 1985a; Tan et al., 1996), rat and mice (Bharti et al., 2013; Kumar and Pakrasi, 1995; Zoeller and Young, 1988). Studies on human patient had shown the application of clomiphene is able to promote response of GnRH secretion (Goerzen et al., 1985; Tan et al., 1996).
Increased, secretion of LH from anterior pituitary [Evidence- Strong]: Good evidence may be acquired from different published articles for the increased secretion of LH increases from anterior pituitary (Plouffe and Siddhanti, 2001; Wright et al., 2012; Shoemaker et al., 2010b). It is also reported that increased secretion of the GnRH in hypothalamus leads to high levelofLH in human (John F Kerin et al., 1985a; Adashi et al., 1980; Bussenot et al., 1990), mice/rat.(Bharti et al., 2013; Kumar and Pakrasi, 1995; Botte et al., 1999) and cow (Fields et al., 2009).
Increased, Steroidogenic acute regulatory protein (StAR) [Evidence- Strong]: Steroidogenic acute regulatory protein (StAR) plays critical role in luteal steroidogenesis by controlling the transport of cholesterol from the outer to inner mitochondrial membrane(Wu et al., 2003; Shoemaker et al., 2010b).It had been reported that increase in LH level leads to increase StAR protein concentration in human(Tsang et al., 1980; Johnson and Bridgham, 2001; Murayama et al., 2012; Rekawiecki et al., 2005), rat(T. Liu et al., 2007; Martinat et al., 2005) and mice(Eacker et al., 2008; Tsuchiya et al., 2003).
Increased, estrogens [Evidence- Strong]: Aromatase is a key enzyme for estrogen formation in human tissues. In female, one of the important sites of estrogen enzyme synthesis is ovarian granulose cells(Holesh et al., 2017; Shoemaker et al., 2010b). Although ovarian aromatase enzyme expression in postmenopausal female is very low, high estrogen level is maintained in the blood through aromatase expression in other tissues. A number of researches had shown increased synthesis of StAR Protein increases the estrogen in ovarian granulosa cellsin human (Kiriakidou et al., 1996; Fang et al., 2016; Men et al., 2017), rat (Ronen-Fuhrmann et al., 1998; Nimrod, 1981) and fish (Kusakabe et al., 2002).
Increased, circulating estrogen levels [Evidence- Strong]: Researches had shown increased synthesis of estrogen in ovarian granulosa cells leads to maintain the high circulating estrogen levels in blood (Holesh et al., 2017; Shoemaker et al., 2010b).
Hyperplasia, ovarian epithelium [Evidence- High]: Ovarian surface is covered by the epithelium cells often called as ovarian mesothelium tissue. High evidence is available which supports that hyperplasia of the stromal cells might lead towards the hyperplasia of the ovarian epithelium tissue(Nyboe Andersen et al., 2008; Kang et al., 2001).
Promotion, ovarian adenomas[Evidence- Moderate]: Ovarian adenoma or cystadenoma is classified as benign tumor in the epithelial tissue. Evidence on the promotion of ovarian adenoma due to the hyperplasia in the ovarian epithelial tissue is available.
Promotion, ovarian cancer [Evidence- Strong]: Promotion of ovarian adenomas  leads to the phenotype outcome of ovarian cancer at individual level (Johansson et al., 2022, Christine Stewart et al., 2019).
<h3>Domain of Applicability</h3>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex: This particular AOP is mainly applicable for the females. Sex hormone regulation in female is more complex compare to the male. Development and growth of the ovaries depend on the hormonal balance in the body. This hormonal balance in female changes often observed during the menstrual cycle and pregnancy. Imbalance in the hormonal levels leads to the abnormal function of the ovaries.Predominant form of estrogen (estradiol) hormone also found in male and plays critical role in sexual behavior and spermatogenesis. However, males more likely experiences imbalance in testosterone hormonelevels.
Life stage: This AOP is closer to the adult female. In particular the females (at the age of 45-55) going through the menopause are having greater chance of developing ovarian cancer compared to the young adult female. Young female undergoing through the hormonal therapy (usually estrogen) also having high risk of developing ovarian cancer. Risk factor of ovarian cancer is high in case of adult females who are taking ovulation stimulating drugs to increase fertility.
Taxonomic: For this AOP taxonomic domain is applicable to the different species like mice, rat, guinea pig and human.
<h3>Essentiality of the Key Events</h3>
In this AOP the essentiality of the proposed events are supported by a number of scientific works.
Kettel et al., had shown the treatment of seventeen females with clomiphene citrate with 150mg/day dose for 5 days enhance the estrogen levels. Analysis of the other hormones (follicle-stimulating hormone, luteinizing hormone, gonadotropin-releasing hormone) levels suggest the clomiphene citrate involved in the modulation in hormonal secretion at the hypothalamic site (Kettel et al., 1993).
Koch et al, had shown female rat injected with the clomiphene citrate (1-100 ng/kg) for 20 days increase the gonadotropin-releasing hormone (GnRH) release in the hypothalamus region (Koch et al., 1971).
Research by Kurosawa et al., on 293T cells (transfectable derivative of human embryonic kidney 293 cells, revealed that effect of clomiphene citrate depend on the concentration of the molecule. Clomiphene citrate at higher concentration (10-10 - 10-12 M) showed the estrogenic activity. However at higher concentration (10-6 - 10-12 M) no estrogenic activity was observed. Results of the study also suggest that clomiphene citrate either act as agonist or as an antagonist depends on the presence of 17β-estradiol (E2) receptor(Kurosawa et al., 2010).
<h3>Weight of Evidence Summary</h3>
Overall assessment of the biological plausibility, empirical support and quantitative understanding of the KEs and KERs associated with this AOP shows that molecular mechanism or signaling pathway of tumor development in the female ovaries due to the suppression of estrogen receptors activities in the hypothalamus is still unclear.
Empirical evidence is available which shows the release of gonadotropin-releasing hormone (GnRH) depends on the concentration of the Selective Estrogen Receptors Modulator (SERM) compound (e.g. clomiphene citrate). However, molecular mechanism for the enhancement of GnRH by suppression of Estrogen receptor activity is poorly known.A number of researches had shown secretion of luteinizing hormone (LH) from anterior pituitary depends on the GnRH concentration or dose. Scientific reports have shown the both stimulatory and inhibitory effects on the GnRH secretion exhibited by the estradiol depending on the concentration of stressor (clomiphene) molecules and presence of types of receptors. The requirement of the GnRH dose for the secretary release of the LH in the different species varies widely.
A number of articles had shown that release of LH from the anterior pituitary regulates the steroidogenic function of cells by controlling the cholesterol transportation to the mitochondria. Biological plausibility of this event is very high as a number of studies have shown the similar results using different biological models (e.g.  granulosa cells of adult female, bovine luteal cells, leydig cells of mice and rat etc.) in their study. Estradiol synthesis during menstrual cycle is governed via expression of StAR protein synthesis. Quantitative estimation of the event has been performed through indirect measurement (e.g. Northern blot analysis of mRNA collected from ovarian follicle granulosa cells). Therefore in many studies finding results are inconsistent. Circulating estrogen levels increases due to the increased estradiol synthesis and concentration controlled by the negative feedback loop of the other steroidal hormone synthesis.Biological evidence of tumor formation in the ovarian granulose cells due to the high circulating estrogen levels in the plasma is pretty high. High circulating estrogen drives the endometrial hyperplasia towards the progression of endometrial cancer.
<h3>Quantitative Consideration</h3>
Quantitative understanding in many KEs and KERs are available. However, exploitation of different biological models and use of different assay techniques provide incoherent results. Inconsistent results also have been mentioned in many KEs and KERs. A few assay techniques such as radioimmunoassay, radioreceptor assay, estrogen receptor binding assay etc. are sensitive enough to measure the concentration of a molecule at pictogram level. Some other techniques such as quantitative real time PCR (qRT-PCR), northern blot analysis of RNA also have been used for quantitative estimation of molecules at low concentration. Some indirect methods such as immunohistochemistry also have been employed for identification and quantitative estimation of biological molecule.
</div>
<div id="considerations_for_potential_applicaitons">
<h2>Considerations for Potential Applications of the AOP (optional)</h2>
This AOP provides the valuable informations regarding chemical messengers and different glands of endocrine system that are related for the risk and promotion of ovarian cancer. Linkage of qualitative and quantitative informations of different chemical messengers for the promotion of ovarian cancer would be beneficial for the cancer therapy and cancer drug development. Further, this AOP would be helpful to evaluate the hazardous long-term effects of the endocrine-disrupting chemicals and drugs which may lead towards the development of the ovarian cancer. This AOP would also help to regulate the uses of these stressor molecules which have inhibitory effects on the hypothalamic Estrogen Receptors.   Understanding of the molecular events related with this AOP would help to screen these molecules and provide guideline to access the risk associated with these stressors.
</div>
<div id="references">
<h2>References</h2>
Adashi, E., A. Hsueh & S. Yen (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, 383-392.
Baez-Jurado, E., M. A. Rincon-Benavides, O. Hidalgo-Lanussa, G. Guio-Vega, G. M. Ashraf, A. Sahebkar, V. Echeverria, L. M. Garcia-Segura & G. E. Barreto (2018) Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells. Front Neuroendocrinol, 52, 44-64.
Bharti, S., M. Misro & U. Rai (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, 140-148. e5.
Botte, M., Y. Lerrant, A. Lozach, A. Berault, R. Counis & M. Kottler (1999) LH down-regulates gonadotropin-releasing hormone (GnRH) receptor, but not GnRH, mRNA levels in the rat testis. Journal of Endocrinology, 162, 409-415.
Bryan J. Herzog, H. M. T. N., Ayman Soubra, and Wayne J.G. Hellstrom (2020) Clomiphene Citrate for Male Hypogonadism and Infertility: An Updated Review. Androgens: Clinical Research and Therapeutics, 1, 62-69.
Bussenot, I., J. Parinaud, C. Clamagirand, G. Vieitez & G. Pontonnier (1990) Effect of clomiphene cirate on oestrogen secretion by human granulosa cells in culture. Human Reproduction, 5, 533-536.
Cassidenti, D. L., R. J. Paulson, R. A. Lobo & M. V. Sauer (1992) The synergistic effects of clomiphene citrate and human menopausal gonadotrophin in the folliculogenesis of stimulated cycles as assessed by the gonadotrophin-releasing hormone antagonist Nal-Glu. Hum Reprod, 7, 344-8.
Christine Stewart, Christine Ralyea & S. Lockwood (2019) Ovarian Cancer: An Integrated Review. Seminars in Oncology Nursing, 35, 151-156.
Cosman, F. (2003) Selective estrogen-receptor modulators. Clin Geriatr Med, 19, 371-9.
Eacker, S. M., N. Agrawal, K. Qian, H. L. Dichek, E. Y. Gong, K. Lee & R. E. Braun (2008) Hormonal regulation of testicular steroid and cholesterol homeostasis. Mol Endocrinol, 22, 623-35.
Fang, L., Y. Yu, R. Zhang, J. He & Y. P. Sun (2016) Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells. Sci Rep, 6, 24917.
Fields, S. D., B. L. Perry & G. A. Perry (2009) Effects of GnRH treatment on initiation of pulses of LH, LH release, and subsequent concentrations of progesterone. Domest Anim Endocrinol, 37, 189-95.
Fooladi, S., H. Akbari, M. Abolhassani, E. Sadeghi & H. Fallah (2020) Estradiol, des-acylated, and total ghrelin levels might be associated with epithelial ovarian cancer in postmenopausal women. medRxiv.
Ghasemnejad-Berenji, M., S. Pashapour & H. Ghasemnejad-Berenji (2020) Therapeutic potential for clomiphene, a selective estrogen receptor modulator, in the treatment of COVID-19. Medical Hypotheses, 145.
Goerzen, J., B. Corenblum & P. J. Taylor (1985) Potentiation of GnRH response by clomiphene citrate. J Reprod Med, 30, 749-52.
Haskell, S. G. (2003) Selective estrogen receptor modulators. South Med J, 96, 469-76.
Holesh, J. E., A. N. Bass & M. Lord (2017) Physiology, Ovulation.
Janson, P. O., L. Hamberger, J. E. Damber, B. Dennefors & F. Knutson (1980) Steroid production in vitro of a hilus cell tumor of the human ovary. Obstet Gynecol, 55, 662-5.
Johansson, Å., D. Schmitz, J. Höglund, F. Hadizadeh, T. Karlsson & W. E. Ek (2022) Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer. J Endocr Soc, 6, bvac100.
Johnson, A. L. & J. T. Bridgham (2001) Regulation of steroidogenic acute regulatory protein and luteinizing hormone receptor messenger ribonucleic acid in hen granulosa cells. Endocrinology, 142, 3116-24.
Kang, S. K., K. C. Choi, C. J. Tai, N. Auersperg & P. C. Leung (2001) Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells. Endocrinology. 2001 Feb;142(2):580-8. doi: 10.1210/endo.142.2.7982.
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</div>
<div id="appendicies">
<h2>Appendix 1</h2>
<h3>List of MIEs in this AOP</h3>
<h4><a href="/events/1046">Event: 1046: Suppression, Estrogen receptor (ER) activity</a></h4>
<h5>Short Name: Suppression, Estrogen receptor (ER) activity</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>estrogen receptor activity</td>
<td>estrogen receptor</td>
<td>decreased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Aop:165 - Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>MolecularInitiatingEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Stressors</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Name</th></tr>
</thead>
<tbody>
<tr><td>Clomiphene citrate (1:1)</td></tr>
<tr><td>Tamoxifen</td></tr>
<tr><td>Raloxifene</td></tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Molecular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>neuron</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>hypothalamus</td></tr>
</tbody>
</table>
</div>
~~<h3>Evidence for Perturbation by Stressor</h3>~~
~~<h4>Overview for Molecular Initiating Event</h4>~~
Clomiphene citrate (a stressor) at 10-10 - 10-12 M concentrations exhibits approximately 30% of the estrogenic activity which is same from 17β-estradiol (at 10-10 M) in ERα-expressing cells where as no activity in ERβ cells.
Clomiphene citrate at the concentration of  10-10 M reveals weak estrogen agonist activity in the presence of 17 β -estradiol (E2) at the concentration of 10-14 M in ERα-expressing cells, and no activity was found in ERβ cells.
Clomiphene citrate at lower doses (10-10 - 10-12 M), but not higher doses (10-6 - 10-8 M) showed estrogenic activity via ERα. However, clomiphene citrate at concentrations between 10-6 M and 10-12 M did not reveal any estrogenic activity via ERβ. In the presence of E2, clomiphene citrate worked as either as an agonist or an antagonist through ERα depending on the concentrations of E2.  Clomiphene citrate worked as antagonistic when it is combined with the higher E2 concentrations and worked as agonistic with the lower E2 concentrations. On the other hand, via ER β, clomiphene citrate acted as an estrogen antagonist irrespective of the concentration of E2. (Kurosawa et al., 2010).
~~ ~~
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Not Otherwise Specified</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Mixed</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Neuronal cell in Hypothalamus
<h4>Key Event Description</h4>
Estrogen receptors are produced in all vertebrates and located in either the cell cytoplasm or nucleus(Bondesson et al., 2015; Eick and Thornton, 2011). Estrogen receptors are localized either in cytoplasm, or on the cell surface.
Site of action: Stressors (e.g., clomiphene) act on neuronal cell in the hypothalamus, where it inhibits hypothalamic Estrogen Receptors selectively.
Responses at the macromolecular level: Stressors activate the Estrogen Receptor α in the presence of lower level of estrogen and partially blocks the same for higher level of estrogen and works as antagonist for the Estrogen Receptor β(Trost and Khera, 2014). Stressors appear to act in the brain's pituitary gland to secrete an increased amount of gonadotropins hormone (GnRH) in hypothalamus leading towards increased GnRH level in blood.
Estrogen Receptor α: ERα (Estrogen Receptor α or NR3A1 or ESR1) - A nuclear receptor and it is activated by the estrogen (sex hormone). Estrogen located at chromosome number 6 ( 6q25.1)
Estrogen Receptor β:  ERβ (Estrogen Receptor β or NR3A2 or  ESR2) – This is also nuclear receptor and  activated by the sex hormone estrogen which is located at chromosome number 14 (14q23.2). I ERβ has  both N-terminal has DNA binding domain and C-terminal has ligand binding domain. This  is localized to the nucleus, cytoplasm, and mitochondria. Selective estrogen receptor modulators (SERM) inhibits the ERβ. Drugs used as SERM are clomiphene, tamoxifen, raloxifene etc.
Biological compartments:  Estrogen receptors (ER) are present in the plasma membrane. Both ERα and ERβ have diverse functions depending on cells and organs. ERs have also been loacated in cytoplasmic organelles including mitochondria and the endoplasmic reticulum(Levin, 2009).
General role in biology: Estrogen receptors (both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) binds the estrogens to promote the the biological functions of estrogens. Depending upon a balance between ERα and ERβ activities in target organs, estrogen signaling is selectively stimulated or inhibited (Welboren et al., 2009). ERβ has a high degree of sequence homology with the classical estrogen receptor. Interestingly, ERβ is detected in many tissues, including those previously assumed to be estrogen insensitive. In tissues where both ERs are expressed, such as the hypothalamus, uterus, mammary glands, and immune system, ERα promotes proliferation whereas ERβ has pro-apoptotic and pro-differentiating functions(Morani et al., 2008). ERα is present mainly in ovary (thecal cells) where as ERβ is found mainly in  ovary (granulosa cells)(Paterni et al., 2014). ERα and ERβ is identical approximately 97% in the DNA-binding domain and approximately 56% in the ligand-binding domain(Dahlman-Wright et al., 2006).
<h4>How it is Measured or Detected</h4>
Radioreceptor assay/The estrogen receptor binding assay (using Rat Uterine Cytosol): This assay identifies chemicals that have the potential to interact with the estrogen receptor (ER) in vitro.  Principle of this particular assay is based on the competitive protein-binding methods. A radiolabelled ligand and an unlabelled ligand are presented together to a specific receptor. The radioactivity measurement provides the quantitative estimation of the bound and unbound fraction of the ligand with the receptor. All cytosolic estrogen receptor subtypes that are expressed in the specific tissue, including ERα and ERβ are used for the determination of estrogen receptor binding. This assay is simple and rapid to perform when optimal conditions for binding are determined. Assay determines if a ligand/chemical can interact and displace the endogenous hormone 17β-estradiol (Freyberger et al., 2010).
<h4>References</h4>
Adashi, E. Y., Hsueh, A. J., & Yen, S. S. (1980). Alterations induced by clomiphene in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus of female rats. J Endocrinol. , 87(3), 383-92.
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.
Bondesson, M., Hao, R., Lin, C.-Y., Williams, C., & Gustafsson, J.-Å. (2015). Estrogen receptor signaling during vertebrate development. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 1849(2), 142-151.
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.
Dahlman-Wright, K., Cavailles, V., Fuqua, S. A., Jordan, V. C., Katzenellenbogen, J. A., Korach, K. S., et al. (2006). International union of pharmacology. LXIV. Estrogen receptors. Pharmacological reviews, 58(4), 773-781.
Dominguez, R., & Micevych, P. (2010). Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. J Neurosci, 30(38), 12589-96. doi:30/38/12589 [pii]10.1523/JNEUROSCI.1038-10.2010.
Eick, G. N., & Thornton, J. W. (2011). Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology, 334(1-2), 31-38.
Freyberger, A., Wilson, V., Weimer, M., Tan, S., Tran, H. S., & Ahr, H. J. (2010). Assessment of a robust model protocol with accelerated throughput for a human recombinant full length estrogen receptor-alpha binding assay: protocol optimization and intralaboratory assay performance as initial steps towards validation. Reprod Toxicol, 30(1), 50-9. doi:S0890-6238(10)00003-1 [pii].
Kerin, J. F., Liu, J. H., Phillipou, G., & Yen, S. S. (1985). Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab. , 61(2), 65-68.
Kettel, L. M., Roseff, S. J., Berga, S. L., Mortola, J. F., & Yen, S. S. (1993). Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril. , 59(3), 532-38.
Koch, Y., Dikstein, S., Superstine, E., & Sulman, F. G. (1971). THE EFFECT OF PROMETHAZINE AND CLOMIPHENE ON GONADOTROPHIN SECRETION IN THE RAT. Journal of Endocrinology, 49(1), 13-17. doi:10.1677/joe.0.0490013.
Kurosawa, T., Hiroi, H., Momoeda, M., Inoue, S., & Taketani, Y. (2010). Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors αand β. Endocrine journal, 57(6), 517-521.
Levin, E. R. (2009). Plasma membrane estrogen receptors. Trends in Endocrinology & Metabolism, 20(10), 477-482.
Morani, A., Warner, M., & Gustafsson, J. Å. (2008). Biological functions and clinical implications of oestrogen receptors alfa and beta in epithelial tissues. Journal of internal medicine, 264(2), 128-142.
Oride, A., Kanasaki, H., Tumurbaatar, T., Zolzaya, T., Okada, H., Hara, T., et al. (2020). Effects of the Fertility Drugs Clomiphene Citrate and Letrozole on Kiss-1 Expression in Hypothalamic Kiss-1-Expressing Cell Models. Reproductive sciences (Thousand Oaks, Calif.), 27. doi:10.1007/s43032-020-00154-1.
Paterni, I., Granchi, C., Katzenellenbogen, J. A., & Minutolo, F. (2014). Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids, 90, 13-29.
Sutaria, U., Crooke, A., Bertrand, P., & Hodgson, C. (1980). Clomiphene citrate and human chorionic gonadotropin in the treatment of anovulatory infertility. International Journal of Gynecology & Obstetrics, 18(6), 435-437.
Taheripanah, R., Kabir-Salmani, M., Favayedi, M., Zamaniyan, M., Malih, N., & Taheripanah, A. (2020). Effects of clomiphene citrate plus estradiol or progesterone on endometrial ultrastructure: An RCT. International Journal of Reproductive BioMedicine, 18(3), 201.
Trost, L. W., & Khera, M. (2014). Alternative treatment modalities for the hypogonadal patient. Current urology reports, 15(7), 1-12.
Wahab, O. A., Princely, A. C., Oluwadamilare, A. A., Ore-Oluwapo, D. O., Blessing, A. O., & Alfred, E. F. (2019). Clomiphene citrate ameliorated lead acetate-induced reproductive toxicity in male Wistar rats. JBRA assisted reproduction, 23(4), 336-343. doi:10.5935/1518-0557.20190038.
Welboren, W.-J., Sweep, F. C., Span, P. N., & Stunnenberg, H. G. (2009). Genomic actions of estrogen receptor?: what are the targets and how are they regulated? Endocrine-related cancer, 16(4), 1073.
<h3>List of Key Events in the AOP</h3>
<h4><a href="/events/1047">Event: 1047: Increased, secretion of GnRH from hypothalamus</a></h4>
<h5>Short Name: Increased, secretion of GnRH from hypothalamus</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>hormone secretion</td>
<td>Gonadotropin Releasing Hormone</td>
~~<td>decreased</td>~~
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Aop:165 - Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/623">Aop:623 - Activation, estrogen receptor alpha leads to persistent vaginal cornification via increased kisspeptin release</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>gonadotropin releasing neuron</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>hypothalamus</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>mammals</td>
<td>mammals</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>Moderate</td>
</tr>
<tr>
<td>Juvenile</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Unspecific</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Life Stage: Adult, reproductively mature, juveniles.
Sex: Applies to both males and females as both sexes require GnRH signalling for regulation of various hormone pathways.
Taxonomic: Primarily studied in laboratory rodents and humans.  Plausible for most mammals due to conserved hormone pathways regulating hypothalamus-pituitary-gonadal axis processes.  GnRH widespread among vertebrates, including amphibians, reptiles, birds, and mammals (Duan and Allard 2020).
<h4>Key Event Description</h4>
Gonadotropin-releasing hormone (GnRH) is a key signalling hormone in the hypothalamus- pituitary-gonadal (HPG) axis in mammals produced by the hypothalamus.  Gonadotropin-releasing hormone is a peptide hormone composed of 10 amino acids (Hassanein et al. 2024).  The C terminal (Pro-Gly-NH2) is involved in receptor binding, with the N-terminal (pGlu-His-Trp-Ser) involved in receptor activation (Hassanein et al. 2024).  Increased levels of GnRH occur due to increased secretion from the hypothalamus.
<h4>How it is Measured or Detected</h4>
GnRH can be measured via immunoassay or Western blotting (studies that utilized this approach include Clarkson et al. 2008; Kriszt et al. 2015; Bo et al. 2022), and include commercially available ELISA kits (e.g. Elabscience E-EL-0071 (universal; no cross-species reactivity); Assay Genie HUFI02509 (human); Cusabio CSB-E06880h (human); Biomatik EKC39138-96T (rat)).  Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
Real time PCR can be used to measure GnRH transcript abundance, which is an indirect – and only semi-quantitative indicator of GnRH hormone levels (studies that utilized this approach include Wang et al. 2014; Kriszt et al. 2015; Zhou et al. 2023).
<h4>References</h4>
Bo T, Liu M, Tang L, Lv J, Wen J, Wang D. 2022.  Effects of High-Fat Diet During Childhood on Precocious Puberty and Gut Microbiota in Mice. Frontiers in Microbiology 13: 930747.
Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH,  Herbison AE. 2008. Kisspeptin–GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. Journal of Neuroscience 28(35): 8691–8697.
Duan C, Allard J. 2020.  Gonadotropin-releasing hormone neuron development in vertebrates. General and Comparative Endocrinology. 292: 113465
Hassanein, E.M., Szelényi, Z., Szenci, O. 2024.  Gonadotropin-Releasing Hormone (GnRH) and Its Agonists in Bovine Reproduction I: Structure, Biosynthesis, Physiological Effects, and Its Role in Estrous Synchronization. Animals 14: 1473.
Kriszt R, Winkler Z, Polyak A, Kuti D, Molnar C, Hrabovszky E, Kallo I, Szoke Z, Ferenczi S, Kovacs KJ. 2015.  Xenoestrogens Ethinyl Estradiol and Zearalenone Cause Precocious Puberty in Female Rats via Central Kisspeptin Signaling. Endocrinology 156(11): 3996-4007.
Wang X, Chang F, Bai Y, Chen F, Zhang J, Chen L. 2014. Bisphenol A enhances kisspeptin neurons in anteroventral periventricular nucleus of female mice. Journal of Endocrinology 28(35): 201-213.
Zhou L, Ren Y, Li D, Zhou W, Li C, Wang Q, Yang X. 2023. Timosaponin AIII attenuates precocious puberty in mice through downregulating the hypothalamic-pituitary-gonadal axis. Acta Biochimica Polonica 70(1): 183-190.
NOTE: Italics indicate edits from John Frisch January 2026.  A full list of updates can be found in the Change Log on the View History page.
<h4><a href="/events/1050">Event: 1050: Increased, secretion of LH from anterior pituitary</a></h4>
<h5>Short Name: Increased, secretion of LH from anterior pituitary</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>luteinizing hormone secretion</td>
<td>Luteinizing hormone</td>
<td>decreased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Aop:165 - Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/1972">Event: 1972: Increased, Steroidogenic acute regulatory protein (StAR) </a></h4>
<h5>Short Name: Increased, Steroidogenic acute regulatory protein (StAR) </h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>increased luteinizing hormone level</td>
<td>StAR-related lipid transfer protein 3</td>
<td>increased</td>
</tr>
<tr>
<td>increased luteinizing hormone level</td>
<td>StAR-related lipid transfer protein 4</td>
<td>increased</td>
</tr>
<tr>
<td>increased luteinizing hormone level</td>
<td>StAR-related lipid transfer protein 5</td>
<td>increased</td>
</tr>
<tr>
<td>increased luteinizing hormone level</td>
<td>StAR-related lipid transfer protein 6</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>steroid hormone secreting cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>reproductive organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>Monkey</td>
<td>Monkey</td>
<td>Low</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
In Granulosa cells
<h4>Key Event Description</h4>
Biological state: Steroidogenic acute regulatory protein (StAR) plays important role in luteal steroidogenesis(Christenson and Devoto, 2003). Steroidogenic acute regulatory protein (StAR) controls the transport of cholesterol from the outer to inner mitochondrial membrane(Stocco, 2000). There are several pathways involved for the transport of cholesterol from different subcellular pools into the inner mitochondria(Martin et al., 2016).
Biological compartments: Cholesterol is one type of lipid which is crystalline solid with yellow colour.  It is <a href="https://en.wikipedia.org/wiki/Biosynthesis" title="Biosynthesis">biosynthesized</a> by animal <a href="https://en.wikipedia.org/wiki/Cell_(biology)#Eukaryotic_cells" title="Cell (biology)">cells</a> and is an essential structural component of <a href="https://en.wikipedia.org/wiki/Animal" title="Animal">animal</a> <a href="https://en.wikipedia.org/wiki/Cell_membrane" title="Cell membrane">cell membranes</a> (Hanukoglu, 1992). It is the precursor molecule for the synthesis all <a href="https://en.wikipedia.org/wiki/Steroid_hormones" title="Steroid hormones">steroid hormones</a>(Payne and Hales, 2004).  Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in <a href="https://en.wikipedia.org/wiki/Hormone" title="Hormone">hormone</a> synthesis in mitochondria using <a href="https://en.wikipedia.org/wiki/Cholesterol" title="Cholesterol">cholesterol</a> as precursor(Poderoso et al., 2013).
General role in biology:  It is been reported that high  in cholesterol levels in mitochondrial resulted several diseases like cancer, neurodegenerative diseases, steatohepatitis ischemia, and influence disease (Martin et al., 2016). The alteration in mitochondrial cholesterol import may change the cholesterol concentrations that may lead to proper mitochondrial function along with biophysical properties of mitochondrial membranes. In absence of StAR protein, cholesterol transport into the mitochondria did not occurs leading to  no conversion of progesterone from cholesterol precursors doesn’t occur(Kiriakidou et al., 1996; Pescador et al., 1996). All Steroidogenic acute regulatory protein (StAR) promoters contain steroidogenic factor 1 binding sites which is responsible for sex hormones regulation(Manna et al., 2002).
One of the important function of the steroid hormones is maintaining reproductive capacity. For this purpose, steroidogenic cells must move large amounts of cholesterol from the outer mitochondrial membrane to the inner membrane. In the granulosa cells, this cholesterol is ultimately converted to progesterone. The initial transport of cholesterol across the mitochondrial membrane requires Steroidogenic Acute Regulatory (StAR) protein. Expression of StAR protein in preovulatory cells of the developing follicle is low. The dramatic upregulation of StAR protein expression within the dominant follicle is found after the luteinizing hormone (LH) surge. This upregulation allows the corpus luteum to produce substantial amounts of progesterone to maintain the reproductive capacity in human/animal (Men et al., 2017; Stocco, 2000).
<h4>How it is Measured or Detected</h4>
StAR protein is measure by quantitative real time PCR (qRT-PCR):
For qRT-PCR analyses, cDNA is synthesized using reagent kit in a 20-μl reaction containing 0.5 μg of total RNA collected from human ovarian granulosa tumor cell line ( KGN cells ), mouse Leydig cells. qPCR is performed in a 25-μl reaction containing 0.5 to 1.5 μl of cDNA using fluorescein in real-time PCR detection systems. PCR was performed by initial denaturation at 95°C for 5 minutes, followed by 40 cycles of 30 seconds at 95°C, 30 seconds at 60°C, and 30 seconds at 72°C. The threshold cycle values of each sample are used to calculate mRNA levels. The PCR primers for the indicated human and mouse genes are as follows (Men et al., 2017).
Human H19 forward: 5′-GCACCTTGGACATCTGGAGT
Human H19 reverse: 5′-TTCTTTCCAGCCCTAGCTCA
Human StAR forward: 5′-GGCATCCTTAGCAACCAAGA
Human StAR reverse: 5′-TCTCCTTGACATTGGGGTTC
Mouse StAR forward: 5′-TTGGGCATACTCAACAACCA
Mouse StAR reverse: 5′-GAAACACCTTGCCCACATCT
Indirect immunohistochemistry for the detection of Steroidogenic Acute Regulatory Protein (StAR):
Ovarian or peritoneal tissues from the human patients are collected. Ovarian or peritoneal tissues from the patient are fixed using 10% paraformaldehyde. Tissues are embedded in paraffin. Serial sections of 5 µm are made using microtome. Tissue sections are prepared by microwave heating in 10× citrate buffer, pH 6.0, for 10 min. Tissues are rinsed three times in 20 mM phosphate buffered saline (PBS), pH 7.2, for 10 min each, before incubation with 1:200 dilutions of polyclonal anti-human StAR antibodies at 37°C for 60 min. Tissue sections were washed three times in 20 mM PBS, pH 7.2, for 2 min each, before incubation with a 1:1000 dilution of secondary mouse– anti-rabbit antibody at 37°C for 30 min. Indirect immunohistochemistry kits were used according to the manufacturer’s instructions to visualize StAR protein stained tissue under microscope and image collected. A pathological image analysis system is used to measure mean optical density (MOD) analysis under high-magnification (×400) microscopy. The MOD, which reflected the positive staining intensity, and the positive staining ratio (area %) of every positively stained area, are measured. The area % is calculated as ([the area of positive staining]/[total nuclear area in the field of view]) × 100. The MOD and area % are used to calculate the expression index, EI (%) = MOD × area %(Tian et al., 2009).
<h4>References</h4>
Baker, B. Y., Epand, R. F., Epand, R. M., & Miller, W. L. (2007). Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR. J Biol Chem, 282(14), 10223-32. doi:S0021-9258(19)57693-1 [pii]
Chaffin, C., Dissen, G., & Stouffer, R. (2000). Hormonal regulation of steroidogenic enzyme expression in granulosa cells during the peri-ovulatory interval in monkeys. Molecular human reproduction, 6(1), 11-18.
Christenson, L. K., & Devoto, L. (2003). Cholesterol transport and steroidogenesis by the corpus luteum. Reproductive Biology and Endocrinology, 1(1), 1-9.
Hanukoglu, I. (1992). Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. The Journal of steroid biochemistry and molecular biology, 43(8), 779-804.
Hasegawa, T., Zhao, L., Caron, K. M., Majdic, G., Suzuki, T., Shizawa, S., et al. (2000). Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol, 14(9), 1462-71. doi:10.1210/mend.14.9.0515.
Kiriakidou, M., Mcallister, J. M., Sugawara, T., & Strauss 3rd, J. (1996). Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. The Journal of Clinical Endocrinology & Metabolism, 81(11), 4122-4128.
Manna, P. R., Dyson, M. T., Eubank, D. W., Clark, B. J., Lalli, E., Sassone-Corsi, P., et al. (2002). Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Molecular Endocrinology, 16(1), 184-199.
Martin, L. A., Kennedy, B. E., & Karten, B. (2016). Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function. Journal of bioenergetics and biomembranes, 48(2), 137-151.
Men, Y., Fan, Y., Shen, Y., Lu, L., & Kallen, A. N. (2017). The Steroidogenic Acute Regulatory Protein (StAR) Is Regulated by the H19/let-7 Axis. Endocrinology, 158(2), 402-409. doi:10.1210/en.2016-1340.
Payne, A. H., & Hales, D. B. (2004). Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews, 25(6), 947-970.
Pescador, N., Soumano, K., Stocco, D. M., Price, C. A., & Murphy, B. D. (1996). Steroidogenic acute regulatory protein in bovine corpora lutea. Biology of reproduction, 55(2), 485-491.
Poderoso, C., Duarte, A., Cooke, M., Orlando, U., Gottifredi, V., Solano, A. R., et al. (2013). The spatial and temporal regulation of the hormonal signal. Role of mitochondria in the formation of a protein complex required for the activation of cholesterol transport and steroids synthesis. Molecular and cellular endocrinology, 371(1-2), 26-33.
Sreerangaraja Urs, D. B., Wu, W.-H., Komrskova, K., Postlerova, P., Lin, Y.-F., Tzeng, C.-R., et al. (2020). Mitochondrial function in modulating human granulosa cell steroidogenesis and female fertility. International journal of molecular sciences, 21(10), 3592.
Stocco, D. (2000). The role of the StAR protein in steroidogenesis: challenges for the future. Journal of Endocrinology, 164(3), 247-253.
Tian, Y., Kong, B., Zhu, W., Su, S., & Kan, Y. (2009). Expression of steroidogenic factor 1 (SF-1) and steroidogenic acute regulatory protein (StAR) in endometriosis is associated with endometriosis severity. J Int Med Res, 37(5), 1389-95. doi:10.1177/147323000903700513.
<h4><a href="/events/1973">Event: 1973: Increased, estrogens </a></h4>
<h5>Short Name: Increased, estrogens </h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>estrogen secretion</td>
<td>Estrogen</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Cellular</td></tr>
</tbody>
</table>
</div>
<h4>Cell term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Cell term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>steroid hormone secreting cell</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>reproductive organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
It is applicable in reproduction system, cell growth and cell function
<h4>Key Event Description</h4>
Biological state: The most predominant form of estrogens is 17β-estradiol (E2) which is sex hormone. In women having premenopausal it is mainly produced in the ovaries. For postmenopausal women, it E2 primarily is sythesized from testosterone by aromatase enzyme in extragonadal tissues(Simpson, 2003). Estradiol stimulates both cell growth and cholesterogenesis in the MCF-7 line (breast cancer cell line) (Cypriani et al., 1988). Cholesterol increases neuronal estradiol release into the medium through synapse formation(Fester et al., 2009).
Biological compartments: Estrogen is considered as the risk of developing cholesterol gallstones by enhancing the hepatic secretion of biliary cholesterol leading to an increase in cholesterol(Wang et al., 2009).
General role in biology: When estrogen levels decline, levels of low-density lipoprotein, the harmful kind of cholesterol increases, and levels of high-density lipoprotein, the positive kind of cholesterol decrease, due to which fat build up in the body and cholesterol in the arteries that causes heart attack and stroke(Fåhraeus, 1988; Wahl et al., 1983). Granulosa cells are the primary cell which provides the support and microenvironment required for the developing oocyte in the ovary(Sen and Hammes, 2010; Sterneck et al., 1997).
<h4>How it is Measured or Detected</h4>
Radioimmunoassay (RIA) and analytical method based on mass spectroscopic are used for estrogen measurement present in serum (Smy and Straseski, 2018; Giese, 2003).
<h4>References</h4>
Adashi, E., & Hsueh, A. (1982). Estrogens augment the stimulation of ovarian aromatase activity by follicle-stimulating hormone in cultured rat granulosa cells. Journal of Biological Chemistry, 257(11), 6077-6083.
Cypriani, B., Tabacik, C., & Descomps, B. (1988). Effect of estradiol and antiestrogens on cholesterol biosynthesis in hormone-dependent and-independent breast cancer cell lines. Biochimica et Biophysica Acta (BBA)-Bioenergetics, 972(2), 167-178.
Darabi, M., Rabbani, M., Ani, M., Zarean, E., Panjehpour, M., & Movahedian, A. (2011). Increased leukocyte ABCA1 gene expression in post-menopausal women on hormone replacement therapy. Gynecological Endocrinology, 27(9), 701-705.
Fåhraeus, L. (1988). The effects of estradiol on blood lipids and lipoproteins in postmenopausal women. Obstetrics and gynecology, 72(5 Suppl), 18S-22S.
Fester, L., Zhou, L., Bütow, A., Huber, C., Von Lossow, R., Prange‐Kiel, J., et al. (2009). Cholesterol‐promoted synaptogenesis requires the conversion of cholesterol to estradiol in the hippocampus. Hippocampus, 19(8), 692-705.
Giese, R. W. (2003). Measurement of endogenous estrogens: analytical challenges and recent advances. Journal of Chromatography A, 1000(1), 401-412. doi:https://doi.org/10.1016/S0021-9673(03)00306-6.
Mao, Z., Li, J., & Zhang, W. (2018). Hormonal regulation of cholesterol homeostasis. Cholesterol-Good, Bad and the Heart.
Park, Y., Maizels, E. T., Feiger, Z. J., Alam, H., Peters, C. A., Woodruff, T. K., et al. (2005). Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. Journal of Biological Chemistry, 280(10), 9135-9148.
Sen, A., & Hammes, S. R. (2010). Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Molecular endocrinology, 24(7), 1393-1403.
Simpson, E. R. (2003). Sources of estrogen and their importance. The Journal of steroid biochemistry and molecular biology, 86(3-5), 225-230.
Smy, L., & Straseski, J. A. (2018). Measuring estrogens in women, men, and children: Recent advances 2012-2017. Clin Biochem, 62, 11-23.
Sterneck, E., Tessarollo, L., & Johnson, P. F. (1997). An essential role for C/EBPβ in female reproduction. Genes & development, 11(17), 2153-2162.
Wahl, P., Walden, C., Knopp, R., Hoover, J., Wallace, R., Heiss, G., et al. (1983). Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol. New England Journal of Medicine, 308(15), 862-867.
Wang, H. H., Liu, M., Clegg, D. J., Portincasa, P., & Wang, D. Q.-H. (2009). New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1791(11), 1037-1047.
<h4><a href="/events/1076">Event: 1076: Increased, circulating estrogen levels</a></h4>
<h5>Short Name: Increased, circulating estrogen levels</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td></td>
<td>estrogen</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/168">Aop:168 - GnRH pulse disruption leading to mammary adenomas and carcinomas in the SD rat.</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/169">Aop:169 - GnRH pulse disruption leading to pituitary adenomas and carcinomas in the SD rat.</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/561">Aop:561 - Aromatase induction leading to estrogen receptor alpha activation via increased estradiol</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Organ</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/1052">Event: 1052: Hyperplasia, ovarian epithelium</a></h4>
<h5>Short Name: Hyperplasia, ovarian epithelium</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>hyperplasia</td>
<td>epithelium of female gonad</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Aop:165 - Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>KeyEvent</td>
</tr>
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>KeyEvent</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Tissue</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>epithelium of female gonad</td></tr>
</tbody>
</table>
</div>
<h3>List of Adverse Outcomes in this AOP</h3>
<h4><a href="/events/1053">Event: 1053: Promotion, ovarian adenomas</a></h4>
<h5>Short Name: Promotion, ovarian adenomas</h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td></td>
<td>Adenoma</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Aop:165 - Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>AdverseOutcome</td>
</tr>
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>AdverseOutcome</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Tissue</td></tr>
</tbody>
</table>
</div>
<h4><a href="/events/2092">Event: 2092: Promotion, Ovarian Cancer </a></h4>
<h5>Short Name: Promotion, Ovarian Cancer </h5>
~~<h4>Key Event Component</h4>~~
<h4>Event Component</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Process</th>
<th scope="col">Object</th>
<th scope="col">Action</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>endocrine signaling</td>
<td>estrone</td>
<td>increased</td>
</tr>
</tbody>
</table>
</div>
<h4>AOPs Including This Key Event</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP ID and Name</th>
<th scope="col">Event Type</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Aop:440 - Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>AdverseOutcome</td>
</tr>
</tbody>
</table>
</div>
<h4>Biological Context</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Level of Biological Organization</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>Organ</td></tr>
</tbody>
</table>
</div>
<h4>Organ term</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr><th scope="col">Organ term</th></tr>
</thead>
<tbody class="tbody-striped">
<tr><td>female reproductive organ</td></tr>
</tbody>
</table>
</div>
<h4>Domain of Applicability</h4>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
It is applicable in ovary for reproductive matured female.
<h4>Key Event Description</h4>
Biological state: Ovarian cancer is fatal gynecological malignancy and ranked as fifth most commonly diagnosed cancer among women.  Generally, mortality rate is highest (~ 50 %) from this cancer as there is lack of proper diagnosis at early stage(Siegel et al. 2019). Ovarian cancers are broadly categorised into three types based on origin of cells namely epithelial, stromal and germ cell cancers (Gilks and Prat 2009). Recent research efforts revealed that numbers of molecular level (genome, transcriptome and proteome level) perturbations are responsible for the development and progression of ovarian cancer (Cheng and Zhan 2017).  There is need to develop a molecular level biomarker for early detection, treatment and development of personalized medicine. Understanding of molecular level interactions in large and complex biological networks using systems biology approach will be key factors to identify the major regulatory motifs (Zhang et al. 2018). This approach not only reduces the animal experiments substantially, but will able to quick detect of key perturbations
Biological compartments: Recent studies have suggested that FSH stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis and facilitates neovascularisation (Tao et al. 2013). Earlier studies also have established that the estrogen (ER) and progesterone (PR) receptors are important prognostic indicators of breast and endometrial cancers, and epithelial ovarian cancer. Despite acceptance regarding the influence of reproductive hormones on ovarian cancer risk and considerable advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, complete understanding of the biologic processes underlying malignant transformation of ovarian surface epithelium is still lacking  (Gharwan et al. 2015).
General role in biology: Malfunctioning of sex hormones (e.g., estradiol, estrone and progesterone) may result ovarian cancer (Fooladi et al. 2020, Meehan and Sadar 2003). Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, etc. are the cause of ovarian cancer (Samtani et al. 2018). Clomiphene which is used as drug to treat infertility and it is reported that this chemical increases the risk of ovarian cancer (McLemore et al. 2009). Clomiphene (molecular initiating event, MIE) stimulates the releasing of gonadotropin-releasing hormone (GnRH) from hypothalamic. Also, it stimulates the secretion of the Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from pituitary (Cassidenti et al. 1992, Mungenast and Thalhammer 2014, Tomao et al. 2014). These hormones regulate the synthesis of sex hormons (e.g., estrogen) level (Shoemaker et al. 2010, Tomao et al. 2014). These sex hormones are primarily produced in the gonads through a series of enzyme-mediated reactions from cholesterol (precursor) and control through complex signalling pathway along hypothalamus – pituitary - gonadal (HPG) axis (Perkins et al. 2019, Shoemaker et al. 2010).  The series of complex signalling pathways in ovary include G-protein cycle, G-protein activation, adenylate cyclase (AC) activation, cyclic AMP (cAMP) activation, protein kinase A (PKA) activation, steroidogenic factor 1 (SF1) and StAR transcription. Ultimately, this signalling pathway activates the StAR protein which regulates the intake of cholesterol into the inner mitochondria where synthesis of sex hormones takes place. It may be noted that cholesterol is the precursor of the sex hormones synthesis.  Again, releasing of LH is regulated by estradiol and testosterone level resulting complex signalling pathway that includes genes, transcritome, proteome and metabolites (Perkins et al. 2019, Shoemaker et al. 2010). Under clomiphene exposure, synthesis of estrogen level becomes high resulting risk of ovarian cancer (McLemore et al. 2009, Tomao et al. 2014). Therefore, perturbations of GnRH, FSH and LH can result adverse phenotype as ovarian cancer.
<h4>How it is Measured or Detected</h4>
Gossmann et al., had shown the effects of angiogenesis inhibition on tumor microvascular permeability was monitored with the help of magnetic resonance imaging (MRI) technique in a rat model of human ovarian cancer (Gossmann et al. 2000).
Gitsch et al., had developed gamma-ray detection probe for overcoming the conventional radio-immunoscintigraphy problems for the detection of ovarian cancer in female patients (Gitsch and Pateisky 1989).
Kim et al., had used the detection of magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) for the detection of ovarian tumor in human patient. Sensitivity and accuracy of the PET/CT technique for detecting the ovarian tumor was reported 73% and 91%. Whereas, the sensitivity and accuracy of the MRI technique was reported 81% and 89% (Kim et al. 2007).
Harrington et al., had used immunotechniques (Anti-CDCP1 immuno-conjugates) for detection of the ovarian cancer. Expression and binding properties of the cell surface protein was detected in ovarian cancer cell (in vitro) using flow cytometry and western blot technique (Harrington et al.).
<h4>Regulatory Significance of the AO</h4>
Informations related with ovarian cancer will be helpful for the regulatory authorities to develop monographs, frame the rules of assesments and monitoring of the process.
<h4>References</h4>
Cassidenti, D.L., Paulson, R.J., Lobo, R.A. and Sauer, M.V. (1992) The synergistic effects of clomiphene citrate and human menopausal gonadotrophin in the folliculogenesis of stimulated cycles as assessed by the gonadotrophin-releasing hormone antagonist Nal-Glu. Hum Reprod 7(3), 344-348.
Cheng, T. and Zhan, X. (2017) Pattern recognition for predictive, preventive, and personalized medicine in cancer. EPMA J 8(1), 51-60.
Fooladi, S., Akbari, H., Abolhassani, M., Sadeghi, E. and Fallah, H. (2020) Estradiol, des-acylated, and total ghrelin levels might be associated with epithelial ovarian cancer in postmenopausal women. medRxiv.
Gharwan, H., Bunch, K.P. and Annunziata, C.M. (2015) The role of reproductive hormones in epithelial ovarian carcinogenesis. Endocr Relat Cancer 22(6), R339-363.
Gilks, C.B. and Prat, J. (2009) Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol 40(9), 1213-1223.
Gitsch, E. and Pateisky, N. (1989) Radio-immunoscintigraphy and intraoperative tumour detection by means of anti-tumour antibodies in patients with ovarian cancer. Baillieres Clin Obstet Gynaecol 3(1), 31-36.
Gossmann, A., Helbich, T.H., Mesiano, S., Shames, D.M., Wendland, M.F., Roberts, T.P., Ferrara, N., Jaffe, R.B. and Brasch, R.C. (2000) Magnetic resonance imaging in an experimental model of human ovarian cancer demonstrating altered microvascular permeability after inhibition of vascular endothelial growth factor. Am J Obstet Gynecol 183(4), 956-963.
Harrington, B.S., He, Y., Khan, T., Puttick, S., Conroy, P.J., Kryza, T., Cuda, T., Sokolowski, K.A., Tse, B.W., Robbins, K.K., Arachchige, B.J., Stehbens, S.J., Pollock, P.M., Reed, S., Weroha, S.J., Haluska, P., Salomon, C., Lourie, R., Perrin, L.C., Law, R.H.P., Whisstock, J.C. and Hooper, J.D. Anti-CDCP1 immuno-conjugates for detection and inhibition of ovarian cancer. Theranostics 10(5), 2095-2114.
Hollis, R.L.J.C.L. (2023) Molecular characteristics and clinical behaviour of epithelial ovarian cancers. 216057.
Jokerst, J.V., Cole, A.J., Van de Sompel, D. and Gambhir, S.S. (2012) Gold nanorods for ovarian cancer detection with photoacoustic imaging and resection guidance via Raman imaging in living mice. ACS Nano 6(11), 10366-10377.
Kim, C.K., Park, B.K., Choi, J.Y., Kim, B.G. and Han, H. (2007) Detection of recurrent ovarian cancer at MRI: comparison with integrated PET/CT. J Comput Assist Tomogr 31(6), 868-875.
Liu, Y., Lin, X., Bao, T., Ni, P., Xie, C., Shen, H., Xu, W., Xu, H. and Su, Z. (2015) [Detection and correlation analysis of miRNAs and myeloid-derived suppressor cells in ovarian cancer-bearing mice]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 31(4), 467-469, 473.
McLemore, M.R., Miaskowski, C., Aouizerat, B.E., Chen, L.M. and Dodd, M.J. (2009) Epidemiological and genetic factors associated with ovarian cancer. Cancer Nurs 32(4), 281-288; quiz 289-290.
Meehan, K.L. and Sadar, M.D. (2003) Androgens and androgen receptor in prostate and ovarian malignancies. Front Biosci 8, d780-800.
Mortlock, S., Corona, R.I., Kho, P.F., Pharoah, P., Seo, J.-H., Freedman, M.L., Gayther, S.A., Siedhoff, M.T., Rogers, P.A. and Leuchter, R.J.C.R.M. (2022) A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes.  3(3), 100542.
Mungenast, F. and Thalhammer, T. (2014) Estrogen biosynthesis and action in ovarian cancer. Front Endocrinol (Lausanne) 5, 192.
Perkins, E.J., Gayen, K., Shoemaker, J.E., Antczak, P., Burgoon, L., Falciani, F., Gutsell, S., Hodges, G., Kienzler, A., Knapen, D., McBride, M., Willett, C., Doyle, F.J. and Garcia-Reyero, N. (2019) Chemical hazard prediction and hypothesis testing using quantitative adverse outcome pathways. ALTEX 36(1), 91-102.
Samtani, R., Sharma, N. and Garg, D. (2018) Effects of Endocrine-Disrupting Chemicals and Epigenetic Modifications in Ovarian Cancer: A Review. Reprod Sci 25(1), 7-18.
Schneider, J., Jimenez, E., Marenbach, K., Romero, H., Marx, D. and Meden, H. (1999) Immunohistochemical detection of HSP60-expression in human ovarian cancer. Correlation with survival in a series of 247 patients. Anticancer Res 19(3A), 2141-2146.
Shoemaker, J.E., Gayen, K., Garcia-Reyero, N., Perkins, E.J., Villeneuve, D.L., Liu, L. and Doyle, F.J. (2010) Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. BMC Systems Biology 4(1), 89.
Siegel, R.L., Miller, K.D. and Jemal, A. (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1), 7-34.
Tao, X., Zhao, N., Jin, H., Zhang, Z., Liu, Y., Wu, J., Bast, R.C., Jr., Yu, Y. and Feng, Y. (2013) FSH enhances the proliferation of ovarian cancer cells by activating transient receptor potential channel C3. Endocr Relat Cancer 20(3), 415-429.
Tomao, F., Lo Russo, G., Spinelli, G.P., Stati, V., Prete, A.A., Prinzi, N., Sinjari, M., Vici, P., Papa, A., Chiotti, M.S., Benedetti Panici, P. and Tomao, S. (2014) Fertility drugs, reproductive strategies and ovarian cancer risk. J Ovarian Res 7, 51.
Zhang, T., Xu, J., Deng, S., Zhou, F., Li, J., Zhang, L., Li, L., Wang, Q.-E. and Li, F. (2018) Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data. PLOS ONE 13(5), e0196351.
<h2>Appendix 2</h2>
<h2>List of Key Event Relationships in the AOP</h2>
<div id="evidence_supporting_links">
<h3>List of Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/2580">Relationship: 2580: Suppression, Estrogen receptor (ER) activity leads to Increased, secretion of GnRH from hypothalamus</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>adjacent</td>
<td>High</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
</div>
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).
<h4>Key Event Relationship Description</h4>
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).
<h4>Evidence Supporting this KER</h4>
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
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Clomiphene citrate
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Adult Rat (female)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Quantification of GnRH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
(1-100 ng/kg, 21-48 days)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
GnRH – 37.0± 3.6 µg/mg (Control)
GnRH – 76.7±5.8 µg/mg (Clomiphene treated)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Koch et al., 1971)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Clomiphene citrate
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Immature female rats (female)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Quantification of pituitary concentra- tion of FSH (ovarian weight augmenta- tion method)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
1.0 mg/kg/day for 20 days
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
FSH-RF – 32.0 (22.3- 41.7) µg/mg (Control)
FSH-RF – 122.0 (29.2- 215.8) µg/mg (Clomiphene treated)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Boyar, 1970)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
17β-estradiol
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Hypothalamic cell line of transgenic mice (GT1–7)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Expression of GnRH mRNA
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
1 nm
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
~55% down regulation of the expression of GnRH mRNA.
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Roy et al., 1999)
</td>
</tr>
</tbody>
</table>
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).
<h4>Quantitative Understanding of the Linkage</h4>
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 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).
Known Feedforward/Feedback loops influencing this KER
Not Specified
<h4>References</h4>
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.
</div>
<div>
<h4><a href="/relationships/1089">Relationship: 1089: Increased, secretion of GnRH from hypothalamus leads to Increased, secretion of LH from anterior pituitary</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>adjacent</td>
<td>High</td>
<td></td>
</tr>
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>adjacent</td>
<td>High</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>cow</td>
<td>Bos taurus</td>
<td>Low</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9913" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
</div>
Adult
<h4>Key Event Relationship Description</h4>
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).
<h4>Evidence Supporting this KER</h4>
<ul>
<li>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).</li>
<li>Nicol et al., reported that high GnRH dose enhances the secretion of LH (Nicol et al., 2002)</li>
</ul>
Biological Plausibility
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).
Empirical Evidence
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
GnRH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Cows
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In-vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
GnRH dose of 100 micro gram
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
GnRH dose increases LH secration
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Fields et al., 2009)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
GnRH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Possums
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In-vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
GnRH dose increases LH secration
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Crawford et al., 2009)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
GnRH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Bitches
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In-vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
GnRH dose of 06.-2.4 microgram/kg
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
GnRH dose increases LH secration
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Concannon et al., 2006)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
GnRH agonist (triptorelin acetate) dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Humans
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In-vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
GnRH dose of 3.75 mg / person
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
GnRH agonist (triptorelin acetate) dose decrease LH seccretion
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Sonntag et al., 2005)
</td>
</tr>
</tbody>
</table>
Uncertainties and Inconsistencies
Not Specified
<h4>Quantitative Understanding of the Linkage</h4>
<ul>
<li>Fields et al., studied the dose response of GnRH (100 micro gram) on cows and observed greater release of LH (25 %) aftrer 12-18 hours (Fields et al., 2009)</li>
<li>Crawford et al., used PCR techniques to study the effect of GnRH on LH in vivo on Possums. They reported the increase of LH quantitavely in absence of pulse of LH(Crawford et al., 2009)</li>
<li>Guillaume et al., studied the two  GnRH antagonist  Antarelix and Cetrorelix (0.01 mg/kg) on mare and observed that there is strong suppression of LH (Guillaume et al., 2002)</li>
<li>Washington et al., developed one mathematical model for the respose of LH under the pulsatile and continuous exposure of GnRH (Washington et al., 2004</li>
<li>Shoemaker et al., developed a mathematical model on steroidogenesis in the fathead minnow. They quantified the relationship between GnRH and LH(Shoemaker et al., 2010)</li>
</ul>
Response-response relationship
Not Specified
Time-scale
<ul>
<li>Generally time scale is in hours (6-18) between GnRH and LH response (Fields et al., 2009). </li>
<li>GnRH is degraded by proteolysis within a few minutes(Kenealy et al., 2011). </li>
<li>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). </li>
</ul>
Known modulating factors
<ul>
<li>Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion (Garrido-Gracia et al., 2006)</li>
</ul>
Known Feedforward/Feedback loops influencing this KER
Not Specified
<h4>References</h4>
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]
10.1016/j.theriogenology.2006.02.007.
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, NatÃ l., 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].
</div>
<div>
<h4><a href="/relationships/2581">Relationship: 2581: Increased, secretion of LH from anterior pituitary leads to Increased, Steroidogenic acute regulatory protein (StAR) </a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>adjacent</td>
<td>High</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>Moderate</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
</div>
Adult
<h4>Key Event Relationship Description</h4>
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).
<h4>Evidence Supporting this KER</h4>
<ul>
<li style="text-align:justify">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).</li>
<li style="text-align:justify">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).</li>
</ul>
Biological Plausibility
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).
Empirical Evidence
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
LH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Bovine ovaries, Human
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vitro
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
5-50 ng/ml LH dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
LH increases StAR protein activity
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Murayama et al., 2012)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
LH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
granulosa cells,Human
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vitro
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
LH dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
LH increases StAR protein activity
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Johnson and Bridgham, 2001)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
LH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Leydig cells, Rat
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
LH dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
LH-induced StAR protein expression
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Martinat et al., 2005)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
LH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Bovine luteal cells, Human
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vitro
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
LH dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
LH increases StAR protein expression
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Rekawiecki et al., 2005)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
LH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Leydig cells, Rat
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
LH dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
LH increases StAR protein expression
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Liu et al., 2007)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
LH
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Leydig cell, Mice
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
LH dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
LH increases five fold StAR protein expression
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Eacker et al., 2008)
</td>
</tr>
</tbody>
</table>
Uncertainties and Inconsistencies
No uncertainties and inconsistencies are observed
<h4>Quantitative Understanding of the Linkage</h4>
<ul>
<li>Rekawieck et al. conducted the in vitro study on Bovine luteal cells to investigate the effect of LH on  steroid acute regulatory protein (StAR). They reported the LH enhances the activity of StAR protein (Rekawiecki et al., 2005).</li>
<li>Liu et al. investigated the effect of LH on StAR protein using rat as model and reported the positive correlation between Lh and StAR protein (Liu et al., 2007)</li>
<li>Eacker et al. reported that LH up regulates the StAR protein (around five fold) using mice model (Eacker et al., 2008)</li>
</ul>
Response-response relationship
Not specified
Time-scale
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 modulating factors
Not specified
Known Feedforward/Feedback loops influencing this KER
Not specified
<h4>References</h4>
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:https://doi.org/10.1016/S0024-3205(03)00698-2.
</div>
<div>
<h4><a href="/relationships/2582">Relationship: 2582: Increased, Steroidogenic acute regulatory protein (StAR) leads to Increased, estrogens </a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>adjacent</td>
<td>High</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>Low</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>Low</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>fish</td>
<td>fish</td>
<td>Low</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=0" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
</div>
Adult
<h4>Key Event Relationship Description</h4>
Steroidogenic acute regulatory (StAR) protein (37-kDa) is synthesized with a mitochondrial leader sequence in response to the cell stimulation to produce steroid and plays a crucial role in steroidogenesis (Hanukoglu, 1992).  Research had shown in human ovary StAR protein was produced in response to the Luteinizing Hormone (LH) surge (Kiriakidou et al., 1996). In particular, StAR protein involved in the transportation of the cholesterol (substrate for steroid hormone) from outer to inner mitochondrial membrane. This step is crucial and rate limiting in steroid biosynthesis. In the inner membrane of the mitochondria with the help of cleaved cholesterol pregnenolone is formed, which is the precursor to the different steroid hormones including estrogen (P. R. Manna et al., 2016). Effects of StAR protein on steroidal biosynthesis had been studied by number of researchers (Pulak R Manna et al., 2002; Pescador et al., 1996; Stocco, 2001).
Estradiol synthesis during menstrual cycle is governed via expression of StAR protein synthesis. Presence of StAR protein allows follicular production of androgens which allows the progesterone dominated microenvironment and help in sexual differentiation, growth, reproduction, development and metabolism. Kusakabe et al., had shown in trout fish (Salvelinus fontinalis) model that peak of StAR protein coincide with the menstrual hormone production peak (Kusakabe et al., 2002). Research had shown some toxic chemicals can caused alteration in steroidal regulation and resulted in the agonist effect on estrogen receptors (Lauretta et al., 2019).
<h4>Evidence Supporting this KER</h4>
Study on immature female rat model had shown rapid changes of the StAR protein level in the ovary during follicular development facilitate the production of estrogen (Ronen-Fuhrmann et al., 1998).
Fang et al., had studied StAR protein expression under the influence of amphiregulin protein in cultured primary human granulosa cells collected from female. Results of the study had shown that human chorionic gonadotropin (hCG) rapidly induces amphiregulin (AREG) expression in the culture cells. Treatment with amphiregulin increase StAR expression and progesterone production in the cells (Fang et al., 2016).
Biological Plausibility
StAR protein catalyzes the movement of cholesterol in the outer mitochondrial membrane to the inner membrane. There, cytochrome P450scc converts cholesterol to the steroid pregnenolone. Studies have shown (in mouse and rat model) some molecules (e.g. 25-hydroxycholesterol) can serve as a substrate for inducing the expression of StAR and influence the steroid production in different tissues. Other oxysterols molecules also capable of increasing STAR expression and pregnenolone synthesis in human endometrial stromal cells (P. R. Manna et al., 2016).
Empirical Evidence
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
StAR Protein
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Trout fish (Salvelinus fontinalis)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
In situ hybridization, cloning of cDNAs, Northern blot analysis of mRNA
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Stressor concentration
(0.5 ml/liter 2-phenoxyethanol)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Increased in StAR transcripts in tissues exhibiting enhanced steroid production and increased circulating levels of 17β-estradiol and maturation inducing steroid ( 17α,20β -dihydroxy-4-pregnen-3-one).
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Kusakabe et al., 2002)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
StAR Protein
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Hen (Single-comb white Leghorn)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Northern blot analysis of mRNA collected from ovarian follicle granulosa cells
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
MAP kinase inhibitor (U0126)-50 mM, Follicle stimulating hormone(FSH) -100 ng/ml, TGFa (50 ng/ml)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Acute increase in progesterone production in response to LH treatment
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Johnson et al., 2002)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
StAR Protein
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
The mouse MA-10 Leydig tumor cell line
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Northern blot analysis of  total RNA
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Fadrozole (100 µM)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
StAR Protein inhibition by antifungal drugs econazole and miconazole
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Walsh et al., 2000)
</td>
</tr>
</tbody>
</table>
Uncertainties and Inconsistencies
Chang et al., had investigated the effects of antimullerian hormone (AMH) on estradiol production in primary culture of human granulosa-lutein (hGL) cells. In the control cell estradiol concentration was found 43.2–93.7 ng/mL. Whereas,treatment with AMH (10 ng/mL) significantly reduced the estradiol accumulation in the cells (Chang et al., 2013).
<h4>Quantitative Understanding of the Linkage</h4>
Pescador et al., had studied the StAR mRNA levels in the bovine corpus luteum. Result of the study had shown that expression of StAR mRNA was low in developing corpus luteum. In mid to late luteal phase the concentration increased 9- to 15-fold compared to the expression of StAR mRNA during developing stage. Results confirms that StAR mRNA and protein are tightly coupled in the corpus luteum cells and present at low levels during CL development and present elevated concentrations during the midluteal phase (Pescador et al., 1996).
Response-response relationship
Not specified
Time-scale
Observed for hours
Known modulating factors
Arukwe had shown nonylphenol (15 µg/L) can induce the StAR protein in juvenile Atlantic salmon (Salmo salar) fish (Arukwe, 2005).
Known Feedforward/Feedback loops influencing this KER
Not specified
<h4>References</h4>
Arukwe, A. (2005). Modulation of brain steroidogenesis by affecting transcriptional changes of steroidogenic acute regulatory (StAR) protein and cholesterol side chain cleavage (P450scc) in juvenile Atlantic salmon (Salmo salar) is a novel aspect of nonylphenol toxicity. Environ Sci Technol, 39(24), 9791-8. doi:10.1021/es0509937.
Chang, H. M., Klausen, C., & Leung, P. C. (2013). Antimullerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. Fertil Steril, 100(2), 585-92 e1. doi:S0015-0282(13)00515-3 [pii]10.1016/j.fertnstert.2013.04.019.
Fang, L., Yu, Y., Zhang, R., He, J., & Sun, Y. P. (2016). Amphiregulin mediates hCG-induced StAR expression and progesterone production in human granulosa cells. Sci Rep, 6, 24917. doi:srep24917 [pii]10.1038/srep24917.
Hanukoglu, I. (1992). Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. The Journal of steroid biochemistry and molecular biology, 43(8), 779-804.
Johnson, A. L., Solovieva Ev Fau - Bridgham, J. T., & Bridgham, J. T. (2002). Relationship between steroidogenic acute regulatory protein expression and progesterone production in hen granulosa cells during follicle development. (0006-3363 (Print)).
Kiriakidou, M., Mcallister, J. M., Sugawara, T., & Strauss 3rd, J. (1996). Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. The Journal of Clinical Endocrinology & Metabolism, 81(11), 4122-4128.
Kusakabe, M., Todo, T., McQuillan, H. J., Goetz, F. W., & Young, G. (2002). Characterization and expression of steroidogenic acute regulatory protein and MLN64 cDNAs in trout. Endocrinology, 143(6), 2062-70. doi:10.1210/endo.143.6.8672.
Lauretta, R., Sansone, A., Sansone, M., Romanelli, F., & Appetecchia, M. (2019). Endocrine Disrupting Chemicals: Effects on Endocrine Glands. Front Endocrinol (Lausanne), 10, 178. doi:10.3389/fendo.2019.00178.
Manna, P. R., Dyson, M. T., Eubank, D. W., Clark, B. J., Lalli, E., Sassone-Corsi, P., et al. (2002). Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Molecular Endocrinology, 16(1), 184-199.
Manna, P. R., Stetson, C. L., Slominski, A. T., & Pruitt, K. (2016). Role of the steroidogenic acute regulatory protein in health and disease. Endocrine, 51(1), 7-21. doi:10.1007/s12020-015-0715-610.1007/s12020-015-0715-6 [pii].
Men, Y., Fan, Y., Shen, Y., Lu, L., & Kallen, A. N. (2017). The Steroidogenic Acute Regulatory Protein (StAR) Is Regulated by the H19/let-7 Axis. Endocrinology, 158(2), 402-409. doi:10.1210/en.2016-1340.
Nimrod, A. (1981). On the synergistic action of androgen and FSH on progestin secretion by cultured rat granulosa cells: cellular and mitochondrial cholesterol metabolism. Molecular and cellular endocrinology, 21(1), 51-62.
Pescador, N., Soumano, K., Stocco, D. M., Price, C. A., & Murphy, B. D. (1996). Steroidogenic acute regulatory protein in bovine corpora lutea. Biology of reproduction, 55(2), 485-491.
Ronen-Fuhrmann, T., Timberg, R., King, S. R., Hales, K. H., Hales, D. B., Stocco, D. M., et al. (1998). Spatio-temporal expression patterns of steroidogenic acute regulatory protein (StAR) during follicular development in the rat ovary. Endocrinology, 139(1), 303-15. doi:10.1210/endo.139.1.5694.
Stocco, D. M. (2001). StAR protein and the regulation of steroid hormone biosynthesis. Annu Rev Physiol. , 63, 193-2013. doi:10.1146/annurev.physiol.63.1.193.
Walsh, L. P., Kuratko, C. N., & Stocco, D. M. (2000). Econazole and miconazole inhibit steroidogenesis and disrupt steroidogenic acute regulatory (StAR) protein expression post-transcriptionally. J Steroid Biochem Mol Biol, 75(4-5), 229-36. doi:S0960076000001709 [pii]10.1016/s0960-0760(00)00170-9.
</div>
<div>
<h4><a href="/relationships/2583">Relationship: 2583: Increased, estrogens leads to Increased, circulating estrogen levels</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>adjacent</td>
<td>High</td>
<td>Moderate</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
<tr>
<td>Male</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
Judd et al, had measured the circulating estrogen level in the male and female lizards (Iguana iguana) (Judd et al., 1976).
Roberts et al., had estimated the circulating estrogen in the plasma collected from human volunteer (Roberts and Szego, 1946).
Truan et al., had shown the high circulating estrogen levels in the mice model  (Truan et al., 2010).
<h4>Key Event Relationship Description</h4>
Ovaries are the principle source of estrogen hormone in premenopausal women. This estrogen functions as a circulating hormone to act on different tissues. In postmenopausal women, estrogen is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. The monthly menstrual cycle in female is controlled through unique co-ordination between secreted hormones by the hypothalamus, the pituitary gland, and the ovary. Estrogen is synthesized from androgen, upon calalysis of aromatse enzyme present in the endoplasmic reticulam of the cells. Presence of aromatase enzyme is found majorly in the ovarian granulosa cells (premenopausal female), in the skin and adipose tissue (postmenopausal woman). Estrogen was synthesized in postmenopausal women due to the aromatization of steroids, found in the adipose and skin tissue.
Aromatase is a key enzyme for estrogen formation in human tissues. In men and postmenopausal women C19 steroids undergoes aromatization in different tissues (e.g. skin, adipose) to generate estrogen. In men, testicular steroidogenesis accounts for 15% of the circulating level of estrogen.
In women, the ovarian granulosa cells are important sites of estrogen formation for local use within the ovary as well as for endocrine signalling to the target tissues (e.g. uterus, skin, breast, brain, bone). In case of postmenopausal female, ovarian aromatase expression is stopped, but estrogen level is maintained in the plasma by the increased aromatase expression in other tissues (adipose and skin). Research had shown elevated circulating estradiol may persist at sufficient levels to cause postmenopausal uterine bleeding, endometrial hyperplasia, and even cancer.
<h4>Evidence Supporting this KER</h4>
Steger et al., had shown the age related changes in steroid productions in the ovaries of rat model. In this work researchers had shown the elevated serum estrone and estradiol level in the rats (mid–aged) (Steger and Peluso, 1982).
Biological Plausibility
Estrogens in humans are classified as estrone (E1) and estradiol (E2). E2 is synthesized  majorly in ovaries and testes by aromatization of testosterone. Small amounts of estrogens are produced in the adrenal glands and some peripheral tissues (e.g. skin, fat tissues). E2 and E1 are interchangeable, and both can be deactivated via hydroxylation. E2 has 1.25 to 5 times higher biological potency of E1. E2 circulates at 1.5 to 4 times more concentration of E1 in premenopausal women. E2 levels in men and postmenopausal women are much lower than in nonpregnant women. E2 levels in premenopausal women fluctuate during the menstrual cycle. An E2 level is lowest during the early follicular phase, then rise gradually until 2 to 3 days before ovulation. In the ovulatory phase E2 levels again declined.
Empirical Evidence
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Circulating estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
lizards (Iguana iguana)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Assay of plasma protein
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
-
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Estrogens mean concentrations were higher in the females compared to males. Estradiol (258 ± 46 pg/ml), Estrone (205 ± 147 pg/ml) – In Females.
Estradiol, 79 ± 42 pglml, Estrone, 37 ± 2 pglml – In Male
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Judd et al., 1976)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Circulating estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Human Plasma
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Assay of plasma protein fractions
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
-
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
1.5 to 2.0 µg of estriol (1.8 µg – in average) per 100 ml. of original plasma.
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Roberts and Szego, 1946)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Circulating estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
Mice
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:72px">
Ovariectomized athymic mice (BALB/c nu/nu, 4–5 wk old)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:64px">
A 100-µL cell suspension (4 x106 MCF-7 cells)
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
High circulating estrogen (E2) concentration (E2 pellet (0.36 mg/ 60-day release) simulating premenopause
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Truan et al., 2010)
</td>
</tr>
</tbody>
</table>
Uncertainties and Inconsistencies
Leung et al., had shown estradiol-17β (I mg) administration in the female rat for 3 days decrease the ovarian androgen levels (13 ± 2 pg/mg) compared to the control  (34 ± 7 pg/mg). Results of the study suggest estrogen levels controlled by the negative feedback loop of testosterone production (Leung et al., 1978).
<h4>Quantitative Understanding of the Linkage</h4>
Estrone concentrations in human
Males: 10-60 pg/mL, Females: Premenopausal: 17-200 pg/mL, Postmenopausal: 7-40 pg/mL
Estradiol concentrations in human
Males: 10-40 pg/mL, Females: Premenopausal: 15-350 pg/mL, Postmenopausal: <10 pg/mL (Cummings et al., 1998; Elmlinger et al., 2002)
Response-response relationship
Leung et al., had shown estradiol-17β (I mg) administration in the female rat for 3 days decrease the ovarian androgen levels (13 ± 2 pg/mg) compared to the control  (34 ± 7 pg/mg) (Leung et al., 1978).
Time-scale
Elevation of the circulating estrogen can be observed in days
Known modulating factors
Estrogen levels changes due to the following reasons.
<ul>
<li>High androgen levels caused by tumors </li>
<li>Androgen therapy </li>
<li>Elevations in estrogen due to aromatization</li>
<li>Obesity with increased tissue production of E1</li>
<li>Decreased estrogen clearance in liver disease</li>
<li>Estrogen producing tumors</li>
<li>Estrogen ingestion</li>
</ul>
Known Feedforward/Feedback loops influencing this KER
Not specified
<h4>References</h4>
Cummings, S. R., Browner, W. S., Bauer, D., Stone, K., Ensrud, K., Jamal, S., et al. (1998). Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med, 339(11), 733-8. doi:10.1056/NEJM199809103391104.
Elmlinger, M. W., Kuhnel, W., & Ranke, M. B. (2002). Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults. Clin Chem Lab Med, 40(11), 1151-60. doi:10.1515/CCLM.2002.202.
Judd, H. L., Laughlin, G. A., Bacon, J. P., & Benirschke, K. (1976). Circulating androgen and estrogen concentrations in lizards (Iguana iguana). Gen Comp Endocrinol, 30(3), 391-5. doi:0016-6480(76)90091-5 [pii]10.1016/0016-6480(76)90091-5.
Leung, P. C., Goff, A. K., Kennedy, T. G., & Armstrong, D. T. (1978). An intraovarian inhibitory action of estrogen on androgen production in vivo. Biol Reprod, 19(3), 641-7. doi:10.1095/biolreprod19.3.641.
Roberts, S., & Szego, C. M. (1946). The nature of circulating estrogen; lipoprotein-bound estrogen in human plasma. Endocrinology, 39, 183-7. doi:10.1210/endo-39-3-183.
Roy, E. J., & Wilson, M. A. (1981). Diurnal rhythm of cytoplasmic estrogen receptors in the rat brain in the absence of circulating estrogens. Science, 213(4515), 1525-7. doi:10.1126/science.7197053.
Steger, R. W., & Peluso, J. J. (1982). Effects of age on hormone levels and in vitro steroidogenesis by rat ovary and adrenal. Exp Aging Res, 8(3-4), 203-8. doi:10.1080/03610738208260367.
Truan, J. S., Chen, J. M., & Thompson, L. U. (2010). Flaxseed oil reduces the growth of human breast tumors (MCF-7) at high levels of circulating estrogen. Mol Nutr Food Res, 54(10), 1414-21. doi:10.1002/mnfr.200900521.
Wu, S., Zhu, Y., Zhang, J., Hu, X., & Yi, Y. (2020). [Effect of circulating estrogen level on the outcome of free fat grafting in nude mice]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 34(2), 220-225. doi:10.7507/1002-1892.201903011.
</div>
<h3>List of Non Adjacent Key Event Relationships</h3>
<div>
<h4><a href="/relationships/2585">Relationship: 2585: Increased, circulating estrogen levels leads to Hyperplasia, ovarian epithelium</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>non-adjacent</td>
<td>High</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>rat</td>
<td>Rattus norvegicus</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10116" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult, reproductively mature</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
Increase in circulating estrogen level causing  increase in the ovarian stromal cells observed in adult female (human) also in rabbit and rodents.
<h4>Key Event Relationship Description</h4>
Hyperplasia of the ovarian epithelial cells characterized by aggregates of tubular like structures or cleft lines. In the mammalian ovary tissue presence of germ cells surrounded by the somatic cells is known as follicles. During the oestrous cycle early stage follicles either go through atresia or ovaluation to produce mature egg for fertilization. With the age ovaries run out of follicles and female undergo menopause. Repetitive rupture and repair of the epithelium tissue of the ovarian cells causes genetic aberrations causing the abnormal growth of these cells ultimately leads towards hyperplasia (Bajwa et al., 2016).
Yamagata et al., studied that the increased estrogen were reflected in such target tissues proliferation, hyperplasia, atypical hyperplasia of the endometrium were observed in patients with ovarian tumors (Yamagata et al., 1989). Goad et al., had shown that unopposed estrogen drives the endometrial hyperplasia leads towards the progression of endometrial cancer in the uterine epithelium (Goad et al., 2018). During the menstrual cycle, epithelium tissue of the ovary proliferate under the influence of higher estrogenic level, and the increased mitotic activity is likely to enhance the risk of the mutation in the cells (Harvey A. Risch, 1998b).
<h4>Evidence Supporting this KER</h4>
Nash et al., had shown 50% increase in the growth rate of the epithelial ovarian cancer cell line (PE04) with the treatment of 17β-estradiol in vitro cell culture study (Nash et al., 1989).
Meissner et al., had shown the endometrial hyperplasias and cancers by excessive estrogenic stimulation in the female rabbit (Meissner et al., 1957).
Biological Plausibility
There are many kinds of ovarian tumors that are related with the estrogen or androgen levels. Granulosa cell tumor and thecoma are well-known estrogen-producing tumors. Metastatic ovarian tumors often have androgen-producing stroma and that mucinous cystadenoma produces estrogens. Many other ovarian tumors also can produce sexual hormones in their stroma (Tanaka et al., 2004).
Empirical Evidence
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:83px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
women
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:83px">
Increase in concentration of estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Atypical hyperplasia of the endometrium
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Yamagata et al., 1989)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
women
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In Vitro
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:83px">
Increase in concentration of estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Endometrial cancer by endometrial hyperplasia
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Goad et al., 2018)
</td>
</tr>
</tbody>
</table>
Uncertainties and Inconsistencies
Ho et al., had shown that steroid hormones, primarily estrogens and progesterone, are implicated in ovarian carcinogenesis and estrogens favor neoplastic transformation of the ovarian surface epithelium (Ho, 2003).
<h4>Quantitative Understanding of the Linkage</h4>
Not specified
Response-response relationship
Vuong  et al., had shown estrogen replacement therapy in the primary culture of the mouse ovarian surface epithelium cells increases the risk of ovarian cancer.  Study had demonstrated that exogenous estradiol accelerates the onset of ovarian cancer in mouse models via the ESR1 pathway to result in the down-regulation of a tumour suppressor gene (Vuong et al., 2017).
Time-scale
Observed in months to years
Known modulating factors
Not specified
Known Feedforward/Feedback loops influencing this KER
Not specified
<h4>References</h4>
Bajwa, P., Nagendra, P., Nielsen, S., Sahoo, S., Bielanowicz, A., Lombard, J., et al. (2016). Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium. Oncotarget, 7. doi:10.18632/oncotarget.8468.
Goad, J., Ko, Y.-A., Kumar, M., Jamaluddin, M. F. B., & Tanwar, P. S. (2018). Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling. Carcinogenesis, 39(9), 1105-1116.
Ho, S.-M. (2003). Estrogen, progesterone and epithelial ovarian cancer. Reproductive Biology and Endocrinology, 1(1), 1-8.
Meissner, W. A., Sommers, S. C., & Sherman, G. (1957). Endometrial hyperplasia, endometrial carcinoma, and endometriosis produced experimentally by estrogen. Cancer, 10(3), 500-509. doi:https://doi.org/10.1002/1097-0142(195705/06)10:3<500::AID-CNCR2820100312>3.0.CO;2-V.
Mirabolghasemi, G., & Kamyab, Z. (2017). Changes of the uterine tissue in rats with polycystic ovary syndrome induced by estradiol valerate. International journal of fertility & sterility, 11(1), 47.
Nash, J. D., Ozols, R. F., Smyth, J. F., & Hamilton, T. C. (1989). Estrogen and anti-estrogen effects on the growth of human epithelial ovarian cancer in vitro. Obstetrics and gynecology, 73(6), 1009-1016.
Nephew, K. P., Long, X., Osborne, E., Burke, K. A., Ahluwalia, A., & Bigsby, R. M. (2000). Effect of estradiol on estrogen receptor expression in rat uterine cell types. Biology of Reproduction, 62(1), 168-177.
Risch, H. A. (1998a). Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. Journal of the National Cancer Institute, 90(23), 1774-1786.
Risch, H. A. (1998b). Hormonal Etiology of Epithelial Ovarian Cancer, With a Hypothesis Concerning the Role of Androgens and Progesterone. JNCI: Journal of the National Cancer Institute, 90(23), 1774-1786. doi:10.1093/jnci/90.23.1774.
Tanaka, Y. O., Tsunoda, H., Kitagawa, Y., Ueno, T., Yoshikawa, H., & Saida, Y. (2004). Functioning Ovarian Tumors: Direct and Indirect Findings at MR Imaging. RadioGraphics, 24(suppl_1), S147-S166. doi:10.1148/rg.24si045501.
Vuong, N. H., Salah Salah, O., & Vanderhyden, B. C. (2017). 17Î²-Estradiol sensitizes ovarian surface epithelium to transformation by suppressing Disabled-2 expression. Scientific Reports, 7(1), 16702. doi:10.1038/s41598-017-16219-2.
Yamagata, S., Yamamoto, K., Tsuchida, S., Kawamura, N., Matsumoto, Y., Ueki, S., et al. (1989). Estrogen production in epithelial tumors of the ovary--clinical and endocrinological study in postmenopausal women. Nihon Sanka Fujinka Gakkai zasshi, 41(11), 1761-1768.
</div>
<div>
<h4><a href="/relationships/1093">Relationship: 1093: Hyperplasia, ovarian epithelium leads to Promotion, ovarian adenomas</a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/165">Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse</a></td>
<td>non-adjacent</td>
<td>High</td>
<td></td>
</tr>
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>non-adjacent</td>
<td>High</td>
<td>Not Specified</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<h4><a href="/relationships/2829">Relationship: 2829: Promotion, ovarian adenomas leads to Promotion, Ovarian Cancer </a></h4>
<h4>AOPs Referencing Relationship</h4>
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">AOP Name</th>
<th scope="col">Adjacency</th>
<th scope="col">Weight of Evidence</th>
<th scope="col">Quantitative Understanding</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td><a href="/aops/440">Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia</a></td>
<td>non-adjacent</td>
<td>Moderate</td>
<td>Low</td>
</tr>
</tbody>
</table>
</div>
<h4>Evidence Supporting Applicability of this Relationship</h4>
<div>
Taxonomic Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Term</th>
<th scope="col">Scientific Term</th>
<th scope="col">Evidence</th>
<th scope="col">Links</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>human</td>
<td>Homo sapiens</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606" target="_blank">NCBI</a></td>
</tr>
<tr>
<td>mice</td>
<td>Mus sp.</td>
<td>High</td>
<td><a href="http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10095" target="_blank">NCBI</a></td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Life Stage Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Life Stage</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Adult</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
Sex Applicability
<div class="table-responsive">
<table class="table table-bordered table-fullwidth">
<thead class="thead-light">
<tr>
<th scope="col">Sex</th>
<th scope="col">Evidence</th>
</tr>
</thead>
<tbody class="tbody-striped">
<tr>
<td>Female</td>
<td>High</td>
</tr>
</tbody>
</table>
</div>
</div>
Observed in adult female (human) also in rodents.
<h4>Key Event Relationship Description</h4>
Ovarian tumors are abnormal mass of tissues grows on or in the ovaries of the aged females. Ovarian adenomas / cystadenomas are very common and benign type of tumors, which are found in epithelial tissues of the ovaries. Almost 60% of the ovarian tumors are due to the epithelial neoplasm (abnormal growth of tissue) of the ovary (Limaiem et al. 2022). Ovarian adenomas are classified into different categories such as serous cystadenoma, mucinous cystadenoma, endometrioid cystadenoma, clear cell cystadenoma and seromucinous systadenoma. Reports have shown that ovarian serous cystadenoma can turn progress to serous carcinoma (Cheng et al. 2004). Frequent mutations of two genes (BRAF and KRAS) are identified as the cause of the serous carcinoma.
<h4>Evidence Supporting this KER</h4>
Nishida et al., had reported the development of adenoma malignum of the uterine cervix associated with the mucinous carcinoma in a female patient (Nishida et al. 1991).
Goedhals et al., had reported development of ovarian mucinous carcinoma arising from the mucinous cystadenoma of the ovary in a 68 yr old female patient (Goedhals et al. 2008).
Smith et al., had shown with the help of immunohistochemistry  the development of sebaceous adenoma arising within a benign ovarian mature cystic teratoma in a 52 yr old female patient (Smith et al. 2011).
Biological Plausibility
Cheng et al., had reported the sub-classification of Ovarian adenomas / cystadenoma based on the cell types such as serous cystadenoma, mucinous cystadenoma and endometrioid cystadenoma (Cheng et al. 2004). Possible molecular genetic alteration associated with the high grade serous and endometrioid cystadenoma are mutation in TP53 gene and dysfunction of BRCA1 and/or BRCA 2 gene. Whereas, low grade serous carcinoma or borderline serous cystadenoma occurred via activation of the RAS-RAF signaling pathway and frequent mutations in BRAF or KRAS genes. Mucinous cystadenoma is originated in germ cells and often related with mutation in KRES gene (Beroukhim et al. 2021). Only 2-4% of the ovarian tumors are accounted for the endometrioid cystadenoma (Tsukahara et al. 1982). Endometrioid cystadenoma is related to the mutations in CTNNB1 and PTEN gene (Bell 2005, Sanseverino et al. 2005, Wei et al. 2012).
Empirical Evidence
<table border="1" class="Table" style="border:solid windowtext 1px">
<tbody>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Compound class
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Species
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
Study type
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:83px">
Dose
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
KER findings
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
Reference
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
women
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In vivo
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:83px">
Increase in concentration of estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Atypical hyperplasia of the endometrium
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Yamagata et al. 1989)
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
Estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black">
women
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:89px">
In Vitro
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:83px">
Increase in concentration of estrogen
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:148px">
Endometrial cancer by endometrial hyperplasia
</td>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; width:129px">
(Goad et al. 2018)
</td>
</tr>
</tbody>
</table>
Uncertainties and Inconsistencies
Balat  et al., had reported the detection of unthreatened late pregnancy with a large mucinous cyst adenoma of the ovary in a female patient (Balat et al. 2002). Vidhale et al., had reported the detection of serous cystadenoma in the ovary, which is benign in nature (Vidhale et al. 2022).  Mittal, et al., had reported the detection of benign type of mucinous cystadenoma in the ovary (Mittal et al. 2008).
<h4>Quantitative Understanding of the Linkage</h4>
Not enough data is available
Response-response relationship
Horn et al., had evaluated the 74 cases of borderline ovarian tumors and shown that majority of the cases are belongs to the serous borderline ovarian tumors (60.8%), followed by the mucinous borderline ovarian tumors (25.7%).  Adenoma in the borderline ovarian tumors was found in  86.5% cases. The report had suggested that the association of papillary tubal hyperplasia and salpingoliths   with the borderline ovarian tumors (Horn et al. 2017).
Time-scale
Observed in months to years
Known modulating factors
<div>
<table class="table table-bordered table-fullwidth">
<thead>
<tr>
<th>Modulating Factor (MF)</th>
<th>MF Specification</th>
<th>Effect(s) on the KER</th>
<th>Reference(s)</th>
</tr>
</thead>
<tbody>
<tr>
<td>Not know</td>
<td> </td>
<td> </td>
<td> </td>
</tr>
</tbody>
</table>
</div>
Known Feedforward/Feedback loops influencing this KER
Not known
<h4>References</h4>
Balat, O., Kutlar, I., Erkilic, S., Sirikci, A., Aksoy, F. and Aydin, A. (2002) Unthreatened late pregnancy with a huge mucinous cyst adenoma of the left ovary: report of an unusual case. Eur J Gynaecol Oncol 23(1), 84-85.
Bell, D.A. (2005) Origins and molecular pathology of ovarian cancer. Mod Pathol 18 Suppl 2, S19-32.
Beroukhim, G., Ozgediz, D., Cohen, P.J., Hui, P., Morotti, R., Schwartz, P.E., Yang, H. and Vash-Margita, A. (2021) Progression of Cystadenoma to Mucinous Borderline Ovarian Tumor in Young Females: Case Series and Literature Review. J Pediatr Adolesc Gynecol 35(3), 359-367.
Cheng, E.J., Kurman, R.J., Wang, M., Oldt, R., Wang, B.G., Berman, D.M. and Shih, I.-M. (2004) Molecular genetic analysis of ovarian serous cystadenomas. Laboratory Investigation 84(6), 778-784.
Chodankar, R., Kwang, S., Sangiorgi, F., Hong, H., Yen, H.Y., Deng, C., Pike, M.C., Shuler, C.F., Maxson, R. and Dubeau, L. (2005) Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells. Curr Biol 15(6), 561-565.
Dey, P., Nakayama, K., Razia, S., Ishikawa, M., Ishibashi, T., Yamashita, H., Kanno, K., Sato, S., Kiyono, T. and Kyo, S. (2022) Development of Low-Grade Serous Ovarian Carcinoma from Benign Ovarian Serous Cystadenoma Cells. Cancers (Basel) 14(6).
Goad, J., Ko, Y.-A., Kumar, M., Jamaluddin, M.F.B. and Tanwar, P.S. (2018) Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling. Carcinogenesis 39(9), 1105-1116.
Goedhals, J., van der Merwe, J., Yazbek, V.A. and Beukes, C.A. (2008) Adenoma malignum-like mucinous ovarian carcinoma. Histopathology 53(3), 352-354.
Horn, L.C., Angermann, K., Hentschel, B., Einenkel, J. and Hohn, A.K. (2017) Frequency of papillary tubal hyperplasia (PTH), salpingoliths and transition from adenoma to borderline ovarian tumors (BOT): A systematic analysis of 74 BOT with different histologic types. Pathol Res Pract 213(4), 305-309.
Limaiem, F., Lekkala, M.R. and Mlika, M. (2022) Ovarian Cystadenoma.
MacDonald, P.C., Grodin, J.M., Edman, C.D., Vellios, F. and Siiteri, P.K. (1976) Origin of estrogen in a postmenopausal woman with a nonendocrine tumor of the ovary and endometrial hyperplasia. Obstet Gynecol 47(6), 644-650.
Mittal, S., Gupta, N., Sharma, A.K. and Dadhwal, V. (2008) Laparoscopic management of a large recurrent benign mucinous cystadenoma of the ovary. Arch Gynecol Obstet 277(4), 379-380.
Nishida, T., Ushijima, K., Oda, T., Sugiyama, T., Tsuji, Y., Imaishi, K. and Yakushiji, M. (1991) Minimal deviation adenocarcinoma (adenoma malignum) of the uterine cervix associated with mucinous ovarian carcinoma. Kurume Med J 38(4), 265-269.
Pascal, R.R. and Grecco, L.A. (1988) Mucinous cystadenoma of the ovary with stromal luteinization and hilar cell hyperplasia during pregnancy. Hum Pathol 19(2), 179-180.
Saloniemi, T., Lamminen, T., Huhtinen, K., Welsh, M., Saunders, P., Kujari, H. and Poutanen, M. (2007) Activation of androgens by hydroxysteroid (17beta) dehydrogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign serous cystadenomas. Mol Endocrinol 21(11), 2627-2636.
Sanseverino, F., D'Andrilli, G., Petraglia, F. and Giordano, A. (2005) Molecular pathology of ovarian cancer. Anal Quant Cytol Histol 27(3), 121-124.
Smith, J., Crowe, K., McGaughran, J. and Robertson, T. (2011) Sebaceous adenoma arising within an ovarian mature cystic teratoma in Muir-Torre syndrome. Ann Diagn Pathol 16(6), 485-488.
Tsukahara, Y., Shiozawa, I., Sakai, Y., Ishii, J., Iwai, S. and Fukuta, T. (1982) Study on the histogenesis of ovarian tumors--with special reference to five clinical cases with common epithelial tumors detected during the preclinical stage. Nihon Sanka Fujinka Gakkai Zasshi 34(7), 959-965.
Vidhale, S.A., Chavarkar, S.P., Sudhamani, S. and Rao, R. (2022) Cholesterolosis of ovary associated with benign serous cystadenoma. Indian J Pathol Microbiol 65(2), 496-498.
Wei, X., Lu, Q.J., Sun, H.X., Qi, Y.F., Wang, J.O. and Cao, C.C. (2012) [Expression and significance of p-AKT, p-GSK3beta and beta-catenin in epithelial carcinoma of ovary]. Zhonghua Bing Li Xue Za Zhi 41(2), 86-90.
Yamagata, S., Yamamoto, K., Tsuchida, S., Kawamura, N., Matsumoto, Y., Ueki, S. and Sugawa, T. (1989) Estrogen production in epithelial tumors of the ovary--clinical and endocrinological study in postmenopausal women. Nihon Sanka Fujinka Gakkai zasshi 41(11), 1761-1768.
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