Aop: 440

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Hypothalamic estrogen receptors inhibition leading to ovarian cancer

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Hypothalamic estrogen receptors inhibition leading to ovarian cancer

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Kalyan Gayen, Department of Chemical Engineering, National Institute of Technology Agartala, India 

Tridib Kumar Bhowmick, Department of Bioengineering, National Institute of Technology Agartala, India 

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Kalyan Gayen   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Kalyan Gayen
  • Tridib Kumar Bhowmick

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.104 Included in OECD Work Plan
This AOP was last modified on July 19, 2022 11:14

Revision dates for related pages

Page Revision Date/Time
Suppression, Estrogen receptor (ER) activity February 28, 2022 23:08
Increased, secretion of GnRH from hypothalamus September 16, 2017 10:17
Increased, secretion of LH from anterior pituitary December 03, 2016 16:37
Increased, Steroidogenic acute regulatory protein (StAR) March 01, 2022 07:00
Increased, estrogens March 01, 2022 06:58
Increased, circulating estrogen levels December 03, 2016 16:37
Hyperplasia, ovarian stromal cells September 16, 2017 10:17
Hyperplasia, ovarian epithelium September 16, 2017 10:17
Promotion, ovarian adenomas December 03, 2016 16:37
Promotion, ovarian granular cell tumors December 03, 2016 16:37
Suppression, Estrogen receptor (ER) activity leads to Increased, secretion of GnRH from hypothalamus March 01, 2022 04:50
Increased, circulating estrogen levels leads to Hyperplasia, ovarian stromal cells March 02, 2022 00:37
Increased, secretion of GnRH from hypothalamus leads to Increased, secretion of LH from anterior pituitary March 01, 2022 06:01
Increased, circulating estrogen levels leads to Hyperplasia, ovarian epithelium March 02, 2022 00:52
Increased, secretion of LH from anterior pituitary leads to Increased, Steroidogenic acute regulatory protein (StAR) March 01, 2022 06:43
Hyperplasia, ovarian epithelium leads to Promotion, ovarian adenomas December 03, 2016 16:38
Increased, Steroidogenic acute regulatory protein (StAR) leads to Increased, estrogens March 01, 2022 22:58
Hyperplasia, ovarian stromal cells leads to Promotion, ovarian granular cell tumors December 03, 2016 16:38
Increased, estrogens leads to Increased, circulating estrogen levels March 01, 2022 23:18
Tamoxifen November 29, 2016 18:42
Raloxifene November 29, 2016 18:42
Clomiphene citrate (1:1) February 26, 2022 23:24

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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 et al., 2018). Some stressorsmolecules (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 bythe 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 (McLemore et al., 2009; Tomao et al., 2014).

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

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 hasthe 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. In females sexual hormone balance protects the ovaries from the tumor development. A number of researchesrevealed that molecular level perturbation leading towards sex hormone imbalance plays important role in the development of the ovarian cancer.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1046 Suppression, Estrogen receptor (ER) activity Suppression, Estrogen receptor (ER) activity
KE 1047 Increased, secretion of GnRH from hypothalamus Increased, secretion of GnRH from hypothalamus
KE 1050 Increased, secretion of LH from anterior pituitary Increased, secretion of LH from anterior pituitary
KE 1972 Increased, Steroidogenic acute regulatory protein (StAR) Increased, Steroidogenic acute regulatory protein (StAR)
KE 1973 Increased, estrogens Increased, estrogens
KE 1076 Increased, circulating estrogen levels Increased, circulating estrogen levels
KE 1051 Hyperplasia, ovarian stromal cells Hyperplasia, ovarian stromal cells
KE 1052 Hyperplasia, ovarian epithelium Hyperplasia, ovarian epithelium
AO 1053 Promotion, ovarian adenomas Promotion, ovarian adenomas
AO 1054 Promotion, ovarian granular cell tumors Promotion, ovarian granular cell tumors

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adult, reproductively mature High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mice Mus sp. High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Female High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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 stromal cells[Evidence- Strong]: High concentration of circulating estrogen drives the endometrial hyperplasia of the stromal cells in the postmenopausal ovaries. Many scientific evidences are available which supports this event. Number of evidence may be found on the formation of tumors in the ovarian granulosa cells due to the high levels of circulating estrogen in the plasma (Janson et al., 1980; Scirpa et al., 1984; 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 granular cell tumors [Evidence- Strong]: Tumors in the granulosa cells is most common type of tumors found in females. High number of evidences is available which shows the association of the ovarian granulosa cell tumors with the hyperplasia of the ovarian epithelium tissue(Nyboe Andersen et al., 2008; Kang et al., 2001).

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

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).

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

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.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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

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

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

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

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.

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(1), 62-69. doi:10.1089/andro.2020.0005.

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.

Cassidenti, D. L., Paulson, R. J., Lobo, R. A., & 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), 344-8. doi:10.1093/oxfordjournals.humrep.a137646.

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.

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.

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.

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.

Fooladi, S., Akbari, H., Abolhassani, M., Sadeghi, E., & Fallah, H. (2020). Estradiol, des-acylated, and total ghrelin levels might be associated with epithelial ovarian cancer in postmenopausal women. medRxiv.

Ghasemnejad-Berenji, M., Pashapour, S., & Ghasemnejad-Berenji, H. (2020). Therapeutic potential for clomiphene, a selective estrogen receptor modulator, in the treatment of COVID-19. Medical Hypotheses, 145. doi:Artn 11035410.1016/J.Mehy.2020.110354.

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.

Holesh, J. E., Bass, A. N., & Lord, M. (2017). Physiology, Ovulation. doi:NBK441996 [bookaccession].

Janson, P. O., Hamberger, L., Damber, J. E., Dennefors, B., & Knutson, F. (1980). Steroid production in vitro of a hilus cell tumor of the human ovary. Obstet Gynecol, 55(5), 662-5.

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.

Kang, S. K., Choi, K. C., Tai, C. J., Auersperg, N., & Leung, P. C. (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.

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

Kerin, J. F., Liu, J. H., Phillipou, G., & Yen, S. S. C. (1985b). Evidence for a Hypothalamic Site of Action of Clomiphene Citrate in Women. The Journal of Clinical Endocrinology & Metabolism, 61(2), 265-268. doi:10.1210/jcem-61-2-265.

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.

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.

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.

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

Kurosawa, T., Hiroi, H., Momoeda, M., Inoue, S., & Taketani, Y. (2010). Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors alpha and beta. Endocr J, 57(6), 517-21. doi:JST.JSTAGE/endocrj/K09E-368 [pii]10.1507/endocrj.k09e-368.

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.

Liu, J. H. (2020). Selective estrogen receptor modulators (SERMS): keys to understanding their function. Menopause-the Journal of the North American Menopause Society, 27(10), 1171-1176. doi:10.1097/Gme.0000000000001585.

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.

Marques P, S. K., George JT, et al. (2018). Physiology of GNRH and Gonadotropin Secretion. [Updated 2018 Jun 19]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279070/.

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.

McLemore, M. R., Miaskowski, C., Aouizerat, B. E., Chen, L. M., & Dodd, M. J. (2009). Epidemiological and genetic factors associated with ovarian cancer. Cancer Nurs, 32(4), 281-8; quiz 289-90. doi:10.1097/NCC.0b013e31819d30d6.

Meehan, K. L., & Sadar, M. D. (2003). Androgens and androgen receptor in prostate and ovarian malignancies. Front Biosci, 8, d780-800.

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.

Moskovic, D. J., Katz, D. J., Akhavan, A., Park, K., & Mulhall, J. P. (2012 ). Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU International, 100, 1524 - 28.

Mungenast, F., & Thalhammer, T. (2014a). Estrogen biosynthesis and action in ovarian cancer. Front Endocrinol (Lausanne), 5, 192. doi:10.3389/fendo.2014.00192.

Mungenast, F., & Thalhammer, T. (2014b). Estrogen biosynthesis and action in ovarian cancer. Front Endocrinol (Lausanne). 2014 Nov 12;5:192. doi: 10.3389/fendo.2014.00192. eCollection 2014.

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.

Ng, Y., Wolfe, A., Novaira, H. J., & Radovick, S. (2009). Estrogen regulation of gene expression in GnRH neurons. Mol Cell Endocrinol. 2009 May 6;303(1-2):25-33. doi: 10.1016/j.mce.2009.01.016. Epub 2009 Feb 2.

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.

Nyboe Andersen, A., Balen, A., Platteau, P., Devroey, P., Helmgaard, L., & Arce, J. C. (2008). Predicting the FSH threshold dose in women with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate. Hum Reprod. 2008 Jun;23(6):1424-30. doi: 10.1093/humrep/den089. Epub 2008 Mar 26.

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, 27(3), 806-814. doi:10.1007/s43032-020-00154-1.

Perkins, E. J., Gayen, K., Shoemaker, J. E., Antczak, P., Burgoon, L., Falciani, F., et al. (2019). Chemical hazard prediction and hypothesis testing using quantitative adverse outcome pathways. ALTEX, 36(1), 91-102. doi:10.14573/altex.1808241.

Plouffe, L., Jr., & Siddhanti, S. (2001). The effect of selective estrogen receptor modulators on parameters of the hypothalamic-pituitary-gonadal axis. Ann N Y Acad Sci, 949, 251-8. doi:10.1111/j.1749-6632.2001.tb04029.x.

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.

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.

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 Neurons1. Endocrinology, 140(11), 5045-5053. doi:10.1210/endo.140.11.7117.

Samtani, R., Sharma, N., & Garg, D. (2018). Effects of Endocrine-Disrupting Chemicals and Epigenetic Modifications in Ovarian Cancer: A Review. Reprod Sci, 25(1), 7-18. doi:10.1177/1933719117711261.

Scirpa, P., Mango, D., Montemurro, A., Battaglia, F., & Cantafio, L. (1984). Androstenedione, 17 beta-estradiol and progesterone plasma levels in gonadotropins induction of ovulation. J Endocrinol Invest, 7(4), 357-62. doi:10.1007/BF03351016.

Shander, D., & Goldman, B. (1978). Ovarian steroid modulation of gonadotropin secretion and pituitary responsiveness to luteinizing hormone-releasing hormone in the female hamster. Endocrinology, 103(4), 1383-93. doi:10.1210/endo-103-4-1383.

Shoemaker, J. E., Gayen, K., Garcia-Reyero, N., Perkins, E. J., Villeneuve, D. L., Liu, L., et al. (2010a). 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.

Shoemaker, J. E., Gayen, K., Garcia-Reyero, Natàl., Perkins, E. J., Villeneuve, D. L., Liu, L., et al. (2010b). 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.

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.

The Practice Committee of the American Society for Reproductive Medicine (2013). Use of clomiphene citrate in infertile women: a committee opinion. Fertility and Sterility, 100(2), 341-348. doi:https://doi.org/10.1016/j.fertnstert.2013.05.033.

Tomao, F., Lo Russo, G., Spinelli, G. P., Stati, V., Prete, A. A., Prinzi, N., et al. (2014). Fertility drugs, reproductive strategies and ovarian cancer risk. J Ovarian Res, 7, 51. doi:10.1186/1757-2215-7-511757-2215-7-51 [pii].

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.

Tsourdi, E., Kourtis, A., Farmakiotis, D., Katsikis, I., Salmas, M., & Panidis, D. (2009). The effect of selective estrogen receptor modulator administration on the hypothalamic-pituitary-testicular axis in men with idiopathic oligozoospermia. Fertil Steril, 91(4 Suppl), 1427-30. doi:S0015-0282(08)01280-6 [pii]10.1016/j.fertnstert.2008.06.002.

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.

Wright, D. J., Earnhardt, J. N., Perry, R., Bailey, S., Komm, B., Minck, D. R., et al. (2012). Carcinogenicity and hormone studies with the tissue-selective estrogen receptor modulator bazadoxifene. J Cell Physiol, 228(4), 724-33. doi:10.1002/jcp.24219.

Wu, Q., Sucheta, S., Azhar, S., & Menon, K. M. (2003). Lipoprotein enhancement of ovarian theca-interstitial cell steroidogenesis: relative contribution of scavenger receptor class B (type I) and adenosine 5'-triphosphate- binding cassette (type A1) transporter in high-density lipoprotein-cholesterol transport and androgen synthesis. Endocrinology, 144(6), 2437-45. doi:10.1210/en.2002-221110.

Zhang, Z., Bartsch, J. W., Benzel, J., Lei, T., Nimsky, C., & Voellger, B. (2020). 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.