Aop: 440

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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 short name should also be provided 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 summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an 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

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Kalyan Gayen   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Kalyan Gayen
  • Tridib Kumar Bhowmick

Status

The status section is used to provide AOP-KB 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. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on March 09, 2022 23:37
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

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

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). 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).

Background (optional)

This optional subsection should be 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. 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.

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 stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence 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 summarises 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.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and 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

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help
Name Evidence Term
Tamoxifen Moderate
Raloxifene Moderate
Clomiphene citrate (1:1) High

Life Stage Applicability

Identify the life stage for which the KE 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 in relation to this KE. 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 authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Female High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. 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

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. 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

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. 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.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  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

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  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.

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. 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)

At their discretion, the developer may include in this section discussion of the 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. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

References

List the bibliographic references to original papers, books or other documents used to support the 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.

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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.

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