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Relationship: 3469

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased, LH Surge leads to Impaired ovulation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, LH Surge

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Impaired ovulation

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Decreased, GnRH pulsatility/release leading to estradiol availability, increased via impaired ovulation	adjacent	High	High	Martina Panzarea (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates		NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Female

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult, reproductively mature

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Luteinizing hormone (LH) is a gonadotropin that is necessary for sexual maturation, ovulation, and therefore fertility. It is part of the glycoprotein hormone family and is organized as a heterodimer with a common α-subunit and a specific β-subunit (Padmanabhan et al., 2018). An LH surge is needed and responsible for the downstream pathways that induce ovulation; this includes resumption of meiosis in the oocyte and cellular changes that allow rupture of the follicle to release the egg for fertilization. It increases intrafollicular proteolytic enzymes, weakening the wall of the ovary and allowing for passage of the mature follicle (Robker et al., 2018).

As follicles grow, estrogen synthesis increases in the female ovary. This in turn promotes GnRH pulses in the hypothalamus and increases the levels of luteinizing hormone (LH) released from the anterior pituitary. The circulating LH can then interact with its receptor (LHCGR) in antral follicles and stimulate ovulation (Duffy et al., 2019). In addition to LH, which is eliminated from the serum quickly, human chorionic gonadotropin (hCG), usually secreted during pregnancy, has a higher affinity with the receptor LHCGR and found longer in the serum than LH. Therefore, hCG is preferentially used for ovulation stimulation in fertility treatments for women and in animal studies (Russell and Robker, 2007).

Without the LH surge, the downstream pathways are not able to function and as a result, ovulation does not occur. If the LH surge is delayed, then ovulation may be delayed as well and fails to occur within the correct time window. This can have a negative impact on the reproductive health of females and perturb the estrous cycle.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The development of the KER is based on structured literature review of records. Description for KER is based on reviews and books on the topic. The method used are described in Annex B.1.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The LH surge is a tightly controlled phenomenon in female reproductive cycles. Ovulation must occur within a specific window in the estrous cycle as the body prepares for a potential pregnancy.

Physiologically, the LH surge induces the activation of many signalling cascades that are needed to provoke ovulation. LH through its receptor, LHCGR, increases the intracellular cAMP that activates the PKA pathway. This is considered the canonical pathway activated by LH. PKA then can activate CREB that is then translocated to the nucleus for transcription of target genes needed for ovulation. In addition, the LH surge is also necessary for the activation of Erk 1/2. The activation of the Erk1/2 and MAPK pathway allows activation of EGF-like ligands important for cumulus oocyte complex (COC) expansion as well as transcription factors such as C/EBPα/β that induce expression of genes essential for follicular rupture, both being important steps for correct ovulation. An increase in progesterone receptor (PGR) expression, due to the LH surge, is observed in granulosa cells of preovulatory follicles in most species examined, including humans, rodents and monkeys, leading to the increase in progesterone locally. Several PGR regulated genes have been demonstrated to play critical roles in ovulation, including proteases ADAMST1 and CTSL that break down the follicular wall at the time of ovulation. Following the LH surge, the granulosa cells have an increase in inflammatory genes (such as COX2) in addition to the proteases (Duffy et al., 2019; Robker et al., 2018).

Issues can arise in one of these pathways leading to subsequent problems in ovulation. In addition, it has been shown in many studies that without this surge or with a delayed surge, ovulation is perturbed.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Evidence in Rodents: A few knockout mouse strains have been studied extensively to investigate ovulation and hormonal changes in female mice. For example, a study generated LHCGR knockouts and characterized their phenotype. As expected, these female mice were sterile with delayed ovulation and decreased level of serum and ovarian estradiol and progesterone with an increase in serum LH but no difference in pituitary LH levels (Lei et al., 2001; Zhang et al., 2001). Another study focused directly on LH action and created a LHβ knockout and found that the female mice were sterile. Although theca cell morphology looked normal, oocytes degenerated, serum levels of progesterone and estradiol reduced and steroidogenic enzyme expression (Cyp11a1, Cyp19a1, Cyp17a1) decreased. In addition, estrous cycles were abnormal, and no ovulation was observed (Ma et al., 2004, see also Table 2).

Evidence in humans: Although mutations in LH or its receptor are rare, in certain families, these mutations were found. Individuals with mutations in the LH receptor were considered “LH resistant” as they do not respond to LH. The women from the different families had similar phenotypes and were shown to exhibit normal puberty but found to have amenorrhea and were not fertile (Latronico et al., 1996, 1998; Prado Arnhold et al., 1997; Stavrou et al., 1998; Toledo et al., 1996, see also Table 3) .

Table 2. Evidence in rodents

Mouse models	Observations	Reference
LHβ KO	Infertility was observed in both sexes as well as perturbed gonadal growth. Estradiol and progesterone level were decreased compared to control and degenerating antral follicles were found. In addition, genes coding for steroid biosynthesis enzymes demonstrated a decreased expression and the expression of COX2, (a marker for ovulation) was also reduced.	(Ma et al., 2004)
LH/hCG receptor KO (Deletion of promotor region and most of exon 1)	Male and female mice were infertile. Females contained smaller gonads with underdeveloped genitalia and no preovulatory follicles were observed.	(Lei et al., 2001)
LuRKO (Deletion of exon 11)	The female Kos ovaries weighed less than control and had delayed vaginal opening to 35-38 days compared to 30-32 days in WT mice. No preovulatory follicles were found.	(Zhang et al., 2001)

Table 3. Evidence in humans

Humans	Observations (case studies)	Reference
LH receptor mutation c.1345G>A (p.Ala449Thr)	The patient had compromised ovulation with normal LH levels, but with LH resistance in a 27-year-old in China from a non-consanguineous family.	(Yuan et al., 2017)
LHCGR heterozygous mutation (inactivating mutation on exon1)	The 33-year-old woman presented ovarian cysts and amenorrhea and low oocyte yield.	(Bentov et al., 2012)
LH receptor mutation (Substitution of K354 into E)	A 46, XX sibling displayed normal external genitalia and breast development but has primary amenorrhea.	(Stavrou et al., 1998)
LH receptor mutation (ΔL608, V609)	The 46, XX woman exhibited oligomenorrhea.	(Latronico et al., 1998)
LH receptor abnormalities	This study shows a woman with normal pubertal development, rare menses, infertility, polycystic ovaries, and no ovulation (lack of corpus luteum). They believe the mutation lies with the receptor due to an absence of response to LH and phenotype of However, they were not able to locate a mutation on the LH receptor.	(Prado Arnhold et al., 1997)
LH receptor mutation (Substitution of Arg554 into a STOP codon)	The 46, XX woman in this family had normal external genitalia but had cystic ovaries of unequal size and amenorrhea. Another woman from a different family also presented this mutation with secondary amenorrhea and elevated levels of LH, anovulation and no corpus luteum formation.	(Latronico et al., 1996; Tsigos et al., 1997)
LH receptor mutation (Substitution of A593 to P)	The female sibling exhibited primary amenorrhea, a smaller uterus, abnormal menses, no preovulatory follicles and infertility.	(Toledo et al., 1996)

Evidence through downstream targets of LH:

Erk1/2 mouse Kos (conditional in granulosa cells): The mice were sterile with lack of meiotic resumption of the oocytes, absence of luteinization as well as inhibition of ovulation (Fan et al., 2009).

C/EBP mouse Kos (conditional in granulosa cells): The mice exhibited a similar phenotype to the Erk1/2 knockouts as expected, since C/EBP is downstream to Erk1/2. However, although there was lack of ovulation, the oocytes were able to resume meiosis and mature but were trapped and could not be released from the follicle (Fan et al., 2011; Sterneck et al., 1997).

PGR KOs; In this case, follicle growth was normal and luteinization was completed, but no ovulation occurred with no corpus luteum because follicle rupture was inhibited and therefore there was no COC release (Kim et al., 2009; Lydon et al., 1995).

Evidence through other factors affecting LH:

Pituitary-specific p62−/− mice: p26 is an important protein in metabolic processes. Lack of p26 in pituitary induces fertility issues. The authors investigated the role of p26 in female reproduction. They found that p26 is important for LH expression and release through mitochondrial oxidative phosphorylation, and without p26, LH levels are very low leading to a decrease in ovulation, lack of corpus luteum and less pups (X. Li et al., 2021).

microRNAs KOs:

miR-29a/b1 KO mice were generated to observe its role in reproduction. MicroRNAs regulate gene expression by inhibiting expression of mRNAs. Part of the miR29 family of mature miRNAs, this KO had ovulatory problems with a strong decrease of observable corpus lutea thought to be due to low LH serum levels. Although the molecular mechanism of miR29 is still unknown, this study shows again a clear correlation between issues with LH levels and anovulation (Guo et al., 2021).

Two other microRNAs also seem to play an essential role in female fertility in mice. miR-200b and miR-429 double KO mice had low levels of LHβ and therefore anovulation. The authors hypothesize that this is due to higher expression of one of their targets, ZEB1, however, the exact mechanism is still unknown (Hasuwa et al., 2013).

Evidence through stressors:

A variety of stressors have been shown to affect the LH surge which in turn disrupts ovulation.

Atrazine: Foradori et al., exposed SD and LE rats to atrazine through gavage for 4 days. No significant effect was observed for LE rats. However, starting from 50mg/kg of atrazine, there was a significant decrease in LH surge as well as a significant decrease in corpus lutea observed and ova shed (Foradori et al., 2014). A different study using human cumulus granulosa cells showed that exposure to 20µM of atrazine for 48h leads to a decrease of LHCGR mRNA expression as well as ovulatory markers EREG and AREG (Pogrmic-Majkic et al., 2018).

TCDD: One study showed that TCDD exposure leads to issues with ovulation that could be due to a decrease in LH levels. The SD rats were first stimulated with eCG and exposed to TCDD (0.3 - 60 µg/kg of TCDD). 72 hrs after the eCG stimulation, the authors observed the decrease of FSH and LH levels and a decrease in the number of rats that ovulated as well as a decrease of ova shed (ED50: 3-10 µg/kg) (X. L. Li et al., 1995).

Similarly, another study examined the effect of TCDD exposure on SD rats and compared it to PCDD exposure. They were exposed to 2-32 µg/kg of TCDD following this time PMSG stimulation. After 72 hours of the highest exposure, there was a decrease in LH levels, as well as FSH. They also noted an effect starting from 4 µg/kg on ovulation and ovarian weight (Gao et al., 1999).

PFOS: Using ICR mice, Wang et al., exposed the mice to PFOS (10mg/kg) for 30 days. Within 7 days, they observed a reduction of ovulation and a decrease of P4, LH, and GnRH (Wang et al., 2018).

In another study, ICR mice were exposed to 0.1mg/kg of PFOS for 6months. After 4 months of exposure there was a reduction of E2, P4, FSH, LH, and GnRH. Less antral and preovulatory follicles were found in these mice as well as less corpus lutea. In this study, they observe loss of body weight after 4 months, so in order to avoid this having an effect on reproductive function, they use mice exposed for 4months and not more. This seems to be an interesting point that most other studies do not underline or pay particular attention to (Feng et al., 2015).

GnRH antagonists: SD rats were exposed to Cetrorelix, a GnRH antagonist, for 30 days. LH levels were measured on day 0, 4, 10, 20, and 30 (before sacrifice). The levels of LH measured were lower on days 4 and 10 compared to control rats but interestingly increased back to a similar level to controls on day 20. The estrous cycle resembled that of anovulatory women. In addition, no corpus lutea were observed at sacrifice and no progesterone increase was measured, indicating a lack of ovulation in SD rats exposed to Cetrorelix (Horvath et al., 2004).

Dose and temporal concordance

See Annex B.3.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Although the phenotypes of the different knockout models in mice resemble that of the women that exhibit mutations in either LH itself or its receptor, these studies investigate the absence of LH or LHCGR and not the surge itself. Animal models would be needed to directly investigate the surge by inhibiting the moment of the LH surge to confirm the direct relationship between this surge and ovulation regulation.

In addition, gain of function mutants may make these conclusions more complex. Transgenic mice were created expressing bovine LHβ tagged with a carboxyl terminal peptide of hCG that extends the half-life of LHβ (LHβ-CTP). When LHβ is highly secreted in pre-pubertal mice, several consequences arise. The authors observed either anovulation or infrequent ovulation as well as enlarged ovaries, cysts, and tumours. In addition, levels of ovarian hormones were affected, with higher levels of estrogen and testosterone (Risma et al., 1995, Risma et al., 1997). This indicates that all changes in LH dynamics may have an adverse effect on ovulation, and not just negative regulation. Interestingly, a study using gain of function for LHCGR (KiLHR (D582G)) in mice shows that some clear difference between species can occur. Unlike women with “activating” LHCGR mutations which have a normal phenotype, mice have irregular estrous cycles and anovulation. This shows that, at least in mice, having an increase in activity of LH receptor can have a negative impact on female fertility, but also shows the care that has to be taken to extrapolate data on rodents to humans (Hai et al., 2015).

Uncertainties and inconsistencies should be further explored.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

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

Arnhold IJ, Latronico AC, Batista MC, Carvalho FM, Chrousos GP and Mendonça BB, 1997. Ovarian resistance to luteinizing hormone: a novel cause of amenorrhea and infertility. Fertil Steril, 67:394-397. doi: 10.1016/s0015-0282(97)81929-2

Bentov Y, Kenigsberg S and Casper RF, 2012. A novel luteinizing hormone/chorionic gonadotropin receptor mutation associated with amenorrhea, low oocyte yield, and recurrent pregnancy loss. Fertil Steril, 97:1165-1168. doi: 10.1016/j.fertnstert.2012.02.002

Duffy DM, Ko C, Jo M, Brannstrom M and Curry TE, 2019. Ovulation: Parallels With Inflammatory Processes. Endocr Rev, 40:369-416. doi: 10.1210/er.2018-00075

Fan HY, Liu Z, Johnson PF and Richards JS, 2011. CCAAT/enhancer-binding proteins (C/EBP)-α and -β are essential for ovulation, luteinization, and the expression of key target genes. Mol Endocrinol, 25:253-268. doi: 10.1210/me.2010-0318

Fan HY, Liu Z, Shimada M, Sterneck E, Johnson PF, Hedrick SM and Richards JS, 2009. MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science, 324:938-941. doi: 10.1126/science.1171396

Feng X, Wang X, Cao X, Xia Y, Zhou R and Chen L, 2015. Chronic Exposure of Female Mice to an Environmental Level of Perfluorooctane Sulfonate Suppresses Estrogen Synthesis Through Reduced Histone H3K14 Acetylation of the StAR Promoter Leading to Deficits in Follicular Development and Ovulation. Toxicol Sci, 148:368-379. doi: 10.1093/toxsci/kfv197

Foradori CD, Sawhney Coder P, Tisdel M, Yi KD, Simpkins JW, Handa RJ and Breckenridge CB, 2014. The effect of atrazine administered by gavage or in diet on the LH surge and reproductive performance in intact female Sprague-Dawley and Long Evans rats. Birth Defects Res B Dev Reprod Toxicol, 101:262-275. doi: 10.1002/bdrb.21109

Gao X, Son D-S, Terranova PF and Rozman KK, 1999. Toxic Equivalency Factors of Polychlorinated Dibenzo-p-dioxins in an Ovulation Model: Validation of the Toxic Equivalency Concept for One Aspect of Endocrine Disruption. Toxicology and Applied Pharmacology, 157:107-116. doi: https://doi.org/10.1006/taap.1999.8649

Guo Y, Wu Y, Shi J, Zhuang H, Ci L, Huang Q, Wan Z, Yang H, Zhang M, Tan Y, Sun R, Xu L, Wang Z, Shen R and Fei J, 2021. miR-29a/b(1) Regulates the Luteinizing Hormone Secretion and Affects Mouse Ovulation. Front Endocrinol (Lausanne), 12:636220. doi: 10.3389/fendo.2021.636220

Hai L, McGee SR, Rabideau AC, Paquet M and Narayan P, 2015. Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries. Biol Reprod, 93:16. doi: 10.1095/biolreprod.115.129072

Hasuwa H, Ueda J, Ikawa M and Okabe M, 2013. miR-200b and miR-429 function in mouse ovulation and are essential for female fertility. Science, 341:71-73. doi: 10.1126/science.1237999

Horvath JE, Toller GL, Schally AV, Bajo AM and Groot K, 2004. Effect of long-term treatment with low doses of the LHRH antagonist Cetrorelix on pituitary receptors for LHRH and gonadal axis in male and female rats. Proc Natl Acad Sci U S A, 101:4996-5001. doi: 10.1073/pnas.0400605101

Kim J, Bagchi IC and Bagchi MK, 2009. Control of ovulation in mice by progesterone receptor-regulated gene networks. Mol Hum Reprod, 15:821-828. doi: 10.1093/molehr/gap082

Latronico AC, Anasti J, Arnhold I, Rapaport R, Mendonca B, Bloise W, Castro M, Tsigos C and Chrousos G, 1996. Testicular and Ovarian Resistance to Luteinizing Hormone Caused by Inactivating Mutations of the Luteinizing Hormone–Receptor Gene. New England Journal of Medicine - N ENGL J MED, 334:507-512. doi: 10.1056/NEJM199602223340805

Latronico AC, Chai Y, Arnhold IJ, Liu X, Mendonca BB and Segaloff DL, 1998. A homozygous microdeletion in helix 7 of the luteinizing hormone receptor associated with familial testicular and ovarian resistance is due to both decreased cell surface expression and impaired effector activation by the cell surface receptor. Mol Endocrinol, 12:442-450. doi: 10.1210/mend.12.3.0077

Lei ZM, Mishra S, Zou W, Xu B, Foltz M, Li X and Rao CV, 2001. Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. Mol Endocrinol, 15:184-200. doi: 10.1210/mend.15.1.0586

Li X, Johnson DC and Rozman KK, 1995. Reproductive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female rats: ovulation, hormonal regulation, and possible mechanism(s). Toxicol Appl Pharmacol, 133:321-327. doi: 10.1006/taap.1995.1157

Li X, Zhou L, Peng G, Liao M, Zhang L, Hu H, Long L, Tang X, Qu H, Shao J, Zheng H and Long M, 2021. Pituitary P62 deficiency leads to female infertility by impairing luteinizing hormone production. Exp Mol Med, 53:1238-1249. doi: 10.1038/s12276-021-00661-4

Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA, Jr., Shyamala G, Conneely OM and O'Malley BW, 1995. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev, 9:2266-2278. doi: 10.1101/gad.9.18.2266

Ma X, Dong Y, Matzuk MM and Kumar TR, 2004. Targeted disruption of luteinizing hormone beta-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility. Proc Natl Acad Sci U S A, 101:17294-17299. doi: 10.1073/pnas.0404743101

Padmanabhan V, Puttabyatappa M and Cardoso R, 2018. Hypothalamus–Pituitary–Ovary Axis.

Pogrmic-Majkic K, Samardzija D, Stojkov-Mimic N, Vukosavljevic J, Trninic-Pjevic A, Kopitovic V and Andric N, 2018. Atrazine suppresses FSH-induced steroidogenesis and LH-dependent expression of ovulatory genes through PDE-cAMP signaling pathway in human cumulus granulosa cells. Mol Cell Endocrinol, 461:79-88. doi: 10.1016/j.mce.2017.08.015

Risma KA, Clay CM, Nett TM, Wagner T, Yun J and Nilson JH, 1995. Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci U S A, 92:1322-1326. doi: 10.1073/pnas.92.5.1322

Risma KA, Hirshfield AN and Nilson JH, 1997. Elevated luteinizing hormone in prepubertal transgenic mice causes hyperandrogenemia, precocious puberty, and substantial ovarian pathology. Endocrinology, 138:3540-3547. doi: 10.1210/endo.138.8.5313

Robker RL, Hennebold JD and Russell DL, 2018. Coordination of Ovulation and Oocyte Maturation: A Good Egg at the Right Time. Endocrinology, 159:3209-3218. doi: 10.1210/en.2018-00485

Russell DL and Robker RL, 2007. Molecular mechanisms of ovulation: co-ordination through the cumulus complex. Hum Reprod Update, 13:289-312. doi: 10.1093/humupd/dml062

Stavrou SS, Zhu YS, Cai LQ, Katz MD, Herrera C, Defillo-Ricart M and Imperato-McGinley J, 1998. A novel mutation of the human luteinizing hormone receptor in 46XY and 46XX sisters. J Clin Endocrinol Metab, 83:2091-2098. doi: 10.1210/jcem.83.6.4855

Sterneck E, Tessarollo L and Johnson PF, 1997. An essential role for C/EBPbeta in female reproduction. Genes Dev, 11:2153-2162. doi: 10.1101/gad.11.17.2153

Toledo SP, Brunner HG, Kraaij R, Post M, Dahia PL, Hayashida CY and Kremer HTAP, 1996. An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female. J Clin Endocrinol Metab, 81:3850-3854. doi: 10.1210/jcem.81.11.8923827

Tsigos C, Latronico C and Chrousos GP, 1997. Luteinizing hormone resistance syndromes. Ann N Y Acad Sci, 816:263-273. doi: 10.1111/j.1749-6632.1997.tb52150.x

Wang X, Bai Y, Tang C, Cao X, Chang F and Chen L, 2018. Impact of Perfluorooctane Sulfonate on Reproductive Ability of Female Mice through Suppression of Estrogen Receptor α-Activated Kisspeptin Neurons. Toxicological Sciences, 165:475-486. doi: 10.1093/toxsci/kfy167

Yuan P, He Z, Zheng L, Wang W, Li Y, Zhao H, Zhang VW, Zhang Q and Yang D, 2017. Genetic evidence of 'genuine' empty follicle syndrome: a novel effective mutation in the LHCGR gene and review of the literature. Hum Reprod, 32:944-953. doi: 10.1093/humrep/dex015

Zhang FP, Poutanen M, Wilbertz J and Huhtaniemi I, 2001. Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Mol Endocrinol, 15:172-183. doi: 10.1210/mend.15.1.0582