The authors have designated this AOP as all rights reserved. Re-use in any form requires advanced permission from the authors.
AOP: 566
Title
Decreased, GnRH pulsatility/release leading to estradiol availability, increased via impaired ovulation
Short name
Graphical Representation
Point of Contact
Contributors
- Travis Karschnik
- Ana-Andreea Cioca
- anna lanzoni
- Martina Panzarea
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
---|---|---|---|---|
This AOP was last modified on January 14, 2025 17:54
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Decreased, GnRH pulsatility/release | January 02, 2025 17:04 |
Decreased, LH Surge | January 13, 2025 16:37 |
Impaired ovulation | January 03, 2025 15:38 |
Increased plasma estradiol to progesterone ratio (estrogen dominance/unopposed estrogen) | January 03, 2025 16:02 |
Estradiol availability, increased | November 21, 2024 17:40 |
Persistent vaginal cornification | January 13, 2025 15:51 |
Decreased, GnRH pulsatility/release leads to Decreased, LH Surge | January 03, 2025 14:46 |
Decreased, LH Surge leads to Impaired ovulation | January 10, 2025 14:30 |
Impaired ovulation leads to Plasma estradiol/progesterone ratio, increase | January 14, 2025 17:29 |
Plasma estradiol/progesterone ratio, increase leads to Increased E2 availability | January 14, 2025 17:29 |
Plasma estradiol/progesterone ratio, increase leads to PVC | January 14, 2025 17:30 |
Abstract
Due to the multiplicity of possible MIEs (Kisspeptin decrease, gamma-aminobutyric acid-ergic (GABAergic) modulation, neuropeptides and vasopressin role, etc.), it was decided to develop this AOP starting from the common relevant KE, the reduced availability of GnRH at pituitary level. However, discussion on plausible MIEs is included under Annex B.4.
Ovarian hormones regulate normal human endometrial cell proliferation, regeneration and function and therefore they are implicated in endometrial carcinogenesis directly or via influencing other hormones and metabolic pathways. The role of unopposed estrogen in the pathogenesis of EC has received considerable attention, together with other hormones, such as androgens and GnRH.
One of the key homeostatic hormonal loops in this system is provided by the ovarian hormones, E2 and P4, that modulate the activity of the neuronal network controlling the release of GnRH. The hypothalamic GnRH neurons release GnRH in an episodic manner into the pituitary portal circulation to generate distinct pulses of luteinising hormone (LH) and follicle-stimulating hormone (FSH) throughout the ovarian cycle. Thus, the brain and pituitary produce an on-going pulsatile pattern of gonadotropin secretion that slows on oestrous to allow appropriate follicular development and a surge pattern of secretion at mid-cycle to initiate ovulation.
Numerous studies have reported that the oestrous-stage decline in LH pulse frequency results from the post-ovulatory secretion of P4 (Soules et al., 1984; Smith et al., 1989; Goodman 2015) and the administration of P4 was found to dramatically slow GnRH pulse generator activity in the mouse (McQuillan et al., 2019). Thus, it seems very likely that P4 is the key gonadal hormone exerting a negative feedback influence upon the pulse generator during the cycle and does so to bring about the post-ovulatory slowing of pulsatility.
As follicles grow, estrogen synthesis increases in the female ovary. This in turn promotes GnRH pulses in the hypothalamus. GnRH binds to its receptor expressed by pituitary gonadotropic cells and induces the release of 2 gonadotropins, LH and FSH. In turn, LH and FSH stimulate gametogenesis and steroidogenesis in the gonads (Duffy 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 fertilisation. It increases intrafollicular proteolytic enzymes, weakening the wall of the ovary and allowing for passage of the mature follicle (Robker et al., 2018).
The suppression of GnRH availability, due to the impairment of regulatory systems or destruction of the peptide, results in a failure of response to pre-ovulatory level of estrogen to produce LH surges. 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 oestrous cycle.
In most cases, if ovulation is blocked or delayed, the ratio of estradiol/progesterone (E2/P4) remains high due to lack of P4 increase that is initiated after ovulation. As a result, ovarian and circulating steroid hormone levels remain in the ‘pre-ovulatory’ state, i.e. high E2, and low P4. In addition, with ovulation disruption, formation of corpus lutea is delayed or inhibited. This overall disrupts the cycle and can lead to persistent oestrous.
Persistent oestrous is characterised by the lack of corpus lutea formation, and observation of cysts and antral follicles. Morphologically, it is demonstrated by persistent vaginal cornification (PVC). It is considered persistent if at least two cycles were perturbed with the appearance of PVC (Finch, 2014; Stewart et al., 2022). A prolonged increased circulating E2/P4 ratio leads to an increase of E2 bioavailability in a variety of estrogenic-responsive organs, including the uterus due to insufficient counterbalance by P4. However, compensatory mechanisms (e.g. intracrine networks) may differ across different tissues. The degree to which E2/P4 ratio should increase to overwhelm these compensatory responses has not been established.
AOP Development Strategy
Context
Strategy
Please refer to the EFSA Scientific Opinion for an overview of the Context and Strategy of the AOP development.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 530 | Decreased, GnRH pulsatility/release | Decreased, GnRH pulsatility/release |
KE | 531 | Decreased, LH Surge | Decreased, LH Surge |
KE | 1695 | Impaired ovulation | Impaired ovulation |
KE | 2303 | Increased plasma estradiol to progesterone ratio (estrogen dominance/unopposed estrogen) | Plasma estradiol/progesterone ratio, increase |
KE | 2251 | Estradiol availability, increased | Increased E2 availability |
KE | 2306 | Persistent vaginal cornification | PVC |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Decreased, GnRH pulsatility/release leads to Decreased, LH Surge | adjacent | High | High |
Decreased, LH Surge leads to Impaired ovulation | adjacent | High | High |
Impaired ovulation leads to Plasma estradiol/progesterone ratio, increase | adjacent | Moderate | Moderate |
Plasma estradiol/progesterone ratio, increase leads to Increased E2 availability | adjacent | ||
Plasma estradiol/progesterone ratio, increase leads to PVC | adjacent |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Adults |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
mammals | mammals | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Male | |
Female |
Overall Assessment of the AOP
Domain of Applicability
Sex Applicability: Males and Females
Taxonomic Applicablity: Restricted to mammals.
Life Stages Applicability: Adulthood.
Essentiality of the Key Events
Evidence Assessment
KER title |
Biological Plausibility |
Empirical Support[KT1] |
Essentiality |
Brief Explanation (summary) |
KER 1: KE1 => KE2 reduced GnRH availability pulsatory release leads to decrease/delayed LH surge |
H |
H |
H |
Biological Plausibility. There is an extensive understanding based on extensive previous documentation and broad acceptance that LH surge depends by GnRH release and availability, it is considered a consolidated scientific concept with a well-established mechanistic basis. As consequence, the KER is considered a high biological plausible KER. Empirical Support. There are multiple studies showing dependent change in both events following exposure to a range of specific stressors i.e., atrazine, tributyltin (TBT), endopeptidases, GABA modulators and light stimulation. Also, the available evidence support a concordance in terms of temporal, dose- response and incidence with no or few critical data gaps or conflicting data (see section “empirical evidence” of this KER). The empirical support was therefore considered high. Essentiality. There is enough direct evidence supporting the essentiality of the current KE, blocking the GnRH receptor with a competitive antagonist led to a full blockage of the LH surge in ewes (Karsch et al., 1997) and rats (Wu, 1997 and Lasdun, 1089). Moreover, different studies demonstrates that the selective deletion of estrogen receptor alpha from kisspeptin neurons (neurons that innervates the GnRH neurons) as well lesions of the AVPv nucleus, resulted in an abolishment of the LH surge leading to persistent estrous (Dubois, 2015). As a matter of facts, estrogens are acting on the kisspeptin neurons, the GnRh neurons have not the estrogen receptor. Indirect evidence (i.e., Goodman 2015) is also available. The essentiality is therefore weighted as high. |
KER 2: KE2 => KE3: Reduced LH surge leads to delayed ovulation |
H |
H |
H |
Biological Plausibility. The biological plausibility of this KERs is linked to the physiological role of LH in mammals which is a consolidated scientific concept (dogma). The biological plausibility is therefore high. Empirical support. There are multiple studies showing dependent change in both events following exposure to a range of specific stressors i.e., atrazine, TCDD, PFOS, and GnRH antagonists. Also, the available evidence (see section “empirical evidence” of this KER) supports a concordance in terms of temporal, dose- response and incidence with no or few critical data gaps or conflicting data. The empirical support was therefore considered high. Essentiality. KO animal models were used to demonstrate that both LH and the LHCGR is necessary to trigger ovulation. This is also corroborated by the evidence that LH or LHCGR mutations found in women from different families presents lack of ovulation and issue on menstrual cycle. Therefore, there is enough direct evidence supporting the essentiality of this KEs. The essentiality is considered high. |
KER3 – KE3 => KE4: Delayed ovulation leads to estrogen dominance |
H |
M |
M |
Biological Plausibility. The biological plausibility of this KERs is linked to the physiology of reproductive system. Being a consolidated scientific concept, the biological plausibility is high. Empirical support. There are few studies showing dependent change in both events. Moreover, the analytical methods used to measure the levels of hormones in plasma, make difficult a comparison of the E2/P4 (Estradiol/Progesteron) ratio among different studies. The empirical support was therefore considered moderate. Essentiality. From the biological perspective it is well established that a lack of ovulation perturbs the estrous cycle due to the absence of the expected increase in progesterone secretion with the formation of corpus lutea. This alters the balance between estrogens and progesterone expected after ovulation. However, it is noted that the empirical evidence found in support of the current AOP development, clearly reported that in the knockout strains of LHβ or its receptor LHCGR, where the ovulation was found to be destroyed, both estradiol and progesterone are decreased in the serum or ovary. This evidence is not supporting the essentiality of this KEs and its impact on the later KE in this AOP i.e., estrogen dominance. The essentiality is therefore weighted as moderate. |
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
Quantitative Understanding
Considerations for Potential Applications of the AOP (optional)
References
Dubois SL, Acosta-Martínez M, DeJoseph MR, Wolfe A, Radovick S, Boehm U, Urban JH and Levine JE, 2015. Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology, 156:1111-1120. doi: 10.1210/en.2014-1851
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
Finch CE, 2014. The menopause and aging, a comparative perspective. J Steroid Biochem Mol Biol, 142:132-141. doi: 10.1016/j.jsbmb.2013.03.010
Karsch FJ, Bowen JM, Caraty A, Evans NP and Moenter SM, 1997. Gonadotropin-releasing hormone requirements for ovulation. Biol Reprod, 56:303-309. doi: 10.1095/biolreprod56.2.303
Lasdun A, Reznik S, Molineaux CJ and Orlowski M, 1989. Inhibition of endopeptidase 24.15 slows the in vivo degradation of luteinizing hormone-releasing hormone. J Pharmacol Exp Ther, 251:439-447
McQuillan HJ, Han SY, Cheong I and Herbison AE, 2019. GnRH Pulse Generator Activity Across the Estrous Cycle of Female Mice. Endocrinology, 160:1480-1491. doi: 10.1210/en.2019-00193
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
Stewart CA, Stewart MD, Wang Y, Mullen RD, Kircher BK, Liang R, Liu Y and Behringer RR, 2022. Chronic Estrus Disrupts Uterine Gland Development and Homeostasis. Endocrinology, 163. doi: 10.1210/endocr/bqac011
Wu TJ, Pierotti AR, Jakubowski M, Sheward WJ, Glucksman MJ, Smith AI, King JC, Fink G and Roberts JL, 1997. Endopeptidase EC 3.4.24.15 presence in the rat median eminence and hypophysial portal blood and its modulation of the luteinizing hormone surge. J Neuroendocrinol, 9:813-822. doi: 10.1046/j.1365-2826.1997.00637.x