Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Arroyo, Amanda; Kim, Beomsu; Yeh, John

doi:10.1007/s43032-019-00137-x

Cited by 75 publications

(55 citation statements)

References 385 publications

(455 reference statements)

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“…The reduced level of Gata4 expression in Erβ null GCs may contribute to reduced GC proliferation and theca cell recruitment, which would impair the maturation of follicles to the preovulatory stage (Bennett et al, 2013;Efimenko et al, 2013;LaVoie, 2014). Additionally, NPR2 plays an important role in GCs by inducing cGMP levels, which inhibits phosphodiesterase 3A, prevents cAMP hydrolysis, and retrieves the oocytes from meiotic arrest (Arroyo et al, 2020;Potter et al, 2006;Zhang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Chakravarthi

Borosha

Ghosh

et al. 2020

Preprint

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Follicle development beyond the preantral stage is dependent on gonadotropins. FSH signaling is crucial for the advancement of preantral follicles to the antral stage, and LH signaling is essential for further maturation of preovulatory follicles. Estrogen is intricately tied to gonadotropin signaling during the advanced stages of folliculogenesis. We observed that Erβnull ovarian follicles fail to develop beyond the antral stage, even after exogenous gonadotropin stimulation. As ERβ is primarily expressed in the granulosa cells (GCs), we explored the gonadotropin-regulated GC genes that induce maturation of antral follicles. Synchronized follicle development was induced by administration of exogenous gonadotropins to wildtype 4-wk-old female rats. The GC transcriptome was analyzed via RNA-sequencing before and after gonadotropin stimulation. An Erβnull mutant model that fails to show follicle maturation was also included in order to identify the ERβ-regulated genes involved at this step. We observed that specific groups of genes were differentially expressed in response to PMSG or hCG administration in wildtype rats. While some of the PMSG or hCG-induced genes showed a similar expression pattern in Erβnull GCs, a subset of PMSG- or hCG-induced genes showed a differential expression in Erβnull GCs. These latter ERβ-regulated genes included previously known FSH or LH target genes including Lhcgr, Cyp11a1, Cyp19a1, Pgr, Runx2, Egfr, Kiss1, and Ptgs2, which are involved in follicle development, oocyte maturation, and ovulation. We also identified novel ERβ-regulated genes including Jaml, Galnt6, Znf750, Dusp9, Wnt16, and Mageb16 that failed to respond to gonadotropin stimulation in Erβnull GCs. Our findings indicate that the gonadotropin-induced spatiotemporal pattern of gene expression is essential for ovarian follicle maturation beyond the antral stage. However, expression of a subset of those gonadotropin-induced genes is dependent on transcriptional regulation by ERβ.

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Section: Discussionmentioning

confidence: 99%

“…GCs. It has been suggested that LH/LHCGR-induced ERK activation is regulated by ADAMTS1, a metalloprotease, which is also involved in cumulus expansion and induction of ovulation (Arroyo et al, 2020;Madan et al, 2003;Shozu et al, 2005;Yung et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Chakravarthi

Borosha

Ghosh

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…The transformation of the proliferative phase of the endometrium to the implantation window is regulated by estrogens, progesterone, and possibly by other unknown factors. The LH peak is the most critical factor to promote oocyte maturation, embryonic development, and synchronous endometrial receptivity [ 16 , 17 ]. The expression of LH/hCG-R on the endometrium prompted that LH/hCG-R may serve as a signal that prompts embryo implantation and development.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Study on the Regulation of Annexin IV and VEGF by hCG in the Human Endometrium

Chen

et al. 2020

Biochemistry Research International

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Objective. Whether changes in vascular endothelial growth factor (VEGF) and annexin IV during implantation are regulated through the LH/hCG-R needs further research. To investigate the mechanism of hCG on the expression of annexin IV and VEGF in human endometrial cells. Methods. Endometrial cells were isolated and identified from human specimens. The proportion of glandular and epithelial cells was analyzed. Annexin IV and VEGF were analyzed by qRT-PCR (mRNA), western blot (proteins), and immunohistochemistry (proteins). Protein location was identified by immunohistochemistry. The cells were cultured with hCG, hCG/PD98059 (a MAPK inhibitor), or no treatment (control). Results. The proportions between the glandular epithelial cells and stromal cells at inoculation and when adding hCG were 25.8 ± 0.2% and 27.8 ± 0.04%, respectively ( P > 0.05 ). LH/hCG-R, annexin IV, and VEGF were found in the cytoplasm of endometrial cells. After 2, 6, 12, and 24 h of hCG treatment, compared with 1 h, VEGF mRNA was increased by 1.25-fold, 3.19-fold, 4.21-fold, and 4.86-fold and annexin IV by 2.23-fold, 3.37-fold, 5.14-fold, and 5.02-fold. Compared with the control group, annexin IV mRNA and protein were increased in the hCG and hCG/PD98059 groups (mRNA/protein: 1.99-fold/1.80-fold and 2.33-fold/1.93-fold, P < 0.05 ). Compared with the control group, VEGF mRNA and protein were increased in the hCG group (mRNA/protein: 2.30-fold/1.86-fold), but not in the hCG/PD98059 group. Conclusion. hCG could upregulate the mRNA and protein expression of annexin IV and VEGF. The upregulation of annexin IV by hCG could not be inhibited by PD98059, but the upregulation of VEGF by hCG could.

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“…Loss of signaling through the LHCGR cascades can cause atresia of mature oocytes in zebrafish (Migliaccio et al 2018 ; Santangeli et al 2016 ) and anovulation in mouse and human (Arroyo et al 2020 ). For instance, increased DNA demethylation of LHCGR is observed in DHEA-induced PCOS mouse model (Zhu et al 2010 ) and human granulosa cells of women with PCOS (Sagvekar et al 2019 ).…”

Section: Adverse Outcome Pathways As They Relate To Key Processes Inmentioning

confidence: 99%

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

et al. 2020

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Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

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Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Cited by 75 publications

References 385 publications

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

Granulosa cell genes that regulate ovarian follicle development beyond the antral stage: the role of estrogen receptor β

In Vitro Study on the Regulation of Annexin IV and VEGF by hCG in the Human Endometrium

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

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