Superovulation Alters the Expression of Endometrial Genes Critical to Tissue Remodeling and Placentation

Overview

Journal J Assist Reprod Genet

Publisher Springer

Specialties Genetics
Reproductive Medicine

Date 2018 Jul 1

PMID 29959621

Citations 27

Authors

Suneeta Senapati

Fan Wang

Teri Ord

Christos Coutifaris

Rui Feng

Monica Mainigi

Affiliations

Soon will be listed here.

Abstract

Purpose: Epidemiologic data suggest that in vitro fertilization (IVF) is associated with an increased risk of disorders of placentation including preeclampsia and fetal growth restriction. Specifically, studies have demonstrated that singleton pregnancies conceived following a fresh embryo transfer are at an increased risk of delivering an infant with low birth weight compared to those conceived following a frozen embryo transfer. The mechanism responsible for this association remains unclear. Procedures utilized in IVF have also been linked with epigenetic changes and gene expression changes in both fetal and maternal tissues. Data suggest that modifications in the maternal endometrium can lead to disordered trophoblast invasion and placentation. This study examines the effect of ovarian stimulation on endometrial gene expression and DNA methylation during the window of implantation to examine potential pathways playing a role in the adverse outcomes associated with IVF.

Methods: Endometrial biopsies were obtained from oocyte donors and age-matched naturally cycling women 11 days following oocyte retrieval in donors or 12 days following luteinizing hormone (LH) surge in naturally cycling women. Global gene expression was analyzed via Affymetrix Human Gene 1.1 ST array and confirmed with RT-qPCR. DNA methylation was assessed with the Infinium DNA methylation 450 K BeadChip.

Results: Analysis of endometrial gene expression from 23 women (11 oocyte donors and 12 controls) demonstrated 165 genes with a greater than twofold change in expression between donors and controls. While there were 785 genes with significant differential methylation in the endometrium of donors when compared with control subjects, none of the genes with altered expression showed significant changes in DNA methylation. Analysis of the differentially expressed genes showed enrichment for genes involved in endometrial remodeling including PLAT, HSPE2, MMP2, and TIMP1. Validation studies using RT-qPCR found a 73% reduction in expression of heparanase 2 (HSPE2) an enzyme associated with both angiogenesis and cell invasion, a greater than twofold increase in tissue-type plasminogen activator (PLAT), a serine protease participating in matrix degradation, and a 70% increase in MMP2, a gelatinase involved in collagen and fibronectin breakdown.

Conclusions: Superovulation alters expression of genes critical to endometrial remodeling during early implantation. Such changes could lead to altered trophoblast migration and impaired endovascular invasion. These findings offer a potential mechanism for the adverse perinatal outcomes observed following embryo transfer during fresh IVF cycles.

Citing Articles

Singleton term pregnancies resulting from frozen-thawed embryo transfer in hormone replacement cycles increase the risk of aberrant placentation, including velamentous umbilical cord insertion.

Furuya S, Yamaguchi T, Ishikawa I, Ishikawa M, Kawanami R, Kasano S Arch Gynecol Obstet. 2025; .

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Risks of Placental Abruption and Preterm Delivery in Patients Undergoing Assisted Reproduction.

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Comparison of Fetal Crown-Rump Length Measurements between Thawed and Fresh Embryo Transfer.

Mitta K, Tsakiridis I, Giougi E, Mamopoulos A, Kalogiannidis I, Dagklis T J Clin Med. 2024; 13(9).

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The impact of ovarian stimulation on the human endometrial microenvironment.

Chemerinski A, Shen M, Valero-Pacheco N, Zhao Q, Murphy T, George L Hum Reprod. 2024; 39(5):1023-1041.

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Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

de Vos E, Mulders A, Koning A, Willemsen S, Rousian M, van Rijn B Hum Reprod. 2024; 39(5):923-935.

PMID: 38503486 PMC: 11063559. DOI: 10.1093/humrep/deae056.

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