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Molecular Research in Embryo Implantation

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 18970

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Prof. Dr. Thomas D'Hooghe

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Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium
Interests: obstetrics; gynaecology; endometriosis
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The probability that a human embryo can have a successful implantation in the uterus that leads to the live birth of a healthy baby is determined by embryo quality, endometrial/uterine receptivity, and maternal/paternal genetic, epigenetic or environmental factors. While the genetic understanding of human embryo quality has improved, the interaction between human embryo and endometrium before, during and after implantation is still poorly understood. Furthermore, it is not clear if and how the human embryo actively influences/activates the endometrium in promoting or rejecting implantation, or vice versa, and how maternal–fetal tolerance is achieved and maintained during early pregnancy. In the context of clinical treatment with medically assisted reproduction, it is not well understood if and how different medicinal products used for ovarian stimulation, ovulation triggering, and hormonal luteal phase support directly affect and influence human ovarian and endometrial function, receptivity and embryo implantation.

This Special Issue of the International Journal of Molecular Sciences invites authors to submit original research or review papers that provide novel concepts, based on human, animal and in vitro molecular, translational or pre-clinical research, to improve our understanding of (immune)biology of human endometrial receptivity, embryo implantation and implantation failure, novel approaches to enhance endometrial receptivity supporting embryo implantation and reducing risk of miscarriage, and novel approaches to support effective ovulation and luteal ovarian function before and after conception during infertility treatment. Please notice that data on molecular mechanisms or pathophysiology are essential, and papers that only contain clinical trials/data are not acceptable.

Prof. Dr. Thomas D'Hooghe
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

embryo implantation
ovulation triggering
luteal phase support
molecular mechanisms

Published Papers (6 papers)

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Research

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19 pages, 5208 KiB

Open AccessArticle

Metabolomics Integration in Assisted Reproductive Technologies for Enhanced Embryo Selection beyond Morphokinetic Analysis

by Soraia Pinto, Bárbara Guerra-Carvalho, Luís Crisóstomo, António Rocha, Alberto Barros, Marco G. Alves and Pedro F. Oliveira

Int. J. Mol. Sci. 2024, 25(1), 491; https://doi.org/10.3390/ijms25010491 - 29 Dec 2023

Cited by 1 | Viewed by 1111

Abstract

Embryo quality evaluation during in vitro development is a crucial factor for the success of assisted reproductive technologies (ARTs). However, the subjectivity inherent in the morphological evaluation by embryologists can introduce inconsistencies that impact the optimal embryo choice for transfer. To provide a more comprehensive evaluation of embryo quality, we undertook the integration of embryo metabolomics alongside standardized morphokinetic classification. The culture medium of 55 embryos (derived from 21 couples undergoing ICSI) was collected at two timepoints (days 3 and 5). Samples were split into Good (n = 29), Lagging (n = 19), and Bad (n = 10) according to embryo morphokinetic evaluation. Embryo metabolic performance was assessed by monitoring the variation in specific metabolites (pyruvate, lactate, alanine, glutamine, acetate, formate) using ¹H-NMR. Adjusted metabolite differentials were observed during the first 3 days of culture and found to be discriminative of embryo quality at the end of day 5. Pyruvate, alanine, glutamine, and acetate were major contributors to this discrimination. Good and Lagging embryos were found to export and accumulate pyruvate and glutamine in the first 3 days of culture, while Bad embryos consumed them. This suggests that Bad embryos have less active metabolic activity than Good and Lagging embryos, and these two metabolites are putative biomarkers for embryo quality. This study provides a more comprehensive evaluation of embryo quality and can lead to improvements in ARTs by enabling the selection of the best embryos. By combining morphological assessment and metabolomics, the selection of high-quality embryos with the potential to result in successful pregnancies may become more accurate and consistent. Full article

(This article belongs to the Special Issue Molecular Research in Embryo Implantation)

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17 pages, 2159 KiB

Open AccessArticle

DNA Methylation of Window of Implantation Genes in Cervical Secretions Predicts Ongoing Pregnancy in Infertility Treatment

by Quang Anh Do, Po-Hsuan Su, Chien-Wen Chen, Hui-Chen Wang, Yi-Xuan Lee, Yu-Chun Weng, Lin-Yu Chen, Yueh-Han Hsu and Hung-Cheng Lai

Int. J. Mol. Sci. 2023, 24(6), 5598; https://doi.org/10.3390/ijms24065598 - 15 Mar 2023

Cited by 3 | Viewed by 2574

Abstract

Window of implantation (WOI) genes have been comprehensively identified at the single cell level. DNA methylation changes in cervical secretions are associated with in vitro fertilization embryo transfer (IVF-ET) outcomes. Using a machine learning (ML) approach, we aimed to determine which methylation changes in WOI genes from cervical secretions best predict ongoing pregnancy during embryo transfer. A total of 2708 promoter probes were extracted from mid-secretory phase cervical secretion methylomic profiles for 158 WOI genes, and 152 differentially methylated probes (DMPs) were selected. Fifteen DMPs in 14 genes (BMP2, CTSA, DEFB1, GRN, MTF1, SERPINE1, SERPINE2, SFRP1, STAT3, TAGLN2, TCF4, THBS1, ZBTB20, ZNF292) were identified as the most relevant to ongoing pregnancy status. These 15 DMPs yielded accuracy rates of 83.53%, 85.26%, 85.78%, and 76.44%, and areas under the receiver operating characteristic curves (AUCs) of 0.90, 0.91, 0.89, and 0.86 for prediction by random forest (RF), naïve Bayes (NB), support vector machine (SVM), and k-nearest neighbors (KNN), respectively. SERPINE1, SERPINE2, and TAGLN2 maintained their methylation difference trends in an independent set of cervical secretion samples, resulting in accuracy rates of 71.46%, 80.06%, 80.72%, and 80.68%, and AUCs of 0.79, 0.84, 0.83, and 0.82 for prediction by RF, NB, SVM, and KNN, respectively. Our findings demonstrate that methylation changes in WOI genes detected noninvasively from cervical secretions are potential markers for predicting IVF-ET outcomes. Further studies of cervical secretion of DNA methylation markers may provide a novel approach for precision embryo transfer. Full article

(This article belongs to the Special Issue Molecular Research in Embryo Implantation)

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13 pages, 2657 KiB

Open AccessArticle

Cervical Secretion Methylation Is Associated with the Pregnancy Outcome of Frozen-Thawed Embryo Transfer

by Yi-Xuan Lee, Po-Hsuan Su, Anh Q. Do, Chii-Ruei Tzeng, Yu-Ming Hu, Chi-Huang Chen, Chien-Wen Chen, Chi-Chun Liao, Lin-Yu Chen, Yu-Chun Weng, Hui-Chen Wang and Hung-Cheng Lai

Int. J. Mol. Sci. 2023, 24(2), 1726; https://doi.org/10.3390/ijms24021726 - 15 Jan 2023

Viewed by 2508

Abstract

The causes of implantation failure remain a black box in reproductive medicine. The exact mechanism behind the regulation of endometrial receptivity is still unknown. Epigenetic modifications influence gene expression patterns and may alter the receptivity of human endometrium. Cervical secretions contain endometrial genetic material, which can be used as an indicator of the endometrial condition. This study evaluates the association between the cervical secretion gene methylation profile and pregnancy outcome in a frozen-thawed embryonic transfer (FET) cycle. Cervical secretions were collected from women who entered the FET cycle with a blastocyst transfer (36 pregnant and 36 non-pregnant women). The DNA methylation profiles of six candidate genes selected from the literature review were measured by quantitative methylation-specific PCR (qMSP). Bioinformatic analysis of six selected candidate genes showed significant differences in DNA methylation between receptive and pre-receptive endometrium. All candidate genes showed different degrees of correlation with the pregnancy outcomes in the logistic regression model. A machine learning approach showed that the combination of candidate genes’ DNA methylation profiles could differentiate pregnant from non-pregnant samples with an accuracy as high as 86.67% and an AUC of 0.81. This study demonstrated the association between cervical secretion methylation profiles and pregnancy outcomes in an FET cycle and provides a basis for potential clinical application as a non-invasive method for implantation prediction. Full article

(This article belongs to the Special Issue Molecular Research in Embryo Implantation)

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Review

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23 pages, 937 KiB

Open AccessReview

Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss

by Xushan Gao, Yvonne V. Louwers, Joop S. E. Laven and Sam Schoenmakers

Int. J. Mol. Sci. 2024, 25(1), 622; https://doi.org/10.3390/ijms25010622 - 3 Jan 2024

Cited by 3 | Viewed by 3235

Abstract

Recent studies have investigated if and how the vaginal and endometrial microbiome might affect endometrial receptivity and reproductive health. Although there is no consensus on the existence of a core uterine microbiome yet, evidence shows that the dominance of Lactobacillus spp. in the female reproductive tract is generally associated with eubiosis and improved chances of successful implantation and an ongoing pregnancy. Conversely, vaginal and endometrial dysbiosis can cause local inflammation and an increase of pro-inflammatory cytokines, compromising the integrity and receptivity of the endometrial mucosa and potentially hampering successful embryonic implantation. This review provides a critical appraisal of the influence of the vaginal and endometrial microbiome as parts of the female reproductive tract on fertility outcomes, focusing on repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It seems that RIF as well as RPL are both associated with an increase in microbiome diversity and a loss of Lactobacillus dominance in the lower female reproductive system. Full article

(This article belongs to the Special Issue Molecular Research in Embryo Implantation)

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25 pages, 5921 KiB

Open AccessReview

Progesterone: The Key Factor of the Beginning of Life

by Carlo Bulletti, Francesco Maria Bulletti, Romualdo Sciorio and Maurizio Guido

Int. J. Mol. Sci. 2022, 23(22), 14138; https://doi.org/10.3390/ijms232214138 - 16 Nov 2022

Cited by 14 | Viewed by 4567

Abstract

Progesterone is the ovarian steroid produced by the granulosa cells of follicles after the LH peak at mid-cycle. Its role is to sustain embryo endometrial implantation and ongoing pregnancy. Other biological effects of progesterone may exert a protective function in supporting pregnancy up to birth. Luteal phase support (LPS) with progesterone is the standard of care for assisted reproductive technology. Progesterone vaginal administration is currently the most widely used treatment for LPS. Physicians and patients have been reluctant to change an administration route that has proven to be effective. However, some questions remain open, namely the need for LPS in fresh and frozen embryo transfer, the route of administration, the optimal duration of LPS, dosage, and the benefit of combination therapies. The aim of this review is to provide an overview of the uterine and extra-uterine effects of progesterone that may play a role in embryo implantation and pregnancy, and to discuss the advantages of the use of progesterone for LPS in the context of Good Medical Practice. Full article

(This article belongs to the Special Issue Molecular Research in Embryo Implantation)

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13 pages, 1452 KiB

Open AccessReview

Does Intrauterine Injection of hCG Improve IVF Outcome? A Systematic Review and a Meta-Analysis

by Alessandro Conforti, Salvatore Longobardi, Luigi Carbone, Giuseppe Gabriele Iorio, Federica Cariati, Maria Rosaria Campitiello, Ida Strina, Michela Palese, Thomas D’Hooghe and Carlo Alviggi

Int. J. Mol. Sci. 2022, 23(20), 12193; https://doi.org/10.3390/ijms232012193 - 13 Oct 2022

Cited by 4 | Viewed by 4330

Abstract

Various interventions have been proposed to improve embryo implantation in IVF. Among these, intrauterine injections of human chorionic gonadotropin seem to have promising results. Consequently, we conducted a review and meta-analysis to assess IVF outcomes by comparing couples who underwent intrauterine hCG injection transfer versus those who underwent embryo transfer with intrauterine injection of placebo, or without any additional intervention. The primary outcome was the clinical pregnancy rate. Secondary outcomes were the implantation rate, miscarriage rate, and live birth rate. A meta-analysis was conducted using the random effects model, while bias within studies was detected using the Cochrane risk of bias tool. Ectopic pregnancies and stillbirths were also assessed. The clinical pregnancy (RR 1.38, 95% CI 1.17–1.62, p < 0.0001) and implantation rate (RR 1.40, 95% CI 1.12–1.75, p = 0.003) were significantly higher in women who underwent hCG injection than in the control group. These significant effects persisted only in women who underwent cleavage-stage embryo transfer. No significant differences between groups were observed in the other secondary outcomes. In conclusion, our systematic review and meta-analysis demonstrate that intrauterine injection of hCG could be a valuable approach in women who undergo cleavage-stage embryo transfer. Given the lack of data about the live birth rate, caution should be exercised in interpreting these data. Full article

(This article belongs to the Special Issue Molecular Research in Embryo Implantation)

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