Spatial and molecular anatomy of the endometrium during embryo implantation: a current overview of key regulators of blastocyst invasion.
The FEBS journal
Embryo implantation is composed of three steps: blastocyst apposition, adhesion/attachment and invasion. Blastocyst invasion has been studied less extensively than the other two events. Historically, studies conducted using electron microscopy have shown the removal of epithelial cells in the vicinity of the attached blastocysts in rodents, although the underlying mechanisms have remained unclear. Here, we describe recent studies using mice with uterine-specific gene deletion that demonstrated important roles for nuclear proteins such as progesterone receptor, hypoxia inducible factor and retinoblastoma in the regulation of embryo invasion. In these mouse models, the detachment of the endometrial luminal epithelium, decidualization in the stroma, and the activation of trophoblasts have been found to be important in ensuring embryo invasion. This review summarizes the molecular signaling associated with these cellular events, mainly evidenced by mouse models.
10.1111/febs.17077
The interaction between the environment and embryo development in assisted reproduction.
Animal reproduction
It can be assumed that the natural processes of selection and developmental condition in the animal provide the best prerequisites for embryogenesis resulting in pregnancy and subsequent birth of a healthy neonate. In contrast, circumventing the natural selection mechanisms and all developmental conditions in a healthy animal harbors the risk of counteracting, preventing or reducing the formation of embryos or substantially restricting their genesis. Considering these facts, it seems to be obvious that assisted reproductive techniques focusing on early embryonic stages serve an expanded and unselected germ cell pool of oocytes and sperm cells, and include the culture of embryos outside their natural habitat during and after fertilization for manipulation and diagnostic purposes, and for storage. A significant influence on the early embryonic development is seen in the extracorporeal culture of bovine embryos (in vitro) or stress on the animal organism (in vivo). The in vitro production per se and metabolic as well as endocrine changes in the natural environment of embryos represent adequate models and serve for a better understanding. The purpose of this review is to give a brief presentation of recent techniques aimed at focusing more on the complex processes in the Fallopian tube to contrast in vivo and in vitro prerequisites and abnormalities in early embryonic development and serve to identify potential new ways to make the use of ARTs more feasible.
10.1590/1984-3143-AR2023-0034
Superovulation alters global DNA methylation in early mouse embryo development.
Yu Bo,Smith Thomas H,Battle Stephanie L,Ferrell Shannon,Hawkins R David
Epigenetics
Assisted reproductive technologies are known to alter the developmental environment of gametes and early embryos during the most dynamic period of establishing the epigenome. This may result in the introduction of errors during active DNA methylation reprogramming. Controlled ovarian hyperstimulation, or superovulation, is a ubiquitously used intervention which has been demonstrated to alter the methylation of certain imprinted genes. The objective of this study was to investigate whether ovarian hyperstimulation results in genome-wide DNA methylation changes in mouse early embryos. Ovarian hyperstimulation was induced by treating mice with either low doses (5 IU) or high doses (10 IU) of PMSG and hCG. Natural mating (NM) control mice received no treatment. Zygotes and 8-cell embryos were collected from each group and DNA methylomes were generated by whole-genome bisulfite sequencing. In the NM group, mean CpG methylation levels slightly decreased from zygote to 8-cell stage, whereas a large decrease in mean CpG methylation level was observed in both superovulated groups. A separate analysis of the mean CpG methylation levels within each developmental stage confirmed that significant genome-wide erasure of CpG methylation from the zygote to 8-cell stage only occurred in the superovulation groups. Our results suggest that superovulation alters the genome-wide DNA methylation erasure process in mouse early pre-implantation embryos. It is not clear whether these changes are transient or persistent. Further studies are ongoing to investigate the impact of ovarian hyperstimulation on DNA methylation re-establishment in later stages of embryo development.
10.1080/15592294.2019.1615353
Embryonic diapause and its regulation.
Lopes Flavia L,Desmarais Joëlle A,Murphy Bruce D
Reproduction (Cambridge, England)
Embryonic diapause, a condition of temporary suspension of development of the mammalian embryo, occurs due to suppression of cell proliferation at the blastocyst stage. It is an evolutionary strategy to ensure the survival of neonates. Obligate diapause occurs in every gestation of some species, while facultative diapause ensues in others, associated with metabolic stress, usually lactation. The onset, maintenance and escape from diapause are regulated by cascades of environmental, hypophyseal, ovarian and uterine mechanisms that vary among species and between the obligate and facultative condition. In the best-known models, the rodents, the uterine environment maintains the embryo in diapause, while estrogens, in combination with growth factors, reinitiate development. Mitotic arrest in the mammalian embryo occurs at the G0 or G1 phase of the cell cycle, and may be due to expression of a specific cell cycle inhibitor. Regulation of proliferation in non- mammalian models of diapause provide clues to orthologous genes whose expression may regulate the reprise of proliferation in the mammalian context.
10.1530/rep.1.00444
Embryo implantation: biology, evaluation, and enhancement.
Koot Yvonne E M,Macklon Nick S
Current opinion in obstetrics & gynecology
PURPOSE OF REVIEW:Implantation is an essential step in the development of a pregnancy, but often fails in humans. In assisted reproductive technologies, implantation failure continues to impair treatment outcomes, with distressing results for patients and physicians. RECENT FINDINGS:Morphokinetics, comprehensive chromosome screening, and the analysis of embryo-derived products detectable in spent culture media offer new means of assessing embryo viability. However, all await validation in randomized controlled trials. Genomic, transcriptomic, and secretomic technologies are similarly being exploited to define specific biomarkers of endometrial receptivity with the aim of identifying novel therapeutic interventions. However, to date no single, clinically relevant molecular marker capable of indicating endometrial receptivity has been reported. Recent work continues to describe the key signalling pathways which result in acceptance or rejection of the implanting embryo. In-vitro studies have revealed that the decidualized endometrium plays an important role in natural embryo selection, which could change our understanding of the aetiology and treatment of reproductive failure. SUMMARY:Recent developments in analytical techniques have initiated a search for biomarkers of embryo quality and endometrial receptivity, and in-vitro studies have revealed novel roles for the decidualized endometrium as a biosensor of embryo quality.
10.1097/GCO.0b013e3283630d94
Ovarian stimulation and embryo quality.
Baart Esther B,Macklon Nick S,Fauser Bart J C M
Reproductive biomedicine online
To study the effects of different ovarian stimulation approaches on oocyte and embryo quality, it is imperative to assess embryo quality with a reliable and objective method. Embryos rated as high quality by standardized morphological assessment are associated with higher implantation and pregnancy rates. However, embryo morphology on day 3 after fertilization is not a reliable indication of a normal chromosomal constitution. Therefore, using embryo morphology as the sole parameter for embryo quality is not ideal. Screening of embryos for chromosomal aneuploidies before transfer can be used to assess the chromosomal competence of embryos, which has been shown to have a direct relationship with the approach used for ovarian stimulation. However, gene expression analysis of cumulus granulosa cells is a promising non-invasive technique for determining embryo quality. Cumulus cells are closely associated with oocytes, and oocyte-cumulus cell communication is vital to oocyte development. Cumulus cells respond to both gonadotrophins and paracrine factors from oocytes, with a distinct gene expression pattern. Future approaches analysing the expression of relevant genes in cumulus cells using real-time polymerase chain reaction may enable us to monitor the consequences of different stimulation protocols and identify the underlying molecular mechanisms by which they influence oocyte/embryo quality.
Maternal physiology and blastocyst morphology are correlated with an inherent difference in peri-implantation human embryo development.
Fertility and sterility
OBJECTIVE:To determine what patient and embryo characteristics are correlated with the developmental potential of the peri-implantation embryo. DESIGN:Retrospective study. SETTING:Research laboratory. PATIENTS:Six hundred fifty-one cryopreserved human blastocysts donated for research with informed patient consent. INTERVENTIONS:Not applicable. MAIN OUTCOME MEASURES:Blastocyst attachment to fibronectin-coated plates, trophectoderm outgrowth area, epiblast cell number, total cell number, human chorionic gonadotropin secretion. RESULTS:Patients' body mass index, age, follicle-stimulating hormone: luteinizing hormone ratio on menstrual cycle day 3, antral follicle count on menstrual cycle day 3, antimüllerian hormone level on menstrual cycle day 3, and blastocyst morphological grade were correlated with peri-implantation development outcomes. After controlling for good-quality morphological grades, blastocysts from patients of advanced maternal age developed fewer epiblast cells than blastocysts from younger patients. CONCLUSIONS:Extended embryo culture during the peri-implantation period mirrors several disparities in fertility treatment outcome that we see clinically, including those from patients with advanced maternal age, high body mass index, and low ovarian reserve and from embryos with lower-quality morphological grades. This model system may be useful by providing an alternative or more sensitive endpoint assessment in studying patient, clinical, or laboratory factors that may influence preimplantation embryo developmental potential.
10.1016/j.fertnstert.2022.02.018
Influence of cleavage-stage embryo quality on the in-vitro fertilization outcome after single embryo transfer in fresh cycles.
Sun Yu,Li Enshu,Feng Guofang,Li Miao,Fu Yanling,You Jiali,Liu Xiaozhen,Zhu Yimin
Taiwanese journal of obstetrics & gynecology
OBJECTIVE:Embryo quality is crucial for determining the outcome of embryo implantation. This study aimed to assess the impact of embryo quality on the outcome of in vitro fertilization/single-embryo transfer (IVF-SET). MATERIALS AND METHODS:This retrospective study included 2531 fresh IVF-SET cycles, including 277 poor-quality and 2254 top-quality embryos. The clinical pregnancy rate, miscarriage rate, live birth, implantation rate, pregnancy outcome and complication were analyzed and compared. Risk factors associated with miscarriage rate and pregnancy complication were identified using logistics regression analysis. RESULTS:Top-quality embryos resulted in higher clinical pregnancy rate (30.5% vs. 12.6%, P < 0.001) and live birth rate (23.9% vs. 9.7%, P < 0.001) compared with poor-quality embryos. Logistics regression analysis revealed that embryo quality was not correlated with miscarriage rate (95% CI 0.33-1.89) and pregnancy complications (95% CI 0.12-7.84). Maternal age and body mass index was a risk factor for miscarriage rate (95% CI 1.05-1.22) and pregnancy complication (95% CI 1.01-1.29), respectively. CONCLUSION:Clinical miscarriage rate and pregnancy complication were embryo quality independent. Maternal age was the risk factor for miscarriage rate. Embryo quality did not affect miscarriage once a clinical pregnancy is achieved.
10.1016/j.tjog.2020.08.003