Dr. William Yeung is a Professor in the Department of Obstetrics and Gynaecology, the University of Hong Kong. He completed his PhD degree at the University of Hong Kong. He did his postdoctoral training in the University of Bristol, United Kingdom. He is currently the Scientific Director of the reproductive medicine program of the University of Hong Kong. He is also the laboratory-in-charge of the University of Hong Kong-Shenzhen Hospital, the University of Hong Kong-Family Planning Association Andrology Laboratory and the Kwong Wah Hospital Reproductive Medicine Centre. He is an Honorary Fellow of the Hong Kong College of Obstetricians and Gynaceologists.
Embryo implantation involves a complex interplay between a competent blastocyst and a receptive endometrium. Implantation failure can result from defects in the embryos, endometrium, or both. Preimplantation genetic testing for aneuploidy (PGT-A) was developed to identify euploid embryos for transfer during assisted reproduction treatment. However, a substantial proportion of the transferred euploid embryos fail to undergo successful implantation. According to the registry of the Society for Assisted Reproductive Technology, USA, females <35 years of age undergoing elective single embryo transfer after PGT-A have a cumulative live birth rate of approximately 55%. This observation highlights the possibility of endometrial defects, at least in part, in cases of failed implantation, though functional defects of the transferred embryos other than aneuploidy cannot be excluded.
Endometrial receptivity is a research hotspot in reproductive medicine. Apart from congenital and acquired anatomical abnormalities, clinical conditions, including endometrial atrophy, Asherman’s syndrome, luteal phase deficiency, endometriosis, and chronic endometritis, are known to cause endometrial dysfunction and have been associated with infertility. Advanced molecular diagnostic tests, such as the endometrial receptivity array, have been developed to determine the period during which the endometrium is receptive to the incoming blastocyst, termed the implantation window. Using these tests, the displaced and/or disrupted implantation window has been associated with repeated implantation failures. However, the clinical use of these tests for personalized embryo transfer is on heated debate.
Although data regarding endometrial gene profiles allow the detection of a defective endometrium, the underlying mechanism through which dysregulated gene expression affects endometrial receptivity and, in turn, implantation remains unknown. Appropriate models are required to decipher the causal relationship between the defective gene expression and cellular functions. This information is critical for development of novel treatment strategies. Previously, the endometrial models available were simple and may have failed to reflect in vivo conditions. With the advent of organoid models and new technologies, scientists are now better positioned to address this question.
The objective of the special issue of Reproductive and Developmental Medicine, comprising five review articles, is to update readers on new developments in endometrial research.
The first review focuses on single-cell analysis in endometrial research. The recent use of single-cell RNA sequencing technology has uncovered heterogeneous molecular activities in individual endometrial cells, which were masked in previously performed bulk-mRNA analysis. The human endometrium undergoes cyclical shedding, repair, and regeneration during the female reproductive life cycle. This article discusses how single-cell technology facilitates our understanding of endometrial regeneration from a physiological perspective, as well as endometrial factors contributing to uterine pathology.
In female patients with Asherman’s syndrome and endometrial atrophy, endometrial regeneration is defective, causing infertility. Currently, there is no effective treatment strategy to address this condition. Mesenchymal stem cells from various sources have been employed to treat the diseases with limited success, given the limited lifespan of the cells in culture for expansion, low viability of the transplanted cells, and a lack of integration of the stem cells in the engrafted tissue. It is well-established that endometrial stem cells are responsible for endometrial regeneration, and their biological activities are regulated by cues from their microenvironment (niche). The second review provides an overview of the endometrial stem cell niche and introduces possibilities for exploring the complex milieu that supports endometrial repair and regeneration for treating patients with endometrial proliferation disorders.
Organoids are artificial microtissue models that resemble the primary tissue of origin and recapitulate their corresponding biological and pathological characteristics. The third review focuses on endometrial organoids. Early endometrial organoids exhibit structural and functional characteristics of endometrial glands and respond appropriately to steroidal hormones. To better recapitulate the endometrium in vivo, assembloids comprising endometrial glandular organoids and stromal cells have recently been developed. These organoids are powerful tools for examining endometrial functions and defects in endometrial diseases. Additionally, this review discusses the characteristics, applications, and limitations of endometrial organoids.
Despite the availability of in vitro endometrial models, our knowledge concerning human implantation remains limited owing to ethical concerns regarding the use of human embryos for research and the failure to apply results directly from animal models to human subjects. The fourth review elaborates on the recent development of blastocyst-like embryo surrogates, termed blastoids, which are likely to address the shortage of human embryos. Given the advances in the differentiation protocol, blastoids could potentially recapitulate the developmental events of early human embryos. Moreover, blastoids can be used in conjunction with endometrial assembloids to investigate human embryo implantation under settings that closely mimic the in vivo condition. An improved understanding of the early implantation process will help explore the pathophysiology of reproductive disorders and enhance the success rate of assisted reproduction technology.
The final review surveys well-known molecules that modulate embryo implantation via their effects on endometrial receptivity. Active biological molecules, including human chorionic gonadotropin, growth hormone, and granulocyte colony-stimulating factor, medicinal extracts from Chinese herbs, and drugs including aspirin, vitamin E, sildenafil, and atosiban, have been shown to affect endometrial functions such as endometrial blood flow, gene expression, and immune functions of the endometrium. The recent development of a high-throughput endometrial cell-trophoblast surrogate screening method will facilitate the discovery of additional molecules that can modulate embryo implantation via their actions on endometrial cells and/or trophoblasts.
. Lee M, Lofgren KT, Thomas A, et al. The cost-effectiveness of preimplantation genetic testing for aneuploidy in the United States: an analysis of cost and birth outcomes from 158,665 in vitro
fertilization cycles. Am J Obstet Gynecol. 2021;225(1):55.e1–55.e17. doi:10.1016/j.ajog.2021.01.021.
. Sebastian-Leon P, Garrido N, Remohí J, et al. Asynchronous and pathological windows of implantation: two causes of recurrent implantation failure. Hum Reprod. 2018;33(4):626–635. doi:10.1093/humrep/dey023.
. Raff M, Jacobs E, Voorhis BV. End of an endometrial receptivity array? Fertil Steril. 2022;118(4):737. doi:10.1016/j.fertnstert.2022.07.031.