Molecular approaches to mammalian uterine receptivity for conceptus implantation.

The improvement of fertility in mammals is a multidisciplinary subject. In obstetric clinics, human reproduction is recognized as unexpectedly inefficient [ 1 , 2 ], and only one in three conceptions can lead to live birth [ 3 , 4 , 5 , 6 , 7 ]. In animal husbandry and veterinary medicine, domestic animal reproduction has been described as less than ideal. For example, the bovine fertility rates have decreased to approximately half or less over several decades [ 8 , 9 , 10 , 11 ]. In these cases, majority of terminated pregnancies are considered to have occurred during periembryonic implantation in the uterus. Furthermore, it has been hypothesized that even later losses during pregnancy may be caused by inadequate implantation and subsequent placentation. These findings indicate that implantation is a critical rate-limiting process that controls reproductive success. Several factors are involved in reproductive failure. Embryonic aneuploidy, the gain or loss of chromosomes, is a well-known primary cause of impaired embryonic quality in humans. Because aneuploidy arises in both pre- and post-zygotic divisions, in the latter case, the embryo is mosaic and has both normal and aneuploid cells. More than 90% of human preimplantation embryos consist of at least one chromosomally abnormal cell [ 12 ], and even though low levels of mosaicism are common, such cells can develop normally [ 13 , 14 ]. Severe aneuploidy is lethal [ 15 , 16 ], and maternal age is known as a risk of higher oocyte chromosomal abnormalities [ 17 ]. Nevertheless, abnormal fetal development with a possibility of critical abortion in older female mice can be restored when their embryos are transferred into the uterus of a younger female, demonstrating that the maternal uterine environment is a major contributor to declining reproductive success with maternal aging [ 18 ]. Assisted reproductive technology (ART) has advanced significantly, generating high-quality/grade embryos for mammalian reproduction, including in humans [ 19 , 20 ] and bovine species [ 21 , 22 , 23 ]. ART includes assistance with fertilization (i.e., intracytoplasmic sperm injection), development of culture media (for embryo development and cryopreservation), and establishment of embryo selection methods (based on grade and karyotype). The state-of-the-art in vitro production of gametes (both sperm and oocytes) has been extensively studied and recently developed [ 24 , 25 , 26 ]. Embryonic aspects of reproduction have been in focus and extensive efforts have been taken on their advance. However, rates of implantation and live births after embryo transfer remain low (50% or less) in humans [ 27 ] and cattle [ 21 , 22 , 23 ]. Understanding and preparing for the maternal environment by establishing a healthy and optimal endometrium will enhance reproductive success.

This review describes the limited number of studies on how mammalian reproduction is inefficient and provides clues to the underlying reasons. Despite tremendous efforts by numerous scientists, physicians, and veterinarians to increase the success rates of pregnancy, rates of successful implantation, which is a key early event in the establishment of pregnancy, and the final outcome (delivery) remain low. Successful implantation requires an activated embryo and a fully receptive uterus. Advances in ART have enabled the generation of high-quality embryos. The optimal endometrial preparation requires further investigation. CRISPR-Cas9 allows mice to be genetically modified as well as other mammals such as cattle and non-human primates, which serve as models for humans [ 105 ]. In addition, in vitro three-dimensional endometrial organoid models are being developed in humans [ 106 , 107 ] and cattle [ 108 , 109 ], recapitulating the in vivo endometrial state. These attractive new tools, when combined with powerful omics analyses such as single-cell transcriptomics, proteomics, and/or metabolomics, will shed light on a comprehensive understanding of uterine receptivity and conceptus implantation, which is necessary for the development of clinical diagnostics and therapeutics for implantation failure, for reproductive success in a wide variety of mammals in the future.

The author declares no conflicts of interest.