Introduction
Embryo Implantation is a very important step in the development of mammalian fetuses. Successful embryo implantation requires a close interaction of the endometrium with the uterus. These mutual interactions in a limited period are known as receptivity window or “window of implantation” [1]. Embryo implantation consists of three stages: Apposition, attachment, and penetration. In mammals, including humans, after entering the uterus, the embryo (blastocyst) leaves the zona pellucida and interacts with the epithelium [2]. 
The uterine receptivity is regulated by the ovarian hormones of estrogen and progesterone. Under their influence, some cytokines and growth factors also play an important role in the blastocyst-uterus interaction during implantation. Knowing the function of these molecules during this process can help understand the causes of embryo implantation failure and infertility [3]. The present study aims to investigate the factors involved in embryo implantation.

Methods
In this review study, a search was conducted for studies published in English or Persian between 2000 and 2023 in national and international databases such as PubMed, Scopus, Science Direct, MagIran, and Google Scholar using the keywords “embryo implantation”, “factors affecting implantation” and “infertility”. The reference lists of the found articles were also manually searched. The case reports, letters to the editor, experimental studies, studies with unavailable full texts, and studies with unclear methodology were excluded. The articles were evaluated separately by two authors to identify related studies. Finally, the results of the studies were presented narratively and analytically.

Results
The main hormones affecting the uterine receptivity are progesterone and estrogen. Progesterone is essential for the implantation and maintenance of pregnancy in all mammals, while estrogen is required for certain species. In mice, progesterone and estrogen are necessary for embryo implantation, while in pigs, guinea pigs, rabbits, and hamsters, estrogen is not required; however, it is considered important for implantation. In humans, although the role of estrogen or the embryo is not fully clear, we know that the effects of estrogen and progesterone are mainly created by estrogen receptor (ER) and progesterone receptor (PR) [4].
The interaction of the blastocyst with the receptive uterus is very important for the production of trophoblastic cytokines and uterine epithelium. They modulate endometrial receptivity by regulating the expression of different molecules of attachment phase [5]. Embryo implantation is a type of inflammatory response. Several cytokines have been identified in the implantation site, many of which have embryonic origin. Interleukin-1 (IL-1), as one of the paracrine factors, modulates the interaction between the endometrium and the embryo, and is the key regulator of the inflammatory response. As a cytokine, it is able to create a wide range of effects in all types of cells [6]. Interleukin-11 (IL-11) expression in human endometrial tissue is also important during decidualization. An in-vitro study showed that leukemia-inhibitory factor (LIF) and IL-11 play a role in the regulation of cell adhesion in endometrial epithelium. In clinical studies, it has been reported that the plasma IL-11 level is lower in women with abortion in the first trimester compared to women with normal pregnancies [7].
The transforming growth factor-β (TGF-β) from the epidermal growth factor family in three different isoforms (TGF-β1, TGF-β2, β3-TGF) has profound effects on extracellular matrix production and enzyme degradation. In addition, TGF-β isoforms are found at the blastocyst-uterus interface and play an important role in the implantation process. TGF- β family members are expressed in the endometrium and play an active role in modulating cellular events, including regulation of cell proliferation, decidualization, and implantation process [8].
HOX genes are transcription factors that have a fundamental role in determining the identity of tissues during embryonic development and are involved in the development of Müllerian ducts (the female reproductive tract) and their expression are continued in the adult uterus. These genes are most likely to be the main regulators of embryo implantation in humans. HOX genes also act as regulators of morphogenesis and embryonic differentiation. Two HOX genes are required for fertility in mice. Female mice with targeted disruption of HOXA10 or HOXA11 are viable, but not fertile. Targeted disruption of HOXA11 can reduce the development of endometrial glands of stromal and also reduce the expression of LIF. The HOX genes may direct the development of the adult endometrium toward implantation. HOX gene expression in maternal endometrium can regulate fertility [9].
Morphogenic molecules cause cell differentiation and patterning in a concentration-dependent manner. The role of morphogens in uterine receptivity and embryo implantation has less been studies. Embryo-uterine interactions during implantation share many features of epithelial-mesenchymal interactions during embryonic development, and both conserve signaling pathways. The importance of hedgehog, Wnt, and BMP signaling pathways in uterine receptivity has been reported [10].

Conclusion
For embryo implantation, different messenger molecules such as cytokines, growth factors, and ovarian hormones are involved in uterine receptivity. Cytokines (LIF, IL-1, IL-6, IL-11), colony-stimulating factor (CSF-1), epidermal growth factor (EGF), and the insulin-like growth factor (IGF) play an important role in embryo- uterine interactions during the implantation process. HOX gene expression in the endometrium can regulate fertility. HOXA10 is regulated by estrogen and progesterone in the adult human uterus. These two hormones increases HOXA10 expression. However, an important part of their dependent or independent function is still unknown. Therefore, efforts in this field seem necessary. It can help to better understand the embryo implantation process and resolve the cause of implantation failure and infertility. Understanding the biology and molecular factors affecting embryo implantation can reduce female infertility and help create new infertility treatments (Figure 1).

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the ethics committee of Kermanshah University of Medical Sciences (Code: IR.KUMS.REC.1400.162).

Funding
This research did not receive any funding from funding organizations in the public, commercial, or non-profit sectors.

Authors' contributions
Study concept and design: Leila Rezakhani; Acquisition, analysis, or interpretation of data, drafting of the manuscript: Leila Rezakhani, Mohammad Rasool Khazaei, Azita Faramarzi; Critical revision: Leila Rezakhani, Mozafar Khazaei, Azita Faramarzi; Administrative, technical, or material support, study supervision: Mozafar Khazaei.

Conflicts of interest
The authors declare that there is no conflict of interest.

Acknowledgements
The authors express their gratitude to the Fertility and Infertility Research Center and the Tissue Engineering Department of Kermanshah University of Medical Sciences for their cooperation.


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