Implantation, also known as nidation, is the stage in the mammalian embryonic development in which the blastocyst hatches, attaches, adheres, and invades into the endometrium of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. An implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow. For implantation to take place the uterus must become receptive. Uterine receptivity involves much cross-talk between the embryo and the uterus, initiating changes to the endometrium. This stage gives a synchrony that opens a window of implantation that enables successful implantation of a viable embryo. The endocannabinoid system plays a vital role in this synchrony in the uterus, influencing uterine receptivity, and embryo implantation. The embryo expresses cannabinoid receptors early in its development that are responsive to anandamide (AEA) secreted in the uterus. AEA is produced at higher levels before implantation and is then down-regulated at the time of implantation. This signaling is of importance in the embryo-uterus crosstalk in regulating the timing of embryonic implantation and uterine receptivity. Adequate concentrations of AEA that are neither too high or too low, are needed for successful implantation. There is an extensive variation in the type of trophoblast cells, and structures of the placenta across the different species of mammals. Of the five recognised stages of implantation including two pre-implantation stages that precede placentation, the first four are similar across the species. The five stages are migration and hatching, pre-contact, attachment, adhesion, and invasion. The two pre-implantation stages are associated with the pre-implantation embryo. In humans, following the stage of hatching that takes place around four to five days after fertilization, the process of implantation begins. By the end of the first week, the blastocyst is superficially attached to the uterine endometrium. By the end of the second week, implantation has completed.
Implantation stages There are five recognized stages of implantation in mammals, including two pre-implantation stages that precede the formation of the placenta. They are: migration and hatching, pre-contact, attachment, adhesion, and invasion. The first four stages are similar across the species with the process of invasion being variable. These three stages of apposition, attachment, and invasion are also alternatively termed contact (apposition), adhesion (attachment), and penetration (invasion), and can only take place during a limited timeframe known as the window of implantation when the uterus is at its most receptive.
Migration and hatching
There are two stages of migration involved in implantation: the first is the migration of the zygote, and the second is the migration of the trophoblast. Fertilization of the oocyte takes place in the ampulla of the fallopian tube. Cilia on the lining of the tube move the zygote in its migration towards the uterus. During this migration the zygote undergoes a number of cell divisions that creates a ball of 16 compacted blastomeres called a morula. The morula enters the uterus after three or four days, and as it does a cavity called the blastocoel is formed in the morula to produce the blastocyst. The blastocyst contains the inner cell mass that will go on to develop into the embryo proper, and an outer cell layer of trophoblasts that will develop into the extraembryonic membranes (fetal membranes). The blastocyst is still enclosed in the egg-coat known as the zona pellucida, and for it to be able to implant into the uterine wall it must rid itself of this covering. This stage is known as zona hatching, and when there is sufficient dissolution the blastocyst is able to initiate the apposition stage of implantation. Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for the breakdown of the egg-coat. Mechanisms in the latter are indicated by the fact that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions. Among the known molecular regulators that promote hatching are predominantly proteases that are stimulated by various growth factors. The blastocyst also produces cytokines, both pro-inflammatory and anti-inflammatory, that have crucial roles during implantation and other stages of pregnancy. Both types of cytokines modulate the activity of proteases, including MMPs, plasminogen activators, and cathepsins. It is unknown whether the cytokines involved in hatching are pro-inflammatory or anti-inflammatory, or which proteases are involved. However, it is well accepted that the pro-inflammatory cytokines are dominant during implantation. Cytokines are also present in the uterine milk which might regulate the development and function of the blastocyst but there is no evidence to support their involvement in hatching. Leukemia inhibitory factor (LIF) is a pro-inflammatory cytokine expressed in the endometrium during the luteal phase of the menstrual cycle, with the highest expression seen during the window of implantation. LIF plays a role in adhesion and invasion. Assisted zona hatching may take place in assisted reproduction, where the zona pellucida may be artificially pierced to facilitate hatching.
Apposition Following zona hatching, the very first loose connection or contact between the blastocyst and the endometrium is called apposition. Apposition is usually made where there is a small crypt in the endometrium, and also where there has been enough breakdown of the zona pellucida to allow the blastocyst trophoblast to directly contact the underlying endometrium. Ultimately, the inner cell mass (also embryoblast), inside the trophoblast layer, is aligned closest to the decidua. If the inner cell mass is not aligned with the decidua at apposition, it has the ability to freely rotate within the trophoblast and achieve this alignment. Apposition is only a weak interaction of the trophectoderm with the uterine epithelium that is unstable to shear stress. Apposition is also reversible allowing repositioning of the blastocyst in the uterus.
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