WRITE UPS - PERI-CONCEPTION - Implantation And Growth


Implantation And Growth

Not quite unexpectedly though, implantation is now known to have a profound effect on growth of the fetus. Implantation of the embryo is a crucial step in human reproduction. It is lively but a poorly understood process. Implantation biology is the new great frontier in reproductive medicine. It occurs about 7 days after ovulation. The fertilized ovum during this interval develops to the blastocyst stage. The blastocyst attaches to and then invades the endometrium to establish a physical and nutritive contact with the mother. This lays the foundation for the proper growth of the fetus. An activated blastocyst and amenable uterus are required for implantation to occur. Both blastocyst and uterus must differentiate in equivalence to reach the appropriate state of maturity so that implantation can occur.

During implantation, fetal trophoblast cells invade and migrate into the maternal decidua. As they migrate, the trophoblast cells destroy the wall of the maternal spiral arteries, converting them from muscular vessels into flaccid sinusoidal sacs. This vascular transformation ensures an adequate blood supply to the feto-placental unit, which leads to proper growth.

The trophoblast is the major component of the human placenta. It is directly involved in blastocyst implantation and in feto-placental growth and development. Human trophoblast follows two major pathways of differentiation: the villous trophoblast, bathing in maternal blood of intervillous spaces and involved in maternal-fetal exchanges and in placental endocrine functions; the extra-villous trophoblast involved in uterine spiral arteries remodeling and in the placental anchorage into the uterine wall. It is essential to understand the cellular and molecular mechanisms involved in human trophoblast differentiation: cellular proliferation, migration, invasion and differentiation by cell-cell fusion. Abnormal trophoblast differentiation is implicated in the major pathologies of human pregnancy such as pre-eclampsia and intrauterine growth retardation

The scientific understanding of normal implantation lags behind what is known in areas such as fertilization. The reason for this is that the implantation process is difficult to analyze for obvious reasons. Recent investigations utilizing molecular biology approaches have scratched the surface of the interaction between the developing trophoblast and the receptive endometrium. The mystery of key mediators of normal implantation like cytokines will soon be unraveled and this will also allow an understanding of failed implantation.

Cytokines are regulatory glycoproteins that can affect virtually every cell type in the body and have pleiotropic regulatory effects on hematopoietic, endocrine, and nervous and immune systems. Chemokines, although considered as members of the cytokine super family, are establishing their own identity. Chemokines mediate leukocyte migration through specific G protein coupled receptors in various tissues. Recently, much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems. Sex steroid hormones, cytokines and chemokines mediate the close correlation between the embryo and endometrium and between the placenta and decidua. As a result of this closely related cross talk, pregnancy is successfully maintained.

Ovulation and fertilization trigger embryonic development and endometrial differentiation by corpus luteum progesterone production. These two synchronous processes couple about one week after fertilization, when the blastocyst begins to implant in the now receptive endometrium (implantation window).

The most intense changes in the relationship of the trophoblast to endometrial tissues occur in the first 5 days after the initiation of implantation. Not only have the earliest stages- adhesion and epithelial penetration- never been seen integument, but also the trophoblastic plate and lacunar stages that follow are not available for modern investigative methods.

Implantation basically occurs in two stages:

Attachment: The first step is the attachment of blastocyst trophoblast to endometrial epithelium. This is also called decidualisation. Decidualisation results in an increase vascular permeability & secretary activity of stromal cells thus allowing efficient placentation at the same restricting trophoblastic invasion going too deep. This if faulty can produce placenta accreta and related problems.

Ad plantation: Ad plantation is the invasion of deciduas by trophoblastic cells: Within hours of attachment trophoblast destroys epithelial cells. The trophoblastic villi invade the deciduas & blood vessel walls resulting in the blood filled lacunae in the bathing trophoblast in maternal blood. These spaces later enlarge to form intervillous space.

During the Attachment/Ad plantation the trophoblast cells adhere to uterine endometrium. The uterine endometrium expresses binding proteins and the blastocyst orients with inner cell mass closet to uterine wall. The trophoblastic cells proliferate on attached side. The entire process is under control of autocrine/paracrine system.

Approximately on day 7 after fertilization, the syncytiotrophoblasts secrete proteolytic enzymes. These enzymes break down extra cellular matrix around cells and allow passage of blastocyst into endometrial wall. The endometrium totally surrounds the blastocyst. The trophoblastic cells secrete human chorionic gonadotropin that maintains decidua and corpus luteum. Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. Some workers used an intrauterine micro-dialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.

  Invasion also generates spaces that fill with maternal blood-the lacunae. A coagulation plug marks the site where the blastocyst has entered the uterine wall. This occurs by day 12 after fertilization.


Correct implantation and placental development are essential to a successful pregnancy. Research on natural conception suggests that in a large percentage of fertilized eggs are lost, both prior to implantation and also following implantation prior to the clinical detection of pregnancy. The reason for such a high loss remains unclear. Defect in implantation/ placentation process can have serious consequences for the pregnancy including miscarriage or even repeated miscarriages. Implantation failure can result in abortion due to improper nidation. Pregnancy induced hypertension can result from inadequate trophoblast invasion resulting in poor perfusion of placenta with maternal blood can further lead to maternal hypertension/ convulsions and/or fetal growth restriction if left untreated. Placental defects including separation resulting in accidental hemorrhage and placenta accreta can also result from improper implantation. Intrauterine growth restriction (IUGR) is a significant cause of infant mortality and morbidity. It is now clear that IUGR infants exhibit higher rates of coronary heart disease, type 2-diabetes, hypertension and stroke as adults. Therefore, fetal growth not only impacts the outcome of the perinatal period, but also impacts adult well-being. The etiologies of IUGR are numerous, but are often associated with abnormalities in placental structure and function. The process of implantation and placentation requires the production of a plethora of growth factors, cell-adhesion molecules, extra cellular matrix proteins, hormones and transcription factors. Many of these exhibit altered expression within the placenta of IUGR pregnancies. However, it has been difficult to fully assess their role during the development of placental insufficiency (PI) in the human, underscoring the need for animal models. Using an ovine model of PI-IUGR changes in the expression of vascular endothelial growth factor, placental growth factor, their common receptors, as well as angiopoietin 2 and its receptor, Tie 2 were observed. It was found that changes in these growth factors can be associated with both acute and chronic changes in placental vascular structure and function. 
Thus, proper implantation and allied events are very important for proper growth and inversely improper implantation leads to growth restriction and its problems. 

- Further reading:

Mehta P: Implantation the inside history in The First Trimester. Ed. Divakar H, Shah D; Pg. 1; Ed. 1, 2001, Prism Books, Bangalore 



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