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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.
CLINICAL IMPORTANCE OF IMPLANTATION:
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 |
