Implantation Prof Aboubakr Elnashar
Benha University Hospital, Egypt Aboubakr Elnashar
Introduction Blastocyst
a preimplantation embryo of varying cell number, from
30 to 200
Formed
4 days after the gonadotropin surge
3 days after ovulation,
Implantation
embedding of the blastocyst in the endometrial
stroma
begins with the loss of the zona pellucida (hatching)
1-3 days after the morula (8 cells) enters uterine
cavity.
Aboubakr Elnashar
Aboubakr Elnashar
Aboubakr Elnashar
Preparation for Implantation
I. The change from proliferative to secretory
endometrium
At the time of implantation
The endometrium is 10-14 mm thick
Secretory activity has reached a peak
This change is the histologic expression of many
biochemical and molecular events.
{The primary endocrine requirement is the presence of
progesterone}.
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II. Endometrial receptivity
heralded by the progesterone-
induced formation of pinopodes
pinopodes absorb fluid from the
uterine cavity forcing the
blastocyst to be in contact with
the endometrial epithelium.
The window of endometrial
receptivity: 20-24 of a 28-day
normal cycle.
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III. A dialogue between endometrium and the early
embryo.
1. Early pregnancy factor (EPF)
detected in the maternal circulation within 1-2 days
after fertilization.
prior to implantation is produced by the ovary in
response to a signal from the embryo.
After implantation is derived from the embryo.
has immunosuppressive properties
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2. HCG
Secreted by blastocysts
beginning days 7-8 after fertilization
enhancing steroid secretion from corpus luteum
3. Prostaglandin E2
Secreted by secretory endometrial epithelial cells
synthesis is increased at the implantation site
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Implantation Define:
process by which an embryo attaches to the uterine
wall and penetrates first the epithelium and then the
circulatory system of the mother to form the placenta.
It is a process that is limited in both time and space.
Timing:
2-3 days after the fertilized egg enters the uterus;
entry is on day 18 or 19 of the cycle.
5-7 days after fertilization.
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First hormonal evidence of implantation
(the appearance of hCG)
occurred on 8, 9, or 10 days after ovulation
the earliest was 6 days and the latest 12 days.
The risk of spontaneous early miscarriage markedly
increases with late implantations (later than 9 days
after ovulation).
Stages:
Apposition,
Adhesion, and
Invasion (also called migration to denote its benign
nature).
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I. Apposition The human blastocyst remains in the uterine
secretions for approximately 1 to 3 days and then
hatches from its zona pellucida in preparation for
attachment.
The implantation site:
usually in the upper, posterior wall in the mid sagittal
plane.
Apposition of the blastocyst to the uterine epithelium,
usually about 2-4 days after the morula enters the
uterine cavity.
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The endometrium produces at least 3 cytokines
involved in implantation.
1. colony-stimulating factor-1 (CSF-1)
2. leukemia-inhibitory factor (LIF)
3. interleukin-1 (IL-1).
LIF displays the same pattern of expression as
CSF-1
Blocking the interleukin-1 receptor in mice: prevents
implantation.
Role of interleukin-1 is less clear
{mice that are deficient in the interleukin receptor have
normal reproduction}.
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II. Adhesion:
{integrin binding}
Peak integrin expression at the time of implantation
Abnormal level of integrin expression may be a
cause of infertility .
Formation of junctional complexes prevents
dislodging the embryo by flushing.
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III. Invasion
{invasion of the trophoblast via degradation of the
extracellular matrix}.
Three subsequent interactions occur:
1. Trophoblasts intrude between the uterine
epithelial cells.
2. Epithelial cells are lifted off the basement
membrane; trophoblasts can interdigitate
underneath.
3. Fusion of trophoblast with the uterine epithelial
cells.
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Aboubakr Elnashar
Process is not destructive.
Embryo does contain proteases, but protease
activity is confined to the removal of dead cells .
Cells move away from the trophoblast: contact
inhibition.
Trophoblast fills the spaces left
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Regulation
Many growth factors and cytokines
1. Integrin expression is critical to the early invasion
of the trnphohlast
2. Laminin: Actively migrating cells preferentially-
bind laminin
3. Fibronectin
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Aboubakr Elnashar
Vascular changes
uterine spiral arterioles are invaded by
cytotrophoblasts.
Maternal endothelium is replaced by
cytotrophoblast tissue as far as the first third of the
myometrium.
This replacement may be governed by the selectin
family of surface molecules.
Failure of this process is noted in preeclampsia.
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Matrix metalloproteinases . Involved in menstruation.
key players in matrix degradation during the
trophoblast invasion.
Include the following:
Collagenases.
Gelatinases.
Stromelysins.
Can be activated by integrin-mediated adhesion.
Production is regulated by the following:
Plasminogen activators.
Cytokines.
Tissue inhibitors (TIMPs).
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Limitation of invasion .
Invasion is mediated by
Serine proteases and
Metalloproteinases (plasminogen activators):
plasmin activator metalloproteinase family, blast
plasminogen activator receptor may control the
plasmin proteolysis.
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Mechanisms of limitation
1. Cytokine secretion from the endometrial
lymphocytes (including natural killer cells) may
limit the invasion.
2. Invasion is limited by the decidual cell layer
Histamine may initiate the decidual response.
Blockage of histamine receptor H1 and H2 may
decrease the rate of implantation.
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3. Plasminogen activator inhibitor-I (PAl-I) is the
major decidual cell product; binds the plasminogen
activator
4. Transforming growth factor-β (TGF- β) is the key
growth factor in limiting invasion.
Induces increase in both PAl-l and TIMP.
Inhibits integrin expression.
Influences cytotrophoblasts to differentiate into
noninvasive syncytiotrophoblasts.
Aboubakr Elnashar
Aboubakr Elnashar
Key Steps in Implantation The early embryo enters the uterine cavity as an 8-
cell morula and becomes a 30 to 200-cell blastocyst
before implantation.
Hatching from the zona pellucida begins about 1-3
days after the morula entered the uterine cavity.
The endometrium is prepared for implantation by the
complex activity of cytokines, growth factors, and lipids
modulated by the sex hormones, especially
progesterone.
The endometrium is receptive for implantation for only
a few days.
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The process of implantation begins with apposition
and adhesion of the blastocyst to the uterine
epithelium, about 2-4 days after the morula enters the
uterine cavity.
This process is mediated by cytokines and involves
adhesion molecules (integrins) that interact with
extracellular components, especially laminin and
fibronectin.
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Trophoblastic invasion rapidly follows adhesion of the
blastocyst, mediated by proteinase degradation of the
extracellular matrix.
The placenta is formed in the second week after
ovulation.
Limitation of trophoblastic invasion is due to a
restraint imposed by proteinase inhibitors, especially
plasminogen activator inhibitor and tissue inhibitors of
metalloproteinases.
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Thank you Aboubakr Elnashar