implantation

1. Implantation
Prof Aboubakr Elnashar
Benha University Hospital, EgyptAboubakr Elnashar

2. 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

3. Aboubakr Elnashar

4. Aboubakr Elnashar

5. 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}.
Aboubakr Elnashar

6. 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.
Aboubakr Elnashar

7. 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
Aboubakr Elnashar

8. 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
Aboubakr Elnashar

9. 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.
Aboubakr Elnashar

10. 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).
Aboubakr Elnashar

11. 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.
Aboubakr Elnashar

12. 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}.
Aboubakr Elnashar

13. 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.
Aboubakr Elnashar

14. 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.
Aboubakr Elnashar

15. Aboubakr Elnashar

16. 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
Aboubakr Elnashar

17. 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
Aboubakr Elnashar

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19. 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.
Aboubakr Elnashar

20. 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).
Aboubakr Elnashar

21. 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.
Aboubakr Elnashar

22.  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.
Aboubakr Elnashar

23. 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

24. Aboubakr Elnashar

25. 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. Aboubakr Elnashar

26. 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.
Aboubakr Elnashar

27. 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.
Aboubakr Elnashar

28. Thank you
Aboubakr Elnashar