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Look The Blastocyst Is Talking
Immunology and genetics are two subjects in
clinical practice that have a widespread subtle bearing but are
always given a “step motherly” treatment. This is not because
they are unimportant but because they are difficult to
understand. Over the period of time our group has felt that not
only are these areas cardinal in understanding the physiology of
many obstetric conditions, but they can be wisely used to treat
a series of clinical situations. Peri-conception care is rapidly
becoming a specialized area in obstetrics. It has got many new
developments and thanks to a high failure rate of nidation and
sustenance of pregnancy in ART, this subject has become all the
more important.
Blastocyst - Endometrium Cross Talk:
A blastocyst is a friendly being. It loves to make friends with
many a mucosa. Its friendliness also causes ectopic pregnancies.
It has got a great enticing capacity. It lures the mucosa to
allow it not only to stick to the mucosa but also burrow
through. It is not an encroacher however. It is a nice being
that knows its limitations and stops burrowing at a particular
point. This has got clinical bearings. The entire process of
cross talk to burrowing and right up to the stoppage of any
further progress, once the limit has reached, is all a series of
immunological changes.
Embryonic implantation requires coordinated
development of the blastocyst and the maternal endometrium.
Nevertheless, communication between these tissues and the
reciprocal effects of these tissues on each other constitutes an
exciting and as yet unsolved paradigm in reproductive medicine.
Crosstalk between the embryo, endometrium and the corpus luteum
is known to occur.
HCG HAS A VITAL ROLE IN THIS!
As the conductor of the orchestra, HCG generates a series of
immunologicaly active substances that act like messengers and
ambassadors of the blastocyst going to the endometrium (now the
decidua) queering the pitch for a successful and lasting
nidation. Clinical result is a successful pregnancy outcome.
This could be one of the bases of the use of HCG in clinical
practice for cases of pregnancy loss.
Not only do levels of HCG rise in very early days of pregnancy
but also this rise is rapid and calibrated. Not only a
deficiency in the quantitative level is detrimental to healthy
nidation but also the rapidity of the rise is equally important.
Either of them failing generates a deficient cross talk and the
conceptus doesn’t nidate well. Clinical result: menstrual
abortions and spontaneous early first trimester abortion.
The normal hormonally regulated human
endometrium is the trigger of molecular events preparing the
blastocyst to efficiently communicate and regulate endometrial
adhesion molecules in order to implant. The embryo is able to
modulate endometrial molecules during the apposition phase (chemokines)
and the adhesion phase (adhesion and anti-adhesion molecules).
Here, we report a coordinated embryonic regulation of hEEC
apoptosis. In the apposition phase, the presence of a blastocyst
rescues hEEC from the apoptotic pathway. However, when the human
blastocyst adheres to the hEEC monolayer, it induces a paracrine
apoptotic reaction. Neutralizing adhesion assays revealed that
the Fas/Fas-L death system may be an important mechanism to
cross the epithelial barrier, which is crucial for embryonic
adhesion, and the manipulation of this system could have
potential clinical implications as an interceptive mechanism.
Recently, a major break through was made in
this area: A discovery of a novel cell adhesion molecule complex
mediating the initial attachment of trophoblast to the
endometrial epithelium: trophinin and tastin. The human
endometrium is an extremely sensitive target for steroid
hormones. During the menstrual cycle, this tissue undergoes
dynamic changes that are reflected on the surface morphology of
the epithelium. The morphologic changes peak at the mid-secretory
phase, with the formation of the so-called pinopodes. Clinical
evidence indicates the existence in the human of a narrow window
of uterine receptivity, which opens during the mid-luteal phase.
At the same time, formation of pinopodes on the apical membranes
of the endometrial epithelial cells occurs.
To develop a specific marker for receptivity in clinical
practice, the kinetics of pinopode formation has been
investigated through sequential endometrial biopsy in natural,
hormone replacement and stimulated cycles. The results show that
pinopodes last <48 h in all cycles, and the timing of their
formation depends both on the hormonal treatment applied and on
the patient's individual response.
On an average, pinopodes form earlier in stimulated cycles and
later in hormone replacement cycles, compared with natural
cycles. Pinopode expression is strongly correlated with
implantation following embryo transfer and furthermore,
detection of pinopodes in assessment cycles may be extremely
useful for the assessment of receptivity on an individual basis
to optimize embryo transfer, resulting in increased implantation
rates. One of the most puzzling problems of endometriosis is
determining which mechanisms link this spectrum of conditions to
infertility. Clinical studies reveal that implantation rates
seem to be lower in women with endometriosis, while spontaneous
abortion rates show variable results.
Biochemical markers (integrins and other cell adhesion
molecules), morphological markers (pinopodes), apoptosis and
ultrasound studies confirm that not only does the endometrium
from women with endometriosis behave differently from the
endometrium of women without endometriosis, but ectopic
endometrium also behaves differently from eutopic endometrium.
Many controlled ovarian hyperstimulation cycles are associated
with synchronous early expression of the expected pattern of
histologic features, estrogen and progesterone receptors, and
pinopodes. The most predictive feature of this premature
expression was the level of progesterone the day after HCG
administration.
Pinopode formation was more pronounced in endometrial biopsies
than in cell cultures. All blastocysts adhered to pinopode
presenting cells. Furthermore, endometrial epithelial pinopodes,
generally considered as a marker of endometrial receptivity,
seem to be directly involved in the adhesion of the blastocyst
to the endometrial surface.
Current clinical studies indicate the
existence in the human of an "implantation/nidation window." The
implantation window in humans, according to this marker, lasts
less than 48 hours, and the timing of its opening is dependent
on the hormonal treatment applied, occurring earlier in cycles
following ovarian stimulation and later in cycles induced by
hormone replacement treatment. Furthermore, the timing varies
among different individuals under the same treatment.
The appearance of pinopodes was found to be strictly
progesterone dependent. When given together with progesterone,
before the development of pinopodes, high doses of estradiol
(plasma level approximately 300 pmol/l) inhibited pinopode
formation; on the contrary, low doses of estradiol (nidatory
doses) did not interfere with the process until the 4th day of
treatment. Pinopodes could be an extremely useful tool to
estimate uterine receptivity. The hormonal treatment applied to
induce ovulation (clomiphene citrate, hMG and hCG) can modify
the normal development of the prenidatory endometrium, and may
thus have a negative effect on the rate of egg implantation.
Endometrial progesterone-induced uterine protein-1 localization shifts
from stromal to epithelial, coinciding with the time of
ovulation, fertilization, and implantation. This observation,
combined with the disappearance of progesterone-induced uterine
protein-1 in late-secretory, non-pregnant endometrium and its
presence in decidua and trophoblast, suggests that
progesterone-induced uterine protein-1 may play a role in
decidualization, endometrial or embryo cross-talk, or placental
physiologic features.
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