An intimate cross-talk between the embryo and the uterus is needed for blastocyst implantation [4,15].
This process, which consists of an interaction between trophoblast
cells and endometrium, can only take place in a restricted period of
time, termed "window of receptivity". It is initially dependent upon
the presence of estrogen and progesterone, although further
morphological and biochemical changes are evoked within the uterine
wall by signals from the embryo and invading trophoblast. The "window
of receptivity" in humans is presumed to span days 20–24 of the
menstrual cycle .
Indeed, out of this period the epithelium apical surface is covered by
a thick glycocalyx, mainly composed of mucin, and in particular MUC1, a
transmembrane glycoprotein characterized by an extended extracellular
domain which prevents blastocyst attachment .
Blastocyst implantation is also impaired by the large number of
desmosomes which exist along lateral epithelial cell surfaces .
In some species the "window of receptivity" is characterized by
down-regulation of MUC1, but this condition has not been observed in
humans. Some researchers have suggested that MUC1 may actually promote
human blastocyst attachment to the uterine wall , whereas others demonstrated a loss of this mucin at the site of blastocyst interaction  thanks to uterine proteases, activated by factors released from the blastocyst itself .
Blastocyst attachment to the uterine wall depends upon the
interaction between adhesion molecules such as selectins, integrins,
and trophinins ,
expressed on both trophoblast cells and uterine epithelium. This
interaction is mediated, in most cases, by bridging ligands including,
at least in the sheep, osteopontin and galectin-15, which are released
in the uterine cavity by endometrial glands .
Invasion is favoured by the simultaneous decrease of desmosome density
and basal membrane digestion, finally leading to nidation in the
decidual stroma .
A key role in the control of human blastocyst implantation is
exerted by endometrial chemokines and cytokines. Chemokines are thought
to be responsible for the promotion of leukocyte migration to the
decidua, where they cause a sort of inflammatory state, a process which
appears to derive from several sources. First, decidualization is
characterized by NK cells interaction with the non-polymorphic HLA
class I antigens expressed by invading trophoblasts .
Furthermore, signalling agents secreted by seminal vesicles and
prostate gland interact with epithelial cells in the cervix and uterus,
recruiting and activating macrophages, granulocytes and dendritic
cells. They are provided with immune-regulatory and tissue remodelling
roles that improve endometrial receptivity to the implanting embryo.
Tumor growth factor β (TGF-β)
and prostaglandins (PGs) present in seminal fluid contribute to enhance
cytokine production and vascular permeability, that appear to be
essential for implantation, due to their effects favouring blastocyst
attraction and attachment to the endometrium .
Moreover chemokines, interacting with G protein-coupled receptors,
induce a structural change in integrins which favours adhesion of the
blastocyst to the decidualized endometrium .
NO favours blastocyst implantation in both animals and humans,
modulating PG release, ovarian steroidogenesis, uterine cell
proliferation, glandular secretion and blood flow, as well as mediating
sex steroid and growth factor actions .
Since normal pregnancy is a physiological process, in our opinion it
should not be defined as a 'controlled state of inflammation' .
However, at an early stage at the implantation site, as well as later
systemically, it is regulated by the same cytokines whose derangement
can trigger the inflammatory pathway, leading to various types of early
and late gestational diseases. Under such profile, the above mentioned
'Th1/Th2' shift hypothesis, that dominated reproductive immunology for
many years, should be more simply interpreted as the expression of the
modulation of the cytokines that regulate the vascular processes of
placentation, rather than a specific mechanism to avoid fetal T-cell