In order for implantation to occur, endometrium has to be changed
into decidua. This process consists in modifying endometrial stromal
cells, uterine glands and vessels, as well as the population of uterine
immune cells. In humans, unlike other species ,
decidualization is independent of the blastocyst's presence in the
uterine cavity and begins in the late secretory phase of the menstrual
cycle. It is evoked by progesterone, as well as by regulatory agents
able to enhance cyclic AMP (cAMP) levels [2,3].
Decidualization continues in pregnancy, and it is thought to regulate
subsequent trophoblast invasion and placenta formation by altering the
expression of regulatory factors such as metalloproteinases, cytokines,
surface integrins, and major histocompatibility complex molecules. The
trophoblast, in turn, releases paracrine signals which modulate
decidual stromal cell gene expression . These cells become round and show ultrastructural similarities with myofibroblasts and epithelial cells .
Moreover, they release several factors including prolactin, relaxin,
renin, insulin-like growth factor binding protein-1 (IGFBP-1) [1,3] and specific extracellular matrix (ECM) proteins such as laminin and fibronectin . In vitro studies
have demonstrated that this event is correlated with changes in steroid
hormone receptor expression and steroid metabolism, remodeling of the
ECM and cytoskeleton, altered expression of enzymes, growth factors and
cytokines, and induction of apoptosis modulators and specific
transcription factors .
Elongation of the spiral arteries occurs through an
endometrium-specific angiogenesis, characterized by proliferation of
both endothelial and smooth muscle cells, with preservation of the
integral structure of the vessel. In the uterine wall, several
leukocyte types, such as T lymphocytes, a few B lymphocytes,
macrophages, and natural killer (NK) cells, are present. However, after
ovulation, a dramatic increase in NK cells is observed. Uterine NK
cells (uNK) are phenotypically and functionally different from
circulating ones. Indeed, they have not cytolytic activity , and express integrins which allow their migration and invasion of the decidualizing endometrium .
It has been suggested that the unique environment resulting from the
transformation of endometrium to decidua plays a crucial role in uNK
cell specificity acquisition [6,9].
Since decidual NK cells decrease in number in the second half of
pregnancy and disappear at delivery, it has been hypothesized that
their main role is confined to early pregnancy, when they modulate
implantation and placentation interacting with both decidual stromal
cells and trophoblast [6,9].
Interestingly, it has been shown that uNK cell recruitment is a
hormonally-controlled maternal function and is independent of the
presence of the implanting embryo .
NK cell survival seems to be dependent upon the presence of
progesterone, whose action, however, is presumably not direct, but
mediated by decidual stromal cells which express hormone receptors . In contrast, it has recently been shown that glucorticoids are able to decrease the number of decidual NK cells .
Decidualization is also characterized by a decrease in Th1 and an
increase in Th2 lymphocytes, an effect which is evoked by progesterone
and cytokines. It has been proposed that Th2 cytokines protect fetus
and trophoblasts inhibiting NK cell cytotoxicity and proliferation,
shifting NK cell cytokine production toward a Th2 phenotype, as well as
suppressing cytotoxic T cells activation [12-14].