Reproductive
function in the female is cyclic. A series of functional
interrelationships between the hypothalamus, the anterior pituitary, and
the ovaries leads to the monthly rupture of an ovarian follicle and
extrusion of an egg (“ovulation”), which is then transported to the
fallopian tubes to be fertilized. Should fertilization fail to occur,
menstruation ensues within 14 days and the hormonal and morphological
events that led to ovulation are repeated.
Ovulation occurs around day 14 of the menstrual cycle, followed by
fertilization as egg and sperm unite within 24 hours. The first three
days of development occur within the fallopian tube. Upon arrival within
the uterus the conceptus develops into a blastocyst (Figure 1) and
begins to make mRNA for human chorionic gonadotropin (hCG), the first
hormone signal from the early embryo. By day 6 after fertilization the
blastocyst initiates implantation into the maternal endometrium or
uterine lining.
Within a few days of fertilization the blastocyst becomes a spherical
structure composed of two layers. The outside layer of cells become
trophoblasts and the inside of a group of cells called the inner cell
mass (Figure 2A) will develop into the fetus and ultimately the baby. In
addition to making hCG, the trophoblasts mediate the implantation
process by attaching to, and eventually invading into the endometrium
(Figure 2B). Once firmly attached to the endometrium the developing
conceptus grows and continues to expand into the endometrium. One of the
basic paradigms which is established even within the first week of
gestation is that the embryonic/fetal cells are always separated from
maternal tissues and blood by a layer of cytotrophoblasts (mononuclear
trophoblasts) and syncytiotrophoblasts (multinucleated trophoblasts)
(Figure 2C-F). This is critical not only for nutrient exchange, but also
to protect the developing fetus from maternal immunologic attack (1).
Implantation is regulated by a complex interplay between trophoblasts
and endometrium. On the one hand trophoblasts have a potent invasive
capacity and if allowed to invade unchecked, spread throughout the
uterus. The endometrium, on the other hand, controls trophoblast
invasion by secreting locally acting factors (i.e. cytokines and
protease inhibitors), which modulate trophoblast invasion. Within the
placenta the syncytiotrophoblasts generate high levels of hCG which
modulates cytotrophoblast differentiation towards a non-invasive hormone
secreting villous-type trophoblast.
The closer the trophoblasts are to the endometrium the less hCG is made,
allowing the trophoblasts to differentiate into anchoring type cells
(2). Trophoblasts that leave the placenta and migrate within the endo
and myometrium are induced to make
proteases and protease inhibitors, to further facilitate trophoblast
invasion into the maternal tissues (2). Ultimately, normal implantation
and placentation is a balance between regulatory gradients created by
both the trophoblasts and the endometrium.
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