Implantation and Development of the Placenta: Introduction and Index

Throughout gestation, the mammalian embryo is a parasite

that survives "at the pleasure" of its mother. Early in
gestation, the embryo is small and has correspondingly small
requirements for nutrients and for waste disposal systems -
it subsists by taking up endometrial secretions and dumping
its metabolic wastes into the lumen of the uterus. This
situation changes rapidly.
As the embryo grows and develops a vascular system, it must
establish a much more efficient means of obtaining nutrients
and eliminating waste products, and does so by establishing an efficient interface between
its vascular system and that of its mother. That interface is the placenta.
In addition to its primary goal of facilitating transport between mother and fetus, the
placenta is also a major endocrine organ. In almost all mammals the placenta synthesizes
and secretes steroid hormones - progestins and estrogens. The placenta also produces a
number of protein hormones. Depending on the species, it is the source of chorionic
gonadotropins, relaxin, and placental lactogens. Placental hormones have profound effects
on both fetal and maternal physiology.
Despite the fact that all placentae carry out the same basic processes of transport and
hormone secretion, there are important differences in structure and function among
families of mammals. The placentae of humans, cattle, horses and dogs are all very
different from one another at both gross and histologic levels. They also differ in certain
functions that are clinically important - for example, in the ability to transport maternal
immunoglobulins to the fetus.
Attachment and Implantation

Implantation is the first stage in development of the placenta. In most cases, implantation is
preceeded by a close interaction of embryonic trophoblast and endometrial epithelial cells
that is known as adhesion or attachment.
Among other things, attachment involves a tight intertwining of microvilli on the maternal
and embryonic cells. Following attachment, the blastocyst is no longer easily flushed from
the lumen of the uterus. In species that carry multiple offspring, attachment is preceeded by
a remarkably even spacing of embryos through the uterus. This process appears to result
from uterine contractions and in some cases involves migration of embryos from one uterine
horn to another (transuterine migration).
The effect of implantation in all cases is to obtain very close apposition between embryonic
and maternal tissues. There are, however, substantial differences among species in the
process of implantation, particularly with regard to "invasiveness," or how much the embryo
erodes into maternal tissue. In species like horses and pigs, attachment and implantation are
essentially equivalent. In contrast, implantation in humans involves the embryo eroding
deeply into the substance of the uterus. Many years ago, three fundamental patterns of
implantation were described, based on the position the blastocyst assumes in the uterus:
 Centric: the embryo expands to a large size before implantation, then remains in the
center of the uterus. Examples include carnivores, ruminants, horses, and pigs.
 Eccentric: The blastocyst is small and implants within the endometrium on the side
of the uterus, usually opposite to the mesometrium. Examples include rats and mice.
 Interstitial: The blastocyst is small and erodes through endometrial epithelium into
subepithelial connective tissue. Such implantation is often called nidation ("nest
making"). Examples include primates, including humans, and guinea pigs.

It has been difficult to attribute any particular advantage to the degree of invasiveness seen
during implantation. One possible exception is that most species having highly invasive
embryos have systems for prenatal transfer of antibodies from the mother to the fetus.
For eccentric and interstitial implantations, what allows the embryo to invade the uterine
substance? In some species it appears that the blastocyst is a passive participant, and the
underlying endometrium degenerates. In other cases, including carnivores and probably
humans, the embryo seems to be the aggressor and trophoblast actively invades into the
endometrium. It's likely that both tissues participate to some degree.
In species that undergo interstitial implantation, an interesting phenomenon called the
decidual cell reaction occurs. This involves transformation of uterine stromal and endothelial
cells into a tissue called the decidua, which becomes a substantial portion of the placenta and
is expelled with the remainder of the placenta at the time of birth. The decidua is a prominent
feature of the human placenta.
It is clear that steroid hormones from the ovary are necessary to prepare the endometrium for
implantation and for the process of implantation itself. In some species, progesterone alone
appears to be adequate, while in others, estrogen and progesterone are required for
implantation.
In addition to the differences among species in the implantation process per se, there are also
situations in which the timing of implantation varies. The usual case is for attachment and
implantation to occur within a few days after the blastocyst reaches the uterus. In many
animals, however, implantation can be delayed for substantial periods of time, during which
the blastocyst enters a quiescent state called embryonic diapause. Delayed
implantationseems to be a strategy used to regulate time of birth so that it occurs when
environmental conditions are favorable.
Placental Structure and Classification

The placentas of all eutherian (placental) mammals provide common structural and
functional features, but there are striking differences among species in gross and microscopic
structure of the placenta. Two characteristics are particularly divergent and form bases for
classification of placental types:
1. The gross shape of the placenta and the distribution of contact sites between fetal
membranes and endometrium.
2. The number of layers of tissue between maternal and fetal vascular systems.
Differences in these two properties allow classification of placentas into several fundamental
types.
Classification Based on Placental Shape and Contact Points
Examination of placentae from different species reveals striking differences in their shape
and the area of contact between fetal and maternal tissue:
 Diffuse: Almost the entire surface of the allantochorion is involved in formation of
the placenta. Seen in horses and pigs.
 Cotyledonary: Multiple, discrete areas of attachment called cotyledons are formed
by interaction of patches of allantochorion with endometrium. The fetal portions of
this type of placenta are called cotyledons, the maternal contact sites (caruncles), and
the cotyledon-caruncle complex a placentome. This type of placentation is observed
in ruminants.
 Zonary: The placenta takes the form of a complete or incomplete band of tissue
surrounding the fetus. Seen in carnivores like dogs and cats, seals, bears, and
elephants.
 Discoid: A single placenta is formed and is discoid in shape. Seen
in primates and rodents.

Classification Based on Layers Between Fetal and Maternal Blood

Just prior to formation of the placenta, there are a total of six layers of tissue separating
maternal and fetal blood. There are three layers of fetal extraembryonic membranes in the
chorioallantoic placenta of all mammals, all of which are components of the mature placenta:
1. Endothelium lining allantoic capillaries
2. Connective tissue in the form of chorioallantoic mesoderm
3. Chorionic epithelium, the outermost layer of fetal membranes derived from
trophoblast
There are also three layers on the maternal side, but the number of these layers which are
retained - that is, not destroyed in the process of placentation - varies greatly among species.
The three potential maternal layers in a placenta are:
1. Endothelium lining endometrial blood vessels
2. Connective tissue of the endometrium
3. Endometrial epithelial cells

One classification scheme for placentas is based on which maternal layers are retained in the
placenta, which of course is the same as stating which maternal tissue is in contact with
chorionic epithelium of the fetus. Each of the possibilities is observed in some group of
mammals.

Maternal Layers Retained

Type of Placenta Endometrial Connective Uterine Examples
Epithelium Tissue Endothelium
Epitheliochorial + + + Horses, swine, ruminants
Endotheliochorial - - + Dogs, cats
Hemochorial - - - Humans, rodents

In humans, fetal chorionic epithelium is bathed in maternal blood because chorionic villi
have eroded through maternal endothelium. In contrast, the chorionic epithelium of horse
and pig fetuses remains separated from maternal blood by 3 layers of tissue. One might thus
be tempted to consider that exchange across the equine placenta is much less efficient that
across the human placenta. In a sense this is true, but other features of placental structure
make up for the extra layers in the diffusion barrier; it has been well stated that "The newborn
foal provides a strong testimonial to the efficiency of the epitheliochorial placenta."
Summary of Species Differences in Placental Architecture
The placental mammals have evolved a variety of placental types which can be broadly
classified using the nomenclature described above. Not all combinations of those
classification schemes are seen or are likely to ever be seen - for instance, no mammal is
known to have a diffuse, endotheliochorial, or a hemoendothelial placenta. Placental types
for "familiar" mammals are summarized below, with supplemental information provided for
a variety of "non-familiar" species.

Type of Placenta Common Examples

Diffuse, epitheliochorial Horses and pigs
Cotyledonary, epitheliochorial Ruminants (cattle, sheep, goats, deer)
Zonary, endotheliochorial Carnivores (dog, cat, ferret)
Discoid, hemochorial Humans, apes, monkeys and rodents
Transport Across the Placenta

The primary function of the placenta in all species is to promote selective transport of
nutrients and waste products between mother and fetus. Such transport is facilitated by
the close approximation of maternal and fetal vascular systems within the placenta.
It is important to recognize that there normally is no mixing of fetal and maternal blood
within the placenta. Entry of small amounts of fetal blood into the maternal circulation
does occasionally occur, and can evoke an immune response in the mother that affects
that fetus after birth or fetuses in subsequent pregnancies that are sired by the same father.
The placenta is a complex tissue and should not be envisioned as simple permiable
membrane. In addition to transporting some molecules unaltered between fetal and
maternal blood, it also consumes a large fraction of certain types of cargo - glucose and
oxygen being good examples. Additionally, a number of molecules that cross the placenta
are metabolized to other things during passage.

There are a number of differences among species in the characteristics of transport across
the placenta, which should not be a big surprise considering the differences in structure
of the placental interface. The following discussions reflect general principles of placental
transport.
Transport of Gases
Gases like oxygen and carbon dioxide diffuse through and across tissues in response to
differences in partial pressure.
In late pregnancy, the mean partial pressure of oxygen (P02) in maternal blood is
considerably higher than in fetal blood. As a consequence, oxygen readily diffuses across
the placenta from maternal to fetal blood. Despite its low PO2, fetal blood is able to
transport essentially the same quantity of oxygen to tissues as maternal blood. This is
because the hemoglobin concentration in fetal blood is about 50% higher than in maternal
blood, and the majority of hemoglobin in the fetus is fetal hemoglobin, which has a higher
oxygen carrying capacity than adult hemoglobin.
Carbon dioxide is produced abundantly in the fetus, and the PCO2 of fetal blood is higher
than maternal blood. Carbon dioxide therefore diffuses from fetal blood, through the
placenta, into the maternal circulation, and is disposed of by expiration from the mother's
lungs.
Nutrients
Glucose is the major energy substrate provided to the placenta and fetus. It is transported
across the placenta by facilitated diffusion via hexose transporters that are not dependent
on insulin (GLUT3 and GLUT1). Although the fetus receives large amounts of intact
glucose, a large amount is oxidized within the placenta to lactate, which is used for fetal
energy production.
Amino acid concentrations in fetal blood are higher than in maternal blood. Amino acids
are therefore transported to the fetus by active transport. A family of at least 10 sodium-
dependent amino acid transporters have been identified in placenta that serve this
function. There is substantial metabolism of some amino acids as they cross the placenta
- for example, much of the serine taken up by the placenta is converted to glycine prior
to delivery to the fetus.
There is much more variability among species in placental permiability to fatty acids than
to glucose or amino acids. In some animals, there is little transport of fatty acids from
mother to fetus, while in others a significant amount of transport takes place.
Antibodies
There are marked differences among species in whether immunoglobulins are transported
across the placenta. In primates and rodents, there is substantial transfer of
immunoglobulin G from maternal to fetal circulations prior to birth. This process requires
immunoglobulin-binding proteins in the placenta.
In contrast, there is no transplacental transfer of immunoglobulins in animals like cattle,
sheep, horses and pigs. In those species, the neonate is essentially devoid of circulating
antibodies until it absorbs them from colostrum (first milk).
Other Molecules
Bilirubin is a waste product derived from the heme in hemoglobin. This lipophilic
molecule is conjugated in the liver to make it water-soluble, and eliminated by excretion
into bile. The fetus also produces bilirubin, but conjugates only a small fraction. This
is good because conjugated bilirubin is transported across the placenta very poorly. In
contrast, unconjugated fetal bilirubin is readily transported from the fetal circulation,
across the placenta, for elimination by the mother.
Many drugs are eliminated in bile through pathways similar to bilirubin. The relative
inability of the fetal liver to metabolize and conjugate means that it is impaired for
eliminating such molecules compared to adults.
Placental Hormones

In addition to its role in transporting molecules between mother and fetus, the placenta is
a major endocrine organ. It turns out that the placenta synthesizes a huge and diverse
number of hormones and cytokines that have major influences on ovarian, uterine,
mammary and fetal physiology, not to mention other endocrine systems of the mother.
This section focuses only on the major steroid and protein hormones produced by the
placenta. Additional details on placental endocrinology can be found in the Placental
Hormones section of the Endocrine System text.
Steroid Hormones
Sex steroids are the best known examples of placental hormones. Two major groups are
produced by all mammals:
Progestins: Progestins are molecules that bind to the progesterone receptor. Progesterone
itself is often called the hormone of pregnancy because of the critical role it plays in
supporting the endometrium and hence on survival of the conceptus.
The placentae of all mammals examined produce progestins, although the quantity varies
significantly. In some species (women, horses, sheep, cats), sufficient progestin is secreted
by the placenta that the ovaries or corpora lutea can be removed after establishment of the
placenta and the pregnancy will continue. In other animals (cattle, pigs, goats, dogs), luteal
progesterone is necessary throughout gestation because the placenta does not produce
sufficient amounts.
Progestins, including progesterone, have two major roles during pregnancy:
 Support of the endometrium to provide an environment conducive to fetal survival.
If the endometrium is deprived of progestins, the pregnancy will inevitably be
terminated.
 Suppression of contractility in uterine smooth muscle, which, if unchecked, would
clearly be a disaster. This is often called the "progesterone block" on the
myometrium. Toward the end of gestation, this myometrial-quieting effect is
antagonized by rising levels of estrogens, thereby facilitating parturition.
Progesterone and other progestins also potently inhibit secretion of the pituitary
gonadotropins luteinizing hormone and follicle stimulating hormone. This effect almost
always prevents ovulation from occurring during pregnancy.
Estrogens: The placenta produces several distinct estrogens. In women, the major
estrogen produced by the placenta is estriol, and the equine placentasynthesizes a unique
group of estrogens not seen in other animals. Depending on the species, placental
estrogens are derived from either fetal androgens, placental progestins, or other steroid
precursors.
With few exceptions, the concentration of estrogens in maternal blood rises to maximal
toward the end of gestation. Two of the principle effects of placental estrogens are:
 Stimulate growth of the myometrium and antagonize the myometrial-suppressing
activity of progesterone. In many species, the high levels of estrogen in late
gestation induces myometrial oxytocin receptors, thereby preparing the uterus for
parturition.
  Stimulate mammary gland development. Estrogens are one in a battery of
hormones necessary for both ductal and alveolar growth in the mammary gland.
Like progestins, estrogens suppress gonadotropin secretion from the pituitary gland. In
species like humans and horses, where placental estrogens are synthesized from androgens
produced by the fetus, maternal estrogen levels are often a useful indicator of fetal well
being.
The image below depicts changes in concentrations of progesterone and estrogens in the
maternal serum of humans through gestation.

Protein Hormones
Several protein and peptide hormones are synthesized in placentae of various species.
They have effects on the mother's endocrine system, fetal metabolism and preparation of
the mother for postpartum support of her offspring.
Chorionic gonadotropins: As the name implies, these hormones have the effect of
stimulating the gonads, similar to the pituitary gonadotropins. The only species known to
produce a placental gonadotropin are primates and equids.
The human hormone is called human chorionic gonadotropin or simply hCG. This
hormone is produced by fetal trophoblast cells. It binds to the luteinizing hormone receptor
on cells of the corpus luteum, which prevents luteal regression. Thus, hCG serves as the
signal for maternal recognition of pregnancy. The first hormone you produced was hCG!
Equine chorionic gonadotropin is also produced by fetal trophoblast cells. It is actually
the same molecule as equine luteinizing hormone.
Placental lactogens: These hormones are molecular relatives of prolactin and growth
hormone. These hormones have been identified in primates, ruminants and rodents, but
not in other species.
The functions of placental lactogens are not well understood. They are thought to
modulate fetal and maternal metabolism, perhaps mobilizing energy substrates for fetal
use. In some species they have been shown to stimulate function of the corpus luteum,
and to participate in development of the mammary gland prior to parturition.
Relaxin: Relaxin is a hormone thought to act synergistically with progesterone to
maintain pregnancy. It also causes relaxation of pelvic ligaments at the end of gestation
and may therefore aid in parturation. In some of the species in which relaxin is known to
be produced, it is produced by the placenta, while in others, the major source is the corpus
luteum. In some species, relaxin is produced by both the corpus luteum and placenta