Female reproductive system

Implantation and formation of placenta

Gwen V. Childs, Ph.D.
Reading assignment: pp 478-482

Test your knowledge of fertilization and implantation

  1. What parts of the ovarian follicle are released during ovulation?
  2. Describe each region of the oviduct and its function
  3. Where does fertilization take place?
  4. What is the role of the Peg cells in the fertilization process?
  5. What is the role of the ciliated cells in the oviduct?
  6. What is the role of the zona pellucida in the fertilization process?
  7. What helps the sperm get close to the oocyte? Define the acrosome reaction.
  8. How is polyspermy prevented? (two mechanisms)
  9. What process is triggered when the sperm enters the egg?  What is lost upon entry?
  10. How is the diploid zygote formed?
  11. What happens as the embryo is transported to the uterus? How long does it take?
  12. Distinguish a morula from a blastocyst.

Test your knowledge of placenta formation and function.

(Review your previous lectures and check out the section in Langman)

  1. What structure is involved in implantation.
  2. How does the embryonic placenta affect the uterine endometrium?
  3. Review the cytotrophoblast and syncytiotrophoblast. What is the role of each in the development of the placenta?
  4. How is the uterine endometrium organized to protect and nourish the embryo? Describe the three regions.
  5. How is the placenta differentiated with respect to the region of the uterus?
  6. Describe the formation of the chorion and chorionic villi?  What is their function?
  7. Describe the cellular barrier to nutrients, comparing that of the young placenta with that of the old placenta.
  8. Compare and contrast the  mechanism of nourishment to the embryo and fetus: pre-vascular (stromal cells); early invasive into maternal vessels;, early and late placenta.
  9. What hormones are produced by the syncytiotrophoblast and what is their function?
  10. What hormone signals pregnancy and rescues the corpus luteum?
  11. Compare the formation of the placenta in monozygotic and dizygotic twins. Do monozygotic twins always share one placenta? 

Ovulation

Ovulation releases fluid, the secondary oocyte and the surrounding follicular cells.  This collection of cells is picked up by the fimbria of the oviduct and transported towards the ampulla by the cilia. The oocyte is nourished by the secretion from the peg cells. Fertilization takes place in the ampulla.  If the oocyte is not fertilized in 24 hours, it dies and becomes absorbed.

Review the regions of the oviduct:

Infundibulum--fimbriated (fringe) end that scans the ovary and captures the secondary oocyte
Ampulla--expanded region (like a trumpet) where the oocyte is fertilized.
Isthmus--narrow region that connects to the uterus at the interstitial (intramural) region

 Smooth muscle in the wall constricts and contracts to allow the fimbia to move over the surface of the ovary. The oocyte enters the infundibulum which is tortuous with many folds in the mucosa. It moves to the ampulla, which is expanded to allow movement, transport and fertilization.   The right hand photo shows the ciliated and Peg cells (the latter have a round projection into the lumen). Peg cells nourish the oocyte and help with sperm capacitation.  Ciliated cells beat fluid towards the uterus.  This motion helps capture and propel the oocyte.

Fertilization

Spermatozoa must swim upstream through the uterus and most of the oviduct to the ampulla.  The sperm that reach the oocyte are aided by two components of the zona pellucida.  ZP3 molecules have two domains for sperm regulation and binding.  First, there is a receptor for the sperm that binds to proteins in the sperm membrane.  Second, there are regions that trigger the "acrosomal reaction" which releases acrosomal enzymes into the zona pellucida. One of these is called "acrosin" which digests the zona pellucida, and permits the sperm to swim closer to the oocyte "perivitelline space"  This is "first contact".

First contact by the successful sperm induces the "cortical reaction" to prevent more than one sperm from entering an oocyte.  There is a "fast component" that prevents contact via a change in the membrane resting potential.  A slower component induces cortical granule release from the oocyte.  These granules contain an enzyme that hydrolyzes ZP3 molecules, thus preventing the binding and acrosomal reaction in another sperm.

The sperm enters the oocyte and most of the tail drops off.  This includes 99% of the mitochondria carried in the tail. The entry of the sperm triggers the completion of the second meiotic division forming  a second polar body and the female pronucleus.  The female pronucleus (haploid) then joins with the male pronucleus (haploid) to form a zygote that is diploid.  

Transport to Uterus

Zygote continues to be transported through the oviduct.  Note from the above photograph that the tube is narrow and simpler so that it does not get "stuck" in any folds or lost in space.  As it moves, it begins to divide and forms a two cell embryo in 30 hours and an 8 cell embryo in 3 days. The spherical clump of cells is initially called the Morula.

 

Then, on the 4th day, the ball of cells is transformed to have a hollow center and that is called the blastocyst. The blastocyst has a layer of peripheral cells called the "trophoblast" cells and a cluster of cells at one pole called "embryoblasts" or inner cell mass.

Implantation

 The blastocyst enters the uterine cavity on day 4 and begins to implant on days 5-6 (embed itself into the uterine wall). If ovulation occurred on day 14 and fertilization on day 15, this is now about the 20th-22nd day of the cycle which is also considered the 22-22nd day of pregnancy. By that time, the corpus luteum has secreted sufficient progesterone to build up the uterine lining and the uterine endometrium is in the secretory stage.  The stroma is dense and the endometrial cells are filled with glycogen. (Review this phase of the uterine cycle). 

The polar trophoblast cells (those at the base of the blastocyst, just under the inner cell mass) are the initial invaders that embed into the uterine wall.  As they do, they stimulate the "decidual reaction", which is a response by the stromal cells.  These cells enlarge and become pale staining and filled with glycogen.  This provides nourishment for the embryo until the placenta is vascularized.

The decidua reaction is seen in the following photograph. Compare these stromal cells with the thinner, stellate cells seen in the secretory phase of the endometrium.

The trophoblast cells invading the uterine wall, proliferate and eventually form two cellular layers.  The innermost layer is called the "cytotrophoblast", which continues to proliferate.  The outermost layer is thicker and in contact with uterine spaces.  It becomes a syncitium (layer of nuclei and cytoplasm without lateral cell borders) and is termed the "syncytiotrophoblast".  This outer layer continues to grow, eroding the endometrium and forming large vacuoles.  Eventually these coalesce into lacunae. As the syncytiotrophoblast digs deeper into the endometrium, eventually (by 11 days) the endometrium encloses the  embryo.

Development of the Placenta

The syncytiotrophoblast continues to invade and erode maternal blood vessels which then empty blood into the lacunae.  This provides a second level of nourishment for the developing embryo and placenta. The uterine endometrium is responding to the trophoblast cells in the meantime.  The decidual reaction continues with regional specialization.  That decidua over the embryo (between it and the uterine lumen, is called the "decidua capsularis").  That decidua between the myometrium and the embryo is called the "decidual basalis".  The remaining decidua is called the decidua parietalis.

Eventually the placenta becomes better organized so it can convey blood vessels to a site nearer to the maternal supply. Also,  the blood of the developing embryo is better separated from that of the mother. This involves the development of the Chorion. This is an invasive mesencymal structure that consists of the chorionic plate and chorionic villi which grow out into the endometrium to anchor at the decidua basalis. The outer two layers of cells lining the chorion are the cytotrophoblast and syncytiotrophoblast cells. Thus, the mesenchymal cells form a connective-tissue like support for the blood vessels growing into the villi.  The cellular gateway from maternal blood and fetal blood begins as the two trophoblast cell layers + mesenchymal cells + endothelial cell and gets simpler as the placenta ages (develops).

By 14--15 days of gestation (or 28-30 days of pregnancy), the chorion  has also organized itself  with respect to its region.  The region in contact with the basalis forms extensive villi (primary, and eventually branches to become secondary villi). This is also called "chorion frondosum". That part next to the decidua capsularis remains relatively smooth. The chorion thus provide routes to the maternal lakes of blood.  The blood vessels will grow from the fetus through the chorionic plate to the primary and then the secondary villi.  The following cartoon summarizes this process.

The upper left photo shows embedded embryo at about 11 days (25 days of pregnancy).  The light pink finger-like projections are the invading syncytiotrophoblast cells.  Note that initially, the embryo appears to be surrounded on three sides by lakes of maternal blood. The cytotrophoblast and syncytiotrophoblast layers are growing into these lakes.   This is the route for nourishment until the fetus can grow blood vessels.

Before the blood vessels can grow, however, the placenta must make a support platform.  That is the chorion.  This is blue in the photograph..it surrounds the embryo and yolk sac. It carves out a space (extraembryonic coelom) and begins to send projections of mesenchyme out into the lakes (lacunae).  It thus has a mesenchyme core that is lined on its outside by the syncytiotrophoblast and cytotrophoblast layers (the syncytium is always on the outside). Note that the layers are still bathed by lakes of maternal blood that are fed by the maternal arteries.  Fetal Blood vessels have not formed, but a connecting stalk leading from the fetus in the lower right panel shows where they will grow out.  These primary villi provide the pathway for the growth of the embryonic vessels once they are formed.

Villi continue to grow out and some become anchored to the decidua basalis.  These are called "anchoring villi".  The rest lie free in the lakes of maternal blood, bathed by the supply. Initially, two layers of cells separate the maternal blood from the fetal capillaries (cytotrophoblast and syncytiotrophoblast). The following photograph shows a villus with the outer syncytiotrophoblast and the inner cytotrophoblast.  Note the fetal capillaries inside the villus supported by the mesenchyme.  Note the amount of connective tissue and number of cellular layers that separate the fetal supply from the maternal blood (just outside the syncytiotrophoblast).

 

 

As the placenta ages, the needs for more efficient transfer of oxygen and nutrients increase (because of the increasing size and complexity of the embryo and fetus).  The cytotrophoblast is joined with the syncytiotrophoblast, leaving only one cell layer between maternal blood and fetal vessel endothelial cells.  The fetal vessels grow out so there is minimal space for passage of nutrients. Note in the photographs below the increase vascularization of the villus and how close the vessels are to the syncytiotrophoblast. In most cases, the nucleus of the endothelial cell is directed inward leaving only a thin rim of cytoplasm, basal lamina, and syncytiotrophoblast cytoplasm as the barrier. Sometimes the nuclei of the syncytium have accumulated in one region (called "syncytial knots").  The function is unknown, but it may relate to the need to have adequate surface area for passage of the material.

 
 

The above placental barrier will allow passage of water, oxygen, small molecules, lipids, carbon dioxide, hormones, drugs and some antibodies.  Large macromolecules cannot pass across the barrier.

Review how the embryo and fetus is nourished as the placenta develops.

Initially, implanting embryo is nourished via the decidual cells in the endometrial stroma.  This level is seen until the trophoblast cells have invaded sufficiently to open up the maternal blood vessels.

The next level is via finger-like projections of trophoblast cells that are bathed in the lakes (lacunae) of maternal blood.

Finally, the chorionic plate and chorionic villi (core mesenchyme) grow out to provide a ct support for the fetal blood vessels.  The fetal vessels grow from the umbilical stalk and branch into the villi.  The numbers of layers between the maternal and fetal blood gradually decrease.

The syncytiotrophoblast as an endocrine organ

One of the first jobs of the syncytiotrophoblast is to signal the mother that she is pregnant.  It does this by producing a hormone that is virtually identical to LH.  This is called human (in the case of the human) chorionic gonadotropin.  The hCG rescues the corpus luteum which becomes the corpus luteum of pregnancy.  This continues for about the first 2 months of pregnancy, until the placenta can produce sufficient estrogen and progesterone to maintain itself and the uterine lining.  This hCG signal can be detected as soon as the syncytiotrophoblast is formed (before the mother misses her first period).  Current pregnancy tests may be sensitive enough to detect hCG in the blood after 11-12 days after ovulation.  However, usually the new parent is advised to wait until the time of the missed period (or a few days after).  Recall that pituitary LH is shut down by the high progesterone and estrogen from the corpus luteum.  So, any hCG found signals the presence of a functional placenta.

Of course, this does not mean that the fetus has formed normally.  A woman may have a positive pregnancy test and an ultrasound may reveal that the placental sac is empty (no embryo or fetus).

As it develops, the placenta produces other hormones that are similar to those in the pituitary including chorionic thyrotropin, and somatomammotropin.  These may have specific developmental functions for the fetus.  In its production of estrogens, the placenta is somewhat like the granulosa cells.  It requires androgen precursors from the fetal adrenal before it can make estrogens.  Thus, a partnership is formed between the fetal adrenal and the placenta that produces a significant rise in maternal estrogen levels.  If the fetus fails to develop a brain (anencephalic), there is a third trimester drop in adrenal androgens, because the fetal pituitary has not continued to provide stimulation to the adrenal.  This results in a precipitous drop in estrogens and is often diagnostic of anencephaly.

The placenta in twin pregnancies.

Monozygotic twins develop from a single fertilized ovum whereas dizygotic twins develop from two separate ova.  In dizytotic twins, usually two separate placentas are formed, however they are so close together that the chorions could fuse.  Monozygotic twins derived early in development (2-cell stage) may have two placentas.  Those that develop later, from the inner cell mass may share some fetal membranes (common chorion, but separate amniotic cavities).  If the monozygotic twins develop at a later stage (from the inner cell mass), they may share one placenta and a common amniotic cavity.


text and most photographs Gwen V. Childs, Ph.D.
childsgwenv@uams.edu
http://www.cytochemistry.net/microanatomy/Medical_Lectures/Implantation_and_Placental_development.htm
12/02/2002 last edited
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