S4: Implantation, Placentation and Hormone Changes in Pregnancy

Question 1

Describe structure of a blastocyst

Answer 1

• Trophoblasts (on outside of blastocyst) = They are the cells of the blastocyst that invade the endometrium and myometrium and will become the placenta. The trophoblast secretes-hCG (human chorionic gonadotrophin) initially.
• Inner cell mass = This forms the foetus.
• Blastocoel = This is the fluid filled cavity.
• The blastocyst has an inner cell mass stuck to its inner wall, is surrounded on the inside by the blastocoele, the trophoblast lines the whole structure. It also has a small zona pellucida around it.

Question 2

What 2 structures forms the amniotic sac?

Answer 2

• Chorion (becomes placenta).

- Amnion.

Question 3

Describe uterine receptivity

Answer 3

• Endometrial changes reach their maximum about 7 days after ovulation. The implantation window 6-10 days after the LH spike.
• Top layer of uterus undergoes pre-decidualizaton 9 to 10 days after ovulation where decidual cells cover surface of uterus.
• Decidualization if pregnancy occurs (under progesterone) and decidual cells are modified and become filled with lipids and glycogen). Decidua becomes maternal part of the placenta.
• Glandular secretions of endometrium contains growth factors, adhesion molecules, nutrients, vitamins, matrix proteins and hormones.
• At day 20, the endometrium is thick, it is approaching its thickest levels. It is very vascular and the glands are well differentiated. This endometrium is ready to receive the blastocyst.

Question 4

Describe what happens post-fertilisation

Answer 4

• The egg gets fertilised in the ampullary region of the uterine tube about 24hrs after it has been released.
• The zygote is wafted down the uterine tube and starts to divide to 2-cell, 4-cell, 8-cell and then by about day 4 becomes a morula (around 32 cells).
• Then the morula undergoes compaction and becomes a blastocyst. The blastocyst appears quite different to the morula and it is the blastocyst that will enter into the uterus around day 5/6. This corresponds to about day 20 of menstrual cycle where the uterus is more receptive and progesterone levels are increasing a lot.
• In order to implant, the embryo has to be at the right stage, if it enters into the uterus at around day 4 it will be unable to implant.
  If the embryo is delayed in its travelling down the uterine tube, it can then implant into the uterine wall resulting in an ectopic pregnancy.

Question 5

Describe gatrulation of blastocyst

Answer 5

• This is differentiation of inner cell mass to form embryo.
• The inner cell mass divides into two different types of cells to form the amniotic cavity and yolk sac.
• Endoderm and Ectoderm –> these two tissues layers give rise to many cells in body’s. Some ectoderm forms the third layer, the mesoderm.
• Ectoderm forms skin, brain, spinal cord, sensory organs etc.
• Mesoderm forms heart, skeletal muscle, kidneys, urogenital, connective tissue etc.
• Endoderm forms lining of gastro-intestinal, respiratory and urogenital tract.
• The notocord sends signals out in all directions giving us the orientation of the trigeminal disc (involved in symmetry along the 3 plane of axis).

Question 6

List the steps involved in implantation and placentation

Answer 6

1. Differentiation of the trophoblast.
2. Trophoblastic invasion of decidua and myometrium
3. Remodelling of the maternal vasculature in the uterus (utero-placental circulation).
4. Development of vasculature within the trophoblast, because the trophoblast will become the placenta and requires a blood supply where exchange will take place.

Question 7

What is the window of implantation?

Answer 7

Day 5-6 after ovulation marks the window of implantation, this window is about 24-36 hours. Implantation can occur in this short window.

Question 8

Role of beta-hCG during implantation

Answer 8

• The trophoblast produces beta-hCG as the trophoblast starts to invade into the woman’s uterus. Beta-hCG is the maternal recognition mechanism of pregnancy, it is very similar in structure to LH and binds to and maintains the corpus luteum.
• By maintaining the corpus luteum, it continues to produce oestrogen and progesterone, the latter prevents menstruation which is why when the period is missed the woman realises she may be pregnant. Under progesterone there is decidualisation of the endometrium.
• The corpus luteum maintains the endometrium in this way until week 7 (so first 7 weeks the ovary maintains the pregnancy). At this point the placenta takes over steroidogenesis.

Question 9

Why is beta-hCG useful to measure clinically?

Answer 9

• Beta-hCG is the basis of urinary pregnancy tests, if the beta-subunit is present in urine it indicates pregnancy. This is a qualitiative test, it is either there or not and its presence indicates positive pregnancy. The sticks used
  are extremely sensitive!
• Sometimes what clinicians do is measure serum beta-hCG and this gives us a quantitative value (measurable) and this is useful in monitoring early pregnancy complications such as ectopic pregnancy and miscarriage.
• If hCG is decreasing in early pregnancy then it indicates a miscarriage. If the hCG is rising very slowly we may be concerned of the possibility of an ectopic pregnancy.

Question 10

Describe fluctuations in levels of beta-hCG during pregnancy

Answer 10

• Beta-hCG is only needed for the 7-8 weeks to maintain the corpus luteum.
• By 8 weeks we see beta-hCG is maximal and then starts to fall as placenta takes over steroidogenesis and the corpus luteum isn’t required. However hCG doesn’t decrease to zero at all.
• So the immediate presence of beta-hCG we can use to determine pregnancy, later on in early pregnancy if we scan the uterus and can’t see the foetus then we may do serum hCG. During early pregnancy (within first 8 weeks) we should see hCG increasing.

Question 11

What is involved in steroidgenesis during pregnancy?

Answer 11

• Corpus luteum in the first 8 weeks.

- After 8 weeks the placenta takes over.

Question 12

Describe functions of the placenta

Answer 12

• Steroidogenesis, the placenta produces and secretes steroids. This includes oestrogens, progesterone, hPL (peptide hormone) and cortisol (same as released from adrenals).
• Exchange where the placenta acts as exchange organ to allow provision of O2, carbohydrates, fats, amino acids, vitamins and antibodies (IgG crosses placenta) to the developing foetus. Also, it allows removal of waste products produced by the foetus like CO2, urea, ammonia and minerals.
• Acts as an barrier so even if the mother has a bacterial, viral infection of is taking certain drugs, placenta can prevent these from getting to the foetus.

Question 13

Why are pregnancy women vaccinated against rubella?

Answer 13

Rubella can get across the placenta and cause harm to the foetus.

Question 14

How is the placenta designed to be good at its function?

Answer 14

• It has a huge maternal uterine blood supply, this is high volume low pressure.
• The placenta also has a reserve in function, this means that if part of it gets damaged it can continue to function and there will not be harmful effects, this is also seen with the liver.
• The placenta has a huge surface area that is in contact with the maternal blood, it is very well perfused. It is well adapted for transfer of substances.

Question 15

Describe implantation day 7-8 after ovulation

Answer 15

The blastocyst reaches the endometrial wall of uterus and starts to implant. The trophoblast invades into the endometrium and differentiates into the syncytiotrophoblast and the cytotrophoblast. The syncytiotrophoblast is like a mesh of cells, it contains no cell membranes and it erodes the endometrium. It results from cell fusion of outer layer of trophoblasts (proliferate and fuse) forms a multi-nucleated cytoplasmic mass and invades the endometrium.

• Decidual cells on surface of endometrium become filled with lipids and glycogen- becomes maternal part of the placenta. Factors in the uterine cavity like enzymes, as well as the blastocyst itself are essential for lysing the zona pellucida enabling direct contact between the trophoblast and decidua (trophoblast cells of embryo to meet epithelial cells of uterus).
• Chorionic gonadotropin is an autocrine growth factor for the blastocyst.
• The syncitotrophoblast and cytotrophoblast invade much further into the uterine wall. There is also formation of the bilaminar germ disc, composed of an epiblast and hypoblast. Cells of the embryonic disc then separate from the amnion and fluid filled amniotic cavity appears and is bound by the epiblast.

Question 16

Describe implantation day 12 blastocyst

Answer 16

12 day blastocyst where implantation is complete as another cell layer comes in called the extraembryonic mesoderm and form a discrete layer beneath to cytotrophoblast. Spaces in the syncitiotrophoblast (lacunae) are filled in with maternal blood setting up a utero-placental circulation that nourishes the foetus.

Question 17

Describe implantation day 16 embryo

Answer 17

The red stalk connecting to the ball of cells is the connecting stalk made of mesoderm. This will become the umbilical cord.
The cavity bound by the extraembryonic mesoderm is the chorionic cavity. Cytotrophoblast and associated mesoderm have become the chorion and chorionic villi are extending. Lacunae filled with maternal blood mingle with villi.

Question 18

What are the three layers of cells from the blastocyst in invasion during implantation? Describe them

Answer 18

• Syncitiotrophoblast.
• Cytotrophoblast.
• Extraembryonic mesoderm.
• The invasion by the syncitiotrophoblast invades further (once already inside uterine wall) and it does so by creating finger like projections into the tissue of the uterine wall. This forms a villus like structure.
• The cytotrophoblast then follows these villi and projects into them.
• Finally the extraembryonic mesoderm then also starts to follow and it develops foetal blood vessels. These then start to exchange nutrients and waste with maternal uterine circulation.

Question 19

Describe implantation day 21 embryo

Answer 19

At 21 days we see mesoderm has differentiated into the blood vessels and have set up the foetal circulation. There is transfer with the lacunae across the cytotrophoblast and syncitiotrophoblast.

Question 20

When does placenta develop?

Answer 20

8 weeks into the pregnancy. Eventually we have the growth and development of the placenta along the wall, it is composed of functional units called cotyledon.
The vessels enter and exchange at the end of the branches of the cotyledon. There are about 50 in the placenta.

Question 21

Describe three main roles of the amniotic cavity

Answer 21

• Homeostasis: It maintains a constant temperature, adequate fluid levels and ion levels keeping the environment of the baby good. The baby has to be bathed in amniotic fluid for it to be normal.
• Vital for the development of certain structures such as the limbs and lungs.
• Protection: The amniotic sac acts as a physical barrier against ascending infection (like how the cervical mucus does) and it also helps protect against some level of physical trauma such as falling over as baby is protected in the watery sac.

Question 22

Describe formation if the amniotic cavity

Answer 22

• Leads off from the bilaminar germ disc and yolk sac conncected to the uterine wall by a connecting stalk (16 day).
• By now, the bilaminar germ disk has developed a new layer and is now the trilaminar germ disc (ectoderm, mesoderm and endoderm).
• As the neural tube starts to develop (neurulation) there is swelling of the cranial and caudal ends of the neural tube and this drags and pulls the amniotic cavity along with it.
• As it does this, the yolk sac starts to get pulled up and out of the way. This gives room for the amniotic cavity to full surround the foetus. The baby will remain in this amniotic cavity for the rest of the pregnancy.

Question 23

Describe placentation

Answer 23

4-5 Weeks: Lucunie and villae system well developed. Foetal circulation formed from chorionic villie. Yolk sac relinquishes its role in vitelline circulation and nutrition. The embryo is nourished via the umbilical vessels that connect to the placenta via the umbilical cord.
13 weeks: Amniotic sac has filled extraembryonic coelom and surrounds the whole foetus. Yolk sac becomes small pear-shaped opening into the digestive tube via vitelline duct.

Question 24

Describe disorders of the placenta

Answer 24

• Miscarriage (is very common!) can often be caused due to an abnormal placenta.
• Pre-eclampsia is caused by problems with the placenta and occurs in 3-4% of pregnancies.
• Hydatidiform mole -> This is too much trophoblastic activity, it is due to genetic reasons.
• Placental insufficiency -> Some women’s placenta do not work as well as they should, as a result the baby ends up being under-perfused with fluid and oxygen. This causes growth restriction (baby doesn’t grow properly).
• Transfer of other substances through the placenta like drugs, toxins or infections that can cause harm to the baby. So avoid/be cautious about prescribing drugs to suspected women with pregnancy or who may become pregnant.

Question 25

Describe disorders of the amnion

Answer 25

• Polyhydramnios: This is excessive fluid in the amniotic cavity. This commonly occurs in diabetic women who are pregnant. They have high plasma sugar that gets transferred to the baby who also then has high blood sugar. This causes the baby to have more glucose in the urine and this draws more water out. Leading to increased volume of urine. The amniontic fluid is mainly the baby’s urine so this increased urine can lead to excessive urine in the cavity. This causes various problems.
• Oligohydramnios: This is having too little fluid in the amniontic cavity, caused by the baby urinating too little volume. Often occurs with growth problems.
• Premature Rupture of Membranes: This is rupturing of the amniotic membrane before going into labour. This can cause very bad problems for foetus.

Question 26

What hormonal changes occur during pregnancy?

Answer 26

• Placental steroids.
• Maternal steroids.
• Foetal steroids.
• Placental peptide hormones.
• Most hormones freely cross the placenta and are very raised in maternal blood. During pregnancy we also see changes in hormones binding proteins, with more hormones being free. Albumin tends to be lower in pregnancy during dilution, meaning there will be more free steroids.

Question 27

Describe placental steroidogenesis of progesterone and oestrogen

Answer 27

• Placental steroidogenesis kicks in around week 7/8, one of the steroids it produces is progesterone. Progesterone causes decidualisation of the endometrium, it also causes smooth muscle relaxation (uterine quiescence). The latter is really important because we don’t want the uterus to contract until labour. Progesterone also has a mineralocorticoid effect, this causes changes in fluid balance that leads to cardiovascular changes. The breast has lots of progesterone receptors, part of its development during pregnancy getting ready for breastfeeding is under progesterone.
• Oestrogens are also released by the placenta, there are three oestrogens (E1,E2,E3). E3 more potent than E2, E2 more potent than E1. To make oestrogen it requires androgens to be present because oestrogens are made from androgens. The placenta itself cannot make its own androgens so it relies on the androgens produced by the foetus and maternal adrenal glands. The placenta then converts these androgens to oestrogens. The placenta produces a new oestrogen called oestetrol but the main oestrogen is ostradiol.

Question 28

What is the function of oestrogen during pregnancy?

Answer 28

• Stimulate uterine hypertrophy.
• The oestrogens are responsible for metabolic changes such as insulin resistance.
• Causes cardiovascular changes.
• Involved in breast development.

Question 29

What is the main steroid present during gestation?

Answer 29

Progesterone.

Question 30

Describe placental steroidogenesis of placental CRH and corticol

Answer 30

• The placenta also synthesises and secretes CRH and cortisol, both of these increase in their secretion from the second trimester onwards.
• Cortisol is important in the metabolic changes experienced during pregnancy, causing the insulin resistance and storage of energy reserves. It is also important for fetal lung maturity, in premature babies whose lungs may not have fully developed we give steroid injections.
• CRH released from the placenta we think may be involved in the initiation of labour (acting as placental biological clock). But we’re still not entirely sure.

Question 31

Describe placental steroidogenesis of human placental lactogen (hPL)

Answer 31

hPL is a peptide hormone, very similar structurally to GH and its main role is in causing the metabolic changes such as the insulin resistance. It can be seen that different hormones synergise to cause these metabolic changes. hPL also has a possible role in lactation.

Question 32

Describe steroidogenesis of prolactin

Answer 32

It’s levels increase throughout pregnancy released by anterior pituitary. It is required once the oestrogen/progesterone starts to fall (after placenta fallen out) and have done their role in breast development. Prolactin allows lactation.