BIOL473 - Unit 7 Pregnancy

Define syngamy

The fusion of the male and female pronuclei coming together in centre of the egg

What 3 steps occur in the one-cell zygote → 2-cell conceptus transition?

1. Nuclei membranes breakdown

2. Mitotic spindle forms and chromosomes line up at the equator

3. Cleavage furrow forms

Define a conceptus

The early stage embryo in the uterus

Describe the pathway of the oocyte throughout fertilization and implantation

Released into the fimbriae by follicle → fertilized in oviduct (ampulla) → hatches and enters uterus for implanting

Compare a zygote, morula, and blastocyst

Zygote → diploid cell resulting from the fusion of two haploids (2 cells become one)

Morula → solid ball of cells

Blastocyst → hollow sphere with liquid (blastocoel) in the middle

What are the first two cell lineages to differentiate in a mammalian embryo? Compare them.

ICM → pluripotent embryonic stem cells

Trophectoderm → produces extra-embryonic structures

How do cell cycle lengths compare in the 1st cell cycle and 2nd cell cycle?

1st → total is 32 hours (G1 phase is 16 hours long! The rest are 8 each)

2nd → total is 13 hours (G1 phase is <1 hour, with most in S phase)

As the morula compacts, compare the changes to the cells on the outside and inside of the embryo

Outside cells → form tight junctions and give rise to trophectoderm

Inside cells → form gap junctions and give rise to inner cell mass

how does a pre-implantation embryo obtain O2/CO2? What about other molecules?

O2 / CO2 → exchanges via diffusion

Other molecules → exchanges via active processes

Upon entering the uterus, what was the point of implantation depend on? (3)

1. Site along the length of the uterus

2. Which side of the horn (if horns are present)

3. Orientation

How does embryo movement differ in duplex, bicornuate, and simplex uterus’?

Duplex → separate uterus (right and left) 

Bicornuate → can travel between horns of the uterus

Simplex → one body of uterus to implant on either side

Compare the collaborative efforts of the embryo and the mother required for implantation

Embryo → must undergo fertilization and rapid cleavage, hatch, and be competent enough to attach

Mother → most ovulate and develop a CL, transport embryo to the uterus, and have a “receptive” uterus

What is the typical implantation window of a human? How is it controlled?

7-10 days after the LH surge (and ovulation?) → Controlled maternally!

What changes in the uterus to allow for implantation in this window?

A transmembrane mucin (glycoprotein) present on the uterine epithelial cells that inhibits embryo attachment must be removed temporarily for the embryo to bind

Define the change in pre-receptive, receptive and post-receptive cells of the uterine wall

Pre-receptive → microvilli (with mucin?) expressed

Receptive → pinopods (balloon shaped protrusions) expressed

Post-receptive → microvilli are back

Before attachment, what does the nutrition of the embryo rely on?

“Histiotrophic nutrition” → dependent on maternal secretions secreted by the uterine glands

How does the nutrition of the embryo change after implantation?

Hemotrophic nutrition → a specialized extra-embryonic vascular area forms in the conceptus and develops on maternal surface tor exchange

What are the 4 extra-embryonic membranes in a nutshell? (From outside to inside)

1. Chorion

2. Allantois

3. Vitelline / Yolk sac

4. Amnion

What does each extra-embryonic membrane form from?

Chorion → derived from trophoblast / trophectoderm

Allantois → outgrowth of hindgut

Yolk sac → outgrowth of midgut

Amnion → derived from embryonic ectoderm

What is the significance of the chorion in fetal health?

It forms the definitive exchange barrier between the mother and fetus and becomes highly vascularized

What are the 2 main roles of the placenta?

1. Gas and nutrient exchange

2. endocrine support

Compare the fetal vs maternal endocrine support by the placenta

Fetal → regulation of growth

Maternal → metabolic / physiological adaptations to pregnancy (i.e. mammary development)

What are the 3 common structural features across Eutherian mammals?

1. Extensive proliferation of chorionic tissue to increase surface area

2. Highly vascularized maternal and fetal components

3. Intimately juxtaposed by with physically separate maternal and fetal blood flows (they do not directly interact)

What are the 3 main variable structural features across Eutherian mammals?

1. Shape and maternal-fetal contact points (villi vs membrane wide)

2. Invasiveness of embryo (how much erosion and invasion of maternal layers)

3. Vascular arrangements on both sides

What are the three main placental strategies? Which is the least vs most invasive?

1. Epitheliochorial (non-invasive!)

2. Endotheliochorial

3. Hemochorial (highly invasive!)

What are the 3 main features of non-invasive placentation

Epitheliochorial

1. Superficial contact of a large area of maternal tissue

2. No erosion of maternal layers

3. Attach to endometrium later

What are the 3 main features of highly invasive placentation?

1. Deep contact over a small area of maternal tissue

2. Erosion of maternal layers

3. Attach / implant into endometrium early

Compare who does invasive vs non-invasive placentation

Invasive → all primates except prosimians, rodents, carnivores

Non-invasive → ungulates, cetaceans (dolphins, whales)

Compare the time of attachment between a mouse or human to a sheep or horse

Mouse and human (invasive) → 4.5 and 7-9 (fast!)

Sheep and horse (non-invasive → 16 and 30-40 (slow!)

What are the 6 potential layers separating maternal and fetal blood?

1. Maternal endothelial cells

2. Maternal connective tissue

3. Endometrial epithelial cells

4. Chorionic epithelial cells

5. Fetal connective tissue

6. Fetal endothelial cells

Compare the layers between maternal blood and fetal blood between epitheliochorial, endotheliochorial, and hemochorial placentation

Epitheliochorial → all 6!

Endotheliochorial → no maternal connective tissue or endometrial epithelial cells

Hemochorial → no maternal side (missing all 3), only fetal barriers

What type of animal performs endotheliochorial placentation?

Dogs and cats!

What are the 4 classifications of placentas based on shape/contact points? Which are invasive / non-invasive

1. Discoid → human (and most extreme invasion, intense microvilli)

2. Zonary → dog/cat (belt where modifications occur, invasive)

3. Cotyledonary → ruminants (tufts that interact with maternal side, non-invasive)

4. Diffuse → pig (exchange on entire surface, non-invasive)

What are the two phases of invasive placentation in humans?

Attachment and invasion

Compare attachment and invasion phases

1. Attachment → interaction between embryonic trophoblast and endometrial epithelial cells

2. Invasion → embryo erodes into the maternal tissue for establishment of the placenta

Compare the primary and secondary decidual reactions

Primary decidual → local stroma reaction where the zona and glycocalyx are lost to allow layers to start to inter-digitate

Secondary decidual → the decidualization has spread out across the entire endometrium to allow imbedding

What structure first penetrates the endometrium of the uterine wall?

the trophoblast! (is what binds to it initially too)

What structure must be lost for endometrial binding?

the zona pellucida!

compare the decidua basalis and decidua parietalis

decidua basalis → maternal contribution to the placenta, interacts directly with embryo

decidua parietalis → general uterine lining everywhere else in the uterus

What is unique about the spiral arteries that form in the endometrium?

these are special arteries in invasive only implantation

Where do maternal and fetal blood interact during implantation?

at the chorionic plate where terminal villi interact with maternal blood spaces

compare amniocentesis and chorionic villus sampling

amniocentesis → removes amniotic fluid from amnion in middle trimester

chorionic villus sampling → transvaginal procedure to remove chunk of chorionic villi (done earlier than amniocentesis)

Compare dizygotic and monozygotic twinning

dizygotic → not identical twins (fraternal). caused by multiple ovulations

monozygotic → genetically identical twins (mostly) caused by embryo split

What are the 3 main possibilities for monozygotic twinning? (timing)

early embryo splitting (40%) → separate chorion and amnion (could fuse chorions later though)

splitting of inner cell mass (60%) → same chorion but separate amnion

shared amnion + chorion (<2%)

What happens in conjoined twins?

There is incomplete splitting very late into development

What does maternal recognition of pregnancy mean?

The early embryo produces a signal to the mother that signals the end of a typical reproductive cycle (and to maintain progesterone)

Where does the luteotrophic signal in primates come from?

Produced by (syncyto)trophoblast of implanting blastocyst

What is the primate signal exactly? when is it detectable?

two subunit glycoprotein (CG) → detectable in maternal circulation by day 8-12

How do we know CG is the primate signal for maintaining pregnancy?

fertile coitus triggers an hCG signal to prevent further cycling, and if antibodies are used to immunosuppress hCG, then the mothers cycle continues as per usual

What is the equivalent signal in sheep/cow for maternal signal?

IFN-tau (𝜏) → a trophoblastin!

How exactly does IFN-tau prevent removal of the corpus luteum?

inhibits synthesis of PGF2a by inhibiting synthesis of oxytocin receptors on endometrium

Who produces IFN-tau? when?

trophoblast → during the critical period (day 12-13?)

What happened when a sheep had its conceptus harvested during “critical time” (days 12-13) and had the conceptus injected into a luteal phase sheep?

the luteal lifespan was substantially prolonged!

What is the common theme of maternal recognition across primates and ruminants?

an early conceptus signal maintains progesterone production to prevent luteal recognition (or provide another P source)

why is the timing of early conceptus signals so important?

failure to either send or receive the signal may well be a significant cause of early embryonic death

How does the conceptus subvert the mother’s metabolic/physiological activities?

by developing the vascularized placenta and taking over the mothers metabolism through placental hormones

What are the 3 main circulating hormones during pregnancy made by the placenta?

estrogen, progesterone, and prolactin

How are humans different than other ruminants in terms of circulating hormones during pregnancy? how are they similar?

different → only humans have a spike of hCG to save the CL (recognition)

similar → all species have relatively rising levels of estrogen, progesterone, and prolactin in pregnancy (except pigs… where P is opposite)

Define the luteal-placental shift

the transition in a mammalian pregnancy where the placenta begins to take over progesterone production from the CL (hCG point as well?)

What are the three groups of animals based on dependence on pituitary/ovary for endocrine support

group 1 → human, sheep guinea pig

group 2 → rat, cat, horse

group 3 → cow, dog, pig

describe the dependence on pituitary and ovary of each group

first group → do not need pituitary or ovarian support for most of the pregnancy

second group → variable dependence on pituitary or ovary

third group → acutely dependent on pituitary and ovary for most of pregnancy (usually to term)

Where is most of the progesterone in the placenta produced from?

The trophoblast (chorion) makes a huge amount of progesterone

Why is progesterone not a useful indicator of fetal well-being?

progesterone is produced at high levels even when chorion is present without the fetus

why is estrogen a better indicator of fetal well-being?

the fetus and placenta must cooperate to make estrogens (estriol)

Summarize the maternal, placental, and fetal contributions to estriol production

maternal → provides cholesterol and receives estriol

placenta → moves cholesterol to fetus and converts DHEA-SO4 / 16OH-DHEA-SO4 to estriol

fetal → uses cholesterol to make DHEA-SO4 (adrenal gland) and 16OH-DHEA-SO4 in liver

What 3 products does the maternal serum “triple screen” look for?

1. a-fetoprotein (AFP) made in fetal liver

2. unconjugated estriol (E3)

3. hCG

Compare the results of the triple screen that would indicate down syndrome, trisomy 18, and an open neural tube

Down syndrone → low AFP/E3 but high hCG

Trisomy 18 → all 3 are low

Open neural tube → high AFP

What is the role of progesterone in the developing uterus? (2)

1. maintains the uterine enviroment for pregnancy

2. suppresses myometrial activity

What are the 3 roles of estrogen in late stage pregnancy?

1. stimulate myometrial growth and antagonize the effects of progesterone on myometrium

2. induce myometrial oxytocin receptors (prepare uterus for parturition)

3. stimulate development of mammary gland

depending on the species, what is the 4th role of estrogen in pregnancy?

produce LH-like molecules (i.e. hCG)

What are the 3 placental somatomammotropic peptides?

1. growth hormone (GH-v)

2. prolactin (PRL)

3. placental lactogen (PL)

How does the placenta contribute to the elevated lactogenic hormones during pregnancy/lactation?

PRL-like molecules from the placenta bypass pituitary regulation!

What is the main role of prolactin in pregnancy?

supports lactation through development of ducts, alveoli, and milk synthesis

What other 5 aspects of the body is prolactin involved in?

1. maternal behaviour (care for offspring0

2. insulin production and glucose for fetus

3. appetite (hyperphagia)

4. calcium homeostasis (increase Ca absorption for fetus)

5. shutdown HPG (mammals) and luteotrophic in rodents

What is the Bruce Effect?

phenomenon in female rats where exposure to a foreign male (not father) right after mating can terminate the pregnancy

What is the mechanism of the bruce effect?

pheromone-induced suppression of PRL is increased via dopamine from TIDA neurons that triggers abortion

define precocial and altricial mammals

precocial = well-developed offspring at birth (feathers, can stand, etc)

altricial = helpless dependent offspring (premature/early)

how does gestation period of body size relate? how does it differ between precocial and altricial mammals?

as body weight increases, so does gestation period → precocial mammals are have consistently longer gestational periods at a given body weight

How do eutherian mammals and marsupials differ in terms of gestation length and cycle length?

sheep = 16 day cycle, 150 days to birth

possum = 26 day cycle (birth at end of cycle), then in pouch for 200 days for more development

What two requirements in the uterus/cervix must occur for parturition?

1. coordinated contractions of the myometrium

2. softening (“ripening”) of the cervix (loosen collagen bundles in connective tissue)

When near term in mammals, how do their hormones change and what is the result?

progesterone decreases and estrogen increases → increases myometrial activity

Where is PGF2a produced? when is it active? what is the role of PGF2a in myometrial contractions?

produced → mostly from uterine endometrium

active → with rising E:P ratio

role → cervical ripening and membrane rupture

How does oxytocin increase myometrial contractions? How does it affect the cervix?

lowers the excitation threshold of myometrial cells and causes cervical ripening when E:P ratio increases

What is the Ferguson Reflex?

uterine contraction causes the baby head to hit the cervix → triggers neuron stimulation → triggers OT release → OT increases contractions (cycle repeats)

Compare the roles of the placenta and endometrium in causing parturition?

placenta → increased estrogen / decreased progesterone (E:P ratio)

endometrium → increased PGF2a synthesis and release

What triggers these changes in the placenta and endometrium?

the maturation of the fetal hypothalamic-pituitary-adrenal axis (HPAA)

Describe the adrenal axis and how it contributes to the changes in placenta and endometrium

activation of HPA releases CRH (cortisol releasing hormone) → CRH triggers ACTH in adrenal gland → ACTH releases cortisol → cortisol has an effect on placenta and endometrium

Summarize the key events leading to the initiation of parturition (and OT release)

fetal HPA maturation → fetal ACTH → fetal cortisol → increase E:P in placenta + PG production (maternal) → increased myometrial contraction → pressure on cervix → OT release → increased myometrial contraction (repeats)

What are the 3 endocrine hormones used in artificial induction of parturition

cortisol, prostaglandin, and oxytocin agonists

What is the usage of cortisol, PG, and OT in artifical parturition?

cortisol → induces production of lung surfactant for lung maturation (if preterm delivery is inevitable)

PG → cervical ripening for parturition

OT → induces myometrial contraction (if dilated cervix and OT receptors expressed)

What are the three mechanical methods of artificial induction of parturition?

1. dilation of cervix

2. membrane stripping (PG release)

3. anmiotomy (OT/PG release)

What is preterm birth? how big of an issue is it?

labour/birth before 37 weeks → leading cause of death in children under 5 (10%)

What is a common cause of preterm labour?

inflammation!

What are three common diseases associated with pre-term birth?

1. autoimmune diseases

2. pro-inflammatory cytokine dysfunction (chronic inflammation like Crohns)

3. Periodontal disease (gum disease?)

What are three suggestions to stop pre-term labour?

1. inhibit smooth muscle contraction (Ca2+ or B2 blockers)

2. inhibit endocrine signals (PG or OT)

3. reduce inflammation (NSAIDs)

How effective are the strategies at stopping pre-term labour?

none have been shown to reduce preterm births or change outcomes → but used because women want to know you’re doing something to help them :)