Embryo Development Quiz

Embryo Development and Implantation

• The conceptus is everything derived from the original zygote. It spends 3-4 days in the fallopian tube, where estrogen and progesterone regulate its movement. Estrogen promotes contraction of the fallopian tube, while progesterone opposes this.
• During this time, the conceptus undergoes cleavage, a series of mitotic divisions without cell growth, creating smaller cells with a higher surface area to volume ratio for better nutrient/oxygen uptake and waste disposal.
• After 36 hours of fertilization, the conceptus consists of two identical cells (blastomeres). This continues to divide, forming a morula (16 or more cells) after 72 hours. These cells are totipotent - they can develop into an entire individual.
• Identical twins occur when dividing cells split into two separate cell masses during cleavage.
• By day 3-4, the conceptus has about 100 cells and floats freely in the uterus, gaining nutrients from its surroundings. Connections form between cells and fluid accumulates inside, forming the blastocyst, a hollow sphere.
• The blastocyst comprises two distinct cell types: the inner cell mass (gives rise to the developing human) and the trophoblast (surrounds the embryo/fetus and plays a crucial role in nutrition and hormone secretion).
• The inner cell mass loses its totipotency as cells differentiate. The inner cell mass is also responsible for some of the membranes around the embryo.

Implantation and Failure

• The window of implantation occurs between days 14-21 of the menstrual cycle, corresponding to the period where the uterine lining is prepared by progesterone for blastocyst reception.

• Implantation typically occurs around day 21, seven days after ovulation. Progesterone levels surge in the blood, increasing endometrial receptivity.

• This surge induces decidualization, a process in which the endometrium undergoes morphological and functional changes to prepare for implantation, including vascular modifications in maternal arteries.

• The trophoblast cells are sticky, with adhesion proteins like integrins and selectins, especially in regions overlying the inner cell mass. This allows the blastocyst to attach to the endometrium and initiate implantation.

• The blastocyst preferentially implants high in the uterus. If the endometrium isn't mature, the blastocyst may detach and re-implant at a lower level.

• Once contact is made, the trophoblast cells proliferate rapidly and secrete proteolytic enzymes, eroding endometrial tissue to allow the blastocyst to burrow into the endometrial layer.

• This process also triggers an inflammatory response, further facilitating implantation. Nutrient-rich endometrial cells provide metabolic fuel and raw materials for early embryo development.

• Implantation failure occurs in 2/3 of all fertilized zygotes. Additionally, 1/3 of remaining embryos miscarry due to genetic defects, uterine malformations, or unknown factors.

• While the exact reasons for implantation failure are unclear, issues with endometrial receptivity, implantation, or decidualization can contribute to infertility.

• A blastocyst implanting lower in the uterus (deferred implantation) can lead to placenta previa, intrauterine growth restriction, pre-eclampsia, or miscarriage.

• Premature decidualescence can result in preterm birth or fetal death. Shallow trophoblast invasion is linked to pre-eclampsia.

Implantation Failure Causes

• Scarring of the uterus (from pelvic inflammatory disease)
• Hormonal imbalances (e.g., Polycystic Ovary Syndrome (PCOS), endometriosis)
• Non-receptive endometrium (lack of appropriate receptors, PCOS, endometriosis)

Other Implantation Issues

• Ectopic pregnancy: The blastocyst implants outside the uterus, usually in the fallopian tubes, but can also occur on the ovary surface or in the abdominal cavity.
• Placenta previa: The blastocyst implants near the cervical opening, potentially covering the vaginal opening and increasing the risk of premature separation.

Placenta

• The endometrium can only nourish the embryo in the first few weeks due to size limitations. The placenta takes over this function as a crucial organ of exchange for the remaining pregnancy.
• The placenta provides all nutrients to the baby and removes fetal waste.
• The placenta also performs endocrine functions, regulating fetal growth and maternal adaptations to pregnancy.
• Doppler ultrasounds of the placenta assess its growth and that of the baby.
• Placental insufficiency can have severe consequences for the fetus or neonate.
• Amniotic fluid has a significant role in fetal development.

Placentation

• Placentation begins during implantation.
• As the blastocyst adheres to the endometrial epithelium, trophoblast cells differentiate into cytotrophoblast and syncytiotrophoblast.
• Cytotrophoblast proliferates, and new cells migrate into the syncytiotrophoblast, losing their cell membranes to form a rapidly expanding multinucleated mass.
• Cytotrophoblast secretes proteolytic enzymes, allowing the blastocyst to embed into the endometrium.
• Lacunae (spaces) form within the syncytiotrophoblast.
• As the syncytiotrophoblast erodes endometrial blood vessels and glands, lacunae fill with maternal blood and granular secretions.
• These lacunae fuse to form a network that allows maternal blood to flow, establishing early uteroplacental circulation.

Placenta Development

• Towards the end of the second week, cytotrophoblast projections expand into the syncytiotrophoblast, forming primary chorionic villi.
• Early in the third week, extraembryonic mesoderm grows into the villi, creating a core of loose connective tissue and forming secondary chorionic villi.
• By the end of the third week, blood vessels form in the extraembryonic mesoderm of the secondary chorionic villi, transforming them into tertiary chorionic villi.
• Cytotrophoblasts from tertiary villi grow towards the decidua basalis and create a cytotrophoblastic shell.
• Villi connected to the decidua basalis through this shell are anchoring villi.
• Villi from the sides of the stem villi are branch villi, surrounded by the intervillous space and serving as the primary exchange point between mother and fetus.
• By the fourth week, fetal blood flow is established. Oxygen-poor blood travels from the fetus to the placenta via paired umbilical arteries, which branch into chorionic villi and divide into capillary networks.
• Carbon dioxide and waste products pass from fetal circulation across the placental membrane into the intervillous space (maternal blood).
• Oxygen and nutrients travel across the placental membrane to the fetal capillaries.
• Oxygenated fetal blood returns through veins to the single umbilical vein, which carries it to the fetus.
• Blood returns to maternal circulation through endometrial veins, forced out by the pressure of incoming arterial blood.
• The placenta nourishes the fetus throughout development and is delivered shortly after birth.

Placentation Glossary

• Placenta: A temporary fetal organ that develops during pregnancy. It facilitates nutrient, gas, and waste exchange between maternal and fetal circulations and produces hormones regulating maternal and fetal physiology.
• Trophoblast: Cells forming the outer layer of the blastocyst. They provide nutrients to the embryo and develop into a large part of the placenta.
• Cytotrophoblast: A layer of mononucleated cells that invades the syncytiotrophoblast matrix and forms chorionic villi.
• Syncytiotrophoblast: A multinucleated epithelial covering of the highly vascular placental villi. It invades the endometrium to establish nutrient circulation between mother and embryo.
• Lacunae: Small spaces or gaps in an organ or tissue.
• Chorionic villi: Villi sprouting from the chorion, maximizing contact with maternal blood.
• Decidua basalis: Part of the endometrium participating in the formation of the placenta alongside the chorion.
• Cytotrophoblastic shell: An external layer of cytotrophoblasts from the fetus found on the maternal surface of the placenta.
• Anchoring villi: Villi connected to the decidua basalis through the cytotrophoblastic shell.
• Branching villi: Villi growing from the sides of stem villi, surrounded by the intervillous space, serving as the main exchange point between mother and fetus.

Placenta

• The placenta is the organ of exchange between the mother and fetus.
• It's composed of interlocking fetal and maternal tissues.
• The outermost layers of the trophoblast (chorion) supply the fetal part of the placenta.
• The endometrium underlying the chorion provides the maternal portion.
• Chorionic villi, finger-like projections of the trophoblast cells, extend into the endometrium.
• The villi contain a rich capillary network, part of the fetal circulatory system.
• Enzymes and molecules secreted by the villi alter the endometrium, creating a pool of maternal blood for exchange.
• Maternal and fetal blood supplies are separate, with the mother's blood entering through the uterine artery and the fetus receiving circulation through the umbilical vein.
• Reduced placental perfusion can impede fetal growth.
• Placental issues are responsible for 88% of intrauterine fetal deaths (IUFD).

Placental Functions

• The placenta acts as a gut, kidney, and lung for the developing fetus.
• It provides substrates for fetal metabolism, disposes of waste products, exchanges respiratory gases, and acts as a partial immunological barrier.
• Produces hormones important for pregnancy, including progesterone, estrogen, hCG, hPL, and CRH.
• Facilitated diffusion and active transport enable the exchange of molecules like blood gases, water, urea, free fatty acids, ketones, and non-conjugated steroids.
• Placental permeability varies, preventing large proteins and blood cells from crossing, but allowing entry of alcohol, nicotine, drugs, and some pathogens.

Extraembryonic Membranes

• Chorion encloses the embryonic body and other membranes, contributing to placenta formation.
• Amnion is a transparent sac filled with amniotic fluid, protecting the embryo and providing optimal developmental conditions.
• Yolk sac decreases in size and importance during early development.
• Allantois is a small outpocketing at the base of the umbilical cord in humans.

Amniotic Fluid

• Consists primarily of fetal urine, increasing from 10mL at 8 weeks to 450mL at 32 weeks.
• Serves as a reservoir for development of anatomical hollow tube structures like lung airways, gut, and renal nephron.
• Cushions the fetus from trauma and provides space for muscle development.
• Prevents uterine compression of the fetus and promotes normal lung development.
• Maintains a constant temperature.

Maternal Adaptations and Pregnancy Hormones

• Estrogen and progesterone levels increase progressively throughout pregnancy.
• Estrogen stimulates uterine growth, while progesterone prevents premature contractions.
• The corpus luteum supplies the majority of estrogen and progesterone in the first two months of pregnancy.
• Human Chorionic Gonadotrophin (hCG) maintains the corpus luteum's viability and leads to increased steroid production.
• hCG levels rise from the first week until the end of the second month.
• After 2-3 months, the placenta takes over estrogen and progesterone production.
• hCG levels fall, allowing the corpus luteum to regress.
• Progesterone plays a key role in maintaining the pregnancy, relaxing smooth muscle throughout the body and preventing uterine contractions.
• The feto-placental unit produces estrogen using androgens from the ovaries, adrenal glands, and fetal adrenal glands.

Maternal Adaptations in Pregnancy

• The female reproductive organs become increasingly vascular and engorged.
• Breasts enlarge under the influence of estrogen and progesterone.
• The uterus undergoes significant enlargement, filling the abdominal cavity and pressing on surrounding organs.
• Increased weight gain is mainly due to fetal and placental growth, maternal organ expansion, and blood volume increase.
• Progesterone stimulates maternal appetite, leading to increased fat deposition.
• hPL, produced by the placenta, mobilizes maternal fat stores and increases glucose production in the liver.
• hCT, released by the placenta, increases maternal metabolic rate.
• Insulin production rises during pregnancy, but it doesn't cross the placenta.

Physiological Changes in Pregnancy

• Cardiovascular system: Blood volume increases by 25-40% by the 32nd week, leading to increased cardiac output and blood pressure.
• Respiratory system: Increased tidal volume, dyspnoea, hyperventilation, and CO2 production are common in later stages of pregnancy.
• Gastrointestinal system: Morning sickness, heartburn, acidity, and constipation may occur due to hormonal changes and physical pressure from the growing uterus.
• Urinary system: Increased urine production, frequent urination, increased blood flow to the kidneys, and fluid retention are typical.

Pre-eclampsia

• Pre-eclampsia, complicating 8% of deliveries, is characterized by abnormal vasoconstriction of maternal blood vessels and inadequate trophoblast invasion.
• Poor placental perfusion results in hypertension, proteinuria, hepatic ischemia, edema, and coagulation system activation.
• Careful monitoring and management are crucial for both mother and fetus.

Fetal Development

• Fertilized egg undergoes cleavage and implantation, forming the blastocyst.
• Development proceeds through distinct stages, with the formation of germ layers, neurulation, and the primitive gut.
• By 7 weeks, most major organs have formed, but the fetus is vulnerable to damage.
• By 10 weeks, fingers and toes separate, the face and genitals form, and urine production begins.
• By 20 weeks, muscles and bones have developed, and fetal movements become noticeable.
• After 25 weeks, the nervous system gains control over some functions, and the respiratory system becomes capable of gas exchange.
• At 30 weeks, rapid fat accumulation, fetal breathing movements, and fully developed bones occur.
• At term, the fetus is 48-51cm long and weighs 2.8 to 4 kg.

Fetal Maturation

• After birth, the fetus needs to mature lungs, prepare the gut for feeding, develop urine-concentrating ability, generate heat, change hemoglobin type, and store energy substrates.
• Glucocorticoids, such as cortisol, accelerate these functions.
• Cortisol production increases in the fetal adrenal cortex towards the end of pregnancy.
• The prepartum surge of cortisol promotes organ differentiation and development, slows growth, and triggers the final maturation of key systems, including the lungs.

Parturition

• The uterus transforms from a relaxed state to a contractile and excitable phenotype to facilitate birth.
• Progesterone maintains uterine quiescence throughout most of pregnancy.
• Estrogen, prostaglandins, and oxytocin mediate uterine contractions at birth.

Preterm Birth

• Delivery before 37 weeks, affecting 11.1% of pregnancies worldwide.
• Leading cause of neonatal death and associated with long-term health complications for the infant.

Labour

• Normal human pregnancy lasts approximately 40 weeks.
• The transformation of the uterus from relaxed to active involves a complex interaction of hormones and signaling pathways.

Hormonal Influences on Labour

• Progesterone promotes uterine quiescence throughout pregnancy.
• Estrogen levels rise towards the end of pregnancy, increasing uterine sensitivity to contractions.
• Prostaglandins contribute to cervical softening, uterine contractions, and fetal membrane rupture.
• Oxytocin stimulates powerful uterine contractions, playing a key role in the final stages of labor.

Lactation

• The process of milk production and secretion by the mammary glands.

• Hormones like prolactin and oxytocin are crucial regulators of lactation.

• Prolactin promotes milk production, while oxytocin facilitates milk ejection (let-down).

• Lactation can be influenced by several factors, including breastfeeding frequency, baby's sucking strength, stress levels, and medication use.### Parturition

• Parturition refers to the process of childbirth, encompassing all events from the initiation of labor to the delivery of the infant and placenta.

• Progesterone's inhibitory effect on uterine contractions is reduced towards the end of pregnancy, making the myometrium more responsive to estrogen, oxytocin, and prostaglandins.

Role of Progesterone Receptors

• Progesterone receptor B dominates during most of pregnancy, preventing the expression of gap junction proteins like connexin 43, which are crucial for rhythmic contractions.
• Progesterone receptor A dominates towards the end of pregnancy, binding progesterone in the cytoplasm but not transporting it to the nucleus.
• The enzyme 20 alpha HSD reduces progesterone signalling, further contributing to the switch in progesterone activity.

Foetal Influence on Labor

• The fetus plays a role in determining its own birth date.
• Increasing placental CRH levels and fetal stress lead to the production of ACTH and cortisol, triggering the release of large amounts of estrogens (via DHEA) from the placenta.

Initiation of Labor - Estrogen's Role

• Estrogen stimulates the synthesis of gap junction proteins (connexins) in the myometrial smooth muscle, enabling coordinated contractions.
• Estrogen promotes collagen breakdown in the cervix, making it softer and more flexible.
• Estrogen increases the expression of oxytocin receptors in the myometrium.

Initiation of Labor - Prostaglandins

• Prostaglandins (PGF2a and PGE2) secreted by the uterus, act as potent stimulators of uterine muscle contraction.
• Prostaglandins contribute to the rhythmic expulsive contractions of true labor and increase cervical compliance.

Oxytocin's Role in Labor

• Pain and uterine distention trigger the release of oxytocin from the posterior pituitary.
• Oxytocin stimulates uterine muscle contraction in a positive feedback loop, increasing levels throughout labor.
• The number of oxytocin receptors in the uterus increases during the final weeks of pregnancy, amplifying the contractile response to oxytocin.

Stages of Labor

Dilation Stage (Stage 1)

• Begins with the onset of labor and ends when the cervix is fully dilated by the baby's head.
• Characterized by weak but regular contractions, increasing in frequency and intensity over time, lasting for 6-12 hours.
• The cervix softens, thins, and dilates to approximately 10 centimeters.
• The amniotic sac may rupture and the amniotic fluid flows out of the vagina ("breaking of the water").

Expulsion Stage (Stage 2)

• Begins when the infant's head enters the true pelvis (engagement).
• Ends with the birth of the infant, lasting for 50 minutes in a first birth and 20 minutes in subsequent births.
• Strong contractions occur every 2-3 minutes, lasting for about 1 minute.
• The mother bears down to increase abdominal pressure, assisting with delivery.
• "Crowning" occurs when the largest dimension of the baby's head distends the vulva.
• The umbilical cord is clamped and cut after birth.
• Breech presentation (baby's body oriented differently than head downwards) may require a Cesarean section.
• Other reasons for a Cesarean section include maternal fatigue or failure to progress during labor.
• Australia has high rates of Cesarean sections (32% in 2013), exceeding the OECD average of 25.7%.
• The WHO recommends a Cesarean section rate of only 10-15%.

Placental Stage (Stage 3)

• The placenta and fetal membranes (afterbirth) are delivered within 30 minutes following the birth of the infant.
• Strong uterine contractions compress blood vessels and detach the placenta from the uterine wall.
• Removal of all placental fragments helps prevent postpartum bleeding.
• Postpartum hemorrhaging can be dangerous for the mother.
• Monash University is leading the development of methods for limiting and treating postpartum bleeding, including a heat-stable, powdered oxytocin formulation for inhalation.

Infant Adjustments

• Birth is a significant shock for the infant.
• The baby is exposed to physical trauma during delivery, transitions from a watery, warm environment, and loses placental support.

Breathing

• CO2 buildup in the baby's blood causes central acidosis, stimulating the respiratory control centers in the brain.
• The baby's first breath is a huge effort, requiring more energy to inflate the airways and lungs.
• Once the lungs are inflated, surfactant production reduces surface tension and breathing becomes easier.
• The respiratory rate is rapid (45 breaths per minute) for the first two weeks, gradually declining.

APGAR Score

• The infant's physical status is assessed at 1 and 5 minutes after birth using the APGAR score, which measures heart rate, respiration, skin tone, muscle tone, and reflex irritability.
• Each observation receives a score of 0-2, with a total APGAR score of 8-10 indicating a healthy baby.

Transition Period

• Infants pass through a transitional period for 6-8 hours after birth, with alternating periods of increased activity and sleep.
• Vital signs are irregular during activity periods, with the baby gagging frequently as it regurgitates mucus and debris.
• The infant stabilizes, waking every 3-4 hours mainly due to hunger.

Lactation

• The mammary glands produce milk.
• Each breast contains numerous mammary glands, with ducts that branch through the tissue and converge at the nipple.
• These ducts originate in structures called alveoli, the sites of milk secretion.

Mammary Histology

• Lobuloalveolar ducts and alveoli are present.
• Microscopic scans show alveoli surrounded by myoepithelial cells, which aid in milk ejection.

Hormones Involved in Lactation

• Lactogenesis I: From mid-pregnancy to day 2 postpartum, rising estrogen, progesterone, and prolactin help differentiate the breast glands.
• Lactogenesis II: Days 3-8, a decrease in estrogen and progesterone alongside high levels of prolactin and oxytocin triggers abundant milk secretion.
• Galactopoiesis: Days 9 to involution, episodic increases in prolactin and oxytocin maintain milk production and ejection.

Lactation in Puberty

• Increased estrogen stimulates duct growth and branching, causing breast enlargement due to fat deposition.
• Increased progesterone promotes alveolar growth.

Lactation During Pregnancy

• Rising estrogen, progesterone, and human placental lactogen stimulate significant breast enlargement.
• Ductal and alveolar structures develop, with alveoli enlarging and acquiring a lumen.
• Rising estrogen causes a surge in prolactin secretion by the anterior pituitary.

Prolactin

• Promotes breast growth and differentiation.
• Stimulates milk production after estrogen and progesterone levels decline at birth.
• Despite high prolactin concentrations and developed breasts in late pregnancy, milk secretion is minimal due to the inhibitory effects of estrogen and progesterone.

Milk Production After Birth

• Placental delivery removes the source of high progesterone and estrogen levels.
• Prolactin is released, initiating milk production.
• Decreased estrogen causes basal prolactin levels to decrease.
• Prolactin levels show secretory bursts during nursing, which are sufficient to maintain milk production.

Lactation Reflexes

• Suckling stimulates mechanoreceptors in the nipples, triggering afferent inputs to the hypothalamus.
• This inhibits the release of dopamine, which inhibits prolactin release.
• The anterior pituitary secretes prolactin, promoting milk production.

Prolactin vs Oxytocin

• Prolactin produces milk, but the infant can't access it without the milk ejection reflex.
• This reflex moves milk from the alveoli to the ducts.

Oxytocin Reflex

• Suckling also triggers the release of oxytocin from the posterior pituitary.
• Oxytocin binds to receptors on myoepithelial cells, causing their contraction and milk release through the nipple ducts.
• This process creates a positive feedback loop, as more milk released leads to more suckling and further oxytocin release.

Oxytocin's Other Effects

• Oxytocin stimulates uterine contractions, helping the uterus return to its pre-pregnancy size.
• Suckling can impede the HPG axis, potentially blocking ovulation due to prolactin's inhibition of GnRH neurons and LH/FSH secretion.
• Prolonged high-frequency suckling can prevent ovulation for months or years, acting as a natural birth control method.

Hormones Involved in Mammary Development

• Estrogen
• Progesterone
• Human placental lactogen
• Prolactin
• Growth hormone? (may promote growth alongside IGF1)

Hormones Involved in Lactogenesis

• Prolactin
• Oxytocin
• Prolactin releasing factor (unidentified)

Breast Milk

• The breasts initially secrete colostrum, a watery, protein-rich fluid.
• Transition to mature milk production occurs after 1-2 days.
• Milk contains six main nutrients: water, proteins, lipids, lactose, minerals, and vitamins.

Colostrum and Milk Components

• Antibodies, leukocytes, complement, lysozyme, interferons, and lactoperoxidase protect infants from infections.
• Growth factors and hormones promote tissue development and maturation.
• Neuropeptides and opioids may influence infant brain development and behavior.

Milk Protein Absorption

• Milk proteins enter the newborn's bloodstream due to low stomach acidity and intestinal permeability.

Breastfeeding Benefits

• The high nutritional value of breast milk makes breastfeeding strongly advocated for by health professionals.
• Cow milk contains many similar constituents but in different concentrations.