Physiology of Pregnancy, Parturition, and Lactation Lecture (Dr. Lopez)

Question 1

Fertilization

Answer 1

• Accomplishes both the recombination of genetic material to form a new, genetically distinct organism & the initiation of events that BEGIN Embryonic Development
• Fertilization typically occurs on day 15 or 16 of the Menstrual Cycle

Question 2

Transport of Gametes

Answer 2

• Following Ovulation, the FIMBRIAE of the Fallopian Tube sweep over the ovarian surface & Pick Up the Cumulus-Oocyte Complex
• SPERMATOZOA present in the Male Ejaculate enter the Vagina near the Cervix & must reach the AMPULLA of the Oviduct where FERTILIZATION OCCURS
• Sperm transport is largely DEPENDENT on the Female Reproductive Tract &, while the sperm are still in the Uterus, is INDEPENDENT of Swimming

Question 3

Transport of Gametes Cont

Answer 3

• Large numbers of sperm in the ejaculate generally are required for successful Fertilization of the egg by one sperm
– However, of the ~300 million sperm typically Ejaculated, only ~200 REACH the Oviduct
– Clinically, males with

Question 4

Review of Capacitation

Answer 4

• Sperm must go through CAPACITATION in the Female Reproductive Tract before Fertilization

• Is Transient event that Occurs largely in the OVIDUCT & MODIFIES the Spermatozoan so that it becomes capable of FERTILIZING the egg
– Acrosome reaction is among the changes associated with Capacitation

• Capacitated sperm reach the egg, surrounded by its expanded CUMULUS cells, in the AMPULLA of the Oviduct
• In vivo, the Sperm must breach 3 barriers during the process of Fertilization:

1) Expanded cumulus
2) Zona Pellucida
3) Plasma Membrane of the Egg (aka OOLEMMA)

Question 5

Fertilization

Answer 5

1) The SPERM HEAD weaves its way past the follicular cells & ATTACHES to the ZONA PELLUCIDA that surrounds the oocyte
• Sperm-ZP3 (glycoprotein) interaction!!!!!!!!!!!!!!!!

2) ACROSOMAL REACTION
• Increase in [Ca 2+ ] inside the sperm cell triggers fusion of the outer acrosomal membrane with the sperm cell’s plasma membrane & results in the exocytosis of most of the acrosomal contents

3) SPERMATOZOON PENETRATES the Zone Pellucida

4) Cell membranes of the sperm & the Oocyte (egg cell) FUSE
• Sperm cell per se does not enter the oocyte

Question 6

Fertilization Cont

Answer 6

5) Triggering of the OOCYTE’S 2nd MEIOTIC Division & CORTICAL REACTION
• Initiated by increase in [Ca 2+ ] inside the oocyte!!!!!!!!

• Massive exocytosis of Cortical Granules seen shortly after Sperm-Oocyte FUSION
• Exocytosis of these Granules releases enzymes that act on Glycoproteins in the Zona Pellucida & cause them to HARDEN
• PREVENTS POLYSPERMY!!!!!!

6) Oocyte COMPLETES its Second Meiotic Division
• Results in the FORMATION of the SECOND Polar Body, which contains a Haploid Number of UNDUPLICATED MATERNAL CHROMOSOMES & lies close to the 1st polar body

• The NUCLEUS of the Oocyte also contains a HAPLOID number of UNDUPLICATED CHROMOSOMES; as its chromosomes DECONDENSE, the Nucleus of this MATURE OVUM becomes the FEMALE PRONUCLES!!!!!!!!!!!!!

7) The Sperm Nucleus DECONDENSES & Transforms into the MALE PRONUCLEUS!!!!!!!!

8 The Male & Female pronuclei FUSE, to form a new cell, the ZYGOTE!!!!!!!

Question 7

Pronuclear formation & first

Embryonic Cleavage

Answer 7

• The activated Egg COMPLETES the 2nd Meiotic Division as the sperm DNA DECONDENSES & a Pronucleus forms around it
• Once the egg has completed Meiosis, a Pronucleus forms around the Female Chromosomes as well
• The Male & Female DNAs REPLICATE as the two Pronuclei are pulled TOGETHER
• Once the Pronuclei contact each other, the Nuclear Membranes BREAK DOWN, the chromosomes align on a common METAPHASE Plate, & the FIRST Embryonic Cleavage!!!!!!!!!
• The mingling of chromosomes (SYNGAMY) can be considered as the END of Fertilization & the BEGINNING of Embryonic Development

Question 8

The first week of Embryogenesis occurs within the Lumina of the Oviduct and Uterus

Answer 8

• Fertilization typically occurs on day 15 or 16 of the menstrual cycle!!!!!!!

• The first two cleavages take
~2 days, & the Embryo reaches a 16-cell MORULA by 3 days!!!!!

• During days 4 & 5 the embryo reaches BLASTOCYST stage!!!!!!
• IMPLANTATION of the human Blastocyst normally occurs 6 to 7 days following Ovulation!!!!!!

Question 9

Cleavage stages in Embryos

Answer 9

• Cells on the OUTER Part of the morula become bound tightly together with the formation of desmosomes & gap juncUons = COMPACTION!!!!!!
• A CAVITY forms inside the morula, by the active transport of Na+ from Trophoblast cells & Osmosis of Water, giving rise to the BLASTOCYST!!!!!

• The Blastocyst’s outer cells will become the TROPHECTODERM, while some cells will remain trapped in the Interior, becoming the INNER CELL MASS (ICM)
– ICM are PLURIPOTENT!!!!!!
– ICM will ultimately form the “EMBRYO PROPER”, while the Trophectoderm will form the PLACENTA & Extra-Embryonic Tissues

Question 10

Uterine secretions Nourish the Preimplantation embryo, promote growth, & prepare it for Implantation

Answer 10

• Before the Embryo Implants in the ENDOMETRIUM & establishes an Indirect lifeline between the mother’s blood & its own, it must receive its Nourishment from Uterine Secretions
• Following CONCEPTION, the Endometrium is primarily Controlled by PROGESTERONE, which Initially comes from the Corpus Luteum
• The Uterine Glandular Epithelium synthesizes & secretes several steroid- dependent protein, which may be important for the nourishment, growth, & Implantation of the embryo

• The presence and action of PINOPODS may Determine the Extent of the Implantation window
– Small, finger-like Protrusions on Endometrial cells

– Appear between day 19 (about the time the embryo would arrive in the uterus) & day 21
(about the time of Implantation) of the menstrual cycle; they persist for only 2 – 3 days

– Their Development is ENHANCED by PROGESTERONE but INHIBITED by ESTROGENS

– During the early stages of embryo Implantation, Pinopods ENDOCYTOSE Macromolecules & Uterine fluid and Absorb most of the fluid in the lumen of the uterus

• Through this action, Pinopods may allow the embryo & the uterine epithelium to Epproximate one another MORE CLOSELY

Question 11

Blastocyst secretes substances that facilitate implanta4on

Answer 11

• The blastocyst must AVOID Rejection by the maternal cellular immune system in order to survive
– Releases IMMUNOSUPPRESSIVE/ Immunoregulatory Agents(e.g.platelet- activating factor, Human Chorionic Gonadotropin, Early Pregnancy Factor, Immunosuppressive factor, Prostaglandin E2, interleukin 1-α, interleukin 6, interferon-α, leukemia inhibitory factor & colony-stimulating factor)
– HUMAN CHORIONIC GONADOTROPIN (hCG) not only acts as an Immunosuppressive but also PREVENTS Menstruation by sustaining the function of the Corpus Luteum, signaling the mother’s body that she is PREGNANT

• The Blastocyst also Synthesizes & Secretes macromolecules that PROMOTE Implantation, the DEVELOPMENT of the Placenta, & the MAINTENANCE of Pregnancy

• hCG is one of the most important of the factors secreted by the TROPHOBLASTS of the Blastocyst, both before & after Implantation!!!!!!!!!!!!!!!!!!!!!!!!!
– Closely related to LH
– Sustains the Corpus Luteum in the presence of rapidly falling levels of maternal LH
– hCG is an Autocrine GROWTH FACTOR that promotes Trophoblast GRWOTH & Placental Development

Question 12

Overview of Implantation

Answer 12

• The TROPHOBLASTS of the Blastocyst secrete proteases that digest the outer-lying ZONA PELLUCIDA
– The HATCHED Blastocyst is able to ADHERE to & implant into the Receptive Uterine Endometrium

• At the time of Attachment & Implantation, the Trophoblasts differentiate into 2 cell types:

1) CYTOTROPHOBLASTS (Inner cell layer)
2) SYNCYTIOTROPHOBLASTS (Outer layer of Multinuclear & Multicellular cells; without cellular boundaries)

** Implantation is initiated when the Blastocyst comes into CONTACT with the Uterine Wall!!!!!!

Question 13

Cytotrophoblasts & Syncytiotrophoblasts

Answer 13

• CYTOTROPHOBLASTS: Rapidly PROLIFERATING
– Initially provide a FEEDER Layer of continuously dividing cells

• SYNCYTIOTROPHOBLASTS: Adhesive, Invasive, & Endocrine funcUons
– Express ADHESIVE surface proteins (cadherins & integrins) that bind to uterine surface epithelia, as the embryo implants, these BIND to Components of the Uterine Extracellular Matrix

– Role in interstitial Implantation: involves ADHESION-SUPPORTED INVASION & migration of Syncytiotrophoblasts into the Endometrium, along with the breakdown of extracellular matrix by the SECRETION of Matrix Metalloproteases & other Hydrolytic Enzymes

– Secrete HUMAN CHORIONIC GONADOTROPIN (hCG) at the onset of Implantation, which MAINTAINS the viability of the Corpus Luteum of Pregnancy

– Make PROGESTERONE at sufficient levels to MAINTAIN Pregnancy Independently of the Corpus Luteum

– As Implantation & Placentation progress, Syncytiotrophoblasts have functions in phagocytosis & bidirectional placental transfer of gases, nutrients, & wastes

Question 14

Before the initiation of Implantation, the Zona Pellucida Degenerates

Answer 14

• HATCHING
– Blastocyst needs to GET RID of its Zona Pellucid

– Occurs ~ 6 – 7 days after Ovulation

– LYTIC FACTORS in the endometrial cavity appear to be essential for the dissolution of the Zona Pellucida
• A factor produced by the blastocyst may activate a lytic factor that is derived from a uterine precursor
– A putative Lytic Factor is PLASMIN
» Plasminogen, the plasmin precursor, is found in the Uterine Cavity, & blastocyst factors may contribute to its conversion to active PLASMIN

Question 15

Implantation occurs in three stages: Apposition, Adhesion, & Invasion

APPOSITION

Answer 15

1) APPOSITION
– Earliest contact between the blastocyst wall, the Trophoectoderm, & the endometrial epithelium

– Usually occurs where there is a Small Crypt in the Endometrium

– On the Blastocyst, it appears that Apposition occurs at a location where there has been enough LYSIS of the Zona Pellucida to have created a RUPTURE to enable DIRECT contact between the cell membranes of the Trophoblast & the Cell Membranes of the Endometrium (DECIDUA)
• It seems that the entire Trophoectoderm has the potential to interact with the Endometrium

– The final correct Orientation (i.e. with the inner cell mass pointing toward the Endometrium) occurs by FREE ROTATION of the INNER CELL MASS within the sphere of overlying Trophectoderm cells

– MUC1 might be involved in Apposition; a transmembrane glycoprotein expressed at the Apical Surface of endometrial epithelial cells during the window of IMPLANTATION!!!!

Question 16

Implantation occurs in three stages: Apposition, Adhesion, & Invasion

ADHESION

Answer 16

2) ADHESION
– Much stronger attachment to the Endometrium than the loose apposition

– Trophoblast appears to attach to the Uterine Epithelium through the MICROVILLI of the Trophoblast

– Ligand-receptor interactions are probably involved
• The receptors for these ligand-receptor interactions are often members of the INTREGRIN family; can be either on the Blastocyst or on the Endometrium

• Ligand-receptor interactions can lead to Cytoskeletal CHANGES in DECIDUAL CELLS

– Adhesion of the trophoblast through ligand-receptor interacUons may dislodge the decidual cells from their connecUon to the underlying basal lamina, which enables the blastocyst to perform the succeeding invasion

Question 17

Implantation occurs in three stages: Apposition, Adhesion, & Invasion

INVASION

Answer 17

• INVASION
– Is an even further establishment of the Blastocyst in the Endometrium

– As the Blastocyst attaches to the Endometrial Epithelium, the Trophoblastic cells RAPIDLY PROLIFERATE, & the Trophoblast differentiates into the Inner Cytotrophoblast & the Outer Syncytiotrophoblast

– During implantation, long Protrusions from the Syncytiotrophoblast extend among the Uterine Epithelial cells

• These protrusions dissociate the endometrial epithelial cells by secreting Tumor Necrosis Factor α (TNF-α), which INTERFERS with the expression of CADHERINS (cell adhesion molecules) & β-CATENIN (an intracellular protein that helps to anchor cadherins to the cytoskeleton)

– The Syncytiotrophoblast protrusions then PENETRATE the basement membrane of the uterine epithelial cells & reach the Uterine STROMA

– The Trophoblast secretes several AUTOCRINE factors, which may stimulate INVASION of the
Endometrial Epithelium, as well as proteases
• HMAN CHORIONIC GONADOTROPIN (hCG) is an AUTOCRINE Growth Factor for the Blastocyst
• Metalloproteases & Serine Proteases DEGRADES the Extracellular Matrix; may control both the ProliferaUon & the Invasion of the Trophoblast into the endometrium

– Around the site of penetration of the Syncytiotrophoblast, Uterine STROMAL cells take on a polyhedral shape and BECOME laden with lipids & glycogen (DECIDUAL CELLS)

– The Blastocyst superficially Implants in the ZONA COMPACTA of the Endometrium & eventually becomes completely embedded in the DECIDUA

– As the finger-like projections of the Syncytiotrophoblast invade the Endometrium, they reach the maternal blood supply & represent a Primordial Form of the Chorionic Villus of the MATURE PLACENTA

Question 18

DECIDUALZATION: Maternal response to Implantation

Answer 18

• Response of maternal cells (Stromal Cells) to PROGESTERONE
– Decidualized Stromal Cells are derived from the FIBROBLAST-like cells within the Endometrium, which maintain their Progesterone RECEPTORS in the presence of Progesterone

– Endometrial STROMA is Transformed into enlarged and glycogen-filled DECIDUAL CELLS

• The Endometrium is now called DECIDUA & it is ready for the implantation of the embryo
– The Decidua forms an Epithelial- like sheet with adhesive junctions that INHIBITS migration of the Implanting Embryo

Question 19

Development of the Placenta

Answer 19

• Shortly after the Blastocyst has Implanted (6 to 7 days amer ferUlizaUon), the SYNCYTIOTROPHOBLAST INVADES the DECIDUA; within the Syncytiotrophoblast are LACUNAE

• The invading Syncytiotrophoblast breaks through into Endometrial veins first, & then later into the Arteries
– Creates Direct communication between LACUNAE & MATERNAL Vessels

– Proliferation of Cytotrophoblasts creates small mounds (i.e. PRIMARY CHORIONIC VILLI)

• The PRIMARY CHORIONIC VILLUS continues to grow with the proliferation of Cytotrophoblastic cells
– Mesenchymal cells from the Extraembryonic Mesoderm INVADE the Primary Chorionic Cilli, forming the SECONDARY CHORIONIC VILLUS

– Eventually, these Mesenchymal cells form FETAL BLOOD VESSELS DE NOVO, Villi are then known as TERITIARY CHORIONIC VILLI

Question 20

The Mature Placenta

Answer 20

• The Mature Placenta is composed of THREE Major Structures:

1) Chorionic Villi
2) Intervillous Space
3) Decidua basalis

• Chorionic Villi represent the FUNCTIONAL UNIT of the Placenta &, through extensive branching, greatly INCREASES the Surface Area for maternal-fetal exchange
• “SPIRAL” arteries from the Mother empty directly into the INTERVILLOUS SPACE, which is DRAINED by Maternal Veins

Question 21

The placenta is the major lifeline between the Mother & the Fetus

Answer 21

• Fetal “GUT”: supplying Nutrients
• Fetal “LUNG”: Exchanging O2 and CO2
• Fetal “KIDNEY”: regulates Fluid Volumes & disposing of Waste Metabolites
• ENDOCRINE GLAND: Synthesizes Steroids & Proteins that affect both Maternal & Fetal Metabolism

Question 22

Maternal Blood Flow

Answer 22

• Blood enters in PULSATILE SPURTS through the wall of the Uterus & moves into the Intervillous Space toward the chorionic plateCHORIONIC PLATE
• Maternal Blood is TRAPPED in the Intervillous Space

• After bathing the Chorionic Villi, the maternal blood Drains through Venous Orifices in the Basal Plate, enters the larger Maternal Placental VEINS, & flows into the uterine & other pelvic veins
– NO CAPILLARIES are present between the Maternal Arterioles & Venules; the intervillous space is the FUNCTIONAL CAPILLARY

• Principal factors regulating maternal blood flow in the intervillous space: Maternal Arterial BLOOD PRESSURE, INTRA-UTERINE PRESSURE, & PATTERN OF UTERINE CONTRACTION
– Uterine contractions attenuate Arterial Inflow & completely INTERRUPT Venous Drainage; the volume of blood in the Intervillous space actually INCREASES, to provide continual, albeit reduced, Exchange

Question 23

Fetal blood flow

Answer 23

• The fetal blood originates from TWO Umbilical Arteries
– Umbilical arteries carry DEOXYGENATED Blood, Unlike Systemic Arteries AFTER Birth

• Blood that has obtained a significantly HIGHER O2 & Nutrient content returns to the Fetus from the Placenta through the SINGLE UMBILICAL VEIN

• Two Important functions of the Amniotic Fluid:
– Serves as a Mechanical buffer protecting the Fetus from External,
Physical Insults
– Fetus excretes WASTE products through it

Question 24

Gases move Across the Placenta

Answer 24

• The maternal blood coming into the Intervillous Space has a gas composition SIMILAR to that of Systemic Arterial Blood: PO2 of ∼100 mm Hg, PCO2 of ∼40 mm Hg, & pH of 7.4

• The diffusion of O2 from the Maternal Blood into the CHORIONIC VILLI of the fetus causes the PO2 of blood in the Intervillous Space to FALL
– Average PO2 is 30 – 35 mmHg
– PO2 of blood in the Umbilical Vein is even LESS

• Despite the relatively Low PO2 of the Maternal blood in the intervillous space, the fetus DOES NOT suffer from a lack of O2
– Fetal Hb has a much HIGHER AFFINITY for O2 than does Maternal Hb, the FETAL Hb can EXTRACT O2 from the Maternal Hb

• Other mechanisms of ensuring adequate Fetal Oxygenation: relatively HIGH Cardiac Output per unit body weight of the fetus & INCREASING O2 -carrying capacity of fetal blood late in pregnancy
– Hb concentration RISES to a Level 50% HIGHER than that of the Adult

Question 25

Movement across the Placenta

Answer 25

• Waste products Urea & Creatinine: passive movement from fetus to mother
• LIPID-SOLUBLE Steroid Hormones: SIMPLE DIFFUSION; shuttle among the mother, the placenta, & the fetus
• GLUCOSE: FACILITATED DIFFUSION – movement from mother to fetus
• AMINO ACIDS: SECONDARY ACTIVE TRANSPORT
• VITAMINS and MINERALS : ACTIVE TRANSPORT

• Low-density lipoproteins (LDL), Transferrin, Hormones (e.g., insulin), & Antibodies (e.g., immunoglobulin G): RECEPTOR MEDIATED ENDOCYTOSIS – Placenta takes up large molecules from the mother
– UPTAKE of these substances Increases throughout Gestation until just before Birth

Question 26

Endocrine function of the Placenta

Answer 26

• The Syncytiotrophoblasts of the Placenta produce several STEROID & PROTEIN HORMONES

• Functions include:
– MAINTAINING the Pregnant state of the uterus

– STIMULATING LOBULOALVEOLAR Growth & function of Maternal Breasts

– Adapting aspects of Maternal METABOLISM & PHYSIOLOGY to support the growing fetus

– Regulating aspects of Fetal DEVELOPMENT

– Regulating the TIMING & PROGRESSION of PARTURITION

Question 27

Human Chorionic Gonadotropin (hCG)

Answer 27

• First hormone produced by the Syncytiotrophoblasts!!!!!!!

• Composed of a common α-GLYCOPROTEIN SUBUNIT (αGSU) & a Hormone-Specific β-subunit, β-hCG!!!!!!!
– ANTIBODIES used to DETECT hCG (as in laboratory assays & over-the-counter PREGNANCY TESTS) are designed to specifically DETECT the β-subunit!!!!!!!!!!

• Binds with HIGH AFFINITY to the LH receptor

• LONGER HALF-LIFE (up to 30 hr)
– Rapidly accumulate in the Maternal Circulation
– Detectable within Maternal serum within 24 hr of IMPLANTATION
– Serum hCG levels double every 2 days for the first 6 weeks until they PEAK AT about 10 weeks, Serum hCG THEN DECLINES to a Constant level

• Its PRIMARY ACTION is to STIMULATE LH Receptors on the CORPUS LUTEUM
– Prevents LUTEOLYSIS & maintains a HIGH level of luteal- derived PROGESTERONE production during the first 10 weeks
– The RAPID INCREASE in hCG is responsible for the nausea of MORNING SICKNESS

Question 28

Human Placental Lactogen (hPL)

Answer 28

• Also called Human Chorionic SOMATOMAMMOTROPIN!!!!
• Produced in the Syncytiotrophoblast; structurally similar to Growth Hormone (GH) & Prolactin (PRL)

• Can be detected within the Syncytiotrophoblast by 10 days AFTER CONCEPTION & in Maternal serum by 3 WEEKS of GESTATION
– Maternal serum levels RISE progressively throughout the REMIANDER of the Pregnancy

• Is Protein-Anabolic & Lipolytic
– Has Antagonistic action to Insulin, contributing to the DIABETOGENICITY of pregnancy
– INCREASES GLUCOSE Availability by inhibiting Maternal Glucose Uptake
– Its lipolytic actions help the mother to shift to the use of FREE FATTY ACIDS for Energy

Question 29

Progesterone

Answer 29

• Syncytiotrophoblasts express HIGH LEVELS of CYP11A1 (side-chain cleavage enzyme or CHOLESTEROL DESMOLASE) & a Placenta-Specific 3β-HYDROXYSTEROID DEHYDROGENASE type 1 (3β-HSD1) but DO NOT EXPRESS 17α-HYDROXYLASE / 17,20 Lyase / 17,20 DESMOLASE (CYP17) !!!!!!!!!!!
• Syncytiotrophoblasts also express LDL Receptors that import Cholesterol from the Maternal Blood

• Placenta PRODUCES a High amount of Progesterone, which is required to MAINTAIN a Quiescent Myometrium & a Pregnant Uterus
– Progesterone is RELEASED PRIMARILY into the Maternal Circulation

• Progesterone Production by the Placenta is largely Unregulated
– The placenta produces as much Progesterone as the supply of Cholesterol & the levels of Cholesterol Desmolase & 3β-HSD will allow

• Maternal Progesterone levels continue to INCREASE throughout Pregnancy

Question 30

Synchronization of the Human Menstrual Cycle with Fertilization & early Embryogenesis: A summary of events

Answer 30

• Just before Ovulation, the ovary is in the late follicular stage & PRODUCES HIGH LEVELS OF ESTROGEN
– Estrogen promotes GROWTH of the Uterine Endometrium & induces EXPRESSION of the Progesterone Receptor
– Estrogen ultimately INDUCES the LH SURGE, which Unduces MEIOTIC Maturation of the Oocyte & Ovulation of the CUMULUS-Oocyte complex

• The events between Fertilization & Implantation take ~ 6 days to complete, & Implantation occurs at ~ day 21 of the menstrual cycle
– The ovary is in the MIDLUTEAL phase; secretes large amounts of PROGESTERONE

Question 31

Synchronization of the Human Menstrual Cycle with Fertilization & early Embryogenesis: A summary of events CONT 1

Answer 31

• Progesterone STIMULATES Secretion from Uterine Glands, which provide nutrients to the EMBRYO (HISTOTROPHIC NUTRITION)
– Histotrophic Nutrition: important mode of maternal-to-fetal TRANSFER of Nutrients for about the 1st Trimester of Pregnancy, after which it is REPLACED by Hemotrophic Nutrition

• Progesterone INHIBITS Myometrial Contraction & Prevents the Release of PRARCRINE FACTORS that lead to Menstruation

Question 32

Synchronization of the Human Menstrual Cycle with Fertilization & early Embryogenesis: A summary of events CONT 2

Answer 32

• PROGESTERONE induces the “WINDOW OF RECEPTIVITY” in the Uterine ENDOMETRIUM, which exists from ~ day 20 – 24 of the Menstrual Cycle

– RECEPTIVE PHASE is associated with Increased Adhesivity of the Endometrial Epithelium & involves the formation of Cellular Extensions on the Apical Surface of Endometrial Epithelia, along with INCREASED Expression of ADHESIVE Proteins (e.g. integrins, cadherins) & DECREASED Expression of ANTIADHESIVE Proteins (e.g. mucins) in the Apical Cell Membrane

Question 33

Synchronization of the Human Menstrual Cycle with Fertilization & early Embryogenesis: A summary of events CONT 3

Answer 33

• During the time it takes a FERTILIZED Egg to implant in the Uterus, the Uterine Endometrium is at its FULL THICKNESS, actively Secretory, & capable of tightly ADHERING to the Implanting Embryo

• Uterine Endometrium is well VASCULARIZED at the time of Implantation
– SPIRAL ARTERIES extend to the Basal Lamina of the surface epithelium & give rise to RICH CAPILLARY BEDS & LACUNAE

– The Extensive Blood Supply immediately adjacent to the surface epithelium plays a CRITICAL ROLE in Capturing Embryonic hCG & Transporting hCG to the Ovary, where it RESCUES the Corpus Luteum

– Endometrial Blood Supply also is IMPORTANT for Efficient DELIVERY of Progesterone to the Endometrium

Question 34

During pregnancy, Progesterone & Estrogens rise to levels that are substantially HIGHER than their peaks in a normal cycle

Answer 34

• Maternal levels of Progesterone & Estrogens (estradiol, estrone, estriol) all INCREASE & reach concentrations substantially higher than those achieved during a normal menstrual cycle

• Elevated levels are NECESSARY for Maintaining Pregnancy
– Progesterone REDUCES Uterine Motility & INHIBITS propagation of CONTRACTIONS

Question 35

During pregnancy, Progesterone & Estrogens rise to levels that are substantially HIGHER than their peaks in a normal cycle CONT 1

Answer 35

• Elevated levels of female steroids achieved are achieved by:
– Early in the 1st trimester, hCG that is manufactured by the Syncytiotrophoblast rescues the Corpus Luteum, which is the major source of Progesterone & Estrogens
a) This function of the Corpus Luteum in the ovary continues INTO Early Pregnancy

b) By itself, the Corpus Luteum is NOT ADEQUATE to generate the very HIGH Steroid levels characteristic of LATE Pregnancy

– The developing Placenta itself augments its production of Progesterone & Estrogens, so by 8 weeks of Gestation, the Placenta has become the MAJOR SOURCE of these STEROIDS
a) The placenta continues to produce LARGE Quantities of Estrogens, Progestins, & other hormones throughout Gestation

b) ESTRIOL is a Major Estrogen during Pregnancy!!!!!!!!!

Question 36

The Maternal-Placental-Fetal unit

Answer 36

• After 8 weeks of Gestation, the coordinated biosynthetic activity of the Maternal-Placental-Fetal unit maintains HIGH levels of Progesterone & Estrogens
• The Placenta CANNOT Synthesize these hormones by ITSELF; it Requires the assistance of both Mother & Fetus

Question 37

The Maternal-Placental-Fetal unit CONT 1

Answer 37

• The placenta is an Imperfect Endocrine Organ
– CANNOT manufacture adequate Cholesterol

– LACKS 17α-HYDROXYLASE & 17,20- DESMOLASE activity that are Needed for synthesizing Estrone & Estradiol

– LACKS 16α-HYDROXYLASE that is needed to Synthesize ESTRIOL

• The Maternal-Placental-Fetal unit OVERCOMES these placental limitations in 2 ways:
1) Mother SUPPLIES most of the CHOLESTEROL as LDL particles!!!!!

2) Fetal Adrenal Gland & Liver SUPPLY the 3 Enzymes LACKING in the Placenta

Question 38

The Maternal-Placental-Fetal unit CONT 2

Answer 38

• The fetus DOES NOT Synthesize Estrogens WITHOUT assistance due to:

1) LACKS 3β-HYDROXYSTEROID DEHYDROGENASE (3β-HSD) & AROMATASE, which catalyze the last two steps in the production of Estrone, the precursor of Estradiol
• 3β-HSD & AROMATASE are also necessary to Synthesize Estriol

2) The fetus SHOULD NOT Synthesize Estrogens WITHOUT assistance
• If the fetus was able to due so, it would Expose itself to Dangerously HIGH Levels of hormones that are needed NOT by the fetus, but by the mother
– This is a problem that is OVERCOME by the Maternal- Placenta-unit

Question 39

The Maternal-Placental-Fetal unit CONT 3

Answer 39

• The Fetus & its Placenta use 3 strategies to solve the previous problem:
1) Since the fetus LACKS 3β-HSD & AROMATASE, it never makes anything beyond DEHYDROEPIANDROSTERONE (DHEA) & 16α-HYDROXY-DHEA
• CANNOT make Progesterone or any of the three key estrogens

2) The Placenta is a massive sink for the Weak Androgens that the Fetus does Synthesize, thus PREVENTING the Masculinization of Female Fetuses

3) The fetus CONJUGATES the necessary Steroid Intermediates to SULFATE, which greatly REDUCES their Biological Activity
• As Pregnenolone moves from the placenta to the fetus, it is Sulfated

• DHEA & 16α-hydroxy-DHEA are also Sulfated while in the fetus

• It is only when DHEA-S & 16α-hydroxy-DHEA-S move to the Placenta that a SULFATASE Removes the Sulfate Groups, & the
Placenta can COMPLETE the process of Steroidogenesis & can export the hormones to the Mother

Question 40

Maternal Response to Pregnancy

Answer 40

• Both Maternal CARDIAC OUTPUT & BLOOD VOLUME Increase during Pregnancy

– BLOOD VOLUME:
• Starts to Increase during the 1st Trimester, expands rapidly during the 2nd Trimester, rises at a much lower rate during the 3rd Trimester, & finally achieves a PLATEAU during the last several weeks of Pregnancy

• Blood volume SLOWLY Increases by 40–50%

• The Increase is mainly DUE TO an Increase in Plasma Volume through Increased ALDOSTERONE
– The RENIN-ANGIOTENSIN-ALDOSTERONE axis responds by Increasing Aldosterone, which augments Renal Reabsorption of Salt and Water

• It results in an Increase in Heart Rate (15 beats/min more than usual), Stroke Volume, & Cardiac Output

Question 41

Maternal Response to Pregnancy CONT 1

Answer 41

• Despite the Large Increase in Plasma Volume, MEAN ARTERIAL PRESSURE (MAP) usually DECREASES during Midpregnancy & then RISES during the 3rd Trimester, although it normally remains at or Lower than Normal
– The reason for this initial FALL in MAP is a DECREASE in Peripheral Vascular Resistance, possibly reflecting, in part, the vasodilating effects of Progesterone & Estradiol

– CARDIAC OUTPUT
• INCREASES appreciably during the 1st trimester of Pregnancy (by 35% - 40%), but it Increases only Slightly during the 2nd & 3rd Trimesters (∼45% at term)
• The Increase in Cardiac Output reflects mainly an INCREASE in STROKE VOLUME but also Heart Rate

Question 42

Maternal Response to Pregnancy CONT 2

Answer 42

• Increased levels of Progesterone during Pregnancy INCREASES ALVEOLAR VENTILATION
– Although pregnancy has little effect on Respiratory Rate, it Increases TIDAL VOLUME markedly—by ∼40%—& thereby Increases Alveolar Ventilation
a) These Increases are some of the Earliest physiological changes during Pregnancy, beginning 6 weeks after Fertilization

• They may reflect, at least in part, a DIRECT Stimulatory effect of Progesterone &, to a lesser extent, Estrogen on the Medullary Respiratory Centers

• GI TRACT CHANGES
– During pregnancy, woman can experience Nausea & Vomiting (morning sickness), which may be due to ELEVATED hCG & should resolve by 14 – 16 weeks!!!!!

– There is Prolonged GASTRIC EMPTY TIME, Decreased Gastroesophageal Sphincter Tone, which can lead to ACID REFLUX

– There is Decreased COLONIC MOTILITY, which leads to Increased Water Absorption & Constipation

– There are INCREASES in the demand for Dietary Protein, Iron, & Folic Acid

Question 43

Parturition

Answer 43

• Uterus is QUIET throughout pregnancy
– Progesterone & Relaxin may promote this INACTIVITY

• BIRTH PROCESS
– 38 weeks after fertilization (fetal age)
– 40 weeks after last menstrual period

• OBSTETRIC DEFINITION OF LABOR: a series of Regular, Rhythmic, & Forceful CONTRACTIONS that develops to facilitate Thinning & Dilation of the Cervix
– These contractions may last for Several hours, a Day, or even Longer & may eventually result in the EXPULSION of the FETUS, PLACENTA, & MEMBRANES

– Process that is NOT Completely Understood, but involves a combination of Mechanical & Hormonal factors

– Once labor is initiated, it is sustained by a series of POSITIVE FEEDBACK MECHANISMS

Question 44

Stages of labor

Answer 44

STAGE 0: Uterine TRANQUILITY and Refractoriness to Contraction

STAGE 1: Uterine AWAKENING, Initiation of Parturition, extending to Complete Cervical Dilation

STAGE 2: Active Labor, from Complete Cervical Dilation to DEVILRY of the Newborn

STAGE 3: From Delivery of the Fetus to EXPULSION of the Placenta and Final Uterine Contraction!!!!

Question 45

Fetus decides “day” of Parturition: Fetal HPA axis

Answer 45

• Signals from the Placenta & fetus may Initiate Labor:
1) Placenta produces CORTICOTROPIN-RELEASING HORMONE (CRH)

2) Placental CRH production & Maternal Serum CRH levels INCREASE Rapidly during late pregnancy & labor
3) Placental CRH also accumulates in the fetal circulaUon & stimulates FETAL ACTH secretion, which stimulates both fetal adrenal CORTISOL & Fetoplacental Estrogen Production
4) In CONTRACT to the Inhibitory effect of Cortisol on Hypothalamic CRH production, CORTISOL STIMULATES PLACENTAL CRH production (self-amplifying POSITIVE FEEDBACK loop)
5) CRH PROMOTES Contractions by Sensitizing Uterus to Prostaglandins & Oxytocin
6) Estrogens also stimulate contractions

Question 46

Increased Uterine Excitability

Answer 46

• Toward the end of Pregnancy, the uterus becomes progressively more excitable, until finally it develops such strong rhythmical contractions that the baby is EXPELLED
• Two major categories of effects lead up to the intense ContracUons:

1) Progressive HORMONE changes
2) Progressive MECHANICAL changes

Question 47

Hormonal Factors & Parturition

Answer 47

• ESTROGEN:
– INCREASES the degree of Uterine Contractility

– Both Estrogen & Progesterone are secreted in progressively LARGER amounts During pregnancy

– From the 7th month, estrogen continues to INCREASE while Progesterone remains constant

– Estrogen stimulates SYNTHESIS of Oxytocin Receptors

• PROSTAGLANDINS
– Believed to INITIATE labor

– Synthesis is stimulated by ESTROGEN from Arachidonic Acid in Fetal Membranes &by OXYTOCIN in Uterine cells

– Increase during Parturition; play a role in enhancing Motility/ Contraction of Uterine Smooth Muscle Cells
• Facilitate delivery
• The prostaglandins PGF 2α & PGE 2 INCREASE Uterine Motility; large doses of these compounds have been used to UNDUCE LABOR!!!!!!!!!!!

– Levels INCREASE in Uterus, Placenta, Amniotic fluid, fetal membranes before onset of LABOR

– Uterine STRETCH stimulates Uterine Prostaglandin PRODUCTION

Question 48

Hormonal Factors & Parturition CONT 1

Answer 48

• OXYTOCIN:
– Estrogen INCREASES the number of Oxytocin Receptors in the Myometrial & DECIDUAL
tissue of Pregnant Women
a) The Uterus actually remains INSENSITIVE to Oxytocin until ∼20 weeks of Gestation, at which time the number of Oxytocin receptors INCREASES to 80X higher than baseline values by ∼36 weeks of Gestation, plateaus just before Labor, then rises again to 200X during EARLY Labor

b) Whereas the uterus is SENSITIVE to Oxytocin only at the end of Pregnancy, it is susceptible to PROSTAGLANDINS throughout Pregnancy

– STIMULATES powerful Uterine Contractions that SUSTAIN LABOR
a) It is released in response to STRETCH of the Cervix (Ferguson reflex), & it stimulates Uterine ContracUons, thereby facilitating DELIVERY

b) However, INCREASED Oxytocin secretion does not initiate the Rhythmic Uterine contractions characteristic of the Onset of Labor
1) Oxytocin & Prostaglandins play an IMPORTANT role in Stimulating the Uterine Contractions that SUSTAIN Labor, however, ONLY PROSTAGLANDINS are believed to have a KEY ROLE in the Initiation of Labor

2) Once labor is initiated (stage 1), Maternal Oxytocin is released in BURSTS, & the Frequency of these Bursts INCREASES as labor progresses

– Also binds receptors on DECIDUAL CELLS, thereby stimulating PGF2 α Production!!!!
a) During the 2nd Stage of labor, Oxytocin release may play a Synergistic role in the EXPULSION of the Fetus by virtue of its ability to stimulate Prostaglandin Release

– Causes the Uterus to CONTACT IMMEDIATELY after the Fetus is EXPELLED, limiting Blood Flow & Blood Loss
a) During the 3rd Stage of labor, uterine contractions INDUCED by Oxytocin are important for constricting Uterine Blood vessels at the site where the Placenta used to be, thus promoting Blood Coagulation

b) Basal MATERNAL Plasma Oxytocin levels are UNCHANGED after Delivery
c) FETAL Plasma Oxytocin levels are HIGHER after VAGINAL Delivery than after delivery by Cesarean Section, presumably because the Maternal Oxytocin triggered by the FERGUSON REFLEX, Crosses the Placenta into the Fetus

Question 49

Hormonal Factors & Parturition CONT 2

Answer 49

• RELAXIN:
– Protein produced by the Corpus Luteum, Placenta, & the Decidua

– Keeps UTERUS QUIESCENT during Pregnancy

– Production & Release of RELAXIN INCREASES during Labor; may Soften & Dilates CERVIX DURING LABOR

Question 50

Effect of Fetal Hormones on the Uterus

Answer 50

• FETAL PITUITARY
– Secretes INCREASING quantities of OXYTOCIN, which
might play a role in exciting the uterus

• FETAL ADRENALS
– Secrete large quantities of CORTISOL, which could also be a Uterine Stimulant

• FETAL PLACENTAL MEMBRANES
– Release PROSTAGLANDINS in high concentration at
the time of labor
– Increase the INTENSITY of Uterine Contractions

Question 51

Mechanical Changes & Parturition

Answer 51

• Simply STRETCHING the Smooth Muscle organs INCREASES their CONTRACTILITY

• Fetal movements can Elicit Smooth Muscle CONTRACTIONS
– Twins are born, on average, 19 days earlier than a single child, which emphasizes the importance of Mechanical Stretch in starting Uterine CONTRACTION

Question 52

Contractions during Pregnancy, onset of Labor & during Labor

Answer 52

• Most of the pregnancy, the uterus undergoes Periodic episodes of Weak & Slow RHYTHMIC Contractions call BRAXTON HICKS CONTRACTIONS!!!!!!!!!!!!!!

• These Contractions become exceptionally STRONG during the last hours of the pregnancy
– The contractions start STRETCHING the cervix, & later FORCE the baby through the birth canal

– At this point, the contractions are called LABOR CONTRACTIONS

• Labor Contractions are thought to be mediated by POSITIVE FEEDBACK MECHANISM
– Stretching of the Cervix by the fetal head INCREASES the Contractility of the uterus; More stretch = more Contractions

Question 53

Positive Feedback Mechanism

Answer 53

• Once Labor is Initiated, several POSITIVE FEEDBACK LOOPS involving PROSTAGLANDINS and OXYTOCIN help to SUSTAIN it
• First, Uterine Contractions STIMULATE Prostaglandin Release, which itself INCREASES the Intensity of Uterine Contractions
• Second, Uterine Activity STRETCHES the Cervix, thus stimulating OXYTOCIN release through the FERGUSON REFLEX!!!!!!!!!!
• Because Oxytocin stimulates further Uterine Contractions, these contractions become SELF-PERPETUATING!!!!!

Question 54

Delivery Phases

Answer 54

• DILATION AND EFFACEMENT
– Effacement is the process by which the cervix PREPARES for Delivery
A) After the baby has engaged in the pelvis, it gradually drops closer to the cervix; the cervix will gradually Soften, Shorten & become Thinner (CERVICAL THINNING)

B) Effacement is measured in Percentages

i) 50%: patient is HALF WAY to being completely effaced
ii) 100%: cervix is PAPER-THIN & labor is right around the corner

– Contractions

Question 55

Some Complications of labor & Delivery

Answer 55

• PROLONGED LABER: labor lasting more than 18 – 24 hrs
– 2 Main Types: one when the LATENT PHASE of Labor is > 8 hrs & the other when the ACTIVE PHASE of Labor is > 12 hrs

– MAIN CAUSES INCLUDE: Poor uterine contractions, the baby’s Position or Size being abnormal, or issues with the pelvis or birth canal

• OBSTRUCTED LABOR OR LABOR DYSTOCIA:
– Even though the Uterus is contracting Normally, the baby does not exit the pelvis during childbirth due to being Physically BLOCKED

– MAIN CAUSES of obstructed Labor Include: a large or Abnormally Positioned Baby, a Small Pelvis, & problems with the birth canal

– It is said to result in PROLONGED LABOR

– Complications for the baby include not getting enough OXYGEN which may result in Death

– It INCREASES the risk of the mother getting an Infection, having Uterine Rupture, or having post-partum Bleeding

– Patient may require CESAREAN SECTION

Question 56

Some Complications of Labor & Delivery CONT 1

Answer 56

• PRETERM LABOR: Labor begins prematurely, before the 37th week of pregnancy
– Occurs in ~ 12% of all pregnancies

– Uterine Contractions cause the cervix to OPEN Earlier than Normal; baby is born Premature & can be at risk for health problems

– Possible Medical Risk Factors: Urinary Tract Infections, certain uterine or cervical abnormalities, Chronic Illness (e.g. high blood pressure, kidney disease, or diabetes), etc

– Possible Lifestyle Risk Factors: smoking, drinking alcohol, drug abuse, high levels of stress, etc

• RUPTURED UTERUS: Integrity of the myometrial wall is breached
– Spontaneous or Traumatic rupture
• Typically occurs during ACTIVE LABOR, but may also develop during late pregnancy

– Risk Factors/Causes: uterine scar from a previous C-section, Dysfunctional/ Prolonged labor, labor augmentation by Oxytocin or Prostaglandins, excessive Manual Pressure applied to the Fundus during delivery

– Signs & Symptoms: abdominal pain & vaginal bleeding, deterioration of the fetal heart rate (a leading sign), loss of fetal station on Manual Vaginal Exam (CARDINAL SIGN), intra-abdominal bleeding leading to hypovolemic shock, etc

Question 57

Some Complications of Labor & Delivery CONT 2

Answer 57

• PREECLAMPSIA:
-­ Occurs only during pregnancy; occurring after week 20 of pregnancy

­- Affects at least 5-8% of pregnancies

­- Characterized by HIGH BLOOD PRESSURE & Signs of damage to another organ system, often the KIDNEYS
a)­ Other symptoms include: PROTEIN IN URINE (proteinuria), & generalized EDEMA

-­ Left Untreated, it can lead to serious — even fatal — complications for BOTH the Mother & the Baby

­- There is NO definitive Known Cause of Preeclampsia, though it is likely related to a number of factors (e.g. abnormal Placentation, Immunologic Factors, prior or existing Maternal Pathology such as preexisting Hypertension, Obesity, & those with history of Preeclampsia

-­ Disease of the placenta might be involved: thought to be associated withLIMITED BLOOD SUPPLY to Uterine arteries, causing Ischemia & Endothelial damage with release of cytokines

­- The Placenta of Women with Preeclampsia is Abnormal & characterized by POOR TROPHOBLAST INVASION!!!!!

Question 58

Fetal Station

Answer 58

• Fetal Station refers to where the presenting part is in the pelvis
– PRESENTING PART: part of the baby that leads the way through the Birth Canal
a) Most often, it is the baby’s Head, but it can be a shoulder, the buttocks, or the feet

– ISCHIAL SPINES: Bone Points on the mother’s Pelvis
a) Normally the Ischial Spines are the NARROWEST part of the pelvis

– 0 STATION: when the baby’s Head is EVEN with the Ischial Spines
• The baby is said to be “ENGGED” when the largest part of the head has Entered the Pelvis

– If the presenting part lies ABOVE the Ischial Spines, the station is reported as a NEGATIVE number from -1 to -5

Question 59

The fundamental Secretory unit of the Breast is the Alveolus

Answer 59

• The breast consists of a series of Secretory Lobules, which empty into Ductules
– The DUCTULES from 15 – 20 lobules combine into a Duct, which widens at the Ampulla (a small reservoir)
– The LACTIFEROUS Duct carries the secretions to the outside

• Alveoli are organized into Lobules, each of which Drains into a Ductule
• Each Alveolus consists of secretory epithelial cells (ALVEOLAR CELLS) that secrete the milk, as well as Contractile Myoepithelial Cells, which are, in turn, surrounded by ADIPOSE CELLS

Question 60

Hormones affecting the Mammary Gland during Pregnancy & Breast-
feeding

Answer 60

• Breast development at Puberty depends on several hormones, but primarily on the ESTROGENS & PROGESTERONE
• During pregnancy, gradual increases in levels of PROLACTIN & HCS, as well as very HIGH levels of Estrogens & Progesterone, lead to full Development of the Breasts

• Hormones affecting the breast are:
1) MAMMOGENIC (promoting the proliferation of Alveolar and Duct Cells)

2) LACTOGENIC (promoting initiation of Milk Production by Alveolar Cells)
3) GALACTOKINETIC (promoting Contraction of Myoepithelial Cells, & thus Milk Ejection)
4) GALACTOPOIETIC (Maintaining Milk Production after it has been established)

Question 61

Epithelial Cells in the Alveoli Secrete the components of Milk by FIVE Major Routes

1) SECRETORY PATHWAY

Answer 61

­- The milk proteins LACTALBUMIN & CASEIN are synthesized in the ER & are sorted to the Golgi Apparatus

­- Alveolar cells add Ca2 + & Phosphate to the Lumen of the Golgi

-­ LACTOSE SYNTHETASE in the lumen of the Golgi catalyzes synthesis of Lactose
• Lactose Synthetase has 2 components, a Galactosyl Transferase & Lactalbumin

• ­ Water enters the secretory vesicle by Osmosis
• ­ Vesicle contents are emptied into Alveolar Lumen by Exocytosis

Question 62

Epithelial Cells in the Alveoli Secrete the components of Milk by FIVE Major Routes

2) TRANSCELLULAR ENDOCYTOSIS AND EXOCYTOSIS

Answer 62

-­ Maternal Immunoglobulins (primarily IGA) are taken up by Endocytosis through the Basolateral Membrane

­- These Immunoglobulins are then transported to the Apical Membrane & SECRETED via Exocytosis
• The GI tract of the infant TAKES UP these Immunoglobulins, which confers TEMPORARY IMMUNITY

Question 63

Epithelial Cells in the Alveoli Secrete the components of Milk by FIVE Major Routes

3) LIPID PATHWAY

Answer 63

­- Fats that predominate in Milk (longer chain fatty acids >16 carbons) originate from Diet or Fat Stores

-­ F.A. form Lipid Droplets (MILK LIPIDS) which move to Apical Membrane

­- As the Apical Membrane surrounds the Droplets & pinches off, it Secretes the Milk Lipids into the Lumen in a Membrane-bound Sac

Question 64

Epithelial Cells in the Alveoli Secrete the components of Milk by FIVE Major Routes

4) TRANSVELLULAR SALT ADN WATER TRANSPORT

Answer 64

­ - Various transport processes at the Apical & Basolateral membranes move Small Electrolytes from the Interstitial fluid into the Lumen of the Alveolus

­ - Water follows an Osmotic gradient generated primarily by LACTOSE (present at a final concentraUon of ∼200 mM) &, to a lesser extent, by the Electrolytes

Question 65

Epithelial Cells in the Alveoli Secrete the components of Milk by FIVE Major Routes

5) PARACELLULAR PATHWAY

Answer 65

­ - Salt & water can also move into the lumen of the alveolus through the Tight Junctions

­ - Cells, primarily Leukocytes, squeeze between cells & enter the MILK

Question 66

Lactation

DURING PREGNANCY

Answer 66

• DURING PREGNANCY:
– Prolactin (PRL) is secreted by Anterior Pituitary gland
during Pregnancy, which stimulates Milk Production

– However, despite the fact that PRL levels INCREASE 20 fold, the action of PRL is INHIBITED by HIGH ESTROGEN & PROGESTERONE levels during pregnancy

– HUMAN PLACENTAL LACTOGEN (also known as Human Chorionic Somatomammotropin) is also Lactogenic

– Towards End of Pregnancy, breasts are fully developed but milk production is Suppressed except for Small amount of COLOSTRUM

** COLOSTRUM is a thin, yellowish milk-like substance secreted the first few days after parturition; contains a High Concentration of Immunoglobulins

Question 67

Lactation

INITIATION OF LACTATION

Answer 67

• INITIATION OF LACTATION:
– Requires coordinated action of several Hormones/ Stimuli:
1) PROLACTIN ↑: Mammogenic, Lactogenic, Galactopoietic

2) ESTROGEN AND PROGESTERONE ↓:
– High Estrogen & Progesterone INHIBIT onset of Lactogenesis

– Initiating milk production necessitates the abrupt fall in estrogens & progesterone that accompanies Parturition

– Placental estrogens increase PRL secreUon during pregnancy • Suckling

3) SUCKLING
– Suckling is the MOST POWERFUL physiological stimulus for PRL Release
– INHIBITS Hypothalamic DOPAMINERGIC Neurons
– Primary neural stimulus Post-Parturition

Question 68

Suckling is required to Maintain Lactation

Answer 68

• PROLACTIN is the classic lactogenic hormone which INCREASES Milk Synthesis by mammary alveolar cells
– Structurally related to Growth Hormone

– Neural signals from SUCKLING feedback to the Hypothalamus to DECREASE Dopamine (Prolactin Inhibitory Factor or PIF) release

– This removes Inhibition & results in an Increase in Prolactin

– Feedback also Decreases release of GnRH with resulting Decreases in LH and FSH

– High levels of prolactin may lead to Lactational Amenorrhea

• ***** Actions of PRL on the mammary glands include:
  1) The Promotion of mammary growth (Mammogenic effect)

2) The Initiation of Milk Secretion (Lactogenic effect)
3) The Maintenance of Milk Production once it has been established (Galactopoietic effect)

• OXYTOCIN,which can promote Uterine Contraction, also enhances Milk Ejection (“let-down”) by stimulating the CONTRACTION of the network of Myoepithelial Cells surrounding the Alveoli & Ducts of the Breast (GALACTOKINETIC EFFECT)

• POSITIVE FEEDBACK by Suckling causes MORE Oxytocin to be Synthesized & Released

Question 69

Other hormonal notes…

Answer 69

• After birth, Estrogen & Progesterone levels DROP and milk is produced in 1-7 days
• PRL levels Return to normal after a few weeks if NO Breast- Feeding occurs
• With continued Breast-Feeding, PRL levels are maintain at a higher baseline level than in Non-Pregnant Females
• Each time an Infant Feeds, Neurohumoral Reflex leads to BURST of PRL Secretion

Question 70

Four effects of suckling on hormone release

Answer 70

1. SUCKLING STIMULI (Or Sight or Sound of Child): activates Afferent neural pathway from Breast to Spinal cord & then to the Hypothalamus
2. DOPAMINE (PIF) RELEASE IS INHIBITED from the Hypothalamus
   ­- Releases inhibition of
   Lactotrophs & results in release of Prolactin, which stimulates Milk PRODUCTION
3. Spinal cord neurons STIMULATE PRODUCTION AND RELEASE OF OXYTOCIN FROM POSTERIOR PITUITARY
   ­- Circulates to interact with receptors on myoepithelial cells of breast resulUng in “let- down” of milk

-­ NEGATIVE Maternal Emotions (Frustration, Anger, Anxiety) can INHIBIT Oxytocin Secretion & SUPPRESS Milk ejection reflex

4. Spinal Cord Neurons INHIBIT THE ARCUATE AND PREOPTIC AREA OF THE HYPOTHALAMUS CAUSING A FALL IN GnRH PRODUCTION
   - ­ Results in decreased release of LH & FSH and INHIBITS THE OVARIAN CYCLE!!!!!!!!

Question 71

Immunology

Answer 71

• Infant Immune System is IMMATURE at Birth
• In Utero, transfer of Antibodies across Placenta
• This protection Tapers off quickly after Birth

• Breast milk contains a number of different agents to protect the infant:
– Secretory IGA
– WBCs: Neutrophils & Macrophages
– Growth Factors: EGF (epidermal growth factor), NFG (nerve growth factor), IGF (insulin-like growth factor)