CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT

Spontaneous, cyclical ovulation: almost 40 years Granulosa cells: Exclusive site of FSH receptor
- 400 opportunities for pregnancy expression
Decidua – transformed myometrium Estrogen Rise in proportion to growth of dominant follicle and to
increase in number of granulosa cells
OVARIAN-ENDOMETRIAL CYCLE 95% of plasma estradiol is secreted by dominant follicle
Hypothalamic-pituitary-ovarian-axis: LH Thecal cells respond to LH
- Pituitary: FSH and LH In late follicular phase, stimulates thecall cell production
- Ovarian sex steroids: estrogen and progesterone of androgens, particularly androstenedione
Average cycle: 28 days Progesterone Secreted by preovulatory granulosa cells after
- 25-32 days appearance of LH
- Follicular and Proliferative phase – phase-length variation Inhibin B In early follicular phase, granulosa cells produce inhibin
- Luteal and secretory phase – constant at 12-14 days B
Inhibits FSH release
Cohort
- Group of antral follicles
- Begin semisynchronous growth during FSH rise in late luteal phse of
previous cycle
- Selection window – FSH increase leading to further follicular development
- Only follicles progressing to this stage develop capacity to produce
estrogen
o Increase FSH receptors → cytochrome w/in granulosa cells have
cytochrome P450 aromatase → converts androstenedione to
estradiol
- Follicle most responsive to FSH is first to produce estradiol and expression
of LH
- Fall in FSH is responsible for failure of other follicles (due to inhibin)
Granulosa Cells Thecal cells
FSH receptors LH receptors
Estrogen Androstenedione
Progesterone
Inhibin B

Ovulation
- Gonadotropin surge from increasing estrogen secretion
- 34-36 hours before ovum release
- LH secretion peaks 10-12 hours before ovulation
o Stimulates resumption of meiosis
Ovarian Cycle
o Releases first polar body
Follicular Phase
- Expansion – mediated by GDF9 and BMP 15
Number of oocytes/follicles o Activates genes to form hyaluronan-rich ECM by cumulus complex
At birth Onset of Puberty Released in female o Cumulus cells lose contact w/ one another
reproductive life o 20-fold augmentation in volume
2 million 400,000 400 o Coincides w/ LH—induced remodeling
- 1000 follicles are depleted per month until age 35 o Allows release of mature oocyte
o Accelerates after this age
Follicular development: Luteal Phase
1. Primordial follicles undergo gonadotropin-independent recruitment Corpus luteum
from resting pool - Develops from Graafian follicle by luteinization
2. Primary follicle o Cells undergo hypertrophy to increase capacity to synthesize
3. Secondary follicle hormones
4. Antral follicle - Basement membrane separating granulosa-lutein and theca-lutein breaks
GDF9 and BMP-15 down
- TGF-B family - Day 2 postovulation: blood vessels and capillaries invade granulosa cell
- Regulators of granulosa cell proliferation and differentiation layer
- Stabilize and expand cumulus oocyte complex - Regress 9-11 days after ovulation
- Produced LH Primary luteotropic factor
by oocytes Extend life luteal life span by 2 weeks
Thecal cells – Progesterone Increased production by granulosa-lutein cells
from surrounding From blood-borne LDL
stromal cells Peaks at 25-50 mg/d in midluteal phase
Continued production in pregnancy due to hCG
Estrogen After ovulation, levels decline
Secondary rise: peak 0.25 mg/d in midluteal phase
Drops again at end of luteal phase

FSH Develops antral follicles ESTROGEN AND PROGESTERONE ACTION

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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
Hormone Description Secreted by Receptors - Fewer microvilli and cilia
17-B estradiol Most biologically Granulosa cells ERa - Luminal protrusions appear on the apical surface
potent of dominant ERB Spiral arteries
follicle and - Lengthen at a rate greater than rate of endometrial thickening → obliges
luteinized coiling
granulosa cells
Progesterone Endometrial glands and stroma have PR-A Menstruation
different expression of receptor PR-B Midluteal-secretory phase
patterns that vary during menstrual GPCR - Critical branch point
cycle Ca++ - w/ Luteolysis and declining luteal progesterone → mens inititated
Late premenstrual-phase endometrium:
- Stroma is invaded by neutrophils → creates pseudoinflammatory
appearance
o Infiltrate on the day or two immediately preceding menses onset
o IL-8 – chemotactive activating factor
- MCP-1 – synthesized by endometrium
o Promotes monocyte recruitment
Leukocyte infiltration
- Key to matrix breakdown and repair
- “Inflammatory tightrope” – ability of macrophages to assume phenotypes
that vary from proinflammatory and phagocytic to immunosuppressive and
reparative
- MMPs from WBC – add to proteases already produced by stroma
ENDOMETRIAL CYCLE Vascular alterations:
Proliferative Phase - Spiral artery coiling becomes sufficiently severe → resistance to blood
Endometrium flow rises → hypoxia
- Lining of glands: Epithelial cells - Stasis – primary cause of endometrial ischemia and tissue degeneration
- Supported by stromal cells and blood vessels - Vasoconstriction precedes menstruation → limits blood loss
o Replicate rapidly and cyclically PGF2a Progesterone
- Superficial – functionalis layer - Induces spiral artery - Increases COX-2
- Deeper – basalis layer vasoconstriction → upper zones expression
Endometrial recovery become hypoxic - Lowers PGDH
- Follicular phase estradiol is the most important factor – ERa and ERB - Mediates myometrium contractions expression – degrades
- Reepithelialization begins even before menstrual bleeding has ceased and uterine ischemia causing pain prostaglandin
- 5th day LMP: epithelial surface has been restored and revascularization Actual menstrual bleeding
begun - Rupture of spiral arterioles and consequent hematoma formation
- Dependent on estrogen and TGFa - Hematoma → superficial endometrium distends and rupture
Preovulatory endometrium - Fissures develop → blood and tissue fragments are sloughed
- Proliferation of glandular, stromal and vascular endothelial cells - Hemorrhage stops with arteriolar constriction
- Usually <2mm thick - Partial necrosis also seal vessel tips
- Glands – narrow, tubular structures with straight and parallel course Endometrial surface restoration
- 5th day of cycle: Mitotic figures are identified - Growth of flanges or collars → epithelial continuity reestablished by fusion
o Persists until day 16 and 17 (2-3 days after ovulation) of edges
Late proliferative phase
- Enometrium thickens from glandular hyperplasia and augmented stromal DECIDUA
ground substance Decidual structure
- Glands 1. Decidua basalis – directly beneath the blastocyst
o In functionalis: widely separated 2. Decidua capsularis – overlies enlarging blastocyst
o In basalis: more crowded a. Separates conceptus from uterine cavity
Midcycle as ovulation nears b. Most prominent during 2nd month of pregnancy
- Glandular epithelium becomes taller and pseudostratified c. Internally it contacts fetal membrane – chorion leave
- Surface acquire numerous microvilli and develop cilia 3. Decidua parietalis – remainder
Decidua vera
Secretory Phase - By 14-16th week expanding sac completely fills the cavity
- Responds to rising progesterone level in highly predictable manner - Apposition of decidua capsularis and decidua parietalis
- Day 17: glycogen accumulates in the basal portion
- Day 18: Vacuoles move to the apical portion of nonciliated cells
- Day 19:
o secrete glycoprotein and mucopolysaccharide contents
o Mitosis ceases d/t rising progesterone (antagonistic)
o Estradiol action diminishes → expression of type 2 isoform 17-B
hydroxysteroid dehydrogenase (main product: estrone)
- Day 22-25: stromal cells enlarge, mitosis becomes apparent
- Days 23-28: Predecidual cells (surround spiral arterioles)
Predicidual transformation
- Days 22 to 25 - Glands – w/ extensive coiling Early pregnancy: Decidua thickens
- Upper 2/3 of functionalis layer - Luminal secretions become Later: Decidua becomes thinner
visible 3 layers of DP and DB:
Windows of implantation: days 20-24
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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
1. Zona compacta – surface or compact zone
2. Zona spongiosa – spongy zone w/ remnants of glands and small blood
vessels
3. Zona basalis – basal zone
a. Remains after delivery
Zona functionalis – both zona compacta and spongiosa
IMPLANTATION AND EARLY TROPHOBLAST TRANSFORMATION
Overview:
- Maternal blood – spurs from uteroplacental vessels into placental
intervillous space
o Bathes outer syncytiotrophoblast
o Allows exchange w/ fetal capillary blood w/in each villus
- Juxtaposition of maternal decidual parietalis and chorion leave – paracrine
system

FERTILIZATION
With ovulation:
- Secondary oocyte and adhered cells are freed
- Oocyte is engulfed by fallopian tube infundibulum
- Further transport is thru cilia and tubal peristalsis
Fertilization
- Normally in the oviduct
- Must take place w/in a few hours and no more than a day after ovulation
- Almost all pregnancies occurs during the 2 days preceding or on the day of
ovulation
- Spermatozoa must pass into zona pellucida and into oocyte cytoplasm
Decidual reaction - Fusion of two nuclei creates a zygote
- Completed only with blastocyst implantation Clinical pregnancy
- Predecidual changes – in midluteal phase - Calculated by LMP
- Spread in waves and then from implantation site - 1 week postfertilization = 3 weeks from the LMP
Stromal cells Zygote
- Enlarge and form polygonal or - Diploid cell → cleavage → blastomeres
round decidual cells o Continue to be surrounded by zona pellucida
- Nuclei – vesicular - Cleavage for 3 days while in fallopian tube
- Cytoplasm clear to basophilic - Morula – mulberry-like ball of cells
w/ transluscent membrane o Enters uterine cavity 3 days after fertilization
Blood supply - Blastocyst – accumulation of fluid between morula cells
- Lost in decidua capsularis
- In decidua basalis, spiral arterioles/arteries are invaded by trophoblasts
o No smooth muscle or endothelial cells remain
o As a result are unresponsive to vasoactive agents
- Fetal chorionic vessels – contain smooth muscle and thus respond to
vasoactive agents

DECIDUAL HISTOLOGY
Zona Spongiosa Decidua basalis
- Distended glands w/ marked - Contributes to formation of
hyperplasia placental basal plate
- Minimal stroma - Spongy zone – consists of
- Glands are lined by typical arteries and dilated veins
cylindrical epithelium w/ - By term, glands have
abundant secretory activity disappeared
- Glandular elements disappear - Invaded by many trophoblasts
later on and giant cells
Nitabuch layer Rohr stria
- Zone of fibrinoid degeneration - More superficial deposition of BLASTOCYST
- Invading trophoblast meet the fibrin surrounding anchoring - 4-5 days after fertilization: 58 cell blastula → five-embryo producing
decidua basalis villi cells (inner cell mass)
- In placenta accrete – absent o Trophoectoderm – 53 outer cell mass → Trophoblast
Necrotic decidua True decidual cells 107-cell blastocyst
- Normal in 1st and 2nd trimester - Differentiated from endometrial - 8 formative embryo-producing cells
- Should not be interpreted as stromal cells - 99 trophoblastic cells
pregnancy loss - Released from zona pellucida
Lymphocytes o Allows blastocyst-produced cytokines and hormones to influence
- Essential to evoke tolerance and invasion and vasculogenesis endometrial reactivity
- Treg cells LIF and follistatin – promote differentiation of endometrial epithelial and stroma
- Decidual macgrophages
- Decidual NK cells IMPLANTATION
- 6-7 days after fertilization: blastocyst implants into uterine wall
DECIDUAL PROLACTIN 3 phases:
- Present in enormous amounts in amniotic fluid 1. Apposition – initial contact
- 20-24 weeks’ gestation: 10,000 ng/mL in amniotic fluid 2. Adhesion – increased physical contact
- Fetal serum levels: 350 ng/mL 3. Invasion – penetration and invasion of trophoblasts
- Maternal serum levels: 150-200 ng/mL Requires receptive endometrium
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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
- Primed estrogen and progesterone by corpus luteum
- Limited to days 20 to 24 of the cycle
At the time of its interaction – blastocyst is composed of 100-250 cells
- Apposes most commonly on upper posterior uterine wall
CAMs
- Integrin – mediate cell adhesions
o Required in successful adhesion
o Hormonally regulated

TROPHOBLAST DEVELOPMENT
Trophoblast Chorion is composed of:
- Invasiveness promotes implantation - Trophoblast
- Nutritional role - Mesechyme → eventually condense to form body stalk
- Endocrine organ function o Joints embryo to the nutrient chorion
8th day postfertilization: Trophoblast differentiates into: o Later becomes umbilical cord
- Syncytiotrophoblast – outer multinucleated syncytium o At the caudal end of embryonic disc
- Cytotrophblast – inner germinal layer 12 days after conception:
Trophoblast further differentiates: - Syncytiotrophoblast is permeated by intercommunicating channels of
- Villous trophoblast – generate chorionic villi trophoblastic lacunae
- Extravillous trophoblast – migrate into decidua and myometrium and also o After invasion of decidual capillary walls, lacunae become filled w/
penetrate maternal vasculature maternal blood
o Interstitial trophoblasts – invade decidua and penetrate myometrium - Decidual reaction intensified – stromal cell enlargement and glycogen
▪ Forms placental-bed giant cells storage
▪ Surrounds spiral arteries
o Endovascular trophoblasts - penetrate spiral artery lumens CHORIONIC VILLI

EARLY INVASION
9th day: Blastocyst wall facing the uterine lumen – single layer of flattened cells
10th day: Blastocyst becomes totally encased w/in
- Wall opposite uterine lumen is thicker and composed of 2 zones:
o Trophoblast Primary villi
o Embryo-forming inner cell mass - Arise from buds of cytotrophoblast that protrude into the primitive
7 ½ days postfertilization: syncytium before 12 days
- Inner cell mass or embryonic disc differentiates into primitive ectoderm and - Composed of cytotrophoblast core covered by syncytiotrophoblast
endoderm - As lacunae join, complicated labyrinth is formed partitioned by
- Small cells b/n embryonic disc and trophoblast will become amnionic cytotrophoblastic columns → form intervillous space
cavity o Solid columns form primary villous stalks
Secondary villi
- Mesenchymal cords from extraembryonic mesoderm invade solid
trophoblast columns
- 12th day after fertilization
Tertiary villi
- Once angiogenesis begins in the mesenchymal cords
15th day Maternal blood enters intervillous space
17th day Fetal blood vessels are functional and placental circulation is
established
Fetal-placental circulation
- Completed when blood vessels of the embryo are connected w/ chorionic
vessels
Extraembryonic mesenchyme
- Hydatidiform mole – angiogenesis fails from lack of circulation
- Groups of isolated cells w/in blastocyst cavity
Villi
- Later mesoderm completely lines this cavity
- Outer layer of syncytiotrophoblast
o Spaces form then fuse w/in mesoderm → form chorionic cavity
- Inner layer of cytotrophoblast aka Langhans cells
(extraembryonic coelom)
o Proliferation produces trophpoblastic cell columns → forms
anchoring villi
▪ Not invaded by fetal mesenchyme
▪ Anchored to basal plate

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Base of intervillous space Base of chorionic plate ENDOMETRIAL INVASION
Faces maternal side Roof of intervillous space Extravillous trophoblasts
Consists of: Consists of: - Highly invasive – occurs under hypoxic conditions
- Cytotrphoblasts, - 2 layers of trophoblasts - Secretes proteolytic enzymes and activates proteinases
- Covering syncytiotrophoblast, externally - Produces urokinase-type plasminogen activator → degrades MMPs
- Maternal decidua of basal plate - Fibrous mesoderm internally o Regulated by pro- and antiinvasive factors
“Definitive” chorionic plate Proinvasive Antiinvasive
- Formed by 8-10 weeks as amnionic and primary chorionic plate Insulin-growth factor II Insulin-like growth factor binding-
mesenchyme fuse Low estradiol in 1st trimester protein type 4
Microscopic structures of placenta: Rise of estradiol in 2nd trimester
- Pinocytic vacuoles and vesicles – absorption and secretory fxns
- Microvilli – increase surface area in direct contact w/ maternal blood SPIRAL ARTERY INVASION
o Defining characteristic of a hemochorial placenta - Extensive modification of maternal vasculature by trophoblast occurs in the
first half of pregnancy
- Integral to pathological conditions:
o Preeclampsia
o FGR
o Preterm birth
Carried out by two populations of extravillous trophoblasts:
Interstitial trophoblasts Endovascular trophoblasts
Surrounds spiral arteries Penetrates spiral-artery lumen
Vessel preparation for endovascular Destroys vascular endothelium via
trophoblast invasion apoptosis and modify vascular
media → fibrinoid material replaces
smooth muscle
Must migrate against arterial flow;
involves only spiral arteries not
PLACENTA AND CHORION veins
CHORION DEVELOPMENT Uteroplacental development proceeds in two waves:
- Villi: Distributed over entire periphery of chorionic membrane in early 1. Before 12 weeks: Spiral arteries are invaded and modified b/n
pregnancy decidua and myometrium
- As blastocyst and trophoblast grows: 2. Between 12-16 weeks: Some invasion of intramyometrial segments
o One pole faces endometrial cavity of spiral arteries
o Opposite pole will form placenta → chorionic villi in contact w/ a. Remodeled into dilated, low-resistance vessels
decidua basalis form chorion frondosum or leafy chorion 1 month after conception
- Blood supply to chorion facing endometrial cavity is restricted - Maternal blood enters intervillous space in fountain-like bursts
o Villi in contact w/ decidua capsularis degenerate → chorion leave or o Directly bathes syncytiotrophoblast
smooth chorion
▪ Composed of cytotrophoblasts and fetal mesodermal VILLUS BRANCHING
mesenchyme - Most villi arborize and end freely w/in intervillous space
- Short, thick early stem villi → progressive finer subdivisions and greater
numbers
- Cotelydon/placental lobule – consists of truncal or main stem villi and their
ramifications
o Each lobule has a single vein
o Functional units of placental architecture

PLACENTAL GROWTH AND MATURATION

1st trimester Placental growth > fetal growth
17th weeks’ AOG Placental weight = fetal weight
Term Placental weight is 1/6 of fetal weight
Until end of 3rd month: Lobes
- Chorion Laeve is separated from amnion by exocoelomic cavity - 10-38
- Incompletely separated by grooves of variable depth
REGULATORS OF TROPHOBLAST INVASION - Total numbers remain the same but individual lobes continue to grow
Population Function throughout pregnancy
dNK 70% in 1st Invasion of trophoblast IL-8 and interferon- Changes in villi:
trimester inducible protein-10 1. Volume and prominence of cytotrophoblast decrease as terminal
Spiral artery VEGF PIGF ramifications of villi become more numerous and smaller
remodeling 2. Fetal vessels become more prominent and lie closer to surface as
Phagocytes cell debris syncytium thins
Decidual 20% in 1st Counter M2- 3. Villous stroma becomes denser and cells are more spindly and
macroph trimester proinflammatory immunomodulatory closely packed
age response phenotype 4. Villous stroma is infiltrated with Hofbauer cells, fetal macrophages
Promotes tissue repair a. Mediators of protection of maternal-fetal interface
b. Immunosuppressive and paracrine regulation of
trophoblastic functions
T regs Promotes immune
c. Zika virus can infect this cell
tolerance
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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
5. By 16 weeks gestation: Apparent continuity of cytotrophoblast is BREAKS IN PLACENTAL “BARRIER”
lost - Best exemplified by erythrocyte D-antigen alloimmunization
Improves transport and exchange: Decreases placental exchange - Fetal cell admixtures are small in most cases
1. Thinner syncytiotrophoblast efficiency: - Fetal cells can also engraft in mother → microchimerisms
2. Reduced cytotrophoblast 1. Thickening of basal lamina of o Implicated in disparate female:male ratio of autoimmune disorders
number trophoblast or capillaries
3. Decreased stroma 2. Obliteration of certain fetal FETAL-MATERNAL INTERFACE
4. Incrased number of capillaries vessels Immunogenicity of the Trophoblasts
3. Greater villous stroma - Trophoblastic cells – only fetus-derived cells in direct contact w/ maternal
4. Fibrin deposition on villous tissues and blood
surface - MHC class I and II antigens are absent from villous trophoblasts
PLACENTAL CIRCULATION o Immunologically inert at all gestational stages
Section through - Invasive extravillous cytotrophoblasts express MHC class I molecules
placenta includes: o Expression of classic HLA-C and nonclassic class 1b HLA-E and
1. Amnion HLA-G
2. Chorion HLA-G
3. Chorionic - Expression restricted to extravillous cytotrophoblasts
villi - Embryos do not implant if they do not express HLA-G
4. Intervillous - Protects from rejection from dNK
space - Abnormal: preeclampsia
5. Decidual dNK cells
(basal) - Unique expression of 3 specific HLA class I genes
plate - Acts in concert to permit and subsequently limit trophoblastic invasion
6. Myometrium
Decidual Immune Cells
Fetal Circulation NK cells
1. Deoxygenated fetal blood flows to placenta through two umbilical arteries - Predominant population of leukocytes in midluteal phase endometrium and
2. Umbilical vessels branch repeatedly and form capillary networks in decidua throughout 1st trimester
terminal villous branches - Regulates invasion
3. Blood w/ higher oxygen content returns via single umbilical vein to fetus - High surface density of CD56 or neural cell adhesion molecules
- Infiltration increased by progesterone, stromal cell IL-16, and decidual
Placental surface or chorionic vessels – branches of umbilical vessels that prolactin
traverse along fetal surface of the placenta in chorionic plate - Not cytotoxic
- Responsive to vasoactive substances Decidual macrophages
- Chorionic arteries always cross over chorionic veins - Express complement receptor CD11
Truncal arteries – perforating branches of surface arteries that pass through - Regulate adaptive T cell responses; controls dNK differentiation,
chorionic plate activation, and cytotoxicity, produces anti-inflammatory fcyokines
- Supplies one cotyledon Dendritic cells
- Loses smooth muscle and caliber increases as it penetrates chorionic - Presents antigen to T cells
plate - Important role in development of receptive endometrium for implantation
Before 10 weeks’ gestation: No end-diastolic flow pattern w/in umbilical artery Maternal T cells
After 10 weeks: End diastolic-flow appears - T regs protect against immune responses
o FOXP3+ cells with defined fetal specificity
Maternal Circulation - Immunosuppressive
1. Maternal blood enters through basal plate driven up by arterial pressure
2. Laterally disperses and bathes external microvillous surface of chorionic AMNION
villi At term, amnion:
3. Drains back through venous orifices - Tough, tenacious pliable membrane
Generally: - Provides almost all tensile strength to fetal membranes → resilience is
Spiral arteries – perpendicular to Spiral veins – parallel to uterine important to successful pregnancy
uterine wall wall o Premature rupture – major cause of preterm delivery
- Arrangement aids closure of veins during uterine contraction 5 layers of amnion:
o Prevents exit of maternal blood from intervillous space 1. Inner surface – bathed by amnionic fluid; simple cuboidal epith
- There are 120 spiral arteries at term 2. Basement membrane
After 30th week 3. Acellular compact layer – consists of interstitial collagens
- Venous plexus lies b/n decidua basalis and myometrium 4. Fibroblast-like mesenchymal cells = widely dispersed at term
o Helps develop cleavage plane needed for placental separation 5. Acellular zona spongiosa – outermost; contiguous with chorion leave
During uterine contraction
- Placental length, thickness, and surface area grew AMNION DEVELOPMENT
o Due to impairment of venous outflow 7th-8th day: amnion is first identifiable
o Rate of flow is decreased but larger volume of blood Is available for - Initially minute vesicle → into small sac that covers dorsal embryo surface
exchange → gradually engulfs embryo
Principal factors regulating intervillous space blood flow End of first trimester:
1. Arterial blood pressure - Apposition of chorion leave and amnion → obliterates extraembryonic
2. Intrauterine pressure coelom
3. Uterine contraction pattern o Can be separated easily
4. Factors that act specifically on arterial walls - Placental amnion – covers placental surface and is in contact w/ adventitial
surface of chorionic vessels
- Umbilical amnion – covers umbilical amnion
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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
Until about 34 weeks’ gestation:
- Normally clear fluid increases in volume
- After this, volume declines
At terms: Fluid averages 1000 mL
AMNION CELL HISTOGENESIS
Epithelial cells
- Derive from fetal ectoderm
- HLA class I gene expression is
more akin to embryonic cells
- Replicates faster than
mesenchymal cells early at
pregnancy
- At term, forms continuous
uninterrupted surface
UMBILICAL CORD
- Embryo – flattened disc between amnion and yolk sac
o Dorsal surface – grows faster than ventral surface
▪ Embryo bulges into the amnion sac
▪ Dorsal part of yolk sac – incorporated into embryo body to form
the gut
Fibroblast-like mesenchymal layer ▪ Allantois – projects into the base of body stalk → forms anterior
- From embryonic mesoderm wall of hindgut
- Early on, it lies immediately
adjacent to basal surface of
amnion epithelium → amnion
surface is two-cell layer
- With growth, collagens are
deposited between the layers
→ forms amnion compact
layer
- Reduced compactness due to
aminonal sac expansion →
becomes sparsely distributed

Amnion Epithelial Cells

- Apical surface: replete w/ highly developed microvilli
o Major site of transfer b/n amniotic fluid and amnion
- Synthesizes: MMP-1, PGE2, and fFN; IL-8 during labor initiation
o fFN – promotes synthesis of MMPs that:
▪ Breakdown strength-bearing collagens and
▪ Enhance prostaglandin synthesis
o Pathway is upregulated in premature rupture of membranes
- Responsive to oxytocin and vasopressin: increases PGE2
- Also synthesizes
o Endothelin And parathyroid hormone-related protein
o BNP and CRH – invoke smooth muscle relaxation
▪ Epidermal growth factor – negative regulator of BNP;
upregulated in membranes at term Pregnancy advances:
- Yolk sac becomes smaller
Amnion Mesenchymal cells - Middle of 3rd month: Expanding amnion obliterates extraembryonic
Synthesis of: coelom and covers bulging placental disc and covers body stalk
- Interstitial collagens – compose compact layer o Latter is then called umbilical cord or funis
o Major source of tensile strength
- Cortisol by 11B-hydroxysteroid dehydrogenase at term → membrane
rupture via reduction of collagen abundance
- IL-6, IL-8, MCP-1 – rise in response to bacterial toxins and IL-1
- PGE2 – greater source than epithelial cells

TENSILE STRENGTH
Almost exclusively resides in the compact layer composed of:
- Collagens I and III – mostly
- Collagens V and IV – lesser At term the cord:
- Has two arteries and one vein
Collagen I Collagen III
o Right umbilical vein disappears early
- Greater tensile - Tissue integrity; tissue extensibility and tensile
- From fetal umbilicus to fetal surface of placenta (chorionic plate)
strength strength
Blood flow:
- Bone and - In elastic tissues: amnionic sac, blood vessels,
- From umbilical vein:
tendon urinary bladder, bile ducts, intestine, gravid
1. Ductus venosus → into verior vena cava
uterus
2. Smaller openings into hepatic circulation → hepatic vein → inferior
Amnion tensile strength vena cava
- Regulated by fibrillar collagen assembly
- To umbilical arteries:
o Influenced by interaction fibrils w/ proteoglycans
1. From anterior Internal iliac artery → becomes medial umbilical
▪ Reduction in proteoglycans – perturb fetal function ligaments
- Membranes overlying cervix – shift in gene expression and lymphocyte
activation → inflammatory cascade → loss of tensile strength PLACENTAL HORMONES
METABOLIC FUNCTIONS - Steroid protein hormones by human trophoblasts is greater in amount and
- Solute and water transport diversity than any single endocrine tissue
- Produces bioactive compounds
- Responsive to acute and chronic mechanical stretch – triggers autocrine HUMAN CHORIONIC GONADOTROPIN
and paracrine responses (MMP, IL-8, collagenase) Biosynthesis
- Highest carbohydrate content of any hormone (30%)
o Terminal sialic acid – protects molecule from catabolism
o 36-hour plasma half-life (LH = 2h)
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- Made of two dissimilar subunits High levels of hCG Low levels of hCG
o Isolated subunits lack biological activity Multifetal pregnancy Early pregnancy
- Produced almost exclusively in placenta; low levels from fetal kidneys Erythroblastosis fetalis – fetal Ectopic pregnancy
- Structurally similar to: LH, FSH, and TSH hemolytic anemia
o Common a-subunit Gestational trophoblastic disease
a-subunit B-subunit Down syndrome
Chromosome 6 – single gene Chromosome 19 – 7 genes
Found in placental tissue and Low to undetectable throughout HUMAN PLACENTAL LACTOGEN
maternal plasma; levels rise pregnancy Biosynthesis
gradually and steadily - Aka chorionic growth hormone
Plateau at 36 weeks’ gestation – - hPL and hGH are strikingly similar (96%)
account for 30-50% of hormone - Chromosome 17 – five genes
Secretion roughly corresponds to - Concentrated in syncytiotrophoblasts but demonstrated in cytotrophoblast
placental mass before 6 weeks
Synthesized as larger precursors → cleaved - Secretion rate is proportional to placental mass
Before 5 weeks 5-10 days after conception: hPL is demonstrable in placenta
- Expressed both in synyctiotrophoblast and cytotrophoblast 3 weeks Detected in maternal serum
- Later in 1st trimester: produced almost solely in syncytiotrophoblast Near term *Production rate 1g/d
Complete hCG molecules: maximal at 8-10 weeks Half-life 10-30 minutes
Late pregnancy, maternal 5-15 ug/mL
Concentrations in Serum and Urine conc’n
Detectable (Plasma) Doubling time: *Greatest of any known hormones
7-9 days after midcycle LH surge 2 days
Peak plasma levels: Peak: Metabolic Actions
50,000 to 100,000 mIU/mL 8-19 weeks’ gestation 1. Promotes maternal lipolysis with increased FFA levels
Decline: Nadir: 2. Inhibits leptin secretion
10-12 weeks’ gestation 16 weeks 3. Aid maternal adaptation to fetal energy requirements
Pattern of hCG appearance in fetal blood: similar to that in mother a. Increased maternal insulin resistance
- Levels only about 3% in maternal plasma 4. Angiogenic hormone
- Amnionic fluid hCG concentration early = similar to mother
o Declines as pregnancy progresses OTHER PLACENTAL HORMONES
o 20% of maternal plasma – near term Analogous to hypothalamic or pituitary hormones – not subject to feedback
Maternal urine: inhibition
- Principal urinary form is terminal product B-core fragment Hypothalamic-Like Releasing Hormones
o Peaks at 10 weeks’ gestation Hormone Fetal effects Maternal
o B-subunit Antibody: Reacts w/ intact intact hCG and with fragments of Effects
hCG GnRH – highest In Regulate Cause of
expression 1st cytotrophoblasts trophoblast hCG elevated
hCG Regulation trimester and trophoblast maternal GnRH
- Placental GnRH – receptors expressed by cytotrophoblasts and invasion levels in
syncytiotrophoblasts pregnancy
- Pituitary GnRH – regulated by inhibin and activin CRH – from 5- Trophoblast, Enhance Smooth muscle
- Renal clearance – 30% of metabolic clearance 10pmol/L (NP) amniochorion, trophoblast relaxation;
o Remainder is liver to 100 pmol/L in decidua express secretion of induces
o Clearance of B- and a-subunits – 10 and 30-fold, respectively, 3rd trimester; CRH-R1 and ACTH myometrial
greater than intact hCG 500 pmol/L last CRH-R2 contraction near
o Chronic renal disease – hCG clearance markedly decreased 5-6 weeks; receptors term; parturition
rises further initiation
Biological Functions during labor
Both subunits are required for binding to LH-hCG receptor in corpus luteum and Urocortin – Placenta Induces
fetal testis lower levels expression of
- Rescue and maintenance of corpus luteum function than CRH proinflammatory
o Luteal progesterone synthesis begins to decline at about 6 weeks markers and
o Stimulates fetal testicular testosterone secretion PGF receptor
▪ LH surrogate to sitmulate Leydig cell replication and expression
testosterone synthesis (before 110 days) GHRH - - -
▪ Promote male sexual differentiation Ghrelin – peaks Trophoblast Paracrine
Maternal thyroid gland – stimulated by large quantities of hCG midpregnancy regulator of
- Some forms of hCG bind to TSH receptors differentiation or
- Acidic isoforms stimulate thyroid activity potential
- Basic isoforms stimulate iodine uptake regulator of
- LH-hCG receptor is expressed by thyrocytes hGH variant
Relaxin secretion
- Promotes uterine vascular vasodilation Pituitary-Like Hormones
- Myometrial smooth muscle relaxation Produced in Function
Regulates expansion of dNK cell numbers during early stages hGH-V Syncytiotrophoblast Growth-promoting and antilipogenic
- Ensures appropriate establishment of pregnancy Present by 21-26w functions; reduced diabetogenic and
Rises until 36w
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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
lactogenic functions; MEDIATES - Requires four key enzymes in syncytiotrophoblasts:
INSULIN RESISTANCE Substrate Enzyme Product
Relaxin Human corpus luteum, Promotes relaxation and quiescence; Conjugated DHEA-S Steroid sulfatase DHEA
decidua, placenta – postpartum regulation of ECM (STS)
levels parallel hCG remodeling; enhances GFR DHEA 3-B-hydroxysteroid Androstenedione)
PTH- In normal adult tissues – Transfer of calcium and other dehydrogenase type 1
RP myometrium, solutes; fetal mineral homeostasis (3BHSD)
endometrium, corpus Androstenedione CYP19 Estrone
luteum, lactating Estrone 17BHSD1 Estradiol
mammary tissue DHEA-S
Leptin Adipocytes; cyto and Antiobesity hormone that decreases - Major precursor of estrogens in pregnancy
syncytiotrophoblasts food intake, regulates bone growth - Fetal adrenal glands – most important source of precursors
and immune function;
Placental amino acid transport and Directional Secretion
fetal growth - >90% of estradiol and estriol = formed in syncytiotrophoblast and enters
Neuro- Brain, sympathetic Causes CRH release plasma
peptide neurons, - >85% of placental estrogen enters maternal plasma
Y cytotrophoblasts Directional movement from basic cx of hemochorioendothelial placentation
Inhibin Receptors are Both: cytotrophoblast fusion - Steroids can enter maternal blood directly
and expressed in placenta Activin: stimulates prod’n of hCG, - Steroids that leave syncytium do not enter fetal blood directly
activin hPL, progesterone, estrogen o Must first traverse cytotrophoblast → enter stroma → fetal capillaries
*Inhibin A: opposes activin Net result: Entry of steroids into maternal circulation > fetal blood
*Elevations in second trimester – indicative of fetal Down syndrome; lower
levels early – pregnancy failure; Increase in both inhibin and activin - FETAL ADRENAL GLAND-PLACENTAL INTERACTIONS
preeclampsia At term: Fetal adrenal glands weigh same as those of the adult
Near term Daily steroid production: 100-200 mg/d
PLACENTAL PROGESTERONE PRODUCTION Resting adult 30-40 mg/d
After 6-7w AOG Little progesterone produced in ovary steroid secretion
7-10th wk Removal of corpus luteum does not decrease rates - >85% of fetal gland – unique fetal zone w/ greater capacity of steroid
of urinary pregnanediol biosynthesis
After 8w Placenta assumes progesterone secretion o Fetal zone is lost in first year of life
By term Levels 10-5000 times in nonpregnant o Growth of adrenal gland is influenced by factors secreted by placenta
Daliy prod’n rate Late normal singleton: 250mg
Multifetal: 600mg PLACENTAL ESTRIOL SYNTHESIS
Synthesis is two-step enzymatic reaction: Estradiol
Substrate Enzyme Product Location - Primary placental estrogen at term
Cholesterol Cytochrome Pregnenolone Mitochondria Estriol and estetrol
p450 - Also rise, particularly late
Pregnenolone 3B- Progesterone Endoplasmic - Hydroxylated forms – use substrates formed by fetal adrenal gland and
hydroxysteroid reticulum liver
dehydrogenase o 16-OHDHEA is converted by placenta to estriol
Progesterone Deoxycortisone Extraadrenal – - Accounted for by placental synthesis principally from 16-OHDHEA-sulfate
most o Near term – fetus is source of 90% of precursors
Syncytiotrophoblast - Used as indicator for fetal well-being
- Limited capacity for cholesterol biosynthesis
o Rate-limiting enzyme: 3-hydroxy-3-methylglutaryl coenzyme A (HMG- FETAL ADRENAL STEROID PRECURSOR
CoA) reductase Cholesterol
- Placenta must rely on exogenous source → maternal cholesterol - Precursor
Trophoblast - Steroidogensis accounts to fourth of total daily LDL turnover
- Preferentially uses LDL cholesterol - Cholesterol must be assimilated from fetal circulation
- Differs from fetal estrogen production w/c relies on fetal adrenal precursors o Most fetal plasma cholesterol arises by de novo synthesis
o Low LDL in fetal plasma – consequence of rapid use
PLACCENTAL ESTROGEN PRODUCTION
2-4 weeks Rising hCG maintain estradiol in maternal corpus FETAL CONDITIONS AFFECTING ESTROGEN PRODUCTION
luteum Fetal death Important source of precursor of placental estrogen
7th week Production in maternal ovaries drops; is eliminated
More than half of estrogen produced in placenta Anencephalic Atrophic adrenal glands from absent hypothalamic-
Near term Hypestrogenic state features pituitary function
Biosynthesis Fetal adrenal Absence of C19 precursors
- Neither cholesterol n or progesterone can serve as precursor cortical hypoplasia
o CYP17A1 is not expressed in human placenta Fetal-placental Precludes hydrolysis of C19 steroid sulfates (first
▪ Converts 17-OH progesterone (C21) to androstenedione (C19) sulfatase deficiency step); X-linked disorder
w/c is an estrogen precursor Associated w/ delayed labor onset w/ development
▪ Conversion of C21 to C19 steroids is not possible of icthyosis in affected males
- C19 steroids DHEA and DHEA-S – produced by maternal and fetal glands Fetal-placental Androstenedione cannot be converted to estradiol,
o Serve as estrogen precursors aromatase rather, androgen metabolites of DHEA are secreted
Placenta deficiency into maternal/fetal circulation causing virilization
- High capacity to convert C19 to estrone and estradiol
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CHAPTER 5 – IMPLANTATION AND PLACENTAL DEVELOPMENT
Trisomy-21 Serum unconjugated estriol levels were low;
inadequate formation of C19 steroids
Fetal Greater placental mass from hypertrophy
erythroblastosis

MATERNAL CONDITIONS AFFECTING ESTROGEN PRODUCTION

Glucocorticoid Inhibits ACTH
treatment
Addison disease Lower levels; fetal adrenal contribution is much more
important
Androgen-producing Elevated androgen levels. Fortunately, placenta is
tumors efficient in aromatization
- All androstenedione is taken up and coverted
to estradiol
- Female fetus is rarely virilized
Complete Lack a fetus and also fetal adrenal source of C19
hydatidiform mole steroid precursors for biosynthesis
and gestational
trophoblastic
neoplasia

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