Implantation , Embryology and placental development

Scope

• The ovarian – endometrial cycle

• The decidua

• Implantation

• Placenta formation

• Fetal membrane development

The Ovarian Cycle

• Follicular phase• 2million oocytes at birth• fffffffff ff fff fffff ff ffffff400,000

f• ff f ffff ff fffffffffffff ffff ffffffff1000

f ffff fffff fff f f 35

• 400Only f ol l i cl es ar e nor mal l y r el eased du ring female reproductive life

Foll icular or preovulatory phase

• () ()

•FSH Granulosa cells fffffff Estradiol

• LH fffff fffff ffffff Androgen (whic

har e conver t ed t o Est r adi ol )

Two-Cell-Two-Gronadotropin

Ovulation

• E stradiol ↑ LH surge

• LH surge 10-12 hr ovulation : causes th

e oocyte to be released from the follicle .

• The ruptured follicle then becomes the cor

pus luteum , which secrets progesterone.

Luteal phase

• The corpus luteum secrets progesterone for only about

11 days in the absence of hCG.

• Progesterone preparation endometrium for implant

ation

– Highly vascularized

– glandular secretions

The decidua

• Decidualization : transformation of secretory endometrium to decidua•D epend on estrogen, progesterone and factors s

ecreted by the implanting blastocyst.

Decidual Structure• Decidua : 3 parts

1.1. Decidua BasalisDecidua Basalis

2.2. Decidua CapsularisDecidua Capsularis

3.3. Decidua ParietalisDecidua Parietalis

Decidua Vera = D. Capsulais + D. Parietalis

• Decidual parietalis + decidual basalis like the secretory endometrium c ompose o f 3 layers

- zona compacta - zona spongiosa - zona basalis

functional zone

New endometrium afterdelivery

Decidual reaction

• The decidual reaction is completed only wit

h blastocyst implantation.

• Predecidual changes

– midluteal phase

– ff fffffffffff fffffff fffff ffffffff ff fff ffffff ffffffff fff fffffffffff

Blood supply of the decidua

• The decidua capsularis is lost as the embry

- o fetus grows

• The decidual parietalis spiral

artery ,remain : smooth muscle,

endothelium responsive to vasoactive agent

• The decidual basalis spiral artery

Decidual histology

• NK are present in the decidua early in pregnancy

• Play an important role in trophoblast invasion and vasculogenesis

Nitabuch layer

•Zone of f ibriniod degeneration in which inva ding trophoblasts meet the decidua

• Prevent excessively deep conceptus implantation (placenta accreta)

Decidual prolactin

•Souce of prolactin • Gene that encodes for anterior pituitary• Prolactin levels

– in amniotic fluid are ext raordinarily high and 10000may reach , ng/mL

– in maternal serum - 150 200 ng/mL– Fetal serum 350 ng/mL (Theproteinpreferentiallyent er s amni oni c f l ui d, and l i t t l e ent er s

maternal blood)

Roles of Decidual prolactin

• Not clear1 . Transmembrane solute and water transport ,

maintenance of amnionic fluid volume2. Regulation of immunological functions duri

ng pregnancy– - Prolactin receptors in bone marrow derived immune c

ells,– Prolactin may stimulate T cells in an autocrine or para

crine manner3. Regulation of angiogenesis during implanta

tion4. Repressing expression of genes detrimental t

o pregnancy maintenance : in mouse

Regulation of decidual prolactin

• Most agents known to inhibit or stimulate pituitary prolactin

• Secretionincluding dopamine, dopamine agonists, and

• do not alter decidual prolactin TRH

Implantation & Formation of the Placenta & Fetal

membrane• Fertilization & Implantation

• Biology of the Trophoblast

• Embryonic development after implantation

• Organization of the placenta

• Chorionic villi

• Placental development

• Placenta = Pulmonary,Hepatic, Renal

• Hemochorial type of placenta

• Fetal-Maternal blood not mixed

Ovum Fertilization and zygote Cleavage

• Ovulation : fffffffff ffffff

Peritoneal cavityffffffffff ffffff

oviduct oviduct

Cilia and tubal peritalsis

Fertilization often takes place in ampulla

Fertilization

• Sperm penetrates zona pellucida of secondary oocyte, trigger meiosis II.• Cortical granule reaction is a propagated response at the site of sperm entry, and is a basis for the block to polyspermy.• Secondary oocyte Meiosis II mature oocyte

• In fallopian tubeIn fallopian tube

: 3 days: 3 days

1st day : Fertilization1st day : Fertilization

Zygote : diploid cellZygote : diploid cell

22ndnd day : 2 cell zygote day : 2 cell zygote

blastomereblastomere

thick zona pellucidathick zona pellucida

3rd day : Morular 3rd day : Morular

16 cells16 cells

Solid mulberry-like ballSolid mulberry-like ball

Enter uterine cavityEnter uterine cavity

• In uterine cavityIn uterine cavity

44thth-5-5thth day day

Morular = 16 cellsMorular = 16 cells

Accumulate fluid - Accumulate fluid -

between cellsbetween cells

Early blastocystEarly blastocyst

( 58 cells = 5+53 )( 58 cells = 5+53 )

Blastocyst 107Blastocyst 107

( 107 cells = 8+99 )( 107 cells = 8+99 )

Zygote fff fffff f ffffff ff

Morula fffff – 1 6

Blastocyst• fffff ffff f fff• Trophoblast

ffffffffff ff ffffffff ffff fff ffff fffffffff - - fffff ffffff fffffffffff 1 α, 1β , :

        

Implantation

1. Apposition : most common occurs on the upp

er post er i or ut er i ne wal l

2. :Adhesion Integrins

3. :Invasion Trophoblast• Implantation occurs 6th or 7th day after

fertilization

• Postovulatory production of estrogen &

progesterone by corpus luteum

• 20th -24th day of ovarian-endometrial cycle

Trophoblast differentiation

• The formation of the human placenta : trophectoderm

• Syncytiotrophoblast : outff f fffffffffff

• Cytotrophoblast : fffff f fffffffff

Trophoblast differentiation

•fffff ffffffffffff ff ffffffffff

2trophoblast differentiates in pathways

– Villous trophoblast : chorionic villi

– Extravillous trophoblast : decidua , myometrium and

maternal vasculature

1 2 t h day af t er f er t i l i zat i on Chorionic villi

• Primary villi : cytot rophoblast core• Secondaryvi l l i : mesenchymal cor e• Tertiaryvi l l i : angi ogenesi s

fffffff ff ffffffffffff ff > > Hydatidiform mole

Anchoring villi• cytrophoblastcells columns• anchore to the decidua atbasal plate

• 9 th day : Implantation : Blastocysts

Blastocyst wall : uterine cavity single layer with flattened cells

Blastocyst wall : Inner wall Thicker wall, 2 zones

1. Trophoblasts

2. Inner cell mass : embryo-forming

• 10 th day : Blastocyst totally encase within the endometrium

Embryonic Development after Implantation

Embryonic Development after Implantation

• 7½ days after fertilization : inner cell mass or embryonic disc >> ectoderm -mesoder

m - endoderm• Enclosing space between embryonic disc a

nd trophoblast : amniotic cavity• Cells within amniotic cavity condense to fo

rm the body stalk >> Umbilical cord

Placental development

• Modification of the maternal vasculature by trophoblast, occur in the first half• Important in preeclampsia and IUGR• Extravillous trophoblast• Interstitial trophoblast• Endovascular trophoblast• Villous trophobast and and anchoring cytotr

ophoblast

• Interstitial trophoblasts - penetrate the decidua and myometrium - preparation of vss for endovasculartrophoblasts

• Endovascular trophoblasts• enter the lumen of spiral a.• forming the cellular plugs within lumen• destroy endothelium• invade & destroy vascular media

• Vascular change involve only in decidual spiral a. not the decidual v.

The chorion

• The chorion is composed of cytotrophoblasts a nd fetal mesodermal mesenchyme that survives i

- n a relatively low oxygen atmosphere.• Chorion frondosum : the area of villi in contact

with the decidua basalis, fetal component of theplacenta

• the chorion laeve : contact with the decidual c apsularis .A portion of the chorion becomes the avascular fetal membrane that abuts the decidu

a parietalis

Maternal Regulation of Trophoblast Invasion and Vascular Growth

• Decidual natural killer cells (dNK)– attract and promote invasion of trophoblas

t into the decidua and promote vascular growth

– - - - 8 10IL andINFinducibleprotein , VEGF and pl acent al gr owt h f act o r (PlGF)

• The extravillous trophoblast : invasion of e ndometrium and spiral arteries

• - urokinase type plasminogen activator: plas minogen plasmin

• Trophoblasts are further secured by fetal fibronectin

• Trophoblast glue• presence of fFN in cervical or vaginal fluid i

s used as a prognostic indicator for pretermlabor

1. Decidua capsularis 2. Uterine wall 3. Uterine cavity 4. Placenta 5. Decidua parietalis 6. Decidua basalis 7. Chorion leave 8. Embryo 9. Connecting stalk

10. Yolk sac 11. Chorion frondosum 12. Amnion 13. Chorionic cavity 14. Amniotic cavity

Uteroplacental vasculature

12Before weeks post fertlization Invasionand modi f i cat i on of t he spi r al a. up t o t he

border of the deciduas and myometrium - 1216 weeks post f er t l i zat i on

Invasion of the intramyometrium segments of spiral a.RRRRRRRRRR : Dilated, l owr esi st ance ut er opl acen

tal vessels

Significance in the pathogenesis of preeclampsia and IUGR

Maternal blood flow

• 1 month after conception , maternal blood enters the intervillous space in -“ fountain l

ike bursts “ from the spiral arteries.• Blood is propelled outside of the maternal v

essels and sweeps over and directly bathe s the syncytiotrophoblast.

• Villous branching : Chorion frondosum >> Cotyledon :single a and v.

Placental growth and maturation

• 1st trimester Placental growth more rapid than fetal growth

• GA 17 wk by LMP placental weight = fetal weight• At term placental weight = 1/6 of fetal weight

At term Diameter 185 mm

Volume 497 ml Thickness 23 mm

508Weight g - fffff :10 38 (fibrou s septa; incomplete p

artition)

Placental maturation

At term• Thin layer of syncytium• Villi : thin wall capillary• Significant reduction of cytotrophoblasts• Decreased stroma• Increased number of capillary

Hofbauer cell

• Fetal macrophage• Round, vesicular, eccentric nuclei• Very granular or vacuolated cytoplasm• Increase in numbers & maturation state out

throughout pregnancy• Phagocytic , immunosuppressive phenotype• Produce a variety of cytokines• Paracrine regulation of trophoblast functions

Changes in placental architecture that can cause decreased efficiency of placental exchange

• Thickening of basal lamina of trophoblast o r capillaries,

• Obliteration of certain fetal vessels• Fibrin deposition on the villi surface

Fetal circulation2 umbillical artery

(deoxygenated blood)

placenta : chor i oni c vessfff : capillary networ

k in villi

Oxygenated blood

1 umbillical vefffff

Fetal circulation

• chorionic plate - chorionic vessels - responsive to vasoactive agents• Truncal artery - perforating branch through chorionic

plate - supply one cotyledon• End diastolic flow within umbilical artery appears at GA 10 wk.

Maternal circulation

Basal plate

Intervillous space

Venous orifice in basal plate

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Maternal circulation

(1) Leave maternal circulation 2( ) Flow into an amorphous space lined by

syncytiotrophoblast, rather than capillary endothelium

3( ) Return through maternal veins without p - roducing arteriovenous like shunts

that would prevent maternal blood from remaiffff ff fffffff f fff fffff ffff ffffff fff ffffffff ffffffff

• Spiral arteries : perpendicular t o t he ut ei ne wa l l

• Spiral veins : parallel to the uterine wall• This arrangement aids closure of veins during a uterin

e contraction and prevents entry of maternal blood fro m the intervillous space

Principal factors regulating blood flow in the in tervillous space

• Arterial blood pressure• Intrauterine pressure• The pattern of uterine contractions• Factors that act specifically on arterial walls.

Breaks in placental barrier

• Maternal leukocytes and platelets• - D antigen isoimmunization• Erythroblastosis fetalis• Fetal cells : Lymphocytes , CD 34+ mesenc

hymal stem cells• Microchimerism : Maternal autoimmune dis

orders ; Lymphocytic thyroiditis , scleroder ma , SLE

Immunological Considerations of the Fetal–Maternal Interface

• Lack of uterine transplantation immunity• Survival of the conceptus in the uterus

– Decidual natural killer cells with their inefficient cytoto xic abilities

– Decidual stromal cells– Invasive trophoblasts

• Placenta : immunologically inert• Villous trophoblast : absent MHC antigen(I,II)• Invasive cytotrophoblast : MHC Class I

• Trophoblast HLA (MHC) Class I Expression– 6Short arm of Chromosome

• Uterine Natural Killer Cells (uNK)

Permit and limit trophoblast invasion

• - HLA G Expression in Trophoblast only in extravillous cytotrophoblasts

in the decidua basalis and in the chorion laeve

ff fffff ffff fff fff ff fff ff fffff - if they do not express this soluble HLA G isoform

Amnion

• the inner most fetal membrane• provide almost all of the tensile strength of the fetal membrane• Collagen + fibrous like mesenchymal cell•avascular• Lacknerve, l ymphat i cs, smoot h muscl e

7th f8 th day of embryonic development :

Small sac cover dorsal surface of the embryo >> e ngulf embryo>>adhere to chorion leave

Structure of Amnion

• The inner– single layer of cuboidal epithelium– embryonic ectoderm

• the outer– - A r owof fi br obl ast l i ke mesenchymal cel l s– Embr yoni c di sc mesoder m

• A few fetal macrophages in the amnion• Lacks smooth muscle cells, nerves, lymphatics,

and importantly, blood vessels

• A few fetal macrophages in the amnion• Lacks smooth muscle cells, nerves, lymphatics,

and importantly, blood vessels

fffffffffff ffff• Fibroblast layer• Synthesis of - interstitial collagens (majority of

tensile strength) - - - -cytokine : IL 6, IL 8, MCP 1

Amnion Epithelial CellsProduce• PGE2 >> initiation of labor• fffff fffffffffff• -1tissue inhibitor of metalloproteinase• brain natriuretic peptide• CRH• vasoactive peptide

Metabolic Function• contain amniotic fluid• sol ut e & wat er t r anspor t ( mai nt ai n

AF homeostasis)• produce bioactive compounds

AMNIOTIC FLUID Increase : until GA 34 weeks

At term : 1000 mL

Umbilical cord

• Dor sal sur f ace gr owt hs f ast er t han vent r al sur f ace

• Yolk sac & Allantois is incorporated to form gut yolk sac: smaller

pedicle: longer• Middle of 3 rd m onth : amnion fuse with fffffff l aeve

• - Body stalk > umbilical cord or funis

At term• Cord : 2 arteries, 1 vein• Rt umbi l i cal v. di ssappear s ear l y dfffff ffffffff fff• Arteries are smaller than vein

Meckel diverticulum f fffffffff fffffff ffffffff : from umbilicus to intestine

The most common vascular anomaly : absence of 1 umbilical artery

Umbilical cord

• - Diameter 0.8 2 cm• - ffffffff f3 0 1005

5 cm)• Abnormalshortcord < 30 cm• Tortious vss which are longer than cord - create nodulation > false knot• Spiral vss in cord, prevent clamping

• Wharton jelly - extracellular metrix - a specialized connective tissff - increases in volume at partur

ition to assist closure of placental blood vss

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