Placental

Development
Marites M Butaran
 FERTILIZATION AND IMPLANTATION
The ovum

• The formation of primary oocytes from which ova are developed is

complete before birth.

• Over the reproductive period only about 4000 of these pass through
maturation to ovulation

• All primary follicles are arrested in the prophase of the first meiotic
division which is completed just before ovulation
• At ovulation the secondary oocytes is expelled with follicular fluid
from the surface of the ovary

• The fimbriated end of the fallopian tube become closely applied over
the follicle so that on rupture the oocyte passes into the fallopian
tube

• It is transported to the uterus by peristalsis and ciliary movement

• Oocytes are fertilized in the fallopian tube, commonly at the

ampullae
 Fertilization

• This involves the penetration of the sperm through the corona radiata,
fusion of the oocyte and sperm cell membranes, completion of the second
meiotic division and the formation of a zygote

• The zygote is formed by the fusion of two haploid gametes and contains 46
chromosomes.

• It then differentiate into blastomeres (2-celled zygote)

• As division progresses 2 cells become 4 cells , then eight and so on until a

ball of cells are formed called Morula
• The morula enters the uterine cavity 3 days after
fertilization

• Fluid gradually gather between the cells of the morula and

form the Blastocyst

• Figure : 1
Fertilization and Implantation
• Implantation and early placental development

• Takes place 6-7 days following fertilization

Placenta formation
• Implantation of the embryo into the uterine wall is a common feature of all
mammals. In women, it takes place 6 or 7 days after fertilization.

• This process can be divided into three phases: (1) apposition—initial

adhesion of the blastocyst to the uterine wall;

• (2) adhesion—increased physical contact between the blastocyst and

uterine epithelium; and

• (3) invasion—penetration and invasion of syncytiotrophoblast and

cytotrophoblast into the endometrium, inner third of the myometrium, and
uterine vasculature
DEVELOPMENT AFTER IMPLANTATION

Prelacunar stage:

• This is from 7-8 days after fertilization

• The syncytiotrophoblast mass increases and become very sticky at

the implantation pole

• It is covered by branching finger-like projections that deeply

penetrate the endometrium

• NB- Syncytiotrophoblast is a continous system, with no synticial units

and without intercellular spaces
Implanted blastocyst

• Figure 3
Blastocyst, Maternal blood and
Lacunar/Trabeculae system
• This stage of solid mass of syncytiotrophoblast with basal extensions
formation represent the prelacunar period

Lacunar stage:

• Begins by the 8th day after fertilization

• Now vacuoles begin to appear in the syncytiotrophoblast at the implantation

pole

• These vacuoles grow and become joined, forming system of lacunae ( gaps
or separation)

• The separating syncytiotrophoblasts are called trabeculae

• The eroding trophoblast or transforming trophoblast by being a
mechanical irritant and by hormonal activity, results in endometrial
stroma proliferation and enlargement, giving rise to the decidual cells

• Invasion of the syncytiotrophoblast causes disintegration of the maternal

endometrial vessel walls and maternal blood enters the lacunae

• The disintegrating capillaries re surrounded by the expanding

syncytiotrophoblast , replacing the capillary walls and forming new
lacunae
• The newly formed lacunae then fuse with the preexisting
lacunae thus establishing maternal perfusion of the entire lacunae
system

• Further invasion of the trophoblast of the capillaries down to the

arteriolar and venular ending provide the anatomic basis for the
final formation of separate arterial inlets into the lacunar system
as well as venous outlets

• With deeper invasion of the endometrium, the spiral arteries are

eroded causing higher intralacunar blood pressure and the first
real maternal circulation of the placenta
 Early Villous stages:

• On about day 12-13, increased cytotrophoblastic proliferation and syncitial

fusion in trabeculae take place

• Longitudinal trabeculae growth is seen with blindly ending syncitial side

branches

• These solid primary villi composed of cytotrophoblast core covered by

syncitium form longitudinal cellular columns which project into the lacunae

• With increased branching and growth primitive villi trees are formed and
when they keep contact with the trophoblastic shell they are referred to as
anchoring villi
• The lacunar system is transformed into the intervillous space

• After 2 days mesenchymal cells from the extraembryonic mesenchymal layer

of the primary chorionic plate invade the villi transforming them into the
secondary villi

• The basal segment of the trabeculae consist of cytotrophoblast surrounded

by syncytiotrophoblast

• These cytotrophoblastic feet of the trabeculae or anchoring villi are called

cell columns

• From days 18-20 the first fetal capillaries are seen in the mesenchyme .
Appearance of these capillaries in the villous stroma marks the development
of the first tertiary villi
Developed placenta
• A complete feto-placental circulation is established by the start of the 5th
week

• NB: Fetal and maternal blood do not come into direct contact in the
intervillous space a nd exchange of gases, nutrients and waste are all by
diffusion

Development of Chorion and Decidua:

• As the implanted blastocyst grows and expands into the decidua, the outer
pole extends the endometrial cavity while the inner implantation pole forms
the placenta

• The decidua at the this (underneath) implantation site is called decidua

basalis
• The chorionic villi on this part proliferate to form the leafy chorion or
chorion frondosum

• The chorionic villi facing the endometrial cavity ceases to grow and
disintegrates thus forming the avascular fetal membrane, the chorion
leave or smooth chorion

• The decidua covering this area ( round the chorion) is the decidua
capsularis and the rest of the decidua is referred to as decidua
parietalis
Simple Decidua representation

• Figure 4:
Organization of the placenta
• Human placenta is described as hemochorial or 21st
hemochorioendonthelial
• Hemo: maternal blood which directly bathes the syncitiotrophoblast.
• Chorio: Chrion-placenta which is separated from fetal blood by the
endothelial wall of the fetal capillaries that traverse the villous core
• Spiral arteries----Diffuse intervillous space
• The maternal blood is outside the confines of the endothelium of the
maternal vascular system.
ARCHITECTURE OF THE NORMAL VILLOUS
TREE
• All come from single precursor i.e mesenchymal villi.
• Classified according to ;Caliber,Stromal structure,Vessel structure and
Position within the villous tree
1. Stem villi
2. Immature intermediate villi
3. Mature intermediate villi
4.Terminal villi
5. Mesenchymal villi
STEM VILLI

• Has a main stem that connects with the chorionic plate.

• 20-25% of the total villous volume of the normal mature placenta.
• Serve to mechanically support the structures of the villous trees.
• Negligible participation in fetomaternal exchange and endocrine
activity.
• Blood flow and blood pressure control in intervillous space is
important. Eg; Dec. pressure ---dec width of the fetoplacental
capillaries---- Increased fetoplacental impedence----- dec. fetal
perfusion of the placenta
• Pathogenesis: malregulation of the IUGR with absence of reversed
end-diastolic (ARED) umbilical flow.
IMMATURE INTERMEDIATE VILLI

• Also known as immature terminal villi

• Villi from maturation of mesenchymal villi which later transform into
stem villi
• Initially found around 8weeks and most by 14-20 weeks.
• Maybe completely absent at term.
• “Placentones” in most cases.
• Function as the growth centers of the villous tree and are the
principal sites of exchange during the first two trimesters.
MATURE INTERMEDIATE VILLI

• Contain numerous capillaries, small terminal arterioles and collecting

venules.
• About one fourth of the villous volume in the normal term placenta is
composed of this villous type.
• Produce terminal villi
• High incidence of fetal vascularization and large exchange surface
making them important for fetomaternal exchange.
• Prominent sites for hormone production.
TERMINAL VILLI

• Final, grape-like branchings of the mature intermediate villi

• 30-40% of the villous surface.
• X’teristics; very high degree of fetal capillaries
• highly dilated sinusoids.
• Main site of fetomaternal exchange.
• In a normal placenta; 40% of villous volume
• 50% of villous surface
• 60% of villous cross section
• A remarkable reduction of terminal villi may lead to fetal hypoxia.
• Inverse relationship between incidence of villous vasculocyncitial
membranes and fetal hypoxia.
MESENCHYMAL VILLI

• 1st and 2nd trimesters mesenchymal villi transform to immature

intermediate villi with branching angiogenesis.
• 3rd trimester; switches to mature intermediate villi
VASCULOGENESIS AND ANGIOGENESIS

• Role in preeclampsia and intrauterine growth restriction.

• VEGF and PIGF regulate normal formation of vessels in the placenta
as well as partial pressure of oxygen in the placenta.
• Any imbalance or abnormality will lead to preeclampsia or IUGR.
FORMATION OF VESSELS IN THE PLACENTA

• 1. Vasculogenesis
• 2. Angiogenesis
• a. branching: 1.Principal type
2. Day 32- week 24
3. Gives rise to a primitive
capillary network
b. Nonbranching: 24 weeks and lasts until term.
REQULATORS OF ANGIOGENESIS

• VEGF: Most potent stimulator of growth and survival of blood vessels

and is driving force of branching angiogenesis.

• PIGF: Responsible for predominance of nonbranching angiogenesis

which results in long filiform terminal villi typical of postplacental
hypoxia.
OXYGEN AND OXYGEN-CONTROLLED GROWTH
FACTORS AS REGULATORS OF VILLOUS AND
VASCULAR DEVELOPMENT
• Villous development is unknown.
• Pathologic conditions and genetic abnormalities affect villous and
fetoplacental vascular development
 DM
Hypertension
Anemia
Smoking

• Maturation processes are influenced by genetic, endocrine,

metabolic and environmental parameters
Role of Oxygen in Placenta

• Villous Growth and differentiation

IN MOST ORGANS
• Low degree of vascularization  inadequate oxygenation of tissue
• Tissue hypoxia stimulates capillary growth to improve vascularization
and tissue oxygentaTion
• If there is a good vascularization and high tissue oxygentation
further angiogenesis is blocked
Role of Oxygen in Placenta

• If low fetal capillary density less oxygen is extracted from the villi
 increasing intraplacental oxygen further blocks angiogenesis

• If high fetal capillary density  high oxygen extraction by fetal

circulation  lowered intraplacental oxygen tensions further
stimulating growth of the already well developed capillary bed
HYPOXIA OF THE FETOPLACENTAL UNIT

1. PREPLACENTAL HYPOXIA
 Mother, placenta and fetus are HYPOXIC
 Peripheral placental villi show increased branching angiogenesisn
with formation of richly branched but shorter terminal capillary
loops
 Main causes:
 High altitude
 Preexisting maternal cardiovascular disease:
• cyanotic heart diseases
• heart failure
• pulmonary hypertension
• Anemia, infection, and chronic inflammation
HYPOXIA OF THE FETOPLACENTAL UNIT

2. UTEROPLACENTAL HYPOXIA
Normal maternal oxygenation
Impaired uteroplacental circulation placenta and fetus are
HYPOXIC
 preeclampsia
HYPOXIA OF THE FETOPLACENTAL UNIT

3. POSTPLACENTAL HYPOXIA
Mother is NORMOXIC
Placenta is hyperoxic - IUGR
Fetus is HYPOXIC:
diminished uterine artery flow
progressive fetal cardiac failure
genetic anomalies

 Terminal villus capillary are poorly developed

Capillary branching is almost absent
HORMONES AS REGULATORS OF VILLOUS
DEVELOPMENT
• OVARIAN STEROIDS
 gestagens and estrogens: anatagonistic effects on villous development and
differentiation
 insulin of diabetic mother: increased proliferation rate of villous trophoblast,
stromal cells and capillaries  large placentas
 maternal thyroid hormone: villous development, influence placental trasfer
functions for nutrients and gases.
NON-VILLOUS PART OF THE PLACENTA

• Chorionic plate
• cell islands
• cell columns
• placental septa
• basal plate
• Marginal zone
• Fibrinoid deposits

 COMPONENTS:
Extraviillous trophoblasts
 Fibrinoid
 Decidualized endometrial stroma
Extravillous Trophoblast

• Generally accepted term for the entire population of trophoblast

cells residing outside the villi.
• 2 different functions:
o Invasion of maternal tissues including infiltration of maternal vessels,
supported by lytic activities proteineases destroying maternal extracellular
matrix
o Anchorage of the placenta and acting as a kind of "glue" between cells of
maternal and fetal origin
• Differentiate into the endovascular trophoblast that are found
o Within the walls of uteroplacental arteries and veins (intramural
trophoblast) replacing the media smooth muscle cells and other vascular
wall structures
o Within the lumen of uteroplacental arteries (intraarterial trophoblast)
replacing the maternal endothelium or forming plugs occluding the arterial
lumen
Factors controlling extravillous trophoblast
differentiation and invasion
1. Cytokines and Hormones
2. Extacellular Matrix and Matrix Receptors (Integrins)
3. Cell adhesion Molecules and Gap Junction Molecules
4. Proteinases, Activators and Inhibitors
5. Nitric Oxide
Cytokines and Homones controlling
differentiation of Extravillous Trophoblast
• Epidermal Growth Factor ( EGFR)
o Potent epithelial mitogen and
o Has stimulatory influence on trophoblast invasion
• Transforming Growth Factor B (TGF-B)
o Present in decidua
o Immunosuppressive factor: modulating the response of maternal leukocytes
to trophoblast.
o Restricts trophoblast invasion, enhances cell adhesiveness and impairs cell
motility
• Transforming Growth Factor a (TGF-a)
o Stimulates trophoblastic growth in contrast to TGF-B
Cytokines and Homones controlling
differentiation of Extravillous Trophoblast
• Tumor Necrosis Factor (TNF-a)
o Limit trophoblast invasion
o Source: decidua macrophages, endometrial natural killer (NK) cells [large
granular lymphocytes, LGL]
• Hepatocyte Growth Factor (HGF)
o Secrted by placental stroma and human decidua
o Increases trophoblastic invasiveness
• Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor
(PIGF), and Angiopoietin-2 (Ang-2)
o Maintenance and turnover of uteroplacental vessels
Cytokines and Homones controlling
differentiation of Extravillous Trophoblast
• Insulin-like growth factor (IGF-I)
o Secreted by the villous mesenchyme and stimulates cytotrophoblast to
detach from cell columns and invade neighboring extracellular matrix
• Interleukins IL Proinflammatory (IL-2) or antiinflammatory cytokines
(IL-4, -6, -10, -13)
o Trigger communication among the maternal immune cells at the
implantation site
• Triiodothyronine (T3)
o Maintenance of early pregnancy
Extracellular Matrix and Matrix Receptors
(Integrins)
Extracellular trophoblasts
Secrete large amounts of extracellular matrix ECM along their invasive
pathway comprise of fibronectin, collagen IV, laminins, vitronectin and
heparin sulfate in a patchy pattern.
Extravillous trophoblast cells
Express the respective ECM receptors (integrins) for ECM molecules
Integrins
Membrane proteins
Act as receptors for ECM molecules
Cell Adhesion Molecules and Gap Junction
Molecules
• Secreted to establish either cell to cell contacts, matrix adhesion or
fill up gap junctions important for cell proliferation
• E-cathedrin,
• N-CAM neural cell adhesion molecule,
• connexin 40, and
• CEACAM1
Proteinases

Matrix Metalloproteinases (MMPs)

• Involved in the turnover of extracellular matrix,
• Acting as "glue" among maternal and fetal tissues

These proteinases are also related to the initiation of labor and to the
separation of the placenta from the uterine wall
Nitric Oxide

Low concentration
Produced by the enzyme nitric oxide synthetase (eNOS)
Causes vasodilation
High NO
Produce by macrophage nitric oxide synthetase (mNOS)
Cytotoxic
Decidua
DECIDUA

Decidualization
Change that occur in the endothelium in response to blastocyst implantation
Decidualized endometrial stromal cells: Decidual Cells
Decidua
Contains a relatively low number of T cells, and B cells are absent at the site
of implantation :classical recognition reaction of the trophoblast is unlikely
Invasive trophoblast cells do not express the classical polymorphic MHC-1
molecules
Human endometrial large granular lymphocytes (LGLs)
Regular constituents of all uterine implantation sites
Closely related to natural killer cells (NK).
DECIDUA

Maternal macrophages
Capable of phagocytosing cellular debris in the maternofetal area and of
clearing immune complexes
Generally found in the decidua basalis
Produce a wide range of cytokines which are involved in limiting or
supporting trophoblast invasion
In normal pregnancy, the walls of spiral arteries are devoid of macrophages
and become invaded by trophoblast cells.
In preeclampsia, deficient arterial trophoblast invasion and increased
apoptotic trophoblast cells around the uteroplacentel arteries correlate with
large numbers of macrophages in the arterial media
Inhibited by high doses of progesterone
Fibrinoid
Fibrinoid

One of the most prominent components of human placenta

Nonfibrinous, noncellular, more or less homogenous
Functions:
• Increases mechanical instability when deposited in stem villi, chorionic and
basal plates
• Represents the "glue" that guarantees adhesiveness of the placenta to the
uterine wall
• Contributes to the regulation of intervillous circulation by fibrinoid
deposition and obstruction of poorly perfused areas
• Possible functional role as a barrier to trophoblast invasion
• Possible invasiveness-promoting activity
Fibrinoid

Fibrinoid
• Possibly provide an effective transfer route for macromolecules bypassing
the syncitiotrophoblast
• Possible morphogenetic function and may be involved in reepithelization of
damaged villous surfaces
• Immunologic significance-may mask fetal antigens thus preventing their
recognition by maternal cells; it is thought to protect fetal cells from already
sensitized maternal lymphocytes
Rohr's fibrinoid
Superficial layer of fibrinoid found in the basal plate facing the
intervillous space
Fibrinoid

Langhan's fibrinoid
Found along the chorionic plate at the intervillous surface
Nitabuch fibrinoid (uteroplacental fibrinoid)
Located in the immediate maternofetal junctional zone
Site of immunologic process
Separates superficially positioned trophoblastic cells from basally
located decidual cells thus marking the maternofetal border
Barrier function –protecting fetal antigens against indentification by
maternal cells
Site of placental separation
Fibrinoid

Deciduo-Trophoblastic Interaction
Trophoblast normally do not penetrate beyod the inner third of the
myometrium
Every cell type in the maternofetal junction has developed both
mechanisms supporting and inhibiting invasion resulting in an
extremely complex but well-balanced control system
Uteroplacental Vessels
• These are branches of myometrial arteries
• They are called spiral arteries as they entey the decidua and basal
plate
• 11-12 days= first contact between endometrial vessels and
intraplacantal lacunar system is established. First maternal
erythrocytes leave the eroded capillaries and enter the lacunae
• 8 weeks= uteroplacental arteries cross the uterine wall
perpendicularly
• 10 weeks= becomes almost parallel to the basal plate
• Trophoblast invasion of uteroplacental arteries convert them into low
resistance vessels that are unable to constrict. Physiologic changes:
1. Apparent replacement of endothelium and media smooth muscle
cells by invasive trophoblast
2. loss of elasticity
3. dilation to wide incontractile tubes
4. loss of vasomotor control
• These changes results in:
1. Reduction of maternal blood flow resistance
2. Increased uteroplacental perfusion
3. Guaranteed maximum maternal blood supply to placenta
Fetal and Maternal Blood Circulation in the
Mature Placenta
• Deoxygented blood to the placenta through two umbilical arteries in
the cord
• Upon entering the placenta, the umbilical vessels begin branching
within the cilli and form capillary networks
• Exchange of substance occurs by diffusion into the villous space,
through the villous trophoblast and out into the intervillous space
where maternal blood bathes the syncitiotrophoblast
• Oxygenated blood returns from the placenta to the fetus through a
single umbilical vein
PLACENTAL HORMONES
Plancental syncitiothrophoblasts synthesize large
amounts of protein and peptide hormones:
• hCG • Relaxin
• hPL • Activins
• ACTH • Inhibins
• hGH-V • Cytokines
• PTH-rP • Atrial natriuretic peptide
• calcitonin
• The human placenta also produces hypothalamic-like releasing and
inhibiting hormones:
• Thyroid releasing hormone ( TRH)
• Gonadotrophin-releasing hormone (GnRH)
• Corticotrophin-releasing hormone (CRH)
• Growth hormone releasing hormone
• somatostatin
Placental Hormones

• For each of the known hypothlamic-releasing or inhibiting hormone,

there is analogous placental hormone mostly coming from
cytothrophoblasts.
• In the fetal compartment, the protein synthesized is alpha-feto
protein and in the maternal compartment there is production of
prolactin, relaxin, and other decidual proteins.
 PROTEINS ASSOCIATED WITH PREGNANCY
FETAL COMPARTMENT PLACENTAL COMPARTMENT MATERNAL COMPARTMENT

Alpha-fetoprotein Hypothalamic-like Hormones Decidual Proteins

-GnRH, TRH, GNRH, CRH, Somatostatin -prolactin, relaxin,
progesterone-associated
endometrial protein, IGF-1,
Interleukin-1, colony
stimulating factor-1

Pituitary-like Hormones Corpus Luteum Proteins

-hCG, hGH, ACTH, hPL, hCT,oxytocin -Relaxin, Prorenin

Cytokines
-IL, IFN, TNF-α, CSF-I

Other Proteins
Opiates,prorerin, pregnancy specific β-1
glycoprotein, pregnancy associated
plasma protein A
HUMAN CHORIONIC GONADOTROPIN (HCG)

• pregnancy hormone
• glycoprotein with biological activity similar to luteinizing hormone
(LH)
• Produced almost exclusively in the placenta
• synthesized in fetal kidney and other fetal tissues
• May be present in some malignant tumores e.g. trophoblastic
neoplasm
• The carbohydrate component, especially the terminal sialic
acid, protects the molecule from catabolism

• Plasma half-life of intact molecule – 36 hours

• molecular weight of 36,000 to 40,000 Da

• It has the highest carbohydrate content of any human hormone—30 %

• composed of two dissimilar subunits
α subunit - composed of 92 amino acids
β - subunit - contains 145 amino acids

• Bioactivity which is binding To LH receptor is only

present if the two units are combined

• structurally related to three other glycoprotein

hormones—LH, FSH, and TSH
amino-acid sequence of the α-subunits of all four
glycoproteins is identical
Concentrations of hCG in Serum and Urine

• hCG molecule is detectable in plasma

7 to 9 days after the midcycle surge of LH that precedes ovulation

hCG enters maternal blood at the time of blastocyst implantation

• Blood levels increase rapidly, doubling every 2 days, with maximal

levels being attained at 8-10 weeks AOG
• Peak levels
Between 60th and 80th days after menses
100,000 mIU/mL
• When hCG titers exceeds 1000-1500 IU/L, vaginal UTZ should identify
gestation
• Beginning 10 to 12 weeks AOG, plasma levels begin to decline
• Nadir at 16 weeks
• Urine concentration follows pattern of maternal plasma
• β-core fragment
principal urinary form of hCG
• Abnormally High hCG Levels
multifetal pregnancy
Single erythroblastotic fetuses with maternal D-antigen isoimmunization
Hydatiform mole or choriocarcinoma
Midtrimester women with a fetus with Down syndrome (used as biochemical
screening)

• Abnormally Low hCG Levels

ectopic pregnancy
Impending spontaneous abortion
BIOSYNTHESIS OF hCG

• Placental GnRH
involved in the regulation of hCG formation

• activin stimulates
GnRH and hCG production

• inhibin
inhibits GnRH and hCG production
Metabolic Clearance of hCG

• Renal clearance accounts for 30 percent of its metabolic clearance

• The remainder is through the liver and other pathways

Biologic Functions of hCG
• rescue and maintenance of function of the corpus luteum - continued
progesterone production

• stimulates fetal testicular testosterone secretion

In the fetus, it acts as an LH surrogate to stimulate replication of Leydig cells and
testosterone synthesis to promote male sexual differentiation

• hCG stimulates maternal thyroid activity via the LH-hCG receptor and by
the TSH receptor

• promotion of relaxin secretion by the corpus luteum

• Promotion of uterine vascular vasodilation and myometrialsmooth

muscle relaxation via LH-hCG receptors
HUMAN PLACENTAL LACTOGEN (HPL)

• A.k.a. human chorionic somatomammotropin or chorionic growth

hormone

• concentrated in syncytiotrophoblast

• detected in throphoblast as early as the 2nd or 3rd week after

fertilization

• demonstrated in cytotrophoblasts before 6 weeks

• single nonglycosylated polypeptide chain
• Structurally similar to human prolactin
• Production rate near term – 1g/day
• HPL is demonstrable in placenta within 5-10 days after conception
• Detectable in maternal serum – 3 weeks post fertilization
• Rises
• Until 34-36 weeks AOG with higher levels in late pregnancy
• Secreted primarily in maternal circulation – very little amount in
maternal urine and fetal blood and urine

• Rate of hPL secretion is proportional to the placental mass

• Stimulated by insulin and insulin-like growth factor-1 and inhibited by

PGE2 and PGF2α

• Prolonged maternal starvation 1st half of pregnancy leads to increase in

plasma concentration of hPL

• Very high levels – found in multiple gestations

Metabolic Actions of hPL
• Maternal lipolysis and increase in levels of circulating free fatty acids
this provides a source of energy for maternal metabolism and fetal nutrition

• anti-insulin or "diabetogenic" action

leads to increase in maternal insulin levels
this favors protein synthesis and provides a readily available source of amino
acids to the fetus

• angiogenic hormone
important role in the formation of fetal vasculature
CHORIONIC ADRENOCORTICOTROPIN
• physiological role is unclear

• Secreted into mother or fetus during pregnancy, but maternal ACTH

does not cross the placenta to the fetus

• increase during pregnancy

CHORIONIC THYROTROPIN

• There is evidence that the placenta produces chorionic thyrotropin

but no evidence that it has a significant biological role in pregnancy
RELAXIN

• Expressed in human corpus luteum, decidua, and placenta

• structurally similar to insulin and insulin-like growth factor

• Function
acts on myometrium to promote relaxation and the quiescence of the uterus
in early pregnancy
PARATHYROID HORMONE-RELATED PROTEIN
(PTH-rP)
• significantly elevated in pregnancy within maternal but not fetal
circulation

• found in myometrium, endometrium, corpus luteum, and lactating

mammary tissue

• Function
may activate trophoblast receptors to promote calcium transport for fetal bone
growth and ossification
Growth Hormone Variant (hGH-V)
• This is not expressed in the pituitary and is referred to
as the placental growth hormone.
• It is synthesized in the syncituim and present in the
maternal plasma by 21-26 weeks.
hGH-V

• It is not regulated by placental GHRH but responds inversely to

maternal glucose level s, protecting glucose availability for the fetus.
• It can stimulate gluconeogenesis and lipolysis in maternal organs,
thus influences fetal growth by affecting maternal metabolism.
Hypothalamic-Like Releasing Hormones
• For each of the known hypothalaminc-releasing or
inhibiting hormones, GnRH, TRH, GHRH, and somatostatin,
there is an analogous placental hormone, indicating
hierarchy of control in the synthesis of chorionic trophic
hormones.

Gonadotrophin-Releasing Hormone (GnRH)

• It functions to regulate tropoblastic production of hCG,
and is likely the cause of elevation of maternal levels of
circulating GnRH in early pregnancy.
Corticotrophin-Releasing Hormone

• Non-pregnant women at low levels of 5-10 pmol/L.

• During pregnancy, levels increase to about 100 pmol/L in the early
third trimester to about 500 pmol/L at 35-36 weeks.
• Receptors for CRH are present in the placenta, adrenal gland,
sympathetic ganglia, lympocytes, gastrointestinal tract, pancreas,
gonads and myometrium.
• Trophoblast , chorion and decidua express CRH-R1 and CRH R2
receptors .
• Other proposed biologic actions are induction of smooth muscle
relaxation in vascular and myometrial tissue and immunosuppression
Growth Hormone-Releasing Hormone (GnRH)

• GnRH’s exact function is unknown.

• Ghrelin, another potential regulator of hGH is expressed in first
trimester of trophoblast.
Other Placental Peptide Hormones

Leptin

• Normally secreted by adipocytes

• Is believed to be anti-obesity hormone and known to regulate bone
growth and immune function.
• It is secreted by cytotrophoblast and syncitiotrophoblast.
• Fetal leptin levels are correlated positively with fetal birthweight and
play an important role in fetal growth and development.
Nueropeptide Y

• This peptide is found in the brain, sympathetic neurons innervating

CVS, respiratory, GI and GU systems and has been isolated from
placental cytotrophoblast.
Inhibin

• Inhibin, a glycoprotein hormone, inhibits pituitary FSH release.

• The placenta produces inhibin A, BA and BB subunits. Inhibin A is the
principal bioactive inhibin secreted during pregnancy.
• Placental inhibin production together with large amounts of placental
sex steroids inhibit FSH secretion and preclude ovulation during
pregnancy.
• Inhibin is not seen in fetal blood before labor but is found in the
umbilical cord after labor begins.
Activin

• Activin is closely related to inhibin.

• Enhances FSH synthesis and secretion and participates in the
regulation of the menstrual cycle.
• It has roles in cell proliferation, embryogenesis, osteogenesis,
differentiation, apoptosis, metabolism, homeostasis, immune
response, wound repair and endocrine function.
• Nerve cell survival factors.
Inhibin and Activin

• Chorionic activin and inhibin are regulators within the placenta for
the production of GnRH, hCG and steroids.
• Placental activin and inhibin early in pregnancy may indicate their
possible roles in embryogenesis and local immune response.
Placental Steroid Hormones
• Progesterone
• Production
• After 6-7 weeks of gestation, ovarian progesterone production is
minimal. After about 8 weeks, the placenta replaces the ovary as the
source of progesterone and continues to increase production
throughout pregnancy.
• Daily production rate is 250 mg.
• In pregnancies with multiple fetuses, the daily production rate maybe
>6000 mg/day.
• Progesterone is synthesized from cholesterol in 2-step enzymatic
procedure.
• First, cholesterol is converted pregnenolone within the mitochondria, in a
reaction catalyzed by cytochrome P450 enzyme.
• Pregnenolone leaves the mitochondria and is converted to progesterone in
the endoplasmic reticulum by 3B-hydroxysteroid dehydrogenase.
• Progesterone is released immediately through the process of diffusion.
Maternal plasma cholesterol is the principal precursor (90%) of
progesterone biosynthesis in the placenta. The trophoblast preferentially
uses LDL cholesterol for progesterone biosynthesis.
• The number of progesterone is dependent on the number of LDL receptors
on the plasma membrane of trophoblasts. Hydrolysis of LDL releases
essential amino acids and cholesterol esters, which in turn yield fatty acids
and cholesterol. Essential amino acids and fatty acids are transported to
the fetus and cholesterol is used for placental progesterone biosynthesis.
 Progesterone and Fetal Well-Being

• There is no relationship between placental progesterone synthesis and

fetal well-being, as progesterone biosynthesis may persist several weeks
after fetal death.
Progesterone Metabolism During Pregnancy

• Progesterone metabolic clearance rate is the same as in non-

pregnant women and men.
• During pregnancy, there is a disproportionate increase in plasma
concentration of 5a-dihydroprogesterone as a result of synthesis in
syncitiotrophoblast from placental progesterone.
• Progesterone is also converted to the potent mineralocorticoid
deoxycorticosterone in pregnant women and in the fetus, thus an
increase of deoxycorticosterone in the maternal and fetal
compartments.
Progesterone Metabolism During Pregnancy

• 30-40% of progesterone is secreted as metabolites in the urine, bile

and feces.
• 5a-reduction of progesterone is the major pathway of progesterone
metabolism. The metabolites of 5a-dihydroprogesterone are
bioactive in the brain, facilitating the action of GABA. With the
delivery of the placenta, the sudden drop in this metabolite may
account for the puerperal depression in some women.
Role of Progesterone

• It prepares and maintains the endometrium to allow implantation,

has a role in suppressing the maternal immunologic response to fetal
antigens thereby preventing maternal rejection of trophoblast and
has role parturition.
• It also serves as a substrate for fetal adrenal gland production of
glucocorticoids and mineralocorticoids
Placental Estrogen

Production
• The placenta produces huge amounts of estrogens using blood-
borne steroidal precursors from maternal and fetal adrenal glands.
• The amount of estrogen produced daily by syncitioblast during the
last few weeks of pregnancy is equivalent to that produced in 1 day
by the ovaries of no less than 1000 ovulatory women.
Placental Estrogen

Production
• During the first 2-4 weeks of pregnancy, rising levels of hCG maintain
production of estradiol in maternal corpus luteum. Maternal corpus
luteum production of estrogen and progesterone decreases
significantly by the 7th week of pregnancy.
Biosynthesis

• The pathways for estrogen synthesis in the human placenta differ

from those in the ovary of non-pregnant women.
• Ovarian theca cells-> granulosa cells-> estradiol.
• Androstenodione is produced de novo from acetate and cholesterol,
catalyzed by aromatase 450 -> estrone, acted upon by estradiol
dehdyogenase -> estradiol.
• In human trophoblast, neither cholesterol nor progesterone can
serve as precursor for estrogen biosynthesis.
Biosynthesis

• Fetal adrenal cortex - most important sources of placental estrogen

precursors in human pregnancy.
• The large amounts of DHEA-S in plasma and its longer half life
uniquely qualify it as a principal circulating precursor for placental
estradiol synthesis.
Placental Estriol Synthesis

• Estriol and estetrol in maternal circulation are increased particularly

in late pregnancy.
• These hydroxylated estrogens are produced in the placenta using
substrates from fetal adrenal gland and liver.
• The fetal liver expresses high levels of the enzyme 16a-hydroxylase
which act on adrenal derived steroids.
• Near term, the fetus is the source of 90% of placental estriol and
estetrol precursor in normal human pregnancy.
Fetal Adrenal Glands

• Compared with adult organs, the adrenal cortex is the largest organ
of the fetus.
• More than 85% of the fetal gland is the fetal zone, which is absent in
adults.
• The fetal zone begins involution immediately after birth.
• Daily production of steroids in fetal adrenal gland near term is around
100-200 mg/day.
Fetal Adrenal Gland Growth

• The enormous size and very great capacity for steroid synthesis made
investigators think that aside from ACTH, there are other stimuli for
growth of the adrenal gland.
• ACTH is necessary for the rapid growth of the adrenal gland during
the latter part of pregnancy.
• The growth of fetal adrenal gland is influenced by factors secreted by
the placenta.
Adrenal Enzymes
• The adrenal fetal zone cells have a severe deficiency in 3BHSD thus
limiting the conversion of pregnenolone to progesterone and 17a-
hydroxyprogesterone, an obligatory step in cortisol biosynthesis.
• However, its principal secretory products are pregnenolone sulfate and
DHEA-S
Fetal Adrenal Steroid Precursor

• The precursor for fetal adrenal steroidogenesis is cholesterol.

• The fetal adrenal glands can synthesize cholesterol from acetate.
• The rate of de novo synthesis by fetal adrenal tissue is extremely high
but still insufficient to acccountfor the steroids produced by the
adrenal glands.
• Fetal adrenal glands are highly dependent on circulating LDL as a
source of cholesterol for steroidogenesis.
 Fetal Conditions That Affect Estrogen
Production
• 1. Fetal death – the important fetal source of precursor for estrogen is
absent.
• 2. Fetal anencephaly – very limited placental synthesis of estrogens,
especially estriol because of limited availability of C19 steroids.
• 3. Fetal adrenal hyperplasia – no fetal adrenal C19 precursor for estriol
synthesis.
• 4. Fetal-placental sulfatase deficiency – no hydrolysis of c19 steroids,
no precursor for estrogen biosynthesis. An X-linked trait that only affects
males with ichthyosis and associated with delayed onset of labor.
Fetal Conditions That Affect Estrogen
Production
• 5. Fetal placental-aromatase deficiency – androstenodione cannot
be converted t estrodiol; with virilization of mother and female fetus;
males have delayed epiphyseal closure during puberty and are very
tall with deficient mineralization.
• 6. Trisomy 21 (Down Syndrome) – second trimester screening shows
abnormal levels of estriol, alpha-feto protein and hCG.
• 7. Deficiency in fetal LDL cholesterol biosynthesis – limits fetal
adrenal production by estrogen precursor.
• 8. Fetal erythroblastosis – elevated levels of estrogens in maternal
plasma due to placental hypertrophy.
Maternal Conditions That Affect Placental
estrogen Production
• 1. Glucocorticoid treatment – glucocorticoids inhibit maternal and
fetal pituitary ACTh secretion resulting in decreased maternal and
fetal adrenal secretion of DHEA-S
• 2. Maternal adrenal function – e.g. Addison;s disease, decrease
principally affects estrone and estradiol
• 3. Maternal ovarian androgen-producing tumors – seen in virilized
female fetus with a tumor that produces a non-aromatized C19-
steroid androgen early in pregnancy that exceeds the capacity of
placental aromatase.
•
Maternal Conditions That Affect Placental
estrogen Production
• 4. Maternal renal disease – lowered urinary estriol in women in
pyelonephritis is the consequence of diminished renal clearance
• 5. Gestational trophoblastic disease – no fetal sources of C19
steroids for estrogen synthesis.
Directional Secretion of Steroids from
Syncitiotrophoblasts
• Estrogens synthesized in the syncitium enter the maternal circulation.
• The major reason for the directional movement towards maternal
circulation is hemochorioendothelial form of placentation.
Directional Secretion of Steroids from
Syncitiotrophoblasts
• Steroids from trophoblast does not enter fetal blood directly; steroids
must traverse cytotrophoblast -> then connective tissue of villous
core -> then traverse wall of fetal capillaries -> fetal blood.
• Steroids in fetal capillary can then reenter the connective tissue of
the villous core to reenter the syncitium.
• Thank you