Williams Chapter 3: Implantation, Embryogenesis, and Placental Development

Chapter 3: Implantation, Embryogenesis, and Placental

Development
The Ovarian-Endometrial Cycle
The Ovarian Cycle
see Speroff Notes

Estrogen Action
Estradiol-17 - is the biologically potent estrogen secreted by the granulosa cell of the dominant ovarian follicle
Estradiol enters cells from blood by simple diffusion, but in estrogen responsive cells, estradiol-17 is sequestered by
binding to estrogen receptor protein molecules; has high affinity but low capacity for estradiol
The estradiol-17-receptor complex, after transformational changes, is a transcriptional factor that becomes associated
with estrogen response elements of specific genes; i.e. stimulates the transcription of progesterone receptor genes

Progesterone Action
Also enters cells by diffusion and in responsive cells becomes associated with progesterone receptors
Commonly the cellular content of progesterone receptors is dependent on previous estrogen action
Transcription of progesterone induced genes causes a decrease in the synthesis of estrogen receptor molecules; by this
means, prog attenuates estrogen action

The Endometrial Cycle

Proliferative Phase of the Endometrium

by Day 5 of the menstrual cycle, the epithelial surface of the endometrium has been restored and revascularization of the
endometrium is in progress; glands are narrow, tubular structures that pursue an almost straight and parallel course
Mitotic figures are identified by the fifth day after commencement of menstruation, and mitotic activity persists until 2-3
days after ovulation
Blood vessels are numerous and prominent, there is no extravasated blood or leukocytic infiltration
Clearly, re-epithelialization and angiogenesis are important to the cessation of endometrial bleeding at the end of
menstruation, and these processes are dependent upon tissue regrowth
Endometrium becomes thicker result of glandular hyperplasia and an increase in stromal ground substance (edema and
proteinaceous material)
Glands in the superficial endometrium are widely separated, compared with the deep zone, where the glands are more
crowded and tortuous, and the stroma is more dense
At midcycle, as ovulation is approached, the glandular epithelium is taller and pseudostratified
Day-by-day dating of the endometrium by histologic criteria is not possible in the proliferative phase, and the secretory
phase is remarkably consistent (12-14 days)

Secretory Phase of the Endometrium

after ovulation, the estrogen primed endometrium responds to the rising levels of progesteronein a highly predictacble
manner
Beginning on day 7 to 8 post-ovulation, the rates of progesterone and estrogen secretion by the corpus luteum begin to
decline and diminish progressively before menstruation
Day 17 glycogen accumulates in the basal portion of the glandular epithelium
this creates vacuoles and pseudostratification and is the st sign of ovulation that can be seen histologically
Day 18 vacuoles move to apical portion of the secretory nonciliated cells
Day 19 cells begin to realease glycoprotein and mucopolysaccharide conetnes into the lumen
With this start of secretory activity, mitosis ceases in response to rising progesterone
Also estrogen effects decrease as estradioil production decreases and estrone (less potent) increases
Days 22-25 predicudual transformation of the upper 2/3 of the funtionalis layer
glands exhibit extensive coiling and secretions becomve visible within the lumen

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Pinopods also develop protrusions of the apical cell surface into the lumen in preparation for blastocyst
also occurring during the luteal phase is an impressive increase in the length of the uterine spiral arteries

Menstruation
towards the end of the cycle the functionalis layer accumulates PMN cells (perhaps in response to IL-8)
the invading PMNs secrete MMP which tip the balance between protease and pretease inhibitors, leading to menstruation
from a vascular perspective, the spiral arteries coils severely enough to increase the resistance to blood flow (this coiling
may be in response to PGF2, endothelins
this causes hpoxia of the endometrium and tissue degeneration
this also helps to limit blood loss during menstruation
Menstrual bleeding is mostly from arterial rather than venous sources
small hematoma formation helps to develop a cleavage plane to shed the endometrium

The Decidua of the Endometrium

A specialized, highly modified endometrium of pregnancy
Transformation of the secretory endometrium to decidua is dependent on estrogen, progesterone and other stimuli
provided by the implanting blastocyst
Decidua basalis the portion of deciduas directly beneath the site of implantation that is modified by trophoblast invasion
Decidua capsularis the portion overlying the blastocyst and initially separating it from the rest of the uterine cavity
most prominent during 2nd month of pregnancy, consisting of decidual cells covered by a single layer of flattened
epithelial cells without traces of glands; this portion of the decidua contacts the avascular, extra-embryonic fetal
membrane the chorion leave
Remainder of the uterus is lined by decidua parietalis sometimes called the decidua vera when decidua capsularis and
decidua basalis are joined
By 14-16 wks the expanding sac is large enough to fill the entire uterine cavity, and the decidua capsularis and parietalis
are fused
The deciduas basalis and capsularis are each composed of 3 layers: the zona compacta, zona spongiosa (middle) and zona
basalis; the compacta and spongiosa fuse to form the zona functionalis, and the zona basalis remains after delivery and
gives rise to the new endometrium
Decidual reaction completed only with blastocyst implantation, but predecidual changes start first in endometrial
stromal cells adjacent to spiral arterioles, and then spread through the mucosa of the uterus and then from the
implantation site
Endometrial stromal cells enlarge to form polygonal or round decidual cells nuclei become round and vesicular,
cytoplasm becomes clear and slightly basophilic, surrounded by a translucent membrane
Blood Supply changes as a consequence of implantation
Blood to deciduas capsularis is lost as it expands with fetus
The supply to the parietalis through the spiral arterioles persists; they are still responsive to vasoactive compounds
The spiral arteriole system supplying the deciduas basalis right under the blastocyst is changed considerably; the
arterioles are invaded by cytotrophoblasts, and the walls of the vessels are destroyed leaving only a shell without
smooth muscle or endothelial cells these are vascular conduits of maternal blood which become the uteroplacental
vessels not responsive to vasoactive substances
Fetal chorionic vessels transport blood between the placenta and fetus, contain smooth muscle and do respond to
vasoactive agents
Histology
Compact layer of the deciduas consists of large, closely packed, epithelioid, polygonal, lightly staining cells with
round vesicular nuclei
Many stromal cells appear stellate
Uterine large granular lymphocytes (a particular type of NK cell) these are bone marrow derived cells that
entered the endometrium from peripheral blood, but then continue to arise primarily by replication in the
endometrium in situ at specific times in the cycle
Spongy layer marked by hyperplasia of the glands (which later disappear) and hypertrophy of the stroma
Decidua basalis contributes to the formation of the basal plate of the placenta, and differs histologically from the deciduas
parietalis by:
Spongy layer of basalis consists mainly of arteries and widely dilated veins, by term the glands have virtually
disappeared

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Decidua basalis is invaded by trophoblastic giant cells which appear at the time of implantation; number and depth
vary greatly
Nitabuch layer is a zone of degeneration where the trophoblasts and decidua meet
defective or absent nitabuch layer is often present in placenta accreta
Decidual necrosis is a normal phenomenon in T1 and T2, and not the cause of SA
Prolactin in the decidua Decidua is the source of prolactin in the amniotic fluid
The concentration of prolactin in the fluid is extraordinarily high compared with the highest level of prolactin in fetal
or maternal plasma
Prolactin enters the fluid preferentially, and little or none enters the maternal blood is a classic example of peculiar
trafficking of molecules between maternal and fetal tissues of the paracrine arm of the fetal-maternal communication
system
Physiological role of prolactin is unknown

Overview of Endometrial Function

Contains epithelial (glandular) cells, stromal (mesenchymal) cells, blood vessels
Superficial 2/3 of the endometrium is shed and regenerated
The single physiologic function of the endometrium/decidua is to serve as the maternal tissue interface of pregnancy
Decidual cells are differentiated from the stromal cells of the endometrium under the influence of progesterone and other
stimuli
The unique spiral arteries persist in the decidua parietalis, but are invaded and modified by trophoblasts in the decidua
basalis underlying the implantation site
Decidua serves as a immunologically specialized tissue
Endometrium/decidua and spiral arteries accept trophoblast invasion, providing for embryo/fetal nutrition
Decidua contributes cytokines, growth factors that promote placental growth, function and the inhibition of trophoblast
apoptosis

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Implantation and Formation of the Placenta and Fetal Membranes

The human placenta is a hemochorioendothelial type placenta
The extra-villous and villous trophoblasts are the embryonic-fetal tissues of the anatomical interface of the placental arm
The avascular fetal membranes amnion and chorion lavae are the fetal tissues of the anatomical interface of the
paracrine arm of the system
Maternal blood directly bathes the syncytiotrophoblast; fetal blood is contained in the fetal capillaries which traverse
within the intervillous spaces of the villi
All cells with direct contact are maternal and extra-embryonic (trophoblasts) not embryonic cells or fetal blood

Zygote the cell that results from the fertilization of the ovum by the sperm
Blastomere Mitotic division of the zygote (cleavage) yields daughter cells called blastomeres
Morula the solid ball of cells formed by ~16 blastomeres
Embryo the embryo forming cells, group together in the inner cell mass and give rise to the embryo, which is designated
when the bilaminar embryonic disc forms. The embryonic period extends until the end of the 7 th week, at which time the
major structures are present
Fetus after the embryonic period, the developing conceptus is called a fetus
Conceptus term refers to all products of conception embryo, placenta, membranes; all tissues which develop from the
zygote

Fertilization and Implantation

Fertilization occurs in the fallopian tube; within minutes to hours of ovulation
Morula enters the uterine cavity ~3 days post fertilization
Gradual accumulation of fluid between blastomeres within the morula results in the blastocyst one end has a compact
group of cells, the inner cell mass (leads to embryo); outer cell mass destined to become trophoblasts
Zona pellucida disappears, and the blastocyst touches the endometrial surface (is composed of 107 256 cells)
Implantation most commonly occurs on the upper part and posterior wall of the uterus; erosion of epithelial endometrial
cells, and invasion by trophoblasts
Eventually the trophoblast becomes encased and covered by endometrium
As the blastocyst and its surrounding trophoblasts grow and expand, one pole extends toward the endometrial cavity, and
the other pole remains buried in the endometrium/decidua
The innermost pole forms the placenta that is anchoring cytotrophoblasts and villous trophoblasts

Biology of the Trophoblast

Trophoblasts are either cytotrophoblasts (inner ones) or syncytiotrophoblasts (outer ones)
cytotrophoblasts are the germinal cells for the syncytiotrophoblasts
the syncytium is composed of syncytiotrophoblasts and is essentially a single contiguous membrane with amorphous
cytoplasm, no cell borders multiple nuclei
the absence of cell borders in the syncytium facilitates nutrient transport
The functions of the trophoblast invading the endometrium is indistinguishable from those of metastasizing malignant
cells

Embryonic Development After Implantation

after erosion of the surface endothmetrium, the invading trophoblasts burrow deeper into the endometrium and by the 10 th
day the blastocyst is totally encased within the endometrium
at day 9, the wall of the blastocyst facing toward the uterine cavity is a single layer of flattened cells
the opposite thicker wall has 2 zones, the trophoblasts and the inner cell mass
the inner cell mass (the embryonic disc) is further differentiated into primitive ectoderm and endoderm
the space between the disc and the trophoblasts will be come the amniotic cavity
The embryonic mesenchyme first appears as isolated cells in the blastocyst cavity, but the cavity is soon lined by
mesoderm now called the chorionic vesicle (lined by chorion composed of trophoblasts and mesenchyme)
The mesenchymal cells are most numerous around the embryo, where they eventually condense to form the body stalk
this serves to join the embryo to the nutrient chorion and later develops into the umbilical cord

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Decidual reaction intensifies in the surrounding stroma this is characterized by enlargement of the decidual stromal cells
and glycogen storage

Chorionic Villi
Chorionic Villi villi can be distinguished 12 days after fertilization
When a mesenchymal cord, presumably derived from cytotrophoblasts, invades the solid trophoblast column, secondary
villi are formed
After angiogenesis occurs from the mesenchymal cords in situ, the resulting villi are termed tertiary
By the 17th day, fetal blood vessels are functional and a placental circulation is established
Fetal-placental circulation is completed when the blood vessels of the embryo are connected with the chorionic blood
vessels
Until the end of month 3, the chorion lavae is separated from the amnion by the exocoelomic cavity thereafter, the
amnion and chorion are in intimate contact
The amnio-chorion constitute the paracrine arm of the fetal-maternal communication system

Placental Developoment

1. Development of the Chorion and Decidua

the trophoblasts at the deepest pole of the blastocyst proliferate to form the chorion frondosum
meanwhile the villi facing the endometrial cavity are restricted in blood supply and stop growing
by the end of the 3rd month the chorion and amnion are in intimate contact
2. Trophoblast Invasion of the Endometrium
3. Decidual Spiral Artery Invasion
The capillary network of the most superficial portion of the endometrium is invaded by cytotrophoblasts
Subsequently the arterioles and then spiral arteries are invaded, and the walls of the vessels are destroyed
During implantation, the spiral arteries acquire a lining of cells within the endothelium that is derived from invading
cytotrophoblasts during this, degenerative changes take place in the arterial wall affecting all layers, but the most
striking is that vascular smooth muscle becomes unrecognizable
Cytotrophoblasts that invade the spiral arteries can pass several cm along the vessel lumen; these vascular changes are not
seen in the decidua parietalis
Intraluminal cytotrophoblasts diminish at term
Invasion of maternal vascular tissue by trophoblasts involves only the decidual spiral arteries, not the decidual veins
4. Establishment of Maternal Blood Flow
at approximately 1 month, maternal blood enters the intervillous space from the spiral arteries and bathes the
syncytiotrophoblasts
5. Villous Branching
some villi of the chorion frondsoum exted to the decidua to serve as anchoring villi
most villi however, end short of this and just end in the intervillous spae

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Placental Growth and Maturation

Placental Growth
in the first trimester placental growth is faster than fetal
by 17 wks, the weights are equal
at term placental weight = 1/6 of fetal
Individual cotyledons grow in size, but same number is maintained
At term, on average: 185mm in diameter, 23 mm in thickness, average volume of 497 ml, and weight of 508g

Placental Maturation
Placental Aging the villi continue to branch and the terminal ramifications become smaller and the volume and
prominence of the cytotrophoblasts decrease
As the syncitium thins, the vessels become more prominent and lie closer to the surface
Stroma also becomes denser packed and the cells more spindly
Hofbauer cells appear in the stroma these are like fetal macrophages round with vesicular, eccentric nuclei and very
granular or vacuolated cytoplasm
By 4 months the apparent continuity of the cytotrophoblasts is broken, and the syncitium forms knots on the more
numerous smaller villi

Fetal and Maternal Blood Circulation in the Mature Placenta

Fetal Circulation
fetal deoxygenated blood or venous-like blood flows to the placenta through two umbilical arteries
At the juncture of the umbilical cord with the placenta, the umbilical vessels branch repeatedly beneath the amnion and
again within the dividing villi
Blood with significantly higher oxygen content returns from the placenta to the fetus through a single umbilical vein
The vessels on the placental surface (chorionic plate) are responsive to vasoactive substances but they are curious
Chorionic arteries always cross over the chorionic veins
Immediately after entering the chorionic plate, the two umbilical arteries are connected transversely by the Hyrtl
Anastomosis (rarely missing)
The 2 umbilical arteries then separate to supply branches to the cotyledons there are 2 patterns of branching
disperse (65%) which are a fine network of vessels that go to the cotyledons, and magistral (35%) which are arteries
that traverse the placenta without appreciable decrease in the diameter of the vessel
truncal arteries are the perforating branches of the surface arteries that ass through the chorionic plate each supplyine
one cotyledon these arteries have decreased smooth muscle
At ~10 post conceptional weeks the pattern of umbilical blood velocity waveforms changes considerably i.e before this
time, there is no end diastolic frequency
definitive chorionic plate is formed by 8-10 weeks as the amnion and the primary chorionic plate mesenchyme fuse
with each other
Maternal Circulation
blood needs to leave the maternal circulation, flow into an amorphous space (lined by trophoblast syncitium, rather than
vascular endothelium) and then return through maternal veins without producing arterio-venous like shunts that would
prevent maternal blood from remaining in contact with the villi long enough for adequate exchange
arterial entrances as well as venous exits are scattered at random over the entire base of the placenta
maternal blood enters through the basal plate pushed by maternal arterial pressure, and then lateral dispersion occurs
trophoblast invasion of the spiral areteries facilitaes creation of low-resistance uteroplacental vessels
after bathing the extravillous surface of the chorionic villi, the maternal blood drains back through the venous orifices in
the basal plate and enters the uterine veins; the veins are usually parallel to the uterine wall and the arteries are
perpendicular, so blood is not squeezed back during a contraction
after week 30, a prominent venous plexus separates the decidua basalis from the myometrium this participates in
providing a plane of cleavage for placental separation

Immunological Considerations of the Fetal-Maternal Interface

Trophoblasts have immunological peculiarity; they are all from conceptus origin i.e. no maternal cells

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It is still an enigma as to why maternal tissues tolerate the fetal graft

HLA antigens are absent from villous trophoblasts - they may be immunologically inert
BUT invasive cytotrophoblasts do express HLA I molecules
Uterine Large Granular Lymphocytes (LGLs)
believed to oiriginate in the bone marrow
infiltration increases in response to progesterone, IL-15, PRL
LGLs may serve to regulate trophoblast invasion
HLA-G Expression in Human Trophoblasts
not expressed in villous trophoblast
it is expressed in cytotrophoblasts that are contiguous with maternal tissues
Trophoblasts express HLA-G this is a monomorphic Ag, and is recognized as self, by the mother; its expression
might be stimulated by hypoxia
there is also abnormal expression of HLA-G in trophoblasts from women with preclampsia)

The Amnion
at term, is a tough, tenacious, pliable membrane
it is the innermost fetal membrane; it is avascular; consists of 5 layers
o innermost single layer of cuboidal cells
o basement membrane
o acellular compact layer of collagens I, III, V
o row of fibroblast-like mesenchymal cells
o acellular zona spongiosa (contiguous with the chorion)
Development
o A space develops between the embryonic cell mass and the adjacent trophoblasts
o Small cells that line this space are called amniogenic cells
o The amnion is first identifiable on day 7-8 of embryo development
o As the amnion enlarges, it engulfs the growing embryo which prolapses into its cavity; distention of the
sac eventually brings it into contact with the chorion
o Amnion and chorion lavae are never intimately connected and can be separated easily, even at term
Histogenesis:
o It is generally accepted that the epithelial cells of the amnion are derived from fetal ectoderm of the
embryonic disc
o The apical surface of the epithelial cells is replete with highly developed microvilli, consistent with a
major site of transfer between amniotic fluid and amnion
o The amnion mesenchymal cells of the fibroblast layer are responsible for the major amnion functions
the synthesis of the collagens, the source of the major tensile strength of the amnion takes place here;
likely mostly collagen III
o The mesenchymal cells can also synthesize cytokines, and do so in response to bacteria
Metabolic functions: involved in solute and water transport, and produces vasoactive peptides, growth factors and
cytokines
o these factors may diffuse into the chorion or into the amniotic fluid for the fetus to swallow
Amniotic fluid: increases in quantity until 34 wks, and then decreases; average volume is ~1000cc at term

Umbilical Cord and Related Structures

Development yolk sac, and umbilical vesicle into which it develops are quite prominent in early pregnancy
At first the embryo is a flattened disc between the amnion and the yolk sac
As the embryo grows, it bulges into the amniotic sac, and the dorsal part of the yolk sac is incorporated into the
body of the embryo to form the gut
The allantois projects into the base of the body stalk from the caudal wall of the yolk sac
As pregnancy advances, the yolk sac becomes smaller, and the pedicle longer
By the third month the expanding amnion obliterates the exocoelom, fuses with the chorion lavae and covers the
bulging placental disc, and the lateral surface of the body stalk which is then called the umbilical cord, or funis
Remanats of the exocoelom in the anterior portion of the cord may contain loops of intestine, which continue to
develop outside the embryo

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The loops are later withdrawn, but the apex of the midgut loop retains its connection with the attenuated vitteline
duct
The duct terminates in a crumpled, highly vascular sac, 3-5cm in diameter, lying on the surface of the placenta
between the amnion and chorion, or in the membranes just beyond the placental margin, where it can be identified
at term
The right umbilical vein usually disappears during development, leaving only one vein (the left one!)
The intra-abdominal portion of the duct of the umbilical vesicle, which extends from the umbilicus to the intestine,
usually atrophies and disappears, but occasionally remains patent, forming a Meckels diverticulum
The most common vascular anomaly is one umbilical artery

Structure and Function

o Surface of the cord is covered by amnion; diameter is 0.8-2cm and average length is 55cm (range 30 100
cm)
o Extracellular matrix is comprised of Whartons jelly
o Blood flows from the umbilical vein via 2 routes the ductus venosus, which empties directly into the
inferior vena cava, and numerous smaller openings into the fetal circulation, then into the IVC by the
hepatic vein

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Placental Hormones
Human trophoblasts produce a large amount of steroid and protein hormones
A unique and obligatory relationship exists between the fetal adrenal secretion of large amounts of C19 steroids
which serve as plasma borne precursors for estrogen synthesis
Human syncitiotrophoblast also takes up maternal LDL cholesterol for use in progesterone biosynthesis
Protein and peptide Hormones produced by the placenta: placental lactogen, hCG, ACTH, proopiomelanocortin,
chorionic thyrotropin, GH variant, PTH-rP, calcitonin, relaxin
Hypothalamic like releasing and inhibiting hormones: TRH, GnRH, CRH, somatostatin, GHRH
Also produces inhibins, activins, and ANP

Human Chorionic Gonadotropin (hCG)

A glycoprotein with biological activity similar to LH
They both act via the LH/hCG receptor
HCG is produced almost exclusively in the placenta, specifically the syncitiotrophoblast cells
Also synthesized by the fetal kidney, and quite a few fetal tissues produce the -subunit or intact hCG molecule
Malignant tumors with neoplastic trophoblast cells also produce hCG
Chemical Characteristics
HCG is a glycoprotien (40,000 D) with the highest CHO content of any human hormone (this protects the
molecule from catabolism)
The plasma half life is 36 hrs
The molecule is made of 2 dissimilar subunits: (92 a.a.) and (145 a.a.), which are noncovalently linked held
together by electrostatic and hydrophobic forces
HCG is related structurally to 3 other glycoprotein hormones: LH, FSH, TSH the a.a. sequence of the -subunit
is identical
Biosynthesis
both subunits are synthesiszed as larger molecular weight precursors which are cleaved by microsomal
endopteptidases
the molecule is released by exocytosis after the subunits are assembled
Cellular Origin of hCG
Less than 5 wks origin is syncytiotrophoblasts and cytotrophoblasts
later in gestation it is produced almost solely by syncytiotrophoblasts
Molecular Forms of hCG in Plasma and Urine
there are variations in form due to varied degradation, synthesis and processing
Free Subunits
o -subunit production is slower so, there really isnt any free subunits about
o -subunit production peaks at 8-10 wks
o -subunit production is dependent on placental size, so when -subunit production is low, the proportion
of free subunit peaks (3rd Trimester)
Nicks in the -HcG Molecule
o these occur naturally the significance is unknown, but their detection is variable
o this is concerning in GTD because the proportion of nicked subunits can be higher
Concentrations of hCG in Serum and Urine
HCG is detectable in plasma on day 7-9 after LH surge
This corresponds to the entry of blastocyst implantation
levels double q2days til max at 8-10 weeks
there is variation in production during the course of a single day
around week 10-12, levels start to decline
nadir is reached ~ 20 wks where they remain stable
fetal serum concentrations are 3% of maternal serum concentrations

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amniotic fluid concentrations is similar to maternal plasma concentration, but by term concentration is only 1/5 of
maternal plasma
Elevated or Depressed hCG Levels in Maternal Plasma or Urine
High hCG found in pregnancies with multiple fetuses, D-Ag isoimmunization, mole or choriocarcinoma
Relatively higher levels are found in mid-trimester in pregnancies with Downs reason for this is unclear, but
speculated that placenta is less mature
Regulation of hCG Synthesis
placental GnRH is likely involved, but in general the in vivo regulation of hCG is not understood
Metabolic Clearance
30% renally cleared and otherwise metabolized in liver and kidney
Biological Functions of hCG
Rescue of the Corpus Luteum: Best known biological function of hCG is rescue and maintenance of the function
of the corpus luteum that is continued progesterone production
HCG Stimulation of Fetal Testis: peak of hCG is at the same time as max fetal testosterone secretion i.e. critical
time of male sexual differentiation the hCG in this case acts as an LH surrogate and stimulates replication of fetal
testicular Leydig cells and testosterone synthesis; reason is the fetal pituitary is not functioning yet so hCG acts as
LH
HCG stimulation of the maternal thyroid: some forms of hCG bind to the TSH receptors of the thyroid cells; there
is also some evidence that there are LH/hCg receptors in the thyroid
Others: hCG acts in vivo to promote relaxin secretion by the corpus luteum and may promote vascular vasodilation
and smooth muscle relaxation in the uterus

Human Placental Lactogen

Has potent lactogenic and growth hormone like bioactivity
Concentrated in the syncitiotrophoblast; however like hCG, hPL is found in the cytotrophoblast from 6 weeks
gestation
Chemical Characteristics:
Single, non-glycosylated polypeptide chain containing 191 a.a., that has a 96% homology to growth hormone
HPL is structurally similar to prolactin (67% a.a. homology)
Gene Structure and Expression
the expression near term is ~ 1 g/day and is the greatest, by far, of any known human hormone
Serum Concentration
hPL is detected in placenta at 5-10 days post conception, and in serum 3 weeks after fertilization
Maternal plasma conc rise steadily to 34-36 wks, and is approximately proportional to placental mass
Half life in maternal plasma is 10-30 minutes
very little is found in fetal blood or urine of mother or babe
amniotic fluid levels are lower than maternal plasma
Metabolic Actions
Maternal Lipolysis and an increase in the levels of circulating ffa thereby providing a source of energy for
maternal metabolism and fetal nutrition
An anti-insulin action, leading to an increase in the maternal insulin levels, which favours protein synthesis and
provides a mobilizable source of a.a. for transport to the fetus
Potent angiogenic hormone may play an important role in formation of fetal vasculature

Other Placental Protein Hormones

Chorionic Adrenocorticotropin
A protein similar to ACTH
Physiological role of placental ACTH is unclear
Relaxin
synthesized as a preprorelaxin molecule that is cleaved into A and B molecules
structurally similar to insulin and insulin-like growth factor

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levels parallel HCG and early production is by corpus luteum

may act on uterus to induce quiescence early inpregnancy
may also play a role in the puerperium
Parathyroid Hormone-Related Protein (PTH-rP)
Present in myometrium, endometrium, corpus luteum and lactating mammary tissue, and a number of fetal tissues
may have a role on the trophoblast to promote calcium transport for fetal bone growth and ossification
levels are elevated in maternal but not fetal circulation
Growth Hormone Variant
Expressed in the placenta, but not in the pituitary
Pattern of synthesis with gestation is not exactly known
May mediate insulin resistance of pregnancy

Hypothalamic-Like Releasing Hormones

Gonadotropin-Releasing Hormone (GnRH)
reulates hCG production and parallels its levels
is also responsible for increased levels of maternal GnRH seen in early pregnancy
Corticotropin-Releasing Hormone (CRH)
exist in low-levels pre-pregnancy, but increase dramatically by the end of gestation
with the onset of labour, CRH levels further increase by 2-3 X
function to increase ACTH secretion
may induce Myometrial relaxation and cause immunosuppression
o yet near the end of gestation, may cause Myometrial contractions
may be involved in a unique positive feedback loop
Growth Hormone-Releasing Hormone (GHRH)
has been found in placenta, but function unknown

Other Placental Peptide Hormones

Leptin
normally secreted by adipocytes
regulates bone growth and immune function
levels correlate with fetal birthweight
Neuropeptide-Y
36 a.a. peptide is widely distributed in the brain
isolated in the cytotrophoblasts
treatment of placental cells with NPY causes release of CRH
Inhibin and Activin
Inhibin a glycoprotein hormone that acts preferentially to inhibit FSH release by the pituitary; produced by
human testes and granulosa cells in ovary, includes CL
Inhibin produced in placenta, along with high sex steroid levels may function to inhibit FSH and preclude
ovulation during pregnancy
Inhibin may act via GnRH to regulate hCG synthesis/secretion in placenta
Activin closely related to inhibin; unknown role

Placental Progesterone Production

After 6-7 weeks of gestation, there is very little progesterone produced by the ovary
after 8 wks, placenta replaces ovarey as the source of progesterone

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there is a gradual increase in levels through remainder of pregnancy and by the end, levels are up to 5000 times of
nonpregnant
Progesterone Production rates 250mg/ day with singleton fetus (> 600 with multiples)
Source of Cholesterol for Placental Progesterone Biosynthesis
Is synthesized in a 2 step reaction
o First, cholesterol converted, in mitochondria to pregnenolone
o Then, pregnenolone is converted to progesterone in endoplasmic reticulum
Placenta relies on exogenous cholesterol for progesterone production
Maternal plasma cholesterol is the principle placental precursor to progesterone biosynthesis in human pregnancy
Progesterone synthesis and fetal well-being unlike estrogen synthesis, progesterone synthesis is not dependent on
a live fetus
Progesterone Metabolism During Pregnancy

Placental Estrogen Production

placenta produces huge amounts of estrogen and progesterone
during the first 2-4 wks of pregnancy, rising levels of hCG maintain production of estradiol in the CL
by the 7th week, 50% of estrogen entering maternal circulation is placental in origin
Placental Estrogen Biosynthesis
Different biosynthesis than from the ovarian follicle
Estrogen is produced in the placenta de novo from acetate or cholesterol reason for this is that steroid 17-
hydroxylase/ 17, 20 desmolase is not expressed in the human placenta
Plasma C19 steroids as estrogen precursors i.e. DHEAS, androstenedione and testosterone are all converted to
estrogens by the placenta using a sulfatase enzyme
o by the 30th week, 30-40% of DHEAS secreted by the maternal adrenal glands is converted to estradiol-17
Placental Aromatase Enzyme principle location is in the syncitiotrophoblast
Secreted Estrogens human placenta secretes 17-estrodiol as well as estriol (via 16-hydroxyandrostenedione
which is converted to 16-hydroxyestrone, then converted to estriol)
Metabolism of Dehydroepiandrosterone Sulfate removed from maternal serum at a high rate via:
o Conversion to 17B-estradiol in the syncitium
o Accelerated 16a-hydroxylation (probably in maternal liver), with 30-40% converted near term to 16a-
DHA sulfate
The maternal adrenal glands do not produce enough DHEAS during pregnancy to account for the large amounts of
placental estrogen, therefore the fetal adrenal glands are the quantitatively important source of placental estrogen
precursors in human pregnancy

Fetal Adrenal Glands

Adrenal cortex in the fetus is the largest organ of the fetus
>85% of the fetal gland is composed of a fetal zone, not found in adults
daily production of steroids by the adrenal fetal gland is 100-200mg/day
Contribution to Placental Estrogen Formation it has been found that women carrying anencephalic fetuses
secrete very little estrogen this is likely because the fetal pituitary is required to produce ACTH to stimulate the
adrenals, and if there is no brain then there is no stimulus for the adrenals to enlarge and start to produce steroid
progenitors
Placental Estriol Synthesis there is a disproportionate amount of estriol produced during pregnancy; this is
accounted for by the placental synthesis of estriol from 16-hydroxydehydroepiandrosterone sulfate which is
synthesized by the fetal adrenal and by 16-hydroxylation of plasma DHEAS by the fetal liver; near term the fetus
is the source of 90% of the estriol precursor
Fetal Adrenal Development primitive adrenal gland is formed by 6-8 wks
o ACTH is not necessary for the early stages of formation, adrenal gland is formed in anemcephalic fetus
o ACTH is required though for gland development later in pregnancy
Fetal Adrenal Morphology inner fetal zone accounts for the bulk of the gland and is the source for steroid
precursors
o the outer zone is called the definitive zone and gives rise to the adult adrenal glomerulosa

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 Williams Chapter 3: Implantation, Embryogenesis, and Placental Development

o adrenal cortex undergoes involution beginning at birth; the weight of the adrenal glands decreases
strinkingly during the first few weeks of life and does not reach that size again until adolescence
Fetal Adrenal Growth continues to grow during pregnancy, and in last 5-6 weeks, there is rapid increase in
adrenal size
Precursor for fetal adrenal steroidogenesis is cholesterol, but cholesterol can also be synthesized from 2-carbon
fragments i.e. acetate
Fetal adrenals are highly dependent on LDL for their cholesterol
adrenals cant make enough cholesterol to keep up, so it gets some from plasma
o majority of plasma cholesterol arises by de novo synthesis in the fetal liver
o low levels of LDL are indicative of high use
o high levels of LDL in anencephalics

Fetal Conditions that affect Estrogen Production

1. Fetal Death huge decrease in estrogen, but not progesterone
2. Fetal Anencephaly all steroids produced are from placental use of maternal DHEAS; estriol production is
also disproportionately decreased
3. Fetal Adrenal Hypoplasia very rare; hypoplasia of adrenal in otherwise normal fetus
4. Placental Sulfatase Deficiency X-linked disorders (all affected fetuses are male) and is associated with
development of ichthyosis in affected males in later life
5. Placental Aromatase Deficiency a few well documented examples; basically aromatase is needed to convert
the androstenedione (from all of the fetal DHEAS) to estriol and estradiol using aromatase enzyme; if there is
not aromatase then there is a build up of androstenedione and testosterone, causing maternal virilization and
virilization of a female fetus
Pregnancies with aromatase deficiency and a male fetus are unremarkable however the estrogen
deficient men do not have proper epiphyseal closure and continue to grow during adulthood, becoming
very tall and having deficient mineralization of bone
6. Down Syndrome unconjugated estriol levels are very low; reason is unknown, but may be due to inadequate
formation of C19 steroids in the adrenal glands
7. Deficiency in Fetal LDL Cholesterol Biosynthesis pregnancy in a woman deficient in LDL has been
described, but estrogen levels were lower than normal
8. Fetal Erythroblastosis in some severe cases, the plasma estrogen level is high; likely due to placental
hypertrophy that occurs
9. Decreased Fetal Adrenal Use of LDL most common cause of decreased placental estrogen formation (aside
from fetal death), is an acquired reduction in fetal adrenal use of plasma LDL this has been observed in
pregnancies complicated by severe diabetes or HTN; the final consequence is decreased estrogen levels

Maternal Conditions that Affect Estrogen Formation

1. Glucocorticoid Treatment moderate to high dose causes striking reduction in placental estrogen formation;
act to inhibit maternal and fetal ACTH secretion, leading to decreased estrogen precursor i.e. DHEAS
2. Maternal Adrenal Dysfunction in women with Addisons disease, estrogen levels are decreased (decrease
primarily affects estrone and 17B-estradiol)
3. Maternal Ovarian Androgen-producing tumors virtually all androstenedione that enters the intervillous space
is taken up by syncitium and converted to 17B-estradiol (none escapes to the fetus so it would be the rare
case that a female fetus is virilized by an androgen secreting maternal tumor only way this could happen is if
a non-aromatizable steroid i.e. 5a-DHT, was produced)
4. Maternal Renal Disease lower levels of maternal urinary estriol are seen with pyelo presumably due to
decreased clearance
5. Maternal Hypertensive disorders and diabetes in disorders where there is decreased uteroplacental blood
flow, fetal adrenal formation of DHEAS is impaired
6. Gestational Trophoblastic Disease in complete mole, there is no fetal adrenal source for C19 steroid
precursor for trophoblast estrogen biosynthesis, so estrogen synthesis is limited by C19 steroids in the
maternal plasma, and the estrogen produced is 17B-estradiol

Directional Secretion of Steroids from Syncitiotrophoblast

Estrogens synthesized in the syncitium preferentially enter the maternal circulation, same is true of progesterone

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 Williams Chapter 3: Implantation, Embryogenesis, and Placental Development

Very little maternal plasma progesterone crosses the placenta to the fetus, and 85% of the placental progesterone
enters the maternal circulation
The placental estrogens that enter the maternal circulation are estriol and 17B-estradiol these both enter the fetus
(in small amounts) also - with estrone preferentially entering
Placentally produced estriol enters both the mother and fetus, with 90% entering the mother
Steroids easily enter the maternal circulation as they are produced by the syncitiotrophoblast cells, since maternal
blood bathes these cells
Steroids from these trophoblasts enter the fetus traverse the cytotrophoblasts and enter the intervillous space, they
must then traverse the walls of the fetal capillaries to reach fetal blood; this is difficult so the majority of steroids
enter the maternal circulation

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