CHAPTER 5: IMPLANTATION AND PLACENTAL DEVELOPMENT

 Follicular development consists of several stages:

THE OVARIAN-ENDOMETRIAL CYCLE gonadotropin-independent recruitment of primordial
follicles from the resting pool and their growth ot the
 Average cycle duration: 28 days (range 25-32 days)
antral stage.
The Ovarian Cycle  Controlled by growth factors:
A. Follicular or Preovulatory Ovarian Phase o 2 members of Transforming growth factor-β
a. Growth Differentiation Factor 9 (GDF9)
 Ovary contains 2million oocytes at birth b. Bone morphogenetic protein 15 (BMP15)
 400,000 follicles at puberty onset o Regulate granulosa cell proliferation and
 Remaining follicles are depleted at approx. 1000 follicles differentiation as primary follicles grow
per month until age 35 (rate accelerates o Stabilize and expand the cumulus oocyte complex in
 400 follicles – released during female reproductive life. the oviduct.
 99.9% of follicles undergo atresia o Produced by oocytes

 Follicle Stimulating Hormone (FSH)  Only the follicles progressing to SW develop the capacity
 Not required for early follicular maturation to produce estrogen.
 Required for further development of large antral follicles  During follicular phase, estrogen levels rise in parallel to
 Each ovarian cycle, a group of antral follicles (aka cohort), growth of a dominant follicle and to the increase in its
begins a phase of semisynchronous growth based on their number of granulosa cells.
maturation state during the FSH rise in the late luteal  Granulosa cells – exclusive site of FSH receptor expression.
phase of the previous cycle.  Rise in FSH levels in the previous late luteal phase
 Selection Window – FSH rise leading to follicle stimulates an increase in FSH receptors increase the
development ability of CYP450 aromatase within granulosa cells to
convert androstenedione into estrodiol
  Requirement for theca cells (responds to LH) and  During synthesis of the matrix, cumulus cells lose contact
granulosa cells (responds to FSH), represents the two- with one another and move outward from the oocyte
gonadotropin, two-cell hypothesis for estrogen along the hyaluronan polymer – called expansion.
biosynthesis.  Results in a 20-fold increase in the complex volume along
with an LH-induced remodeling of the ovarian
extracellular matrix to allow release of the mature oocyte
and its surrounding cumulus cells through the surface
epithelium.

C. Luteal or Postovulatory Ovarian Phase

 Luteinization – the corpus luteum develops from the

dominant or Graafian follicle remains
 Basement membrane separating the granulosa-lutein and
theca-lutein cells breaks down
o By day 2 postovulation, blood vessels and capillaries
invade the granulosa cell layer
 Rapid neovascularization of the once-avascular granulosa
due to:
 As shown above, FSH induces aromatase and expansion of o angiogenic factors that include vascular endothelial
the antrum of growing follicles. growth factor (VEGF)
 The follicle within the cohort that is most responsive to o Others produced in response to LH by theca-lutein
FSH is likely to be the 1st to produce estradiol and initiate and granulosa-lutein cells.
expression of LH receptors. o During luteinization, these cells undergo hypertrophy
 After the appearance of LH receptors: and increase their capacity to synthesize hormones
o Preovulatory granulosa cells begin to secrete small  Primary luteotropic factor responsible for corpus luteum
quantities of progesterone. maintenance: Luteinizing Hormone
o Then exerts positive feedback on the estrogen-primed  Corpus luteum maintained by; low-frequency, high-
pituitary to either cause or augment LH release. amplitude LH pulses secreted by gonadotropes in the
 During the late follicular phase: anterior pituitary.
o LH stimulates thecal cell production of androgens  Increased capacity of granulosa-lutein cells to produce
(androstendione) progesterone is the result of increased access to
o Then transferred to the adjacent follicles where they considerably more steroidogenic precursors – blood-
are aromatized to estradiol. borne LDL-derived cholesterol.
 In early follicular phase, granulosa cells begin to produce  LDL is important in progesterone biosynthesis.
inhibin B which can feed back on the pituitary to inhibit o Women with extremely low LDL cholesterol levels
FSH release. exhibit minimal progesterone secretion during luteal
 As the dominant follicle begins to grow, production of phase.
estradiol and the inhibins increases and results in a  HDL – contributes to progesterone production in
decline of Follicular-phase FSH. granulosa-lutein cells.
 Drop in FSH levels – responsible for the failure of other  Estrogen levels follow a more complex pattern of
follicles to reach preovularoty status (Graafian follicle secretion:
stage) duing any one cycle. o Just after ovulation: ↓Estrogen followed by a
 Thus, 95% of plasma estradiol produced at this time is secondary rise that reaches a peak production of
secreted by the dominant follicle (one destined to 0.25mg/day of 17β-estradiol at the midluteal phase.
ovulate) o Toward the end of luteal phase: secondary decline
 Ovarian progesterone production peaks at 25-50mg/day
B. Ovulation
during midluteal phase.
 Predictor of ovulation:  Corpus luteum:
 Onset of the gonadotropin surge resulting from o In pregnancy, continues progesterone production in
increasing estrogen secretion by preovulatory follicles response to embryonic hCG, which binds to the same
 Occurs: 34-36 hrs before ovum release from the follicle receptor as LH.
 LH secretion: peaks 10-12 hrs before ovulation o A transient endocrine organ
o stimulates resumption of meiosis in the ovum o Absence of pregnancy: regresses 9-11 days after
o release of the first polar body ovulation via apoptotic cell death.
 In response to LH:  Luteolysis:
o Increased progesterone and prostaglandin production o Mechanism of control is unkown
by the cumulus cells and GDF9 and BMP-15 by the o In part, it results from ↓ levels of circulating LH in the
oocyte  activates espression of genes critical to late luteal phase and ↓ LH sensitivity of luteal cells.
formation of a hyaluronan-rich extracellular matrix by  Endocrine Effects:
cumulus complex.
 o Drop in circulating estradiol and progesterone levels – o Proliferation of glandular, stromal and vascular
for follicular development and ovulation during the endothelial cells
next ovarian cycle.  Early part of the proliferative phase:
o Corpus luteum regression and decline in circulating o Endometrium is usually less than 2mm thick.
steroid concentrations signal the endometrium to o Glands are narrow, tubular stuctures that pursue
initiate molecular events  menstruation. almost a straight and parallel course from the basalis
layer toward the endometrial cavity
D. Estrogen and Progesterone Action o Day 5: mitotic figures, glandular epithelium, are
identified.
 The fluctuating levels of ovarian steroids are the direct
 Mitotic activity in both epithelium and stroma persists
cause of the endometrial cycle.
until Day 16-17, or 2-3 days after ovulation.
 Most biologically potent naturally occurring estrogen:
 Although blood vessels are numerous and prominent,
o 17β-estradiol
there is no extravascular blood or leukocyte infiltration in
o Secreted by granulosa cells of the dominant follicle
the endometrium.
and luteinized granulosa cells of the corpus luteum.
 Estrogen is the essential hormonal signal on which most
 Reepithelization and angiogenesis are dependent on
events in the normal menstrual cycle depend.
tissue regrowth, which is estrogen regulated.
 Estradiol involves 2 classic nuclear hormone receptors
 Epidermal Growth Factor (EGF) and transforming growth
designated estrogen receptor α (ERα) and β (ERβ):
factor α (TGFα).
o Acts as transcriptional factors that become associated
with the estrogen response element of specific gene.  Stromal cell proliferation appears to increase through
o Both are expressed in the uterine endometrium paracrine and autocrine actions of estrogen and increased
local levels of FGF-9
 Estrogen
- To regulate follicular development, uterine  Estrogens also increase local production of VEGF – causes
receptivity, or blood flow. angiogenesis through vessel elongation in the basalis

 Most progesterone actions on the female reproductive  Late Proliferative phase:

tract are mediated through the nuclear hormone o Endometrium thickens from both glandular
receptors: Progesterone receptor type A (PR-A) and B (PR- hyperplasia and increased stromal substance – edema
B) and proteinaceous material.
 Progesterone enters cells by diffusion and in responsive  Loose stroma – prominent
tissues becomes associated with progesterone receptors.  Glands in the functionalis layer – widely separated.
 Both receptors: Glands in basalis layer – more crowded and stroma is
o From a single gene denser
o Members of the steroid receptor superfamily or  At midcycle, as ovulation nears:
transcription factors o Glandular epithelium becomes taller and
o Regulate transcription of target genes. pseudostratified.
o Surface epithelial cells acquire numerous microvilli
 If both are coexpressed – PR-A can inhibit PR-B gene
regulation. (↑surface area) and cilia (aid in mov’t of endometrial
secretions during the secretory phase).
 Progesterone can evoke rapid responses:
o Changes in intracellular free calcium levels
 Dating the menstrual cycle day by endometrial histological
The Endometrial Cycle criteria is difficult during the proliferative phase because
of considerable phase-length variation among women.
A. Proliferative or Preovulatory Endometrial Phase  Follicular phase:
 Epithelial (glandular cells), o Normally – 5 to 7 days or as long as 21 to 30 days.
Stromal (mesenchymal cells),  Luteal/secretory postovulatory phase:
Blood vessels of the endometrium replicate cyclically in o Constant at 12-14 days
reproductive-aged women at a rapid rate. B. Secretory or Postovulatory Endometrial Phase
 Endometrium is regenerated during each ovarian-  Early secretory phase: endometrial dating is based on
endometrial cycle. glandular epithelium histology.
 Functionalis layer is shed and regenerated from the  After ovulation: estrogen-primed endometrium responds
deeper basalis layer almost 400 times during the to rising progesterone levels in a highly predictable
reproductive lifetime of most women. manner.
 Follicular-phase estradriol production – most important  Day 17: glycogen accumulates in the basal portion of
factor in endometrial recovery following menstruation. glandular epithelium – creating subnuclear vacuoles and
 5th day of endometrial cycle – 5th day of menses: pseudostratification. (1st sign of ovulation that is histo-
o Epithelial surface of the endometrium has been
restored
o Revascularization is in progress.
 Preovulatory endometrium is characterized by:
 Logically evident) o Continuing growth and development of the spiral
 Day 18: vacuoles move to the apical portion of the secretory arteries.
nonciliated cells o From the radial arteries, which are myometrial branches
 Day 19: these cells begin to secrete glycoprotein and of the arcuate and ultimately, uterine vessels
mucopolysaccharide contents into the lumen.  During endometrial growth:
o Glandular cell mitosis ceases with secretory activity d/t o Spiral arteries lengthen at a rate greater than the rate of
rising progesterone levels, which antagonize the mitotic endometrial tissue thickening.
effects of estrogen. o Obliges greater coiling of the already spiraling vessels.
 Estradiol action is also decreased d/t glandular expression of
the type 2 isoform of 17β-hydroxysteroid dehydrogenase –
converts estradiol to the less active estrone.
 Dating in the mid- to late-secretory phase relies on
endometrial stromal changes
 Day 21-24: stroma becomes apparent.
 Day 23-28: characterized by predecidual cells, which surround
spiral areterioles.

 Important feature of secretory-phase endometrium between

days 22 and 25:
o Striking changes associated with predecidual
transformation of the upper 2/3 of the functionalis layer.
o Glands exhibit extensive coiling, and luminal secretions
become visible.
o Can mark the so-called window of impantation seen on
days 20-24.  Spiral artery dev’t reflects a marked induction of angiogenesis
 Epithelial surface cells: decreased microvilli and cilia, – widespread vessel sprouting and extension.
appearance of luminal protrusions on the apical surface.  Regulated by: estrogen- and progesterone-regulated
o These pinopodes are important in preparation for synthesis of VEGF
blastocyst implantation. C. Menstruation
o Also coincide with changes in the surface glycocalyx  Midluteal-secertory phase is a critical branch point in
that allow acceptance of blastocyst. endometrial dev’t and differentiation

 Secretory phase is also highlighted:

  Decidualization process continues – CL rescue and contd o increased prostaglandin-receptor density on blood
progesterone secretion. vessels and surrounding cells.
 Menstruation initiated: ↓ luteal progesterone with luteolysis
Role of prostaglandins, especially vasoconstricting PGF2α
 Histological characteristic of late premenstrual-phase  PGF2α administration to nonpregnant women prompts
endometrium: menstruation and sx that mimic dysmenorrhea.
o Stromal infiltration by neutrophils, giving a a  Painful menstruation is common and likely caused by
pseudoinflammatory appearance to the tissue. mypmentrial contractions and uterine ishchemia.
o Infiltrate day 1 or 2 immediately preceding menses onset.  Believed to be mediated by PGF2α – causes the uppermost
 Endometrial stromal and epithelial cells produce: endometrial zones to become hypoxic.
o IL-8 – a chemotactic-activating factor for neutrophils  Hypoxic environment:
 Endometrium produce: MCP-1 – promotes monocyte o Potent inducer of angiogenesis and vascular permeability
recruitment. factors (VEGF).
 Leukocyte infiltration – key to both endometrial and  Prostaglandin function:
extracellular matrix breakdown and repair of the functionalis o Vasoconstriction
layer. o Myometrial contractions
 Inflammatory tightrope – the ability of macrophages to o Upregulation of proinflammatory responses
assume phenotypes that vary from proinflammatory and F. Activation of Lytic Mechanisms
phagocytic to immunosuppressive and reparative.  Following vasoconstriction and endometrial cytokine changes,
o Relevant to menstruation protease activation within stromal cells and leukocyte
o Tissue breakdown and restoration occur invasion is required to degrade the endometrial interstitial
simultaneously matrix.
 Invading leukocytes secrete enzymes that are members of the  Matrix metalloproteases (MMP-1 and MMP-3):
matrix metalloprotease (MMP) family. o Released from stromal cells an may activate other
D.Anatomical Events During Menstruation neutrophilic proteases such as MMP-8 and MMP-9.
G. Origin of Menstrual Blood
Tissue and vascular changes:  Menstrual bleeding is arterial rather than venous bleeding.
o Follows rupture of a spiral arteriole and consequent
 With endometrial regression, spiral artery coiling becomes
hematoma formation
sufficiently severe that resistance to blood flow increases
o w/ a hematoma – superficial endometrium is distended
causing endometrial hypoxia.
and ruptures.
 Resultant stasis – primary cause of endometrial ischemia and
o Fissures develop in the adjacent functionalis layer, blood
tissue degeneration.
and tissue fragments are sloughed.
 Vasoconstriction precedes menstruation – most striking and
o Hemorrhage stops with arteriolar constriction and
constant event in the cycle.
changes that accompany partial tissue necrosis.
 Intense spiral artery vasoconstriction – serves to limit
 Endometrial surface restoredby:
menstrual blood loss.
o Growth of flanges or collars
 Blood flow – regulated in an endocrine manner by sex steroid
- Forms the everted free ends of the endometrial
hormone-induced modifications of a paracrine-mediated
glands.
vasoactive peptide system.
- Increase in diameter rapidly
E. Prostaglandins and Menstruation
- Epithelial continuity is reestablished by fusion of the
Progesterone withdrawal:
edges of these sheets of migrating cells.
 increases expression of cyclocooxygenase 2 (COX-2):
H.Interval between Menses
o Also called prostaglandin synthase 2
 Modal interval of menstruation: 28 days
o To synthesize prostaglandins.
 Variation is considerable among women, as well as the cycle
 Decreases expression of 15-hydroxyprostaglandin
lengths.
dehydrogenase (PGDH)
 Marked differences in the intervals between menstrual cycles
o Degrades prostaglandins
are not necessarily indicative of infertility.
 Net result:
o increased prostaglandin production by endometrial Decidua
stromal cells  Specialized, highly modified endometrium of pregnancy
 Essential for hemochorial placentation
 o Maternal blood contacts trophoblast  predecidual changes commence first during the midluteal
 Decidualization phase in endometrial stromal cells adjacent to the spiral
o Transformation of secretory endometrium to arteries and arterioles-> spread in waves throughout the
decidua uterine endometrium and then from the implantation
o Dependent on on estrogen and progesterone site
and factors secreted by implanting blastocyst  endometrial stromal cells enlarge to from polygonal or
round decidual cells
Decidual Structure
 nuclei become round and vesicular
1. Decidua basalis
 Decidua directly beneath blastocyst implantation is  cytoplasm becomes clear, slightly basophilic, and
modified by trophoblast invasion surrounded by a pericellular membrane
2. Decidua capsularis  human decidual cells clearly build walls around
 Overlies the enlarging blastocyst and initially themselves and possibly around the fetus
separates the conceptus from the rest of the uterine  the pericellular matrix surrounding the decidual cells may
cavity allow attachment of cytotrophoblasts through cellular
 Most prominent during the 2nd month of pregnancy adhesion molecules
and consists of decidual cells covered by a single  the cell membrane may provide cell protection against
layer of flattened epithelial cells selected cytotrophoblastic proteases
 Contacts the avascular, extraembryonic fetal
membrane- chorion leave Decidual Blood Supply
3. Decidua parietalis
 blood supply to the decidua capsularis is lost as the
 Remainder of the uterus
embryo-fetus grows
During early pregnancy  blood supply to the decidua parietalis through spiral
 there is a space between the decidua capsularis and arteries persists- these arteries retain a smooth-muscle
parietalis because the gestational sac does not fill wall and endothelium thereby remaining responsive to
the entire uterine cavity vasoactive agents
By 14-16 weeks gestation  spiral arterial system supplying the decidua basalis
 the expanding sac has enlarged to completely fill the directly beneath the implanting blastocyst and the
uterine cavity intervillous space is altered remarkably
o these arterioles and arteries are invaded by
Decidua vera cytotrophoblasts
 resulting apposition of the decidua capsularis and o vessel walls are destroyed
parietalis o only a shell without smooth muscle or
 thus, the uterine cavity is functionally obliterated endothelial cells remain
o these vascular conduits of maternal blood-
Early in pregnancy
which become the uteroplacental vessels- are
 decidua begins to thicken, eventually attaining a depth of
not responsive to vasoactive agents
5 to 10 mm
o fetal chorionic vessels
 furrows and numerous small openings, representing the
 transport blood between the placenta
mouths of uterine glands, can be detected with
magnification and the fetus
Later in pregnancy  contain smooth muscle and respond to
 decidua becomes thinner vasoactive agents
 presumably because of pressure exerted by the
expanding uterine contents Decidual Histology
 Early in pregnancy, the zona spongiosa of the decidua
Three layers of the decidua basalis and parietalis: consists of large distended glands, often exhibiting
1. zona compacta- surface or compact zone marked hyperplasia and separated by minimal stroma.
2. zona spongiosa- middle portion or spongy zone with  At first, the glands are lined by typical cylindrical uterine
remnants of glands and numerous small blood vessels epithelium with abundant secretory activity that
3. zona basalis- basal zone; remains after delivery and gives contributes to blastocyst nourishment.
rise to new endometrium  As pregnancy progresses, the epithelium gradually
becomes cuboidal or even flattened and later
zona functionalis- zona compacta and zona spongiosa degenerates and sloughs to a greater extent into the
gland lumens.
Decidual Reaction  With advanced pregnancy, the glandular elements largely
 completed only with blastocyst implantation disappear.
  In comparing the decidua parietalis at 16 weeks’  is not to be confused with placental lactogen (hPL), which
gestation with the early proliferative endometrium of a is produced only by syncytiotrophoblast
nonpregnant woman, there is marked hypertrophy but  a product of the same gene that encodes for anterior
only slight hyperplasia of the endometrial stroma during pituitary prolactin
decidual transformation.  Prolactin preferentially enters amnionic fluid, and little
 decidua basalis enters maternal blood.
o contributes to formation of the placental basal  prolactin levels in amnionic fluid
plate o are extraordinarily high and may reach 10,000
o differs histologically from the decidua parietalis ng/ mL at 20 to 24 weeks’ gestation
in two important respects:  fetal serum levels
 the spongy zone of the decidua basalis o 350 ng/mL
consists mainly of arteries and widely  maternal serum levels
dilated veins, and by term, glands have o 150 to 200 ng/mL
virtually disappeared  possible roles for decidual prolactin:
 invaded by many interstitial o most or all of this protein hormone enters
trophoblast amnionic fluid; it may serve in transmembrane
 cells and trophoblastic giant cells solute and water transport and in amnionic fluid
 Nitabuch layer volume maintenance
o a zone of fibrinoid degeneration in which o there are prolactin receptors in several bone
invading trophoblasts meet the decidua basalis marrow-derived immune cells, and prolactin
o If the decidua is defective, as in placenta may stimulate T cells in an autocrine or
accreta, the Nitabuch layer is usually absent paracrine manner
 Rohr stria o may act in regulating immunological functions
o a more superficial, but inconsistent, deposition during pregnancy
of fibrin at the bottom of the intervillous space o may play a role in angiogenesis regulation
and surrounding the anchoring villi during implantation
 decidual necrosis o has been shown in the mouse to have a
o is a normal phenomenon in the first and protective function by repressing expression of
probably second trimesters genes detrimental to pregnancy maintenance
o necrotic decidua obtained through curettage  Most agents known to inhibit or stimulate pituitary
after spontaneous abortion in the first trimester prolactin secretion—including dopamine, dopamine
should not necessarily be interpreted as either a agonists, and thyrotropin-releasing hormone—do not
cause or an effect of the pregnancy loss alter decidual prolactin secretion either in vivo or in vitro.
 primary cellular components  the level of progesterone receptor expression may
o are the true decidual cells determine the decidualization process, at least as marked
o which differentiated from the endometrial by prolactin production
stromal cells, and numerous maternal bone  various cytokines and growth factors— endothelin-1, IL-
marrow–derived cells 1, IL-2, and epidermal growth factor—decrease decidual
 Decidual natural killer cells prolactin secretion
o large, granular lymphocytes
o present in the decidua in striking abundance Implantation and Early Trophoblast Formation
early in pregnancy  The fetus is dependent on the placenta for pulmonary,
o In peripheral blood: hepatic, and renal functions.
 Approximately 90 percent are highly  Maternal blood spurts from uteroplacental vessels into
cytolytic the placental intervillous space and bathes the outer
 Ten percent show less cytolytic ability syncytiotrophoblast.
but increased cytokine secretion  This allows exchange of gases, nutrients, and other
o In decidua: substances with fetal capillary blood within the villous
 95 percent secrete cytokines, and core.
about half of these unique cells also  fetal and maternal blood are not normally mixed in this
express angiogenic factors hemochorial placenta
 likely play an important  There is also a paracrine system that links mother and
role in trophoblast invasion and fetus through the anatomical and biochemical
vasculogenesis juxtaposition of the maternal decidua parietalis and the
extraembryonic chorion laeve, which is fetal.
Decidual Prolactin
 The decidua is the source of prolactin that is present in Fertillization and Implantation
enormous amounts in amnionic fluid  With ovulation, the secondary oocyte and adhered cells
of the cumulus-oocyte complex are freed from the ovary.
  Although technically this mass of cells is released into the  At this stage, the eight formative, embryo-producing cells
peritoneal cavity, the oocyte is quickly engulfed by the are surrounded by 99 trophoblastic cells.
fallopian tube infundibulum.  the blastocyst is released from the zona pellucida
 Further transport through the tube is accomplished by secondary to secretion of specific proteases from the
directional movement of cilia and tubal peristalsis. secretory-phase endometrial glands
 Fertilization, which normally occurs in the oviduct, must o directly influence endometrial receptivity
take place within a few hours, and no more than a day  The receptive endometrium is thought to respond by
after ovulation. producing leukemia inhibitory factor (LIF) and colony
 Because of this narrow opportunity window, stimulating factor-1 (CSF-1).
spermatozoa must be present in the fallopian tube at the o These serve to increase trophoblast protease
time of oocyte arrival production.
 Almost all pregnancies result when intercourse occurs o This degrades selected endometrial extracellular
during the 2 days preceding or on the day of ovulation. matrix proteins and allows trophoblast invasion.
 postovulatory and postfertilization developmental ages  embryo “hatching”
are similar. o is a critical step toward successful pregnancy as
 Zygote it allows association of trophoblasts with
o Created by the fusion of the two nuclei and endometrial epithelial cells and permits release
intermingling of maternal and paternal of trophoblast-produced hormones into the
chromosomes uterine cavity
 clinical pregnancy dating is calculated from the start of
the last menses Blastocyst Implantation
 the follicular phase length is more variable than the  Six or 7 days after fertilization, the embryo implants the
luteal phase uterine wall.
 1 week postfertilization corresponds to approximately 3  can be divided into three phases:
weeks from the last o apposition—initial contact of the blastocyst to
menstrual period in women with regular 28-day cycle the uterine wall
o adhesion—increased physical contact between
The Zygote the blastocyst and uterine epithelium
 a diploid cell with 46 chromosomes o invasion—penetration and invasion of
 undergoes cleavage after fertilization syncytiotrophoblast and cytotrophoblasts into
 blastomeres the endometrium, inner third of the
o zygote cells produced by this division are called myometrium, and uterine vasculature
 In the two-cell zygote, the blastomeres and polar body  Successful implantation requires a receptive
continue to be surrounded by the zona pellucida endometrium appropriately primed with estrogen and
 undergoes slow cleavage for 3 days while still within the progesterone by the corpus luteum.
fallopian tube  Such uterine receptivity is limited to days 20 to 24 of the
 Morula cycle.
o a solid mulberry-like ball of cell  Adherence is mediated by cell-surface receptors at the
o enters the uterine cavity about 3 days after implantation site that interact with blastocyst receptors
fertilization  If the blastocyst approaches the endometrium after cycle
 blastocyst day 24, the potential for adhesion is diminished because
o gradual accumulation of fluid between the antiadhesive glycoprotein synthesis prevents receptor
morula cells interactions
 At the time of its interaction with the endometrium, the
The Blastocyst blastocyst is composed of 100 to 250 cells.
 As early as 4 to 5 days after fertilization, the 58-cell  The blastocyst loosely adheres to the endometrial
blastula differentiates into five embryo-producing cells— epithelium by apposition.
the inner cell mass, and 53 cells destined to form o most commonly occurs on the upper posterior
trophoblast uterine wall
 In a 58-cell blastocyst, the outer cells, called the  Attachment of the blastocyst trophectoderm to the
trophectoderm, can be distinguished from the inner cell endometrial surface by apposition and adherence
mass that forms the embryo. appears to be closely regulated by paracrine interactions
 the 107-cell blastocyst between these two tissues.
o no larger than the earlier cleavage stages,  Successful endometrial blastocyst adhesion involves
despite the accumulated fluid modification in expression of cellular adhesion molecules
o measures approximately 0.155 mm in diameter (CAMs).
which is similar to the size of the initial  Integrins
postfertilization zygote o one of four families of CAMs
 o are cell-surface receptors that mediate cell o endovascular trophoblasts
adhesion to extracellular matrix proteins  penetrate the spiral artery lumens
 Great diversity of cell binding to several different
extracellular matrix proteins is possible by differential Early Trophoblast Implantation
regulation of the integrin receptors.  After gentle erosion between epithelial cells of the
 Endometrial integrins are hormonally regulated and a surface endometrium, invading trophoblasts burrow
specific set of integrins is expressed at implantation deeper.
 Recognition-site blockade on integrins for binding to  By the 10th day, the blastocyst becomes totally encased
extracellular matrix molecules such as fibronectin will within the endometrium.
prevent blastocyst attachment  At 9 days of development, the blastocyst wall facing the
uterine lumen is a single layer of flattened cells
The Trophoblast  The opposite, thicker wall comprises two zones:
 Human placental formation begins with the o the trophoblasts
trophectoderm, which appears at the morula stage. o embryo-forming inner cell mass
 It gives rise to a trophoblast cell layer encircling the  As early as 71⁄2⁄ days after fertilization, the inner cell
blastocyst. mass or embryonic disc is differentiated into a thick plate
 From then until term, the trophoblast plays a critical part of primitive ectoderm and an underlying layer of
at the fetal-maternal interface. endoderm.
 exhibits the most variable structure, function, and  Some small cells appear between the embryonic disc and
developmental pattern of all placental components the trophoblast and enclose a space that will become the
 Its invasiveness promotes implantation, its nutritional amnionic cavity.
role for the conceptus is reflected in its name, and its  Embryonic mesenchyme first appears as isolated cells
endocrine organ function is essential to maternal within the blastocyst cavity
physiological adaptations and to pregnancy maintenance.  Chorionic vesicle
o When the cavity is completely lined with this
Trophoblast Differentiation mesoderm
By eighth day:  Chorion
 Syncytiotrophoblast o its membrane
o an outer multinucleated syncytium o composed of trophoblasts and mesenchyme
o it has an amorphous cytoplasm without cell  Body Stalk
borders, nuclei that are multiple and diverse in o Formed when some mesenchymal cells
size and shape, and a continuous syncytial lining eventually condense
o aids transport o joins the embryo to the nutrient chorion and
 Cytotrrophoblast later develops into the umbilical cord
o inner layer of primitive mononuclear cells o can be recognized at an early stage at the caudal
o germinal cells for the syncytium end of the embryonic disc
o has a well-demarcated cell border, a single
nucleus, and ability to undergo DNA synthesis Lacunae Formation within the Syncytiotrophoblast
and mitosis  As the embryo enlarges, more maternal decidua basalis is
 After implantation is complete, trophoblast further invaded by syncytiotrophoblast.
differentiate along two main pathways, giving rise to  Beginning approximately 12 days after conception, the
villous and extravillous trophoblast syncytiotrophoblast is permeated by a system of
 villous trophoblast intercommunicating channels called trophoblastic
o gives rise to the chorionic villi, which primarily lacunae.
transport oxygen, nutrients, and other  After invasion of superficial decidual capillary walls,
compounds between the fetus and mother lacunae become filled with maternal blood
 Extravillous trophoblasts  At the same time, the decidual reaction intensifies in the
o migrate into the decidua and myometrium and surrounding stroma.
also penetrate maternal vasculature, thus o This is characterized by decidual stromal cell
coming into contact with various maternal cell enlargement and glycogen storage.
types
o further classified as: Placental Organization
interstitial trophoblasts and endovascular Chorionic Villi
trophoblasts  With deeper blastocyst invasion into the decidua, the
o interstitial trophoblasts extravillous cytotrophoblasts give rise to solid primary
 invade the decidua and eventually villi composed of a cytotrophoblast core covered by
penetrate the myometrium to form syncytiotrophoblast.
placental bed giant cells
 surround spiral arteries
 These arise from buds of cytotrophoblast that protrude Villus Ultrastructure
into the primitive syncytium before 12 days  There are prominent microvilli on the syncytial surface
postfertilization. that correspond to the so-called brush border described
 As the lacunae join, a complicated labyrinth is formed by light microscopy.
that is partitioned by these solid cytotrophoblastic  Associated pinocytotic vacuoles and vesicles are related
columns. to absorptive and secretory placental functions.
 The trophoblast-lined labyrinthine channels form the  Microvilli
intervillous space, and the solid cellular columns form the o Act to increase surface area in direct contact
primary villous stalks. with maternal blood
 The villi initially are located over the entire blastocyst  This contact between the trophoblast and maternal
surface. blood is the defining characteristic of a hemochorial
 They later disappear except over the most deeply placenta.
implanted portion, which is destined to form the  human hemochorial placenta can be subdivided into:
placenta. o hemodichorial
 Secondary villi  more prominent during the first
o Beginning on approximately the 12th day after trimester of gestation
fertilization, mesenchymal cords derived from  It consists of the inner layer of the
extraembryonic mesoderm invade the solid cytotrophoblasts and associated basal
trophoblast columns. lamina, covered by a
 Tertiary villi syncytiotrophoblast
o Once angiogenesis begins in the mesenchymal layer
cores o Hemomonochorial
 Although maternal venous sinuses are tapped early in  Later in gestation the inner layer of
implantation, maternal arterial blood does not enter the cytotrophoblasts is no longer
intervillous space until around day 15. continuous, and by term, there are only
 By approximately the 17th day scattered cells present
o fetal blood vessels are functional  narrower barrier that aids nutrient and
o a placental circulation is established oxygen transport to the fetus
 The fetal–placental circulation PLACENTA AND CHORION DEVELOPMENT
o completed when the blood vessels of the I. Chorion and Decidua Development
embryo are connected with chorionic vessels  In early pregnancy, the villi are distributed over the entire
 In some villi, angiogenesis fails from lack of circulation. periphery of the chorionic membrane. As the blastocyst with its
o They can be seen normally, but the most surrounding trophoblasts grows and expands into the decidua,
striking exaggeration of this process is seen with 1. One pole faces the endometrial cavity.
hydatidiform mole 2. The opposite pole will form the placenta from villous
 Villi are covered by an outer layer of syncytium and an
trophoblasts and anchoring cytotrophoblasts.
inner layer of cytotrophoblasts, which are also known as
 Chorion frondosum (leafy chorion)
Langhans cells.
– formed chorionic villi in contact with the decidua basalis
 Cytotrophoblast proliferation at the villous tips produces
the trophoblastic cell columns that form anchoring villi. – fetal component of the placenta
 They are not invaded by fetal mesenchyme, and they are  As growth of embryonic and extraembryonic tissues continues,
anchored to the decidua at the basal plate. the blood supply to the chorion facing the endometrial cavity is
 base of the intervillous space faces the maternal side and restricted. Because of this, villi in contact with the decidua
consists of cytotrophoblasts from cell columns, the capsularis cease to grow and then degenerate.
covering shell of syncytiotrophoblast, and maternal  This portion of the chorion becomes the avascular fetal
decidua of the basal plate membrane that abuts the decidua parietalis, that is, the chorion
 base of the chorionic plate forms the roof of the laeve—or smooth chorion.
intervillous space
 Smooth chorion is composed of cytotrophoblasts and fetal
o consists of two layers of trophoblasts externally
mesodermal mesenchyme that survives in a relatively low-
and fibrous mesoderm internally
oxygen atmosphere.
 “definitive” chorionic plate
o is formed by 8 to 10 weeks as the amnionic and  Until near the end of the third month, the chorion laeve is
primary chorionic plate mesenchyme fuse separated from the amnion by the exocoelomic cavity.
together  Amniochorion – combination of chorion leave and the amnion
o this formation is accomplished by expansion of  The chorion laeve is generally more translucent than the amnion
the amnionic sac, which also surrounds the and rarely exceeds 1-mm thickness.
connective stalk and the allantois and joins  Amnion and chorion leave are important sites of molecular
these structures to form the umbilical cord transfer and metabolic activity. Moreover, they constitute an
 important paracrine arm of the fetal–maternal communication  The degree of trophoblast invasion is controlled by matrix
system. degradation regulation and by factors that cause trophoblast
migration.
Maternal Regulation of Trophoblast Invasion and Vascular  Low estradiol levels in the first trimester are critical for
Growth trophoblast invasion and remodeling of the spiral arteries.
 Decidual natural killer cells (dNK)  Recent studies in nonhuman primates suggest that the increase
– accumulate in the decidua during the first half of pregnancy and in second trimester estradiol levels suppresses and limits vessel
are found in direct contact with trophoblasts. remodeling by reducing trophoblast expression of VEGF and
– these cells lack cytotoxic functions and are able to dampen specific integrin receptors).
inflammatory T(H)17 cells. That distinguishes dNK cells from  As the extravillous trophoblast differentiates, it gains expression
circulating natural killer cells and from natural killer cells in the of integrin receptors that recognize the extracellular matrix
proteins collagen IV, laminin, and fibronectin.
endometrium before pregnancy.
 Binding of extracellular matrix proteins to specific integrin
– studies suggest that decidual macrophages play a regulatory
receptors initiates signals that promote trophoblast cell
role in inhibiting NK cell killing during pregnancy, and that
migration and differentiation.
importantly prevents dNK from recognizing and destroying fetal
 As pregnancy advances, increasing estradiol levels repress and
cells as “foreign.”
thus control the extent of uterine vessel transformation via
– have the ability to attract and promote trophoblast invasion down-regulation of VEGF and integrin receptor expression.
into the decidua and promote vascular growth
– express both IL-8 and interferon-inducible protein-10, which II. Invasion of Spiral Arteries
bind to receptors on invasive trophoblast cells to promote their  One of the most remarkable features of human placental
decidual invasion toward the spiral arteries. development is the extensive modification of maternal
–also produce proangiogenic factors, including VEGF and vasculature by trophoblasts, which are by definition of fetal
placental growth factor (PlGF), which promote vascular growth origin. These events occur in the first half of pregnancy and are
in the decidua. considered in detail because of their importance to
 In addition, trophoblasts secrete specific chemokines that attract uteroplacental blood flow. They are also integral to some
the dNK cells to the maternal-fetal interface. Thus, both cell types pathological conditions such as preeclampsia, fetal-growth
simultaneously attract each other. restriction, and preterm birth.
 Spiral artery modifications are carried out by two populations of
Trophoblast Invasion of the Endometrium extravillous trophoblast—interstitial trophoblasts, which
 Extravillous trophoblasts of the first-trimester placenta are highly surround the arteries, and endovascular trophoblasts, which
invasive. They form cell columns that extend from the penetrate the spiral artery lumen.
endometrium to the inner third of the myometrium. This process  These interstitial cells constitute a major portion of the placental
occurs under low-oxygen conditions, and regulatory factors that bed and penetrate the decidua and adjacent myometrium.
are induced under hypoxic conditions contribute in part to  They aggregate around spiral arteries, and their functions may
invasive trophoblast activation. include vessel preparation for endovascular trophoblast
 Invasive trophoblasts secrete numerous proteolytic enzymes invasion.
that digest extracellular matrix and activate proteinases already  PROCESS:
present in the endometrium.  Endovascular trophoblasts first enter the spiral-artery lumens
 Trophoblasts produce urokinase-type plasminogen activator, and initially form cellular plugs.
which converts plasminogen into the broadly acting serine  They then destroy vascular endothelium via an apoptosis
protease, plasmin. This in turn both degrades matrix proteins and mechanism and invade and modify the vascular media. Thus,
activates matrix metalloproteases. fibrinoid material replaces smooth muscle and connective
 MMP-9 – critical for human trophoblast invasion. tissue of the vessel media.
 The timing and extent of trophoblast invasion is regulated by a  Spiral arteries later regenerate endothelium. Invading
balanced interplay between pro- and anti- invasive factors. endovascular trophoblasts can extend several centimeters
 The relative ability to invade maternal tissue in early pregnancy along the vessel lumen, and they must migrate against
compared with limited invasiveness in late pregnancy is arterial flow.
controlled by autocrine and paracrine trophoblastic and *These vascular changes are not observed in the decidua
endometrial factors. parietalis, that is, in decidual sites removed from the invading
 Trophoblasts secrete insulin-like growth factor II, which acts in an cytotrophoblasts.
autocrine manner. It promotes invasion into the endometrium,  Of note, invasion by trophoblasts involves only the decidual spiral
 Decidual cells secrete insulin-like growth factor binding-protein arteries and not decidual veins.
type 4, which blocks autocrine loop.
 In their summary of uteroplacental vasculature, Ramsey and Placental Maturation
Donner (1980) described uteroplacental vessel development as  As villi continue to branch and the terminal ramifications become
proceeding in two waves or stages. more numerous and smaller, the volume and prominence of
1. The first wave occurs before 12 weeks’ post-fertilization and cytotrophoblasts decrease.
consists of invasion and modification of spiral arteries up to the  As the syncytium thins, the fetal vessels become more prominent
border between the decidua and myometrium. and lie closer to the surface.
2. The second wave is between 12 and 16 weeks and involves  The villous stroma also exhibits changes as gestation progresses.
some invasion of the intramyometrial segments of spiral  In early pregnancy, the branching connective-tissue cells are
arteries. separated by an abundant loose intercellular matrix. Later, the
villous stroma becomes denser, and the cells more spindly and
 Remodeling converts narrow-lumen, muscular spiral arteries into more closely packed.
dilated, low-resistance uteroplacental vessels.  Another change in the stroma involves the infiltration of
Hofbauer cells, which are fetal macrophages.
Establishment of Maternal Blood Flow  Hofbauer cells – nearly round with vesicular, often eccentric
 Approximately 1 month after conception, maternal blood enters nuclei and very granular or vacuolated cytoplasm.
the intervillous space in fountain-like bursts from the spiral –characterized histochemically by intracytoplasmic lipid and by
arteries. phenotypic markers specific for macrophages.
 Blood is propelled outside of the maternal vessels and sweeps –They increase in numbers and maturational state throughout
over and directly bathes the syncytiotrophoblast. T pregnancy and appear to be important mediators of protection
 he apical surface of the syncytiotrophoblast consists of a complex at the maternal-fetal interface.
microvillous structure that undergoes continual shedding and –These macrophages are phagocytic, have an
reformation during pregnancy. immunosuppressive phenotype, can produce various cytokines,
and are capable of paracrine regulation of trophoblast functions.
III. Villus Branching
 Histological changes that accompany placental growth and
 Although certain villi of the chorion frondosum extend from the maturation, and which provides an increased efficiency of
chorionic plate to the decidua to serve as anchoring villi, most transport and exchange to meet increasing fetal metabolic
villi arborize and end freely within the intervillous space. requirements:
 As gestation proceeds, the short, thick, early stem villi branch to  decreased syncytiotrophoblast thickness,
form progressively finer subdivisions and greater numbers of  significantly reduced cytotrophoblast number
increasingly smaller villi.  decreased stroma
 Each of the truncal or main stem villi and their ramifications  and increased number of capillaries with close approximation
(rami) constitutes a placental lobule, or cotyledon. to the syncytial surface.
 Each lobule is supplied with a single truncal branch of the  By 16 weeks, the apparent continuity of the cytotrophoblasts is
chorionic artery. And each lobule has a single vein so that lobules lost.
constitute functional units of placental architecture.  At term, villi may be focally reduced to a thin layer of syncytium
covering minimal villous connective tissue in which thin-walled
IV. Placental Growth and Maturation fetal capillaries abut the trophoblast and dominate the villi.
Placental Growth  Changes in placental architecture that can cause decreased
 In the first trimester, placental growth is more rapid than that of placental exchange efficiency if they are substantive:
the fetus. But by approximately 17 postmenstrual weeks,  thickening of the basal lamina of trophoblast or capillaries
placental and fetal weights are approximately equal.  obliteration of certain fetal vessels
 By term, placental weight is approximately one sixth of fetal  increased villous stroma
weight.  fibrin deposition on the villous surface.
 Briefly, when viewed from the maternal surface, the number of
slightly elevated convex areas, called lobes, varies from 10 to 38. V. Fetal and Maternal Blood Circulation in the Mature Placenta
 Lobes are incompletely separated by grooves of variable depth  Placenta is functionally an intimate approximation of the fetal
that overlie placental septa, which arise from folding of the basal capillary bed to maternal blood, its gross anatomy primarily
plate. concerns vascular relations.
 The total number of placental lobes remains the same  The fetal surface is covered by the transparent amnion, beneath
throughout gestation, and individual lobes continue to grow— which chorionic vessels course.
although less actively in the final weeks.  A section through the placenta includes amnion, chorion,
 Cotyledons – grossly visible lobes of the placenta (this is not chorionic villi and intervillous space, decidual (basal) plate, and
accurate); correctly used, lobules or cotyledons are the myometrium (Figs. 5-16 and 5-17).
functional units supplied by each main stem villus.
  Maternal blood enters through the basal plate and is driven
high up toward the chorionic plate by arterial pressure before
laterally dispersing.
 After bathing the external microvillous surface of chorionic
villi, maternal blood drains back through venous orifices in the
basal plate and enters uterine veins. Thus, maternal blood
traverses the placenta randomly without preformed channels.
 The previously described trophoblast invasion of the spiral
arteries creates low-resistance vessels that can accommodate
massive increase in uterine perfusion during gestation.
 Generally, spiral arteries are perpendicular to, but veins are
parallel to, the uterine wall. This arrangement aids closure of
Fetal Circulation veins during a uterine contraction and prevents the exit of
 Deoxygenated venous-like fetal blood flows to the placenta maternal blood from the intervillous space.
through the two umbilical arteries.  The number of arterial openings into the intervillous space
 As the cord joins the placenta, these umbilical vessels branch becomes gradually reduced by cytotrophoblast invasion.
repeatedly beneath the amnion and again within the villi, finally  According to Brosens and Dixon, there are about 120 spiral
forming capillary networks in the terminal villous branches. arterial entries into the intervillous space at term. These
 Blood with significantly higher oxygen content returns from the discharge blood in spurts that bathes the adjacent villi.
placenta via a single umbilical vein to the fetus.  After the 30th week, a prominent venous plexus separates the
 The branches of the umbilical vessels that traverse along the fetal decidua basalis from the myometrium and thus participates in
surface of the placenta in the chorionic plate are referred to as providing a cleavage plane for placental separation.
the placental surface or chorionic vessels. These vessels are  As discussed, both inflow and outflow are curtailed during
responsive to vasoactive substances, but anatomically, uterine contractions.
morphologically, histologically, and functionally, they are unique.  During contractions, therefore, a somewhat larger volume of
 Chorionic arteries always cross over chorionic veins. blood is available for exchange even though the rate of flow is
 In 65 percent of placentas, chorionic arteries form a fine network decreased.
supplying the cotyledons—a pattern of disperse-type branching.  diastolic flow velocity in spiral arteries is diminished during
In the remaining 35 percent, the arteries radiate to the edge of uterine contractions.
the placenta without narrowing. Both types are end arteries that *Thus, principal factors regulating intervillous space blood flow are
supply one cotyledon as each branch turns downward to pierce arterial blood pressure, intrauterine pressure, uterine contraction
the chorionic plate. pattern, and factors that act specifically on arterial walls.
 Truncal arteries are perforating branches of the surface arteries
that pass through the chorionic plate. Each truncal artery VI. Breaks in the Placental “Barrier”
supplies one main stem villus and thus one cotyledon.
 The placenta does not maintain absolute integrity of the fetal and
 The amount of vessel wall smooth muscle decreases, and the maternal circulations. There are numerous examples of
vessel caliber increases as it penetrates the chorionic plate.
trafficking cells between mother and fetus in both directions.
 The loss in muscle continues as the truncal arteries and veins
 This situation is best exemplified clinically by erythrocyte D-
branch into their smaller rami.
antigen alloimmunization and resulting erythroblastosis fetalis.
 Before 10 weeks, there is no end-diastolic flow pattern within
 Although fetal cell admixtures likely are small in most cases,
the umbilical artery at the end of the fetal cardiac cycle. After 10
occasionally the fetus exsanguinates into the maternal
weeks, end-diastolic flow appears and is maintained throughout
circulation.
normal pregnancy.
 It is indisputable that fetal cells can become engrafted in the
mother during pregnancy and can be identified decades later.
Maternal Circulation
 Fetal lymphocytes, CD34+ mesenchymal stem cells, and
 Maternal–placental circulation is requisite. endothelial colony-forming cells reside in maternal blood, bone
 An adequate mechanism must explain how blood can: (1) leave marrow, or uterine vasculature.
maternal circulation; (2) flow into an amorphous space lined by  Termed microchimerism, such residual stem cells may
syncytiotrophoblast, rather than endothelium; and (3) return participate in maternal tissue regeneration and have been
through maternal veins without producing arteriovenous-like implicated in the disparate female:male ratio of autoimmune
shunts that would prevent maternal blood from remaining in disorders; are associated with the pathogenesis of lymphocytic
contact with villi long enough for adequate thyroiditis, scleroderma, and systemic lupus erythematosus.
 Physiology of maternal-placental circulation:
VII. Immunological Considerations of the Fetal–Maternal
Interface
 The lack of uterine transplantation immunity is unique compared  Class I antigens in extravillous cytotrophoblasts are accounted
with that of other tissues, and there have been many attempts for by the expression of classic HLA-C and nonclassic class Ib
to explain survival of the semiallogenic fetal graft. molecules of HLA-E and HLA-G.
 Immunological peculiarity of cells involved in implantation and  HLA-G antigen is expressed only in humans, with expression
fetal-placental development: restricted to extravillous cytotrophoblasts contiguous with
 decidual natural killer cells with their inefficient cytotoxic maternal tissues, that is, decidual and uNK cells. Indeed, HLA-G
abilities antigen expression is identified only in extravillous
 decidual stromal cells, and invasive trophoblasts that populate cytotrophoblasts in the decidua basalis and in the chorion laeve.
the decidua  During pregnancy, a soluble major isoform—HLA-G2—has
 The trophoblasts are the only fetal-derived cells in direct contact increased levels. Embryos used for in vitro fertilization do not
with maternal tissues. implant if they do not express this soluble HLA-G isoform. Thus,
 Hanna and coworkers (2006) reported a “peaceful” model of HLA-G may be immunologically permissive of the maternal-fetal
trophoblast invasion and maternal vascular remodeling. In this antigen mismatch.
scheme, decidual natural killer cells work in concert with stromal  HLA-G has a proposed role in protecting extravillous trophoblasts
cells. They mediate angiogenesis through production of from immune rejection via modulation of uNK functions.
proangiogenic factors such as VEGF and control trophoblast  Finally, Goldman-Wohl and associates (2000) have provided
chemoattraction toward spiral arteries by production of IL-8 and evidence for abnormal HLA-G expression in extravillous
interferon inducible protein-10. trophoblasts from women with preeclampsia.

Immunogenicity of the Trophoblasts Uterine Natural Killer Cells (uNK)

 More than 50 years ago, Sir Peter Medawar (1953) suggested  These distinctive lymphocytes are believed to originate in bone
that fetal semiallograft survival might be explained by marrow and belong to the natural killer cell lineage.
immunological neutrality.  They are the predominant population of leukocytes present in
 The placenta was considered immunologically inert and midluteal phase endometrium at the expected time of
therefore unable to create a maternal immune response. implantation
 Subsequently, research was focused on defining expression of  These uNKs have a distinct phenotype characterized by a high
the major histocompatibility complex (MHC) antigens on surface density of CD56 or neural cell adhesion molecule.
trophoblasts.  Their infiltration is increased by progesterone and by stromal
 Human leukocyte antigens (HLAs) are the human analogue of cell production of IL-15 and decidual prolactin.
the MHC.  Near the end of the luteal phase of nonfertile ovulatory cycles,
 MHC class I and II antigens are absent from villous trophoblasts, uterine NK cell nuclei begin to disintegrate. But if implantation
which appear to be immunologically inert at all gestational proceeds, they persist in large numbers in the decidua during
stages. early pregnancy.
 Invasive extravillous cytotrophoblasts do express MHC class I  By term, however, there are relatively few uNK cells in the
molecules, which have been the focus of considerable study. decidua. In first-trimester decidua, there are many uNK cells in
close proximity to extravillous trophoblast, where it is
Trophoblast HLA Class I Expression speculated that they serve to regulate trophoblast invasion.
 The HLA genes are the products of multiple genetic loci of the  These uNK cells secrete large amounts of
major histocompatibility complex located within the short arm of granulocytemacrophage–colony-stimulating factor (GM-CSF),
chromosome 6. which suggests that they are in an activated state.
 There are 17 HLA class I genes, including three classic genes, HLA-  Jokhi and coworkers (1999) speculate that GM-CSF may
A, -B, and -C, that encode the major class I (class Ia) function primarily to forestall trophoblast apoptosis and not to
transplantation antigens. Three other class I genes, designated promote trophoblast replication.
HLA-E, -F, and -G, encode class Ib HLA antigens.  Expression of angiogenic factors by uNK cells also suggests a
 Moffett-King (2002) reasoned that normal implantation depends function in decidual vascular remodeling.
on controlled trophoblastic invasion of maternal endometrium–  In this case, it is uNKs, rather than the T lymphocytes, that are
decidua and spiral arteries. Such invasion must proceed far primarily responsible for decidual immunosurveillance.
enough to provide for normal fetal growth and development, but
there must be a mechanism for regulating its depth. She suggests THE AMNION
that uterine decidual natural killer (uNK) cells combined with
unique expression of three specific HLA class I genes in AMNION
extravillous cytotrophoblasts act in concert to permit and  At term, ...tough and tenacious but pliable membrane
subsequently limit trophoblast invasion.  Avascular fetal membrane
 Contiguous with amnionic fluid
 Incredible importance in preganancy  MMP-1
 Provides almost all tensile strength of the fetal membrane  prostaglandin E2 (PGE2)
 Resilient to rupture  fetal fibronectin (fFN)
o important to successful pregnancy o Amnionic epithelium also synthesizes vasoactive peptide
 Preterm delivery  ...including endothelin and parathyroid hormone-related
o major cause is preterm rupture of fetal membranes protein
 Five (5) separate amnion layers  Vasoactive peptides produced in amnion gain access to the
1) Inner surface; bathed by amnionic fluid; uninterrupted, adventitial surface of the chorionic vessel
single layer of cuboidal epithelium (Fig. 5-19) □ Thus, the amnion may be involved in modulating
2) Basement membrane to which the epithelium is firmly chorionic vessels tone and blood flow.
attached o Amnionic derived vasoactive peptides function in both
3) Acellular compact layer composed of interstitial collagens maternal and fetal tissues in diverse physiological
4) Fibroblast-like mesenchymal cell, wide dispersed at term processes.
- There are also few fetal macrophages in the amnion.  Amnion Mesenchymal Cells
5) Outermost amnion layer, relatively acellular zona spongioza, o Responsible for other major functions.
which is contiguous with the chorion leave (second fetal  Synthesis of interstitial collagens that compose the
membrane) compact layer of the amnion—the major source of its
tensile strength—takes place in mesenchymal cells.
 Synthesize cytokines that include IL-6, IL-8, and monocyte
chemoattractant protein-1.
□ Cytokine synthesis increases in response to bacterial
toxins and IL-1.
 Mesenchymal cells may be a greater source of PGE2 than
epithelial cells, in particular in the case of premature
membrane rupture.

AMNION TENSILE STRENGTH

 During tests of tensile strength, the decidua and then the

chorion laeve give way long before the amnion ruptures.
 The amnion tensile strength resides almost exclusively in the
compact layer,
o Composed of cross-linked interstitial collagens I and III and
lesser amounts of collagens V and VI.
 Collagens
o the primary macromolecules of most connective tissues and
are the most abundant proteins in the body
o Collagen I is the major interstitial collagen in tissues
AMNION DEVELOPMENT characterized by great tensile strength, such as bone and
tendon
 A space develops between the embryonic cell mass and adjacent  Amnion tensile strength is regulated in part by fibrillar collagen
trophoblast early during implantation. interacting with proteoglycans such as decorin, which promote
 The amnion is first identifiable in the 7th or 8th day. tissue strength.
 Distention of the amnionic sac eventually brings it into contact  Compositional changes at the time of labor include a decline in
with the interior surface of the chorion leave. decorin and increase in hyaluronan. This leads to a loss of
 Amnion and chorion leave are slightly adhered but never tensile strength.
intimately connected. They can be separated easily.
AMNION METABOLIC FUNCTIONS
Amnion Cell Histogenesis
 The amnion is more than a simple avascular membrane that
 Epithelial cells are thought to be derived from fetal ectoderm of contains amnionic fluid.
the embryonic disc. o metabolically active
 They do not arise by delamination from trophoblast. o involved in solute and water transport for amnionic fluid
 Amnion Epithelial Cells homeostasis
o Apical surface of the ammonic epithelium is replete with o produces an impressive array of bioactive compounds
highly developed microvilli. o responsive both acutely and chronically to mechanical
o Metabolically active stretch, which alters amnionic gene expression
o Its cell synthesize
 - may trigger both autocrine and paracrine responses to CORD FUNCTIONS
include production of MMPs, IL-8, and collagenase
 The umbilical cord extends from the fetal umbilicus to the fetal
surface of the placenta, that is, the chorionic plate.
AMNIONIC FLUID  Blood flows from the umbilical vein and takes a path of least
resistance via two routes within the fetus.
 Until about 34 weeks’ gestation - Ductus venosus
o Te normally clear fluid that collects within the amnionic - Empties directly into the inferior vena cava
cavity increases as pregnancy progresses. o Other route consists of numerous smaller openings into the
o After this, the volume declines. hepatic circulation
 At term,  Blood exits the fetus via the two umbilical arteries.
o The average volume is approximately 1000 mL o These are anterior branches of the internal iliac artery and
o Although this may vary widely in normal and especially become obliterated after birth.
abnormal conditions o Remnants can be seen as the medial umbilical ligaments.

THE UMBILICAL CORD

PLACENTAL HORMONES
CORD DEVELOPMENT
 The production of steroid and protein hormones by human
 The yolk sac and the umbilical vesicle into which it develops are trophoblasts is greater in amount and diversity than that of any
prominent early in pregnancy. single endocrine tissue in all of mammalian physiology.
 At first, the embryo is a flattened disc interposed between  Average production rates for various steroid hormones in
amnion and yolk sac. nonpregnant and in near-term pregnant women is given in Table
o Its dorsal surface grows faster than the ventral surface, in 5-1.
association with the elongation of its neural tube.  Human placenta also synthesizes an enormous amount of
 As pregnancy advances, the yolk sac becomes smaller and its protein and peptide hormones a summarized in Table 5-2.
pedicle relatively longer.
 At term, normally has 2 arteries and 1 vein (Fig. 5-20).
o Right umbilical vein usually disappears early during fetal
development, leaving only the original left vein.
HUMAN CHORIONIC GONADOTROPIN (HCG)  Circulating free β-subunit levels are low to undetectable
throughout pregnancy.
 This so-called pregnancy hormone is a glycoprotein with
biological activity similar to luteinizing hormone (LH).
o Both act via the same plasma membrane LH-hCG Concentrations of hCG in Serum and Urine
receptor.
 Various malignant tumors also produce hCG, sometimes in  The combined hCG molecule is detectable in plasma of
large amounts—especially trophoblastic neoplasms pregnant women 7 to 9 days after the midcycle surge of LH
that precedes ovulation.

Chemical Chracteristics
Regulation of hCG Synthesis and Clearance
 Chorionic gonadotropin is a glycoprotein with a molecular
weight of 36,000 to 40,000 Da.  Placental gonadotropin-releasing hormone (GnRH) is likely
 Has the highest carbohydrate content of any human involved in the regulation of hCG formation.
hormone—30 %.  Renal clearance of hCG accounts for 30 % of its metabolic
 Structurally related to three other glycoprotein hormones— clearance.
LH, FSH, and TSH.  The remainder is likely cleared by metabolism in the liver.
o All four glycoproteins share a common α-subunit.  Clearances of β- and α-subunits are approximately 10-fold
and 30-fold, respectively, greater than that of intact hCG.

Biosynthesis
Biological Functions
 Syntheses of the α- and β-chains of hCG are regulated
separately.  Both hCG subunits are required for binding to the LH-hCG
 α-subunit receptor in the corpus luteum and the fetal testis.
o common to hCG, LH, FSH, and TSH  The best-known biological function of hCG is the so-called
o encoded by a single gene located on chromosome 6 rescue and maintenance of corpus luteum function—that
 β-hCG–β-LH family of subunits is, continued progesterone production.
o encoded by 7 genes on chromosome 19  Stimulation of fetal testicular testosterone secretion,
o Six genes code for β-hCG and one for β-LH which is maximum approximately when hCG levels peak.
 Before 5 weeks, hCG is expressed in both  The maternal thyroid gland is also stimulated by large
syncytiotrophoblast and cytotrophoblast quantities of hCG.
 in the first trimester when maternal serum levels peak, hCG  Promotion of relaxin secretion by the corpus luteum.
is produced almost solely in the syncytiotrophoblast  Regulates expansion of uterine natural killer cell numbers
during early stages of placentation, thus ensuring
appropriate establishment of pregnancy
Abnormally High or Low hCG Levels  Levels of mRNA for hPL in syncytiotrophoblast remain
relatively constant throughout pregnancy.
 There are several clinical circumstances in which  Prolonged maternal starvation in the first half of pregnancy
substantively higher maternal plasma hCG levels are found. leads to increased hPL plasma concentrations.
 Examples:
- multifetal pregnancy
- erythroblastosis fetalis associated with fetal hemolytic Metabolic Actions
anemia
- gestational trophoblastic disease.  Placental lactogen has putative actions in several important
 Relatively higher hCG levels may be found at midtrimester metabolic processes.
in women carrying a fetus with Down syndrome—an 1) hPL promotes maternal lipolysis with increased
observation used in biochemical screening tests. circulating free fatty acid levels.
o …reason is not clear. - This provides an energy source for maternal
 Relatively lower hCG plasma levels are found in women metabolism and fetal nutrition.
with early pregnancy wastage, including ectopic pregnancy. 2) hPL may aid maternal adaptation to fetal energy
requirements.
- The increased maternal insulin resistance ensures
HUMAN PLACENTAL LACTOGEN (hPL) nutrient flow to the fetus.
- To counterbalance the increased insulin resistance and
 Because of its potent lactogenic and growth hormone-like prevent maternal hyperglycemia, maternal insulin
bioactivity, as well as an immunochemical resemblance to levels are increased.
human growth hormone (hGH), it was called human 3) hPL is a potent angiogenic hormone.
placental lactogen or chorionic growth hormone. - It may serve an important function in fetal vasculature
 Concentrated in syncytiotrophoblast. formation
 Detected as early as the 2nd or 3rd week after fertilization.
 Also similar to hCG, hPL is demonstrated in cytotrophoblast OTHER PLACENTAL PROTEIN HORMONES
before 6 weeks.
 Placenta has a remarkable capacity to synthesize
numerous peptide hormes
Chemical Characteristics and Synthesis
 The placental peptide/protein hormones are not subject
 Human placental lactogen is a single, nonglycosylated to feedback inhibition
polypeptide chain with a molecular weight of 22,279 Da.
 There are five genes in the growth hormone–placental 1. Chorionic Adrenocorticotropin
lactogen gene cluster that are linked and located on o Proteolytic products of pro-opiomelanocor-β-
chromosome 17. endorphin that are recovered from placental
o Two of these—hPL2 and hPL3—encode hPL, and the
extracts
amount of mRNA in the term placenta is similar for
each. 1. Adrenocorticotropic hormone
 Within 5 to 10 days after conception, hPL is demonstrable 2. Lipotropin
in the placenta and can be detected in maternal serum as 3. Β-endorphin
early as 3 weeks. o Phyisological action is unclear
 In late pregnancy, maternal serum concentrations reach o Placental corticotropin-releasing hormone(CRH)
levels of 5 to 15 μg/mL (Fig. 5-21). stimulates synthesis and release of chorionic
 Very little hPL is detected in fetal blood or in the urine of
ACTH
the mother or newborn.
o Placental CRH production is positively regulated
by cortisol = positive feedback loop
o Important for:
 Controlling fetal lung maturation
 Parturition timing
2. Growth Hormone Variant
o A growth hormone variant(hGH-V) that is not
expressed in the pituitary
o Sometimes referred to as placental growth
hormone
o Retains growth-promoting and antilipogenic
functions similar to hGH
o Reduced diabetogenic and lactogenic functions
relative to hGH
o Synthesized in the syncytium
o Present in maternal plasma by 21-26 weeks
gestation
o Increases in concentration until approx. 36
weeks and remain constant thereafter
Regulation of hPL Biosynthesis o There is a correlation between the levels of
hGH-V in maternal plasma and those of insulin-
like growth factor-1
 o Overexpression of hGH-V is a likely candidate to  Immunosuppresion
mediate insulin resistance of pregnancy o CRH treatment increases prostaglandin
3. Hypothalamic-Like Releasing Hormone formation in:
o Known hypothalamic-releasing or inhibiting  Placenta
hormones  Amnion
 GnRH  Chorion leave
 CRH  Decidua
 Thyroid-releasing hormone (TRH) o Glucocorticoids act in the hypothalamus to
 GHRH inhibit CRH release
 Somatostatin o In the trophoblast, glucocorticoids stimulate
o There is an analogous hormone produced in the CRH gene expression
human placenta
4. Gonadotropin-Releasing Hormone
o There is a large amount of immunoreactive
GnRH in the placenta
6. Growth Hormone-Releasing Hormone
o It it is found in cytotrophoblasts, but not
o Role of placental GHRH is not known
syncytiotrophoblast
o Ghrelin is another regulator of hGH secretion
o The human placenta could synthesize both
that is produced by placental tissue
GnRH and TRH in vitro
o Trophoblast ghrelin
o Placental-derived GnRH functions to regulate
 Expression peaks at midpregnancy
trophoblas hCG production = GnRH levels are
 Potential regulator of hGH-V
higher early in pregnancy
production
o Placental-derived GnRH is also the likely cause
 Paracrine regulator of differentiation
of elevated maternal GnRH levels in pregnancy
7. Relaxin
5. Corticotropin-Releasing Hormone
o Expression of relaxin is demonstated in:
o This hormone is a member of a larger family of
 Human corpus luteum
CRH-related peptides that includes
 Decidua
 CRH
 Placenta
 Urocortin
o Structurally similar to insulin and insulin-like
 Urocortin II
growth factor.
 Urocortin III
o The rise in maternal circulating relaxin levels
o Urocortin also is produced by the placenta and
seen in early pregnancy is attributed to corpus
secreted into the maternal circulation, but at
luteum secretion and levels of hCG
much lower levels than seen for CRH
o May act on myometrium to promote relaxation
o After labor begins, maternal plasma CRH levels
and the quiescence of early pregnancy
increase further by 2-3x
o Production of relaxin and relaxin-like factors in
o CRH receptors are present in many tissues
the placenta and fetal membranes may play an
 Placenta
autocrine-paracrine role in postpartum
 Adrenal gland
regulation of ECM degradation.
 Sympathetic ganglia
o Function:
 Lymphocytes
 Enhance the glomerular filtration rate
 Gastrointestinal tract
8. Parathyroid Hormone-Related Prtoein
 Pancreas
o Significantly elevated in pregnancy within
 Gonads
maternal but not fetal circulation
 Myometrium
o PTH-rP synthesis is found in several normal
o CRH can act through 2 major families
adult tissues:
 Type 1 CRH Receptors (CRH-R1)
 Myometrium
 Type 2 CRH Receptors (CRH-R2)
 Endometrium
o Both express Type 1 & Type 2 CRH Receptors
 Corpus Lutuem
 Trophoblast
 Lactating mammary tissue
 Amniochorion
o Function:
 Decidua
 Regulate genes involved in transfer of
o CRH and urocortin increase trophoblast ACTH
calcium and other solutes
secretion supporting an autocrine-paracrine role
 Contributes to fetal mineral
o Large amounts of trophoblast CRH enter
homeostasis in bone, amniotic fluid,
maternal blood = there is also a large
and the fetal circulation
concentration of specific CRH-biding protein in
9. Leptin
maternal plasma.
o Secreted by adipocytes
o Biological Roles:
o Synthesized by both cytotrophoblast and
 Induction of smooth muscle relaxation
syncytiotrophoblast
in vascular and myometrial tissue
 o Maternal serum levels are higher than those in 1. Cholesterol is converted to pregnenolone within
nonpregnant women the mitochondria catalyzed by cytochrome P450
o Function: 2. Pregnenolone is converted to progesterone in
 Antiobesity hormone the endoplasmic reticulum by 3β-hydroxysteroid
 Decreases food intake through its dehydrogenase
hypothalamic receptor  Progesterone is released through diffusion
 Regulates bone growth and immune  The rate-limiting enzyme in cholesterol biosynthesis is 3-
function hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
 Inhibits apoptosis reductase
 Promotes trophoblast  The trophoblast uses LDL cholesterol for progesterone
10. Neuropeptide Y biosynthesis
o Widely distributed in the brain
o Found also in sympathetic neurons innervating Progesterone Synthesis and Fetal Relationships
the:
 Conditions associated with very low maternal plasma
 Cardiovascular
levels and low urinary excretion of estrogen:
 Respiratory
o Fetal demise
 GIT
o Ligation of the umbilical cord with fetus and
 GUT
placenta remaining in situ
o Isolated from the placenta
o Anencephaly
o Localized in cytotrophoblasts
 There is not a concomitant decrease in progesterone
o Treatment of placental cells with neuropeptide
levels until some indeterminate time after fetal death.
Y causes CRH release
11. Inhibin  Placental endocrine function may persist for long
o Produced by: periods(weeks) after fetal demise
 Human testis
Progesterone Metabolism During Pregnancy
 Ovarian granulosa cells
 Corpus lutuem  The metabolic clearance rate of progesterone in
o Function: pregnant
 Inhibit FSH secretion  The concentration ratio of progesterone metabolite to
 Inhibit ovulation during pregnancy progesterone is increased in pregnancy
 Regulate placental hCG synthesis  Progesterone is converted to potent mineralocorticoid
12. Activin deoxycorticosterone in pregnant women and in the
o Closely related to inhibin fetus.
o Not detectable in fetal blood before labor but is
present in umbilical cord blood after labor PLACENTAL ESTROGEN PRODUCTION
begins
o Not clear if activin is involved in placental  Placenta produces huge amounts of estrogen using
metabolic processes blood-borne steroidal precursors from the maternal and
fetal adrenal glands.
PLACENTAL PROGESTERONE PRODUCTION  Near term, normal human pregnancy is a
hyperestrogenic state.
 After 6 to 7 weeks gestation, little progesterone is  The amount of estrogen produced each day by
produced in the ovary syncytiotrophoblast during the last few weeks of
 Removal during 7th to 10th week does not decrease pregnancy is equivalent to the produced in 1 day by the
urinary pregnanediol levels ovaries of no fewer than 1000 ovulatory women.
 Pregnanediol – principal urinary metabolite of  During the 2-4 weeks of pregnancy, rising hCg levels
progesterone maintain production of estradiol in the maternal corpus
 Removal before 6 weeks of gestation can result in luteum.
spontaneous abortion.  Production of both progesterone and estrogens in the
 After 8 weeks, the placenta assumes progesterone maternal ovaries decreases significantly by the 7th week
secretion, resulting in a gradual increase in maternal of pregnancy in which there is luteal-placental transition.
serum levels throughout pregnancy.  By the 7th week, more than half of estrogen entering
maternal circulation is produced in the placenta.
Progesterone Production Rates
Placental Estrogen Biosynthesis
 Daily production rate of progesterone in late, normal,
singleton pregnancies = 250mg.  The estrogen synthesis pathways in the placenta differ
 Daily production rate of progesterone in multifetal from those in the ovary of nonpregnant women.
pregnancies = >600mg/day  Estrogen is produced during the follicular and luteal
 Progesterone is synthesized from cholesterol in a 2 step phases through the interaction of theca and granulosa
enzymatic reaction cells that surround the follicles.
 In human trophoblast, neither cholesterol nor  Daily steroid production of fetal adrenal glands near term
progesterone can serve as precursor for estrogen is 100-200mg/day in comparison to adult steroid
biosynthesis. secretion of 30-40mg/day
 CYP17 is a crucial enzyme necessary for sex steroid  The fetal zone is lost in the first year of life and is not
synthesis and is not expressed in human placenta. present in the adult.
 Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S)  Adrenal gland growth is influenced by factors secreted by
are C19 steroids and are often called adrenal androgens the placenta and ACTH.
that can also serve as estrogen precursors.
 The placenta has a high capacity to convert appropriate PLACENTAL ESTRIOL SYNTHESIS
C19 steroids to estrone and estradiol.
 Estradiol is the primary placental estrogen secretory
 The conversion of DHEA-S to estradiol requires placental
product at term.
expression of 4 key enzymes that are located in the
 Significant levels of estriol and estetrol are found in the
synctiotrophoblast
maternal circulation and they increase particularly late in
o Steroid sulfatase(STS) – converts DHEA-S to
gestation.
DHEA
 Important fetal-maternal interactions through the fetal
o 3β-hydroxysteroid dehydrogenase type
liver
1(3βHSD) – DHEA to androstenedione
o High levels of fetal hepatic 16α-hydrolase act on
o Cytochrome P450 aromatase (CYP19) –
adrenal-derived steroids
androstenedione to estrone
o 16α-hydroxydehydroepiandrosterone(16-
o 17β-hydroxysteroid dehydrogenase type
OHDHEA) is converted to estriol by placental
1(17βHSD1) – estrone to estradiol
tissue.
Plasma C19 Steroids as Estrogen Precursors  Near term, the fetus is the source of 90% of placental
estriol and estetrol precursor in normal human
 DHEA-S was found to be a major precursor of estrogens pregnancy.
in pregnancy  The placenta secretes several estrogens
 There is a 10-20x increased metabolic clearance rate of o Estradiol
plasma DHEA-S in women at term compared with that in o Estrone
men and nonpregnant women o Estriol
 This rapid use results in a progressive decrease in plasma o Estetrol
DHEA-S concentration as pregnancy progresses  Most placental estrogens are released into the maternal
 Maternal adrenal glands do not produce sufficient circulation.
amounts of DHEA-S to account for more than a fraction  Maternal estriol and estetrol are produced almost solely
of total placental estrogen biosynthesis. by fetal steroid precurors.
 The fetal adrenal glands are qunatitavely the most
important source of placental estrogen precursors in ENZYMATIC CONSIDERATIONS
human pregnancy.
 There is a very active steroid sulfotransferase activity in
 The estrogen production during pregnancy reflects the
the fetal adrenal glands.
unique interactions among fetal adrenal glands, fetal
 The principal secretory products of the fetal adrenal
liver, placenta, and maternal adrenal glands.
glands:
Directional Secretion of Steroids from Syncytiotrophoblast o Pregnenolone sulfate
o DHEA-S
 More than 90% of estradiol and estriol formed in  Cortisol arises primarily in the neocortex and tranisitional
syncytiotrophoblast enters maternal plasma zone of the fetal adrenal glands and is a minor secretory
 85% or more of placental progesterone enters maternal product until late in gestation.
plasma
 The major reason for directional movement of newly FETAL ADRENAL STEROID PRECURSOR
formed steroid into the maternal circulation is the nature
 The precursor for fetal adrenal steroidgenesis is
of hemochorioendothelial placentation.
cholesterol.
 The net result of this hemochorial arrangement is that
 Steroidogenesis in the fetal gland is equivalent to a
there is substantially greater entry of steroids into the
fourth of the total daily LDL cholesterol turnover in
maternal circulation compared with the amount that
adults.
enters fetal blood.
 Fetal adrenal glands synthesize cholesterol from acetate.
FETAL ADRENAL GLAND-PLACENTAL INTERACTIONS  De nove cholesterol synthesis rate by fetal adrenal tissue
is extremely high.
 At term, the fetal adrenal glands weigh the same as  Fetal glands take up lipoproteins as a source of
those of the adult. cholesterol for steroidogenesis
 More than 85% of the fetal gland is composed of a o LDL – most effective
unique fetal zone, which has a great capacity for steroid o HDL – less effective
biosynthesis. o VLDL – devoid of stimulatory activity
 Fetal adrenal glands are highly dependent on circulating o It is due to inadequate formation of of C19-
LDL as a source of cholesterol for optimum steroids in the adrenal glands of these trisomic
steroidogenesis. fetuses.
 Most fetal plasma cholesterol arises by de novo synthesis 7. Defienciency in Fetal LDL Cholesterol Biosynthesis
in the fetal liver o The absence of LDL in the maternal serum
 The low LDL cholesterol level in fetal plasma is not the restricted progesterone formation in both the
consequence of impaired fetal LDL synthesis, but results corpus luteum and placenta
from the rapid use of LDL by the fetal adrenal glands for o Estriol levels were lower than normal
steroidogenesis. o The diminished estrogen production was the
result of decreased fetal LDL formation, which
FETAL CONDITIONS THAT AFFECT ESTROGEN PRODUCTION limited fetal adrenal production of estrogen
precursors.
1. Fetal Death
8. Fetal Erythroblastosis
o Fetal death is followed by a reduction in urinary
o Severe fetal D-antigen alloimmunization that
estrogen levels
causes maternal plasma estrogen levels to be
o After ligation of the umbilical cord with the
elevated.
fetus and placenta left in situ, placental
o The cause is increased placental mass from
estrogens decline markedly.
hypertrophy which can be seen with fetal
o Placental progesterone production is
hemolytic anemia.
maintained.
2. Fetal Anencephaly MATERNAL CONDITIONS THAT AFFECT PLACENTAL
o There is absence of the adrenal cortex fetal zone ESTROGEN PRODUCTION
in which the placental estrogen formation rate is
severely limited because of diminished 1. Glucocorticoid Treatment
availability of C19-steroids precursors. o The administration of glucocorticoids to
o All estrogens produced in women pregnant with pregnant women causes a striking reduction in
an anencephalic fetus arise from placental use placental estrogen formation.
of maternal plasma DHEA-S o Glucocorticoids inhibit ACTH secretion from the
o Placental estrogen production is decreased in maternal and fetal pituitary glands.
women pregnant with an anencephalic fetus  Decreased maternal and fetal adrenal
when a potent glucocorticoid is given to the secretion of the placental estrogen
mother. precursor, DHEA-S
 Suppresses ACTH secretion 2. Maternal Adrenal Dysfunction
 Decrease DHEA-S secretion rate from o Pregnant women with Addison disease cause
the maternal adrenal cortex maternal urinary estrogen levels to decrease
3. Fetal Adrenal Hypoplasia o The decrease principally affects estrone and
o Estrogen production in these pregnancies is estradiol
limited, which suggest the absence of of C19 3. Maternal Ovarian Androgen-Producing Tumors
precursors. o All androstenedione entering the intervillous
4. Fetal-Placental Sulfatase Deficiency space is taken up by synytiotrophoblast and
o Placental sulfatase deficiency associated with converted to estradiol. None of this of C 19-
very low estrogen levels in otherwise normal steroid enters the fetus.
pregnancies. o A female fetus is rarely virilized if there is
o Sulfatase deficiency precludes the hydrolysis of maternal androgen-secreting ovation tumor.
C19-steroid sulfates, the 1st enzymatic step for o The placenta efficiently converts aromatizable
estrogen biosynthesis C19-steroids, including testosterone, to
o X-linked disorder and all affected fetuses are estrogens, thus precluding transplacental
male. passage.
o Associated with the development of ichthyosis 4. Gestational Trophoblastic Disease
in affected males later in life o With complete hydatidiform mole or
5. Fetal-Placental Aromatase Deficiency choriocarcinoma, there is no fetal adrenal
o Androstenedione cannot be converted to source of C19-steroid precursor for trophoblast
estradiol estrogen biosynthesis
o Androgen metabolites of DHEA produced in the o Placental estrogen formation is limited to the
placenta, including androstenedione and use of C19-steroids in the maternal plasma, and
testosterone are secreted in the maternal or therefore the estrogen produced is principally
fetal circulation or both. estradiol.
o This results to virilization of the mother and thte o Great variation is observed in the rates of both
female fetus estradiol and progesterone formation in molar
6. Trisomy 21- Down Syndrome pregnancies.
o Serum unconjugated estriol levels were low in
women with Down Syndrome fetuses
CHAPTER 6: PLACENTAL ABNORMALITIES - Villi are enlarged and edematous and fetal parts
NORMAL PLACENTA are present
- 470 g, round to oval, 22 cm diameter, 2.5 cm Placental mesenchymal dysplasia
central thickness - Vesicles correspond to enlarged stem villi, not
- Composed of: placental disc, extraplacental excessive trophoblast proliferation
membranes, 3-vessel umbilical cord - Placentomegaly may result from collections of
- Maternal surface: basal plate, which is divided blood or fibrin
by clefts into portions—termed cotyledons. B. Extrachorial Placentation
- Fetal surface: chorionic plate, into which the - Normally, chorionic plate extends to the periphery of
umbilical cord inserts, typically in the center. the placenta and has a diameter similar to that of the
- Sonographically: the placenta is homogenous 2 basal plate
to 4 cm thick, lies against the myometrium, and - chorionic plate fails to extend to this periphery and
indents into the amnionic sac leads to a chorionic plate that is smaller than the basal
- During prenatal sonographic examinations, plate
placental location and relationship to the Circummarginate placenta
internal cervical os are recorded, umbilical cord, - ring does not have a central depression
its fetal and placental insertion sites examined, - fibrin and old hemorrhage lie between the
and its vessels counted. placenta and the overlying amniochorion
Circumvallate placenta
ABNORMALITIES OF THE PLACENTA - peripheral chorion is a thickened, opaque, gray-
A. Shape and Size white circular ridge composed of a double fold
Bilobate Placenta/ Bipartite Placenta/ Placenta Duplex of chorion and amnion; on cross section
- placenta is infrequently formed as separate, appears as a “shelf”
nearly equally sized discs - fetal surface has central depression with grayish
- the cord inserts between 2 placental lobes— white ring
connecting chorionic bridge - Clinical significance: Double fold location may
or intervening membranes help to differentiate this shelf from amnionic
Multilobate bands and amnionic sheets; circumvallate
- Placenta containing 3 or more equally sized placenta was associated with increased risk for
lobes, rare antepartum bleeding and preterm birth but
- 1 or more small accessory lobes—succenturiate reported these as transient and benign
lobes—may develop in the membranes at a C. Placenta accrete, increta and percreta
distance from the main placenta - Develop when trophoblast invades the myometrium to
- These lobes have vessels that course through varying depths to cause abnormal adherence
the membranes. If these vessels overlie the - More likely when there is placenta previa or when the
cervix to create a vasa previa, they can cause placenta implants over a prior uterine incision or
dangerous fetal hemorrhage if torn. perforation.
- An accessory lobe may also be retained in the - Torrential hemorrhage is a frequent complication
uterus after delivery and cause postpartum D. Circulatory Disturbances
uterine atony and hemorrhage - grouped into: (1) those in which there is disrupted
Placenta membranacea maternal blood flow to or within the
- All or nearly all of the membranes are covered intervillous space and (2) those with disturbed fetal
with villi blood flow through the villi
- Give rise to serious hemorrhage because of - identified in normal, mature placenta
associated placenta previa or accrete Maternal Blood Flow Disruption
Ring shaped placenta 1. Subchorionic Fibrin Disposition
- Placenta is annular in shape and sometimes a - Slowing of maternal blood flow within the intervillous
complete ring of placental tissue is present space with subsequent fibrin deposition
- Variant of placenta membranacea - Blood stasis specifically occurs in the subchorionic area
Placenta Fenestrata - Lesions are commonly seen as white or yellow firm
- Central portion of the placenta is missing plaques on the fetal surface.
- Defect only involves villous tissue and chorionic 2. Perivillous Fibrin Deposition
plate remains intact - Maternal blood flow stasis around an individual villus
- Clinically may erroneously prompt a search for a - Diminished villous oxygenation and
retained placental cotyledon syncytiotrophoblastic necrosis
 Normal placenta increases thickness at approx. - Within limits, the small yellow-white placental nodules
1mm/wk and not exceed 40mm. are considered to be normal
Placentomegaly placental aging
- thicker than 40 mm, commonly results from 3. Maternal Floor Infarction
striking villous enlargement - Dense fibrinoid layer within the placental basal plate,
- Secondary to maternal diabetes or severe erroneously termed an infarction
maternal anemia, or to fetal hydrops or - Has a thick, white, firm, corrugated surface that
infection caused by syphilis, toxoplasmosis, or impedes normal maternal blood flow into the
cytomegalovirus. intervillous space
- Associated with miscarriage, fetal-growth restriction, 1. Gestational Trophoblastic Disease - pregnancy-
preterm delivery, and stillbirths related trophoblastic proliferative abnormalities.
- Etiopathogenesis is associated with lupus 2. Chorioangioma
anticoagulant or with maternal thrombophilias. - Benign and incidence of 1%
- These lesions create a thicker basal plate - maternal serum alphafetoprotein (MSAFP) levels may
4. Intervillous Thrombus be elevated with these tumors, an important diagnostic
- Collection of coagulated maternal blood found in finding
intervillous space mixed - sonographic appearance: well-circumscribed, rounded,
with fetal blood from a break in a villus predominantly hypoechoic lesion near the chorionic
- These collections vary in size up to several surface and protruding into the amnionic cavity
centimeters; appear red if recent or white-yellow if - Small chorioangiomas: usually asymptomatic
older - Large tumors: measures > 5 cm, may be associated
- Develop at any placental depth with significant arteriovenous shunting within the
- Intervillous thrombi are common, not associated with placenta that can cause fetal anemia and hydrops
adverse fetal sequelae 3. Tumors Metastatic to the Placenta
- Can cause elevated maternal serum alphafetoprotein - Metastasis to placenta uncommon but seen in
levels melanomas, leukemias and lymphomas, and breast
5. Infarction Cancer
- Obstruction of the maternal circulation that supplies - Tumor cells are confined within the intervillous space,
oxygen to the chorionic villi thus metastasis to the fetus is uncommon but is most
can result in infarction of individual villus often seen with melanoma
- Common in mature placentas and are benign in limited
numbers ABNORMALITIES OF THE MEMBRANES
- If numerous, placental insufficiency develops A. Meconium Staining
- Associated with preeclampsia or lupus anticoagulant - Fetal passage of meconium before or during labor is
when they are thick, centrally located, and randomly common, incidence of 12 to 20 percent
distributed - staining of the amnion can be obvious within 1 to 3
6. Hematoma hours but passage cannot be timed or dated accurately
a) retroplacental hematoma-between the placenta and B. Chorioamnionitis
its adjacent decidua - Colonization of normal genital-tract flora in
b) marginal hematoma-between the chorion and membranes, umbilical cord, and fetus
decidua and also clinically called subchorionic - Bacteria ascend after prolonged membrane rupture
hemorrhage and during labor
c) subchorial thrombosis, also known as Breus mole- - Chorioamnionitis – infection that leads to full-
along the roof of the intervillous space and beneath the thickness involvement of the membranes
chorionic plate - Funisitis – inflammation of the chorionic plate and of
d) subamnionic hematoma- of fetal vessel origin and the umbilical cord
found beneath the amnion but above the chorionic - Fetal infection: result from hematogenous spread if
plate the mother has bacteremia; from aspiration,
Fetal Blood Flow Disruption swallowing, or other direct contact with infected
1. Fetal Thrombolytic Vasculopathy amnionic fluid
- Deoxygenated fetal blood flows from 2 umbilical - associated with unexplained cases of ruptured
arteries into arteries within the chorionic plate that membranes and/or preterm labor
supply individual stem villi and their thrombosis will - characterized by membrane clouding accompanied by
obstruct fetal blood flow a foul odor
- Distal to the obstruction, affected portions of the villus C. Other Membrane Abnormalities
become infarcted and nonfunctional 1) Amnion nodosum
- Clinical Significance: if many villi become infarcted - Tiny light tan creamy nodules in the amnion that are
2. Subamnionic Hematoma scraped off the fetal surface and contain deposits of
- lie between the placenta and amnion fetal squames and fibrin that reflect prolonged
- most often are acute events during third-stage labor and severe oligohydramnios
when cord traction ruptures a vessel near the cord 2) Amnionic bands
insertion - Caused when disruption of the amnion leads to
- Doppler interrogation will show absence of internal formation of bands or strings that entrap the fetus and
blood flow that permits differentiation of hematomas impair growth and development of the involved
from other placental masses structure
E. Placental Calcification - commonly involve the extremities to
- Calcium salts may be deposited throughout the cause limb-reduction defects and more subtle
placenta, but are most common on maternal surface in deformations
the basal plate. - may also affect other fetal structures such as the
- Associated with nulliparity, higher socioeconomic cranium, causing encephalocele
status, and greater maternal serum calcium levels 3) Amnionic sheets
F. Placental Tumors - formed by normal amniochorion draped over a
preexisting uterine synechia
- little fetal risk, but has higher rates of preterm which they reach surrounded only by a fold of amnion;
membrane rupture and placental abruption vessels are vulnerable to compression,
which may lead to fetal hypoperfusion and acidemia;
ABNORMALITIES OF THE UMBILICAL CORD incidence is approximately 1 percent, but it is more
A. Length commonly seen with placenta previa and multifetal
- Normal length: 40 to 70 cm long, very few measure gestations
< 32 cm or > 100 cm - Furcate insertion: very uncommon; site of cord
- Short cords: associated with fetal-growth restriction, connection onto the placental disc is central, but
congenital malformations, intrapartum distress, and a umbilical vessels lose their protective Wharton jelly
twofold risk of death shortly before they insert; covered only by an amnion
- Long cords: linked with cord entanglement or prolapse sheath and prone to compression, twisting, and
and with fetal anomalies, acidemia, and demise Thrombosis
- cord diameter has been used as a predictive marker - Vasa Previa: associated with velamentous insertion
because antenatal cord length determination is limited when some of the fetal vessels in the membranes cross
- lean cords: poor fetal growth the region of the cervical os below the presenting fetal
- large diameter cords: macrosomia part; membrane rupture may be accompanied by
B. Coiling tearing of a fetal vessel with exsanguination
- Normally umbilical vessels spiral through the cord in a F. Knots, Strictures and Loops
sinistral, left-twisting direction - vascular abnormalities can impede cord vessel blood
- umbilical coiling index: no. of complete coils per flow either toward or away from the fetus and cause
centimeter of cord length, which is 0.4 at antepartum fetal harm
(sonography) and 0.2 postpartum by actual 1) Knots
measurement - True knots: result from active fetal movement; when
- Hypocoiled cords: meconium staining,preterm birth associated with singleton fetuses, the stillbirth risk is
and fetal distress increased four- to tenfold
- Hypercoiled cords: higher incidence of preterm - False knots: result from kinking of the vessels to
delivery and cocaine abuse accommodate the length of the cord
C. Vessel Number - Venous stasis may lead to mural thrombosis and fetal
- Normal: two thick-walled arteries and one thin, larger hypoxia causing death or neurological morbidity
umbilical vein 2) Stricture
1) Single umbilical artery: major malformations, - focal narrowing of its diameter that usually develops
cardiovascular and genitourinary anomaly, fetal-growth near the fetal cord insertion
2) Fused umbilical artery with a shared lumen: arises - characteristic pathological features: absence of
from failure of the 2 arteries to split during Wharton jelly and stenosis or obliteration of cord
embryological dev’t vessels at the narrow segment
- common lumen may extend through the entire cord, - fetus is stillborn; less common is a cord stricture
but if partial, is typically found near the placental caused by an amnionic band
insertion 3) Loops
- associated with a higher incidence of marginal or - caused by coiling around various fetal parts during
velamentous cord insertion, but not congenital fetal movement, more common with longer cords
anomalies - cord around the neck—a nuchal cord—is extremely
D. Remnants and Cysts common
- remnants of vitelline duct, allantoic duct, and - during labor: can result in fetal heart rate
embryonic vessels; not associated with congenital decelerations that persist during a contraction
malformations or perinatal complications - nuchal cords are relatively uncommon causes of
- True cysts: epithelium-lined remnants of the allantoic adverse perinatal outcome
or vitelline ducts; located closer to the fetal insertion 4) Funic presentation
site - umbilical cord is the presenting part in labor
- Pseudocysts: form from local degeneration - associated with fetal malpresentation
of Wharton jelly and occur anywhere along the cord - identified with placental sonography and color flow
- Single umbilical cord cysts identified in the first Doppler
trimester tend to resolve completely; multiple cysts - fetal heart rate abnormalities and overt or occult cord
may portend miscarriage or aneuploidy prolapse may complicate labor and lead to cesarean
- Persisting cysts are associated with a risk for structural delivery.
defects and chromosomal anomalies G. Vascular
E. Insertion 1) Cord hematoma – associated with abnormal cord
- Normal insertion: centrally into the placental disc length, umbilical vessel aneurysm, trauma,
- Marginal insertion: common, sometimes referred to as entanglement, umbilical vessel venipuncture, and
battledore placenta, cord anchors at the placental funisitis
margin; rarely causes problems - hypoechoic masses that lack blood flow
- Velamentous insertion: with clinical importance; 2) Umbilical cord vessel thromboses – in utero event; 70
umbilical vessels characteristically spread within the percent are venous, 20 percent are venous and arterial,
membranes at a distance from the placental margin, and 10 percent are arterial thromboses
- artery have higher perinatal morbidity and mortality
rates and are associated with fetal-growth restriction,
fetal acidosis, and stillbirths
3) Umbilical vein varix – marked focal dilatation that can
be within either the intraamnionic or fetal
intraabdominal portion of the umbilical vein
- complications: rupture or thrombosis, compression
of the umbilical artery, and fetal cardiac failure due
to increased preload
- cystic dilatation of the umbilical vein
4) Umbilical artery aneurysm – caused by congenital
thinning of the vessel wall with diminished support
from
Wharton jelly
- most form at or near the cord’s placental insertion,
where support is absent
- associated with single umbilical artery, trisomy 18,
amnionic fluid volume abnormalities, fetal-growth
restriction, and stillbirth
- could cause fetal compromise and death by
compression of the umbilical vein
- a cyst with a hyperechoic rim