36
CHAPTER 3
Implantation,
Embryogenesis, and
Placental Development
THE OVARIAN–ENDOMETRIAL CYCLE . . . . . . . . . . . . . . . .
THE DECIDUA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IMPLANTATION, PLACENTAL FORMATION, AND FETAL
MEMBRANE DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . .
PLACENTAL HORMONES . . . . . . . . . . . . . . . . . . . . . . . . .
FETAL ADRENAL GLAND HORMONES . . . . . . . . . . . . . . . .
All obstetricians should be aware of the basic reproductive bio-
logical processes required for women to successfully achieve
pregnancy. A number of abnormalities can affect each of these
processes and lead to infertility or pregnancy loss. In most
women, spontaneous, cyclical ovulation at 25- to 35-day inter-
vals continues during almost 40 years between menarche and
menopause. Without contraception, there are approximately
400 opportunities for pregnancy, which may occur with inter-
course on any of 1200 days—the day of ovulation and its two
preceding days. This narrow window for fertilization is con-
trolled by tightly regulated production of ovarian steroids. These
hormones promote optimal regeneration of endometrium after
menstruation ends in preparation for the next implantation
window.
Should fertilization occur, the events that unfold after initial
implantation of the blastocyst onto the endometrium and
through to parturition result from a unique interaction between
fetal trophoblasts and maternal endometrium-decidua. The
ability of mother and fetus to coexist as two distinct immuno-
logical systems results from endocrine, paracrine, and immuno-
logical modification of fetal and maternal tissues in a manner
not seen elsewhere. The placenta mediates a unique fetal–ma-
ternal communication system, which creates a hormonal envi-
ronment that helps initially to maintain pregnancy and eventu-
36 ally initiates the events leading to parturition. The following
sections address the physiology of the ovarian-endometrial cy-
44 cle, implantation, placenta, and fetal membranes, and special-
ized endocrine arrangements between fetus and mother.
47
62 THE OVARIAN–ENDOMETRIAL CYCLE
69 The endometrium-decidua is the anatomical site of blastocyst
apposition, implantation, and placental development. From an
evolutionary perspective, the human endometrium is highly de-
veloped to accommodate endometrial implantation and a hemo-
chorial type of placentation. Endometrial development of a
magnitude similar to that observed in women—that is, with
special spiral (or coiling) arteries—is restricted to only a few pri-
mates, such as humans, great apes, and Old World monkeys.
Trophoblasts of the blastocyst invade these endometrial arteries
during implantation and placentation to establish uteroplacen-
tal vessels.
These primates are the only mammals that menstruate,
which is a process of endometrial tissue shedding with hemor-
rhage and is dependent on sex steroid hormone-directed
changes in blood flow in the spiral arteries. With nonfertile, but
ovulatory, ovarian cycles, menstruation effects endometrial
desquamation. New growth and development must be initiated
with each cycle so that endometrial maturation corresponds
rather precisely with the next opportunity for implantation and
pregnancy. There seems to be a narrow window of endometrial
receptivity to blastocyst implantation that corresponds approx-
imately to menstrual cycle days 20 to 24.
■ The Ovarian Cycle
The development of predictable, regular, cyclical, and sponta-
neous ovulatory menstrual cycles is regulated by complex interac-
tions of the hypothalamic-pituitary axis, the ovaries, and the gen-
ital tract (Fig. 3-1). The average cycle duration is approximately
 Implantation, Embryogenesis, and Placental Development 37

Follicular phase Luteal phase Follicular phase Fertilization / implantation

80

Hormone levels
Gonadotropins

CHAPTER 3
(IU/L)
hCG 40

LH
FSH

250 20
Steroid hormones

Estradiol
(pg/mL)

Progesterone
Estradiol Progesterone

(ng/mL)
125 10
Ovarian cycle

Antral Dominant Corpus Antral Dominant Fertilization & CL of

CL
follicles follicle luteum (CL) follicles follicle implantation pregnancy
Endometrial cycle

Uterine gland

Spiral artery

Menses

Basalis

Menstrual cycle day 14 28 14

1 5 10 15
Embryonic age

Gestational age 14 20

FIGURE 3-1 Gonadotropin control of the ovarian and endometrial cycles. The ovarian-endometrial cycle has been structured as a 28-day
cycle. The follicular phase (days 1 to 14) is characterized by rising levels of estrogen, thickening of the endometrium, and selection of
the dominant “ovulatory” follicle. During the luteal phase (days 14 to 21), the corpus luteum (CL) produces estrogen and progesterone,
which prepare the endometrium for implantation. If implantation occurs, the developing blastocysts will begin to produce human chori-
onic gonadotropin (hCG) and rescue the corpus luteum, thus maintaining progesterone production. FSH  follicle-stimulating hormone;
LH-luteinizing hormone.

28 days, with a range of 25 to 32 days. The sequence of hor-
monal events leading to ovulation directs the menstrual cycle.
The cyclical changes in endometrial histology are faithfully re-
produced during each ovulatory cycle.
In 1937, Rock and Bartlett suggested that endometrial his-
tological features were sufficiently characteristic to permit “dat-
ing” of the cycle. These changes are illustrated in Figure 3-2.
The follicular—proliferative—phase and the postovulatory-
luteal or secretory—phase of the cycle are customarily divided
into early and late stages.
Follicular or Preovulatory Ovarian Phase
There are 2 million oocytes in the human ovary at birth, and
about 400,000 follicles are present at the onset of puberty
(Baker, 1963). The remaining follicles are depleted at a rate of
approximately 1000 follicles per month until age 35, when this
rate accelerates (Faddy and colleagues, 1992). Only 400 follicles
are normally released during female reproductive life. There-
fore, more than 99.9 percent of follicles undergo atresia through
a process of cell death termed apoptosis (Gougeon, 1996; Kaipia
and Hsueh, 1997).
Follicular development consists of several stages, which in-
clude the gonadotropin-independent recruitment of primordial
follicles from the resting pool and their growth to the antral
stage. This appears to be under the control of locally produced
growth factors. Two members of the transforming growth fac-
tor- family—growth differentiation factor 9 (GDF9) and bone
morphogenetic protein 15 (BMP-15)—regulate proliferation and
differentiation of granulosa cells as primary follicles grow
(Trombly and co-workers, 2009; Yan and colleagues, 2001). They
 38 Maternal and Fetal Anatomy and Physiology
SECTION 2

A B

C D

FIGURE 3-2 Photomicrographs illustrating endometrial changes

during the menstrual cycle. A. Proliferative phase: straight to
slightly coiled, tubular glands are lined by pseudostratified colum-
nar epithelium with scattered mitoses. B. Early secretory phase:
coiled glands with a slightly widened diameter are lined by sim-
ple columnar epithelium that contains clear subnuclear vacuoles.
Luminal secretions are seen. C. Late secretory phase: serrated, di-
lated glands with intraluminal secretion are lined by short colum-
nar cells. D. Menstrual phase: fragmented endometrium with con-
densed stroma and glands with secretory vacuoles are seen in a
background of blood. (Courtesy of Dr. Kelley Carrick.) E. Early
E pregnancy: a hypersecretory effect demonstrated by cell clearing
and cytoplasmic blebs is seen. (Courtesy of Dr. Raheela Ashfaq.)

also stabilize and expand the cumulus oocyte complex (COC)
in the oviduct (Aaltonen and associates, 1999; Hreinsson and
colleagues, 2002). These factors are produced by oocytes, sug-
gesting that the early steps in follicular development are, in
part, oocyte controlled. As antral follicles develop, surrounding
stromal cells are recruited, by a yet-to-be-defined mechanism,
to become thecal cells.
Although not required for early stages of follicular devel-
opment, follicle-stimulating hormone (FSH) is required for
further development of large antral follicles (Hillier, 2001).
During each ovarian cycle, a group of antral follicles, known
as a cohort, begins a phase of semisynchronous growth as a re-
sult of their maturation state during the FSH rise of the late
luteal phase of the previous cycle. This FSH rise leading to
 Implantation, Embryogenesis, and Placental Development 39

Follicular phase LH Luteal phase/pregnancy LH/hCG

Theca cell Theca–lutein cell

CHAPTER 3
cAMP cAMP

Cholesterol Androstenedione Cholesterol Androstenedione

Circulation Circulation

Basement membrane

Estradiol Androstenedione Estradiol Androstenedione

Progesterone

LDL

cAMP Cholesterol cAMP

Granulosa cell Granulosa-lutein cell

FSH LH/hCG
FIGURE 3-3 The two-cell-two-gonadotropin principle of ovarian steroid hormone production. During the follicular phase (left panel),
luteinizing hormone (LH) controls theca cell production of androstenedione, which diffuses into the adjacent granulosa cells and acts as
precursor for estradiol biosynthesis. The capacity for the granulosa cell to convert androstenedione to estradiol is controlled by follicle-
stimulating hormone (FSH). After ovulation (right panel), the corpus luteum forms and both theca-lutein and granulosa-lutein cells respond
to LH. The theca-lutein cells continue to produce androstenedione, whereas granulosa-lutein cells greatly increase their capacity to produce
progesterone and to convert androstenedione to estradiol. If pregnancy occurs, the production of human chorionic gonadotropin (hCG) by
the placenta rescues the corpus luteum through the LH receptor. Low-density lipoproteins (LDL) are an important source of cholesterol for
steroidogenesis. cAMP  cyclic adenosine monophosphate.

follicle development is called the selection window of the
ovarian cycle (Macklon and Fauser, 2001). Only the follicles
progressing to this stage develop the capacity to produce es-
trogen.
During the follicular phase, estrogen levels rise in parallel
to growth of a dominant follicle and the increase in its num-
ber of granulosa cells (see Fig. 3-1). These cells are the exclu-
sive site of FSH receptor expression. The increase in circu-
lating FSH during the late luteal phase of the previous cycle
stimulates an increase in FSH receptors and subsequently,
the ability of cytochrome P 450 aromatase to convert an-
drostenedione into estradiol. The requirement for thecal
cells, which respond to luteinizing hormone (LH), and gran-
ulosa cells, which respond to FSH, represents the two-go-
nadotropin, two-cell hypothesis for estrogen biosynthesis
(Short, 1962). As shown in Figure 3-3, FSH induces aro-
matase and expansion of the antrum of growing follicles.
The follicle within the cohort that is most responsive to FSH
is likely to be the first to produce estradiol and initiate ex-
pression of LH receptors.
After the appearance of LH receptors, the preovulatory
granulosa cells begin to secrete small quantities of proges-
terone. The preovulatory progesterone secretion, although
somewhat limited, is believed to exert positive feedback on the
estrogen-primed pituitary to either cause or augment LH re-
lease. In addition, during the late follicular phase, LH stimu-
lates thecal cell production of androgens, particularly an-
drostenedione, which are then transferred to the adjacent
follicles where they are aromatized to estradiol (see Fig. 3-3).
During the early follicular phase, granulosa cells also produce
inhibin B, which can feed back on the pituitary to inhibit FSH
release (Groome and colleagues, 1996). As the dominant folli-
cle begins to grow, the production of estradiol and the inhibins
increases, resulting in a decline of follicular-phase FSH. This
drop in FSH is responsible for the failure of other follicles to
reach preovulatory status—the Graafian follicle stage—during
any one cycle. Thus, 95 percent of plasma estradiol produced
at this time is secreted by the dominant follicle—the follicle
destined to ovulate. During this time, the contralateral ovary is
relatively inactive.
 40 Maternal and Fetal Anatomy and Physiology
SECTION 2
FIGURE 3-4 An ovulated cumulus-oocyte complex (COC). An
oocyte is at the center of the complex. Cumulus cells are widely
separated from each other in the cumulus layer by the hyaluro-
nan-rich extracellular matrix. (Courtesy of Dr. Kevin J. Doody.)
Ovulation
The onset of the gonadotropin surge resulting from increasing
estrogen secretion by preovulatory follicles is a relatively precise
predictor of ovulation. It occurs 34 to 36 hours before release of
the ovum from the follicle (see Fig. 3-1). LH secretion peaks 10
to 12 hours before ovulation and stimulates the resumption of
meiosis in the ovum with the release of the first polar body. Cur-
rent studies suggest that in response to LH, increased proges-
terone and prostaglandin production by the cumulus cells, as
well as GDF9 and BMP-15 by the oocyte, activates expression
of genes critical to formation of a hyaluronan-rich extracellular
matrix by the COC (Richards, 2007). As seen in Figure 3-4,
during synthesis of this matrix, cumulus cells lose contact with
one another and move outward from the oocyte along the
hyaluronan polymer—this process is called expansion. This re-
sults in a 20-fold increase in the volume of the complex. Stud-
ies in mice indicate that COC expansion is critical for mainte-
nance of fertility. In addition, LH induces remodeling of the
ovarian extracellular matrix to allow release of the mature
oocyte with surrounding cumulus cells through the surface ep-
ithelium. Activation of proteases likely plays a pivotal role in
weakening of the follicular basement membrane and ovulation
(Curry and Smith, 2006; Ny and colleagues, 2002).
Luteal or Postovulatory Ovarian Phase
Following ovulation, the corpus luteum develops from the re-
mains of the dominant or Graafian follicle in a process referred to
as luteinization. Rupture of the follicle initiates a series of mor-
phological and chemical changes leading to transformation into
the corpus luteum (Browning, 1973). The basement membrane
separating the granulosa-lutein and theca-lutein cells breaks
down, and by day 2 postovulation, blood vessels and capillaries
invade the granulosa cell layer. The rapid neovascularization of
the once avascular granulosa may be due to angiogenic factors
that include vascular endothelial growth factor (VEGF) and oth-
ers produced in response to LH by theca-lutein and granulosa-
lutein cells (Albrecht and Pepe, 2003; Fraser and Wulff, 2001).
During luteinization, these cells undergo hypertrophy and in-
crease their capacity to synthesize hormones (see Fig. 3-1).
It has been well established in studies of hypophysectomized
women that LH is the primary luteotropic factor (Vande Wiele
and colleagues, 1970). The life span of the corpus luteum in
these women is dependent on repeated injections of LH or hu-
man chorionic gonadotropin (hCG). In addition, LH injec-
tions can extend the life span of the corpus luteum in normal
women by 2 weeks (Segaloff and colleagues, 1951). In normal
cycling women, the corpus luteum is maintained by low-fre-
quency, high-amplitude pulses of LH secreted by gonadotropes
in the anterior pituitary (Filicori and colleagues, 1986).
The pattern of hormone secretion by the corpus luteum is dif-
ferent from that of the follicle (see Fig. 3-1). The increased capac-
ity of granulosa-lutein cells to produce progesterone is the result of
increased access to considerably more steroidogenic precursors
through blood-borne low-density lipoprotein (LDL)-derived
cholesterol (see Fig. 3-3)(Carr and colleagues, 1981b). It is also
due to increases in the level of steroidogenic acute regulatory pro-
tein. This protein transports cholesterol from the outer to the in-
ner mitochondria, where the enzyme that metabolizes cholesterol
to progesterone is found (Devoto and colleagues, 2002). The im-
portant role for LDL in progesterone biosynthesis is supported by
the observation that women with extremely low levels of LDL
cholesterol exhibit low progesterone secretion during the luteal
phase (Illingworth and colleagues, 1982). In addition, high-
density lipoprotein (HDL) may contribute to progesterone pro-
duction in granulosa-lutein cells (Ragoobir and colleagues, 2002).
Estrogen levels follow a more complex pattern of secretion.
Specifically, just after ovulation, estrogen levels decrease fol-
lowed by a secondary rise that reaches a peak production of
0.25 mg/day of 17-estradiol at the midluteal phase. Toward
the end of the luteal phase, there is a secondary decrease in
estradiol production.
Ovarian progesterone production peaks at 25 to 50 mg/day
during the midluteal phase. With pregnancy, the corpus luteum
continues progesterone production in response to embryonic
hCG, which will bind and activate luteal cell LH receptors (see
Fig. 3-3).
The human corpus luteum is a transient endocrine organ
that, in the absence of pregnancy, will rapidly regress 9 to
11 days after ovulation. The mechanisms that control luteoly-
sis remain unclear. However, in part, it results from decreased
levels of circulating LH in the late luteal phase and decreased
LH sensitivity of luteal cells (Duncan and colleagues, 1996;
Filicori and colleagues, 1986). The role of other luteotropic
factors is less clear, however, prostaglandin F2 (PGF2) appears
to be luteolytic in nonhuman primates (Auletta, 1987; Wentz
and Jones, 1973). Within the corpus luteum, luteolysis is char-
acterized by a loss of luteal cells by apoptotic cell death (Vask-
ivuo and colleagues, 2002). The endocrine effects, consisting
of a dramatic drop in circulating estradiol and progesterone
levels, are critical to allow the follicular development and
ovulation during the next ovarian cycle. In addition, corpus
luteum regression and decrease in circulating steroids signal
the endometrium to initiate molecular events that lead to
menstruation.

■ Estrogen and Progesterone Action
Estrogen Effects
The fluctuating levels of ovarian steroids are the direct cause of
the endometrial cycle. Recent advances in the molecular biol-
ogy of estrogen and progesterone receptors have greatly im-
proved our understanding of their function. The most biologi-
cally potent naturally occurring estrogen—17-estradiol—is
secreted by granulosa cells of the dominant follicle and
luteinized granulosa cells of the corpus luteum (see Fig. 3-3).
Estrogen is the essential hormonal signal on which most events
in the normal menstrual cycle depend. Estradiol action is com-
plex and appears to involve two classic nuclear hormone recep-
tors designated estrogen receptor  (ER) and  (ER)
(Katzenellenbogen and colleagues, 2001). These isoforms are
the product of separate genes and can exhibit distinct tissue ex-
pression. Both estradiol-receptor complexes act as transcrip-
tional factors that become associated with the estrogen re-
sponse element of specific genes. They share a robust activation
by estradiol. However, differences in their binding affinities of
other estrogens and their cell-specific expression patterns sug-
gest that ER and ER receptors may have both distinct and
overlapping function (Saunders, 2005). Both receptors are ex-
pressed in the uterine endometrium (Bombail and co-workers,
2008; Lecce and colleagues, 2001).
The interaction with steroid ligands brings about estrogen
receptor–specific initiation of gene transcription. This in turn
promotes synthesis of specific messenger RNAs, and thereafter,
the synthesis of specific proteins. Among the many proteins up-
regulated in most estrogen-responsive cells are estrogen and
progesterone receptors themselves. In addition, estradiol has
been proposed to act at the endothelial cell surface to stimulate
nitric oxide production, leading to its rapid vasoactive proper-
ties (Shaul, 2002). The ability of estradiol to work in the cell
nucleus through classic ligand-regulated nuclear hormone re-
ceptors and at the cell surface to cause rapid changes in cell sig-
naling molecules is one explanation for the complex responses
seen with estrogen therapies.
Progesterone Effects
Most progesterone actions on the female reproductive tract
are mediated through nuclear hormone receptors. Proges-
terone enters cells by diffusion and in responsive tissues be-
comes associated with progesterone receptors (Conneely and
colleagues, 2002). There are multiple isoforms of the human
progesterone receptor. The best understood isoforms are the
progesterone receptor type A (PR-A) and B (PR-B). Both
arise from a single gene, are members of the steroid receptor
superfamily of transcription factors, and regulate transcrip-
tion of target genes. These receptors have unique actions.
When PR-A and PR-B receptors are co-expressed, it appears
that PR-A can inhibit PR-B gene regulation. The inhibitory
effect of PR-A may extend to actions on other steroid recep-
tors, including estrogen receptors. In addition, progesterone
can evoke rapid responses such as changes in intracellular
free calcium levels that cannot be explained by genomic
mechanisms. G-protein-coupled membrane receptors for
Implantation, Embryogenesis, and Placental Development 41
progesterone have been identified recently, but their role in
the ovarian-endometrium cycle remains to be elucidated
(Peluso, 2007).
Expression patterns of PR-A and PR-B endometrial recep-
CHAPTER 3
tors have been examined using immunohistochemistry (Mote
and colleagues, 1999). The endometrial glands and stroma ap-
pear to have different expression patterns for these receptors
that vary over the menstrual cycle. The glands express both re-
ceptors in the proliferative phase, suggesting that both receptors
are involved with subnuclear vacuole formation. After ovula-
tion, the glands continue to express PR-B through the mid-
luteal phase, suggesting that glandular secretion seen during the
luteal phase is PR-B regulated. In contrast, the stroma and pre-
decidual cells express only PR-A throughout the menstrual cy-
cle, suggesting that progesterone-stimulated events within the
stroma are mediated by this receptor.
Progesterone receptor expression has not been found in in-
flammatory cells or in endothelial cells of endometrial vessels.
The role of these two receptor isoforms in the regulation of hu-
man menstruation is unclear, but they likely play distinct roles.
Animal models suggest that PR-A regulates the antiproliferative
effects of progesterone during the secretory phase.
■ The Endometrial Cycle
Proliferative or Preovulatory Endometrial Phase
Fluctuations in estrogen and progesterone levels produce strik-
ing effects on the reproductive tract, particularly the en-
dometrium (Fig. 3-2). The growth and functional characteris-
tics of the human endometrium are unique. Epithelial—
glandular cells; stromal—mesenchymal cells; and blood vessels
of the endometrium replicate cyclically in reproductive-aged
women at a rapid rate. The endometrium is regenerated during
each ovarian–endometrial cycle. The superficial endometrium,
termed functionalis layer, is shed and regenerated from the
deeper basalis layer almost 400 times during the reproductive
lifetime of most women (Fig. 3-5). There is no other example in
humans of such cyclical shedding and regrowth of an entire
tissue.
Follicular-phase production of estradiol is the most impor-
tant factor in endometrial recovery following menstruation. Al-
though up to two thirds of the functionalis endometrium is
fragmented and shed during menstruation, re-epithelialization
begins even before menstrual bleeding has ceased. By the fifth
day of the endometrial cycle—fifth day of menses, the epithelial
surface of the endometrium has been restored, and revascular-
ization is in progress. The preovulatory endometrium is charac-
terized by proliferation of vascular endothelial, stromal, and
glandular cells (see Fig. 3-2). During the early part of the pro-
liferative phase, the endometrium is thin, usually less than
2 mm thick. The glands at this stage are narrow, tubular struc-
tures that pursue almost a straight and parallel course from the
basalis layer toward the surface of the endometrial cavity.
Mitotic figures, especially in the glandular epithelium, are iden-
tified by the fifth cycle day, and mitotic activity in both epithe-
lium and stroma persists until day 16 to 17, or 2 to 3 days after
ovulation. Although blood vessels are numerous and prominent,
 42 Maternal and Fetal Anatomy and Physiology

Early proliferative Late proliferative Secretory Uterine

phase phase phase lumen
SECTION 2

Epithelium

Capillaries

Venous sinus
Functionalis
Endometrial gland layer

Spiral artery

Straight artery
Basalis layer

Radial artery
Myometrium
Arcuate artery

Uterine artery

FIGURE 3-5 The endometrium consists of two layers, the functionalis layer and basalis layer. These layers are supplied by the spiral and
straight arteries, respectively. Numerous glands also span these layers. As the menstrual cycle progresses, greater coiling of the spiral ar-
teries and increased folds in the glands can be seen. Near the end of the menstrual cycle (day 27), the coiled arteries constrict, deprive
blood supply to the functionalis layer, and lead to necrosis and sloughing of this layer.

there is no extravascular blood or leukocyte infiltration in the
endometrium at this stage.
Clearly, re-epithelialization and angiogenesis are important
to cessation of endometrial bleeding (Chennazhi and Nayak,
2009; Rogers and associates, 2009). These are dependent on
tissue regrowth, which is estrogen regulated. Epithelial cell
growth also is regulated in part by epidermal growth factor
(EGF) and transforming growth factor  (TGF). Stromal cell
proliferation appears to increase through paracrine and au-
tocrine action of estrogen and increased local levels of fibrob-
last growth factor-9 (Tsai and colleagues, 2002). Estrogens also
increase local production of VEGF, which causes angiogenesis
through vessel elongation in the basalis (Bausero and col-
leagues, 1998; Gargett and Rogers, 2001; Sugino and co-
workers, 2002).
By the late proliferative phase, the endometrium thickens
from both glandular hyperplasia and increased stromal ground
substance, which is edema and proteinaceous material. The
loose stroma is especially prominent, and the glands in the func-
tionalis layer are widely separated. This is compared with those
of the basalis layer, in which the glands are more crowded and
the stroma is denser. At midcycle, as ovulation nears, glandular
epithelium becomes taller and pseudostratified. The surface ep-
ithelial cells acquire numerous microvilli, which increase
epithelial surface area, and cilia, which aid in the movement of
endometrial secretions during the secretory phase (Ferenczy,
1976).
Determining the menstrual cycle day by endometrial histo-
logical criteria, termed dating, is difficult during the prolifera-
tive phase because of the considerable variation of phase length
among women. Specifically, the follicular phase normally may
be as short as 5 to 7 days or as long as 21 to 30 days. In contrast,
the luteal or secretory postovulatory phase of the cycle is re-
markably constant at 12 to 14 days.
Secretory or Postovulatory Endometrial Phase
During the early secretory phase, endometrial dating is based on
glandular epithelium histology. After ovulation, the estrogen-
primed endometrium responds to rising progesterone levels in a
highly predictable manner (see Fig. 3-1). By day 17, glycogen ac-
cumulates in the basal portion of glandular epithelium, creating
subnuclear vacuoles and pseudostratification. This is the first
sign of ovulation that is histologically evident. It is likely the re-
sult of direct progesterone action through receptors expressed in
glandular cells (Mote and colleagues, 2000). On day 18, vac-
uoles move to the apical portion of the secretory nonciliated
cells. By day 19, these cells begin to secrete glycoprotein and mu-
copolysaccharide contents into the lumen (Hafez and colleagues,
1975). Glandular cell mitosis ceases with secretory activity on
day 19 due to rising progesterone levels, which antagonize the
mitotic effects of estrogen. Estradiol action is also decreased be-
cause of glandular expression of the type 2 isoform of 17-hy-
droxysteroid dehydrogenase. This converts estradiol to the less
active estrone (Casey and MacDonald, 1996).
Dating in the mid- to late-secretory phase relies on changes
in the endometrial stroma (see Fig. 3-2). On days 21 to 24, the
stroma becomes edematous. On days 22 to 25, stromal cells sur-
rounding the spiral arterioles begin to enlarge, and stromal mi-
tosis becomes apparent. Days 23 to 28 are characterized by pre-
decidual cells, which surround spiral arterioles.
An important feature of secretory-phase endometrium be-
tween days 22 and 25 is striking changes associated with prede-
cidual transformation of the upper two thirds of the functionalis
layer. The glands exhibit extensive coiling and luminal secretions

Exc
essiv
e coiling of spiral ar teries
Day 24
Tissue volume
decreases Day 25 Day 26
Severe coiling of
spiral arteries;
stasis of blood
FIGURE 3-6 The spiral arteries of human endometrium are modified during the ovulatory cycle. Initially, changes in blood flow through
these vessels aid endometrial growth. Excessive coiling and stasis in blood flow coincide with regression of corpus luteum function and
lead to a decline in endometrial tissue volume. Finally, spiral artery coiling leads to endometrial hypoxia and necrosis. Prior to endome-
trial bleeding, intense spiral artery vasospasm serves to limit blood loss with menstruation.
become visible. Changes within the endometrium also can mark
the so-called window of implantation seen on days 20 to 24. Ep-
ithelial surface cells show decreased microvilli and cilia but ap-
pearance of luminal protrusions on the apical cell surface (Nikas,
2003). These pinopodes are important in preparation for blasto-
cyst implantation. They also coincide with changes in the surface
glycocalyx that allow acceptance of a blastocyst (Aplin, 2003).
The secretory phase is also highlighted by the continuing
growth and development of the spiral arteries. Boyd and
Hamilton (1970) emphasized the extraordinary importance
of the endometrial spiraling or coiled arteries. They arise from
arcuate arteries, which are myometrial branches of the uterine
vessels (see Fig. 3-5). The morphological and functional prop-
erties of spiral arteries are unique and essential for establishing
changes in blood flow to permit either menstruation or im-
plantation. During endometrial growth, spiral arteries
lengthen at a rate appreciably greater than the rate of increase
in endometrial tissue height or thickness (Fig. 3-6). This
growth discordance obliges even greater coiling of the already
spiraling vessels. Spiral artery development reflects a marked
induction of angiogenesis, consisting of widespread vessel
sprouting and extension. Perrot-Applanat and associates
(1988) described progesterone and estrogen receptors in the
smooth muscle cells of the uterus and spiral arteries. They fur-
ther demonstrated that such rapid angiogenesis is regulated, in
part, through estrogen- and progesterone-regulated synthesis
of VEGF (Ancelin and colleagues, 2002; Chennazhi and
Implantation, Embryogenesis, and Placental Development 43
Lengt
heni
ng
of s
CHAPTER 3
pir
al
a
rte
rie
s
ies
er
a rt
iral
Extensive coiling of sp
Day 27 Day 28
Hypoxia, vasodilatation
Vasoconstriction
limits bleeding
Nayak, 2009). This protein is secreted by stromal cells and
glandular epithelium and stimulates endothelial cell prolifera-
tion and increases vascular permeability. Thus, steroid hor-
mone influences on growth and vasculature are directed to a
large degree through the local production of growth factors.
■ Menstruation
The midluteal–secretory phase of the endometrial cycle is a crit-
ical branch point in endometrial development and differentia-
tion. With corpus luteum rescue and continued progesterone
secretion, the process of decidualization continues. If luteal
progesterone production decreases with luteolysis, events leading
to menstruation are initiated. Many molecular mechanisms in-
volving endometrial progesterone withdrawal, as well as the
subsequent inflammatory response that causes endometrial
sloughing, have been defined (Critchley and colleagues, 2006).
A notable histological characteristic of late premenstrual-phase
endometrium is stromal infiltration by neutrophils, giving a
pseudoinflammatory appearance to the tissue. These cells infiltrate
primarily on the day or two immediately preceding menses onset.
The endometrial stromal and epithelial cells produce interleukin-
8 (IL-8), which is a chemotactic–activating factor for neutrophils
(Arici and colleagues, 1993). IL-8 may be one agent that serves to
recruit neutrophils just prior to menstruation. Similarly, monocyte
chemotactic protein-1 (MCP-1) is synthesized by endometrium
(Arici and colleagues, 1995).
 44 Maternal and Fetal Anatomy and Physiology
Leukocyte infiltration is considered key to extracellular matrix
breakdown of the functionalis layer. Invading leukocytes secrete en-
zymes that are members of the matrix metalloproteinase (MMP)
family. These add to the proteases already produced by endometrial
SECTION 2
stromal cells. The rising level of MMPs tips the balance between
proteases and protease inhibitors, effectively initiating matrix
degradation. This phenomenon has been proposed to initiate the
events leading to menstruation (Dong and colleagues, 2002).
Anatomical Events During Menstruation
The classic study by Markee (1940) described tissue and vascu-
lar changes in endometrium before menstruation. First, there
were marked changes in endometrial blood flow essential for
menstruation. With endometrial regression, coiling of spiral ar-
teries becomes sufficiently severe that resistance to blood flow
increases strikingly, causing hypoxia of the endometrium. Re-
sultant stasis is the primary cause of endometrial ischemia and
tissue degeneration (Fig. 3-6). A period of vasoconstriction pre-
cedes menstruation and is the most striking and constant event
observed in the cycle. Intense vasoconstriction of the spiral ar-
teries also serves to limit menstrual blood loss. Blood flow ap-
pears to be regulated in an endocrine manner by sex steroid hor-
mone–induced modifications of a paracrine-mediated vasoactive
peptide system as described subsequently.
Prostaglandins and Menstruation
Progesterone withdrawal increases expression of inducible cy-
clooxygenase 2 (COX-2) enzyme to synthesize prostaglandins
and decreases expression of 15-hydroxyprostaglandin dehydro-
genase (PGDH), which degrades prostaglandins (Casey and col-
leagues, 1980, 1989). The net result is increased prostaglandin
production by stromal cells along with increased prostaglandin
receptor density on blood vessels and surrounding cells.
A role for prostaglandins—especially vasoconstricting pro-
staglandin F2 (PGF2)—in initiation of menstruation has been
suggested (Abel, 2002). Large amounts of prostaglandins are
present in menstrual blood. PGF2 administration prompts
symptoms that mimic dysmenorrhea, which is commonly asso-
ciated with normal menses and likely caused by myometrial con-
tractions and uterine ischemia. PGF2 administration to non-
pregnant women also will cause menstruation. This response is
believed to be mediated by PGF2-induced vasoconstriction of
spiral arteries, causing the uppermost endometrial zones to be-
come hypoxic. This is a potent inducer of angiogenesis and vas-
cular permeability factors such as VEGF. Prostaglandins play an
important role in the cascade of events leading to menstruation
that include vasoconstriction, myometrial contractions, and up-
regulation of proinflammatory responses.
Vasoactive Peptides and Menstruation
A number of peptides may comprise a hormone-responsive
paracrine system in the endometrium to regulate spiral artery
blood flow. One is the endothelin–enkephalinase system (Casey
and MacDonald, 1996). The endothelins—ET-1, ET-2, and
ET-3—are small, 21-amino-acid peptides. Endothelin-1 (ET-1)
is a potent vasoconstrictor first identified as a product of vascular
endothelial cells (Yanagisawa and colleagues, 1988). Endothelins
are degraded by enkephalinase, which is localized in endometrial
stromal cells. Its specific activity in these cells increases strikingly
and in parallel with the increase in progesterone blood levels after
ovulation. The specific activity of enkephalinase is highest during
the midluteal phase and declines steadily thereafter as proges-
terone plasma levels decrease (Casey and colleagues, 1991).
Activation of Lytic Mechanisms
Following vasoconstriction and endometrial cytokine changes,
activation of proteases within stromal cells and leukocyte inva-
sion is required to degrade the endometrial interstitial matrix.
And matrix metalloproteases—MMP-1 and MMP-3—are re-
leased from stromal cells and may activate other neutrophilic
proteases such as MMP-8 and MMP-9.
Origin of Menstrual Blood
Menstrual bleeding is from both systems, but arterial bleeding
is appreciably greater than venous. Endometrial bleeding ap-
pears to follow rupture of an arteriole of a coiled artery, with
consequent hematoma formation. With a hematoma, the su-
perficial endometrium is distended and ruptures. Subsequently,
fissures develop in the adjacent functionalis layer, and blood, as
well as tissue fragments of various sizes, are sloughed. Hemor-
rhage stops with arteriolar constriction. Changes that accom-
pany partial tissue necrosis also serve to seal vessel tips.
The endometrial surface is restored by growth of flanges, or
collars, that form the everted free ends of the endometrial
glands (Markee, 1940). These flanges increase in diameter very
rapidly, and epithelial continuity is reestablished by fusion of
the edges of these sheets of migrating thin cells.
Interval between Menses
The modal interval of menstruation is considered to be 28
days, but there is considerable variation among women, as
well as in the cycle lengths of a given woman. Marked differ-
ences in the intervals between menstrual cycles are not neces-
sarily indicative of infertility. Arey (1939) analyzed 12 studies
comprising about 20,000 calendar records from 1500
women. He concluded that there is no evidence of perfect
menstrual cycle regularity. Among average adult women, a
third of cycles departed by more than 2 days from the mean
of all cycle lengths. In his analysis of 5322 cycles in 485 nor-
mal women, an average interval of 28.4 days was estimated.
Average cycle length in pubertal girls was 33.9 days. Haman
(1942) surveyed 2460 cycles in 150 women, and the distri-
bution curve for cycle length is shown in Figure 3-7.
THE DECIDUA
The decidua is a specialized, highly modified endometrium of
pregnancy and is a function of hemochorial placentation. The
latter has in common the process of trophoblast invasion, and
considerable research has focused on the interaction between
decidual cells and invading trophoblasts. Decidualization—
transformation of secretory endometrium to decidua—is de-
pendent on estrogen and progesterone and factors secreted by
the implanting blastocyst. The special relationship that exists
between the decidua and the invading trophoblast seemingly
defies the laws of transplantation immunology (Beer and
 Implantation, Embryogenesis, and Placental Development 45

16 (1985), membrana denoted its gross anatomical appearance,

whereas decidua was an analogy to deciduous leaves to indicate
that it is shed after childbirth. The decidua is classified into three
parts based on anatomical location. Decidua directly beneath

CHAPTER 3
12 blastocyst implantation is modified by trophoblast invasion and
becomes the decidua basalis. The decidua capsularis overlies the
enlarging blastocyst, and initially separates it from the rest of the
Incidence (%)

uterine cavity (Fig. 3-8). This portion is most prominent during

8
4
0 has enlarged to completely fill the uterine cavity. With fusion of
20 22 24 26 28 30 32 34 36 38
Length of menstrual cycle in days
FIGURE 3–7. Duration of menstrual cycle. (Based on distribution
data of Arey, 1939, and Haman, 1942.)
Billingham, 1971). The success of this unique semiallograft not
only is of great scientific interest but may involve processes that
harbor insights leading to more successful transplantation sur-
gery and perhaps even immunological treatment of neoplasia
(Billingham and Head, 1986; Lala and colleagues, 2002).
■ Decidual Structure
The first scientific description of the membrana decidua was in
the 18th century by William Hunter. According to Damjanov
the second month of pregnancy, consisting of decidual cells cov-
ered by a single layer of flattened epithelial cells. Internally, it
contacts the avascular, extraembryonic fetal membrane—the
chorion laeve. The remainder of the uterus is lined by decidua
parietalis—sometimes called decidua vera when decidua capsu-
laris and parietalis are joined.
During early pregnancy, there is a space between the decidua
capsularis and parietalis because the gestational sac does not fill
the entire uterine cavity. By 14 to 16 weeks, the expanding sac
40 the decidua capsularis and parietalis, the uterine cavity is func-
tionally obliterated. In early pregnancy, the decidua begins to
thicken, eventually attaining a depth of 5 to 10 mm. With mag-
nification, furrows and numerous small openings, representing
the mouths of uterine glands, can be detected. Later in preg-
nancy, the decidua becomes thinner, presumably because of
pressure exerted by the expanding uterine contents.
The decidua parietalis and basalis, like the secretory en-
dometrium, are composed of three layers. There is a surface,
or compact zone—zona compacta; a middle portion, or spongy
zone—zona spongiosa—with remnants of glands and numerous
small blood vessels; and a basal zone—zona basalis. The zona com-
pacta and spongiosa together form the zona functionalis. The basal
zone remains after delivery and gives rise to new endometrium.

■ Decidual Reaction
In human pregnancy, the decidual reac-
Yolk sac tion is completed only with blastocyst
Decidua parietalis implantation. Predecidual changes,
Embryo in amnionic sac however, commence first during the
Chorionic midluteal phase in endometrial stromal
villi Chorionic villi cells adjacent to the spiral arteries and
arterioles. Thereafter, they spread in
Decidua Decidua basalis waves throughout the uterine en-
capsularis dometrium and then from the site of
implantation. The endometrial stro-
Exocoelomic mal cells enlarge to form polygonal or
cavity round decidual cells. The nuclei be-
come round and vesicular, and the cyto-
plasm becomes clear, slightly basophilic,
Cervical and surrounded by a translucent mem-
Uterine cavity
canal brane. Each mature decidual cell be-
comes surrounded by a pericellular
membrane. Thus, the human decidual
cells clearly build walls around them-
selves and possibly around the fetus.
The pericellular matrix surrounding
FIGURE 3-8 Decidualized endometrium covers the early embryo. Three portions of the de- the decidual cells may allow attach-
cidua (basalis, capsularis, and parietalis) also are illustrated. ment of cytotrophoblasts through
 46 Maternal and Fetal Anatomy and Physiology

cellular adhesion molecules. The cell membrane also may pro-

vide decidual cell protection against selected cytotrophoblastic
Chorion
proteases.
SECTION 2

■ Decidual Blood Supply

As a consequence of implantation, the blood supply to the de-
cidua capsularis is lost as the embryo-fetus grows. Blood supply Villus
to the decidua parietalis through spiral arteries persists, as in the
endometrium during the luteal phase of the cycle. The spiral ar-
teries in the decidua parietalis retain a smooth muscle wall and
endothelium and thereby remain responsive to vasoactive agents
that act on their smooth muscle or endothelial cells.
The spiral arterial system supplying the decidua basalis di-
rectly beneath the implanting blastocyst, and ultimately the in-
tervillous space, is altered remarkably. These spiral arterioles and
Extracellular trophoblast
arteries are invaded by cytotrophoblasts. During this process, the
walls of vessels in the basalis are destroyed. Only a shell without
smooth muscle or endothelial cells remains. Importantly, as a
consequence, these vascular conduits of maternal blood—which
become the uteroplacental vessels—are not responsive to vasoac-
tive agents. By contrast, the fetal chorionic vessels, which trans-
port blood between the placenta and the fetus, contain smooth
muscle and thus do respond to vasoactive agents. Decidua

■ Decidual Histology
The decidua contains numerous cell types, whose composition
varies with the stage of gestation (Loke and King, 1995). The pri-
mary cellular components are the true decidual cells, which dif-
ferentiated from the endometrial stromal cells, and numerous
maternal bone marrow–derived cells. The zona compacta consists
of large, closely packed, epithelioid, polygonal, light-staining cells
with round nuclei. Many stromal cells appear stellate, with long
protoplasmic processes that anastomose with those of adjacent
cells. This is particularly so when the decidua is edematous.
A striking abundance of large, granular lymphocytes termed
decidual natural killer cells (NK) are present in the decidua
early in pregnancy. In peripheral blood, there are two subsets of
NK cells. About 90 percent are highly cytolytic and 10 percent
show less cytolytic ability but increased secretion of cytokines.
In contrast to peripheral blood, 95 percent of NK cells in
decidua secrete cytokines. About half of these unique cells also
express angiogenic factors. These decidua NK cells likely play
an important role in trophoblast invasion and vasculogenesis.
Early in pregnancy, zona spongiosa of the decidua consists of
large distended glands, often exhibiting marked hyperplasia and
separated by minimal stroma. At first, the glands are lined by
typical cylindrical uterine epithelium with abundant secretory
activity that contributes to nourishment of the blastocyst. As
pregnancy progresses, the epithelium gradually becomes
cuboidal or even flattened, later degenerating and sloughing to
a greater extent into the gland lumens. Later in pregnancy, the
glandular elements largely disappear. In comparing the decidua
parietalis at 16 weeks with the early proliferative endometrium
of a nonpregnant woman, it is clear that there is marked hyper-
trophy but only slight hyperplasia of the endometrial stroma
during decidual transformation.
FIGURE 3-9 Section through junction of chorion, villi, and decidua
basalis in early first-trimester pregnancy. (Used with permission
from Dr. Kurt Benirschke.)
The decidua basalis contributes to the formation of the basal
plate of the placenta (Fig. 3-9). It differs histologically from the
decidua parietalis in two important respects. First, the spongy
zone of the basalis consists mainly of arteries and widely dilated
veins, and by term, the glands have virtually disappeared. Sec-
ond, the decidua basalis is invaded by large numbers of intersti-
tial trophoblast cells and trophoblastic giant cells. Although
most abundant in the decidua, the giant cells commonly pene-
trate the upper myometrium. Their number and invasiveness
may be so extensive as to resemble choriocarcinoma.
The Nitabuch layer is a zone of fibrinoid degeneration in
which invading trophoblasts meet the decidua. If the decidua is
defective, as in placenta accreta, the Nitabuch layer is usually
absent (see Chap. 35, p. 776). There is also a more superficial,
but inconsistent, deposition of fibrin—Rohr stria—at the bot-
tom of the intervillous space and surrounding the anchoring
villi. McCombs and Craig (1964) found that decidual necrosis
is a normal phenomenon in the first and probably second
trimesters. Thus, necrotic decidua obtained through curettage
after spontaneous abortion in the first trimester should not nec-
essarily be interpreted as either a cause or an effect of the preg-
nancy loss.
■ Decidual Prolactin
Convincing evidence has been presented that the decidua is
the source of prolactin that is present in enormous amounts
in amnionic fluid (Golander and colleagues, 1978; Riddick

and co-workers, 1979). Decidual prolactin is not to be con-
fused with placental lactogen (hPL), which is produced only
by the syncytiotrophoblast. Rather, decidual prolactin is a
product of the same gene that encodes for anterior pituitary
prolactin. And although the amino acid sequence of prolactin
in both tissues is identical, an alternative promoter is used
within the prolactin gene to initiate transcription in decidua
(Telgmann and Gellersen, 1998). The latter is thought to ex-
plain the different mechanisms that regulate expression in the
decidua versus pituitary (Christian and colleagues, 2002a,
2000b).
The protein preferentially enters amnionic fluid, and little en-
ters maternal blood. Consequently, prolactin levels in amnionic
fluid are extraordinarily high and may reach 10,000 ng/mL during
weeks 20 to 24 (Tyson and colleagues, 1972). This compares with
fetal serum levels of 350 ng/mL and maternal serum levels of 150
to 200 ng/mL. As a result, decidual prolactin is a classic example
of paracrine function between maternal and fetal tissues.
Role(s) of Decidual Prolactin
The exact physiological roles of decidual prolactin are still un-
known. Its action is mediated by relative expression of two unique
prolactin receptors as well as the amount of intact or full-length
prolactin protein compared with the truncated 16-kDa form
(Jabbour and Critchley, 2001). Receptor expression has been
demonstrated in decidua, chorionic cytotrophoblasts, amnionic
epithelium, and placental syncytiotrophoblast (Maaskant and col-
leagues, 1996). There are a number of possible roles for decidual
prolactin. First, because most or all decidual prolactin enters am-
nionic fluid, there may be a role for this hormone in transmem-
brane solute and water transport, and thus, in maintenance of am-
nionic fluid volume. Second, there are prolactin receptors in a
number of bone marrow-derived immune cells, and prolactin may
stimulate T cells in an autocrine or paracrine manner (Pellegrini
and colleagues, 1992). This raises the possibility that decidual pro-
lactin may act in regulating immunological functions during preg-
nancy. Prolactin may play a role in regulation of angiogenesis dur-
ing implantation. In this regard, intact prolactin protein enhances
angiogenesis, whereas the proteolytic fragment can inhibit new
vessel growth. Lastly, decidual prolactin has been shown in the
mouse to have a protective function by repressing expression of
genes detrimental to pregnancy maintenance (Bao and colleagues,
2007).
Regulation of Decidual Prolactin
Factors that regulate decidual prolactin production are not clearly
defined. Most agents known to inhibit or stimulate pituitary pro-
lactin secretion—including dopamine, dopamine agonists, and
thyrotropin-releasing hormone—do not alter decidual prolactin
secretion either in vivo or in vitro. Brosens and colleagues (2000)
demonstrated that progestins act synergistically with cyclic adeno-
sine monophosphate on endometrial stromal cells in culture to in-
crease prolactin expression. This suggests that the level of proges-
terone receptor expression may determine the decidualization
process, at least as marked by prolactin production. And arachi-
donic acid, but not PGF2 or PGE2, attenuates the rate of decidual
prolactin secretion (Handwerger and colleagues, 1981). Con-
versely, a variety of cytokines and growth factors—ET-1, IL-1,
Implantation, Embryogenesis, and Placental Development 47
IL-2, and epidermal growth factor—decrease decidual prolactin
secretion (Chao and colleagues, 1994; Frank and associates, 1995).
IMPLANTATION, PLACENTAL FORMATION,
CHAPTER 3
AND FETAL MEMBRANE DEVELOPMENT
Human placental development is as uniquely intriguing as fe-
tal embryology. During its brief intrauterine passage, the fetus
is dependent on the placenta for pulmonary, hepatic, and re-
nal functions. These are accomplished through the unique
placental anatomical association with the maternal interface.
The placenta links mother and fetus by indirect interaction
with maternal blood that spurts into the intervillous space
from uteroplacental vessels. Maternal blood bathes the outer
syncytiotrophoblast to allow exchange of gases and nutrients
with fetal capillary blood within connective tissue at the vil-
lous core. Fetal and maternal blood are not normally mixed in
this hemochorial placenta. There is also a paracrine system
that links mother and fetus through the anatomical and bio-
chemical juxtaposition of extraembryonic chorion laeve of fe-
tal origin and maternal decidua parietalis. This is an extraor-
dinarily important arrangement for communication between
fetus and mother and for maternal immunological acceptance
of the conceptus (Guzeloglu-Kayisli and associate, 2009).
■ Fertilization and Implantation
Ovum Fertilization and Zygote Cleavage
The union of egg and sperm at fertilization represents one of
the most important and fascinating processes in biology. Ovu-
lation frees the secondary oocyte and adherent cells of the cu-
mulus-oocyte complex from the ovary. Although technically
this mass of cells is released into the peritoneal cavity, the oocyte
is quickly engulfed by the infundibulum of the fallopian tube.
Further transport through the oviduct is accomplished by direc-
tional movement of cilia and tubal peristalsis. Fertilization nor-
mally occurs in the oviduct, and it is generally agreed that it
must take place within a few hours, and no more than a day af-
ter ovulation.
Because of this narrow window of opportunity, spermatozoa
must be present in the tube at the time of oocyte arrival. Almost
all pregnancies result when intercourse occurs during the 2 days
preceding or on the day of ovulation. Thus, the postovulatory
and postfertilization developmental ages are similar.
Steps involved with fertilization are highly complex. Molec-
ular mechanisms allow passage of spermatozoa between follicu-
lar cells, through the zona pellucida, and into the oocyte cyto-
plasm leading to the formation of the zygote. These are
reviewed by Primakoff and Myles (2002).
The timing of events in early human development is described
as days or weeks postfertilization, that is, postconceptional. By
contrast, in most chapters of this book, clinical pregnancy dating
is calculated from the start of the last menstrual period. As dis-
cussed earlier, the length of the follicular phase of the cycle is sub-
ject to more variability than the luteal phase. Thus, 1 week post-
fertilization corresponds to approximately 3 weeks from the last
menstrual period in women with regular 28-day cycles.