An understanding of the complex embryology of the female

reproductive system often aids in clarifying the structure of

malformations and their association with other genitourinary
anomalies (Shatzkes, 1991; Yin, 2005). Like most organ systems, the
female urogenital tract develops from multiple cell types that
undergo important spatial growth and differentiation. Development
occurs during relatively narrow time windows and is governed by
time-linked patterns of gene expression (Park, 2005). Some of the
molecular mechanisms underlying this process have recently been
uncovered with modern molecular genetics and are discussed later.
The urogenital tract is functionally divided into the urinary system
and genital system. The urinary organs include the kidneys, ureters,
bladder, and urethra. The reproductive organs consist of the gonads,
ductal system, and external genitalia.
Both the urinary and genital systems develop from intermediate
mesoderm, which extends along the entire embryo length.
During initial embryo folding, a longitudinal ridge of this
intermediate mesoderm develops along each side of the primitive
abdominal aorta and is called the urogenital ridge (Fig. 18-1).
Primordial germ cells first appear in the outer ectodermal layer of
the embryo. At approximately 40 days of gestation, these germ cells
migrate along the hindgut to the urogenital ridge (Fig. 18-1B). This
ridge then divides into the nephrogenic and genital ridges.
At approximately 60 days of gestation, the nephrogenic ridges
develop into the mesonephric kidneys (mesonephros) and paired
mesonephric ducts, also termed Wolffian ducts (Figs. 18-1B and Fig.
18-2A). These mesonephric ducts connect the mesonephric kidneys
(destined for resorption) to the cloaca, which is a common opening
into which the embryonic urinary, genital, and alimentary tracts join
(Fig. 18-2B). Recall that evolution of the renal system passes
sequentially through the pronephric and mesonephric stages to
reach the permanent metanephric system. The ureteric bud arises
from the mesonephric duct at approximately the fifth week of fetal
life. It lengthens to become the metanephric duct (ureter) and
induces differentiation of the metanephros, which will eventually
become the final functional kidney.
The paired paramesonephric ducts, also termed the mllerian ducts,
develop from an invagination of the coelomic epithelium at
approximately the sixth week and grow alongside the mesonephric
ducts (Figs. 18-1B and 18-2B). The caudal portions of the mllerian
ducts approximate one another in the midline and end behind the
cloaca (Fig. 18-2C). The cloaca is divided by formation of the
urorectal septum by the seventh week and is separated to create
the rectum and the urogenital sinus (Fig. 18-2D). The urogenital
sinus is considered in three parts: (1) the cephalad or vesicle
portion, which will form the urinary bladder; (2) the middle or pelvic

portion, which creates the female urethra; and (3) the caudal or
phallic part, which will give rise to the distal vagina and to the
greater vestibular (Bartholin), urethral, and paraurethral (Skene)
glands. During differentiation of the urinary bladder, the caudal
portion of the mesonephric ducts is incorporated into the trigone
portion of the bladder wall. Consequently, the caudal portion of the
metanephric ducts (ureters) penetrates the bladder with distinct and
separate orifices (Fig. 18-2D).
The close association between the mesonephric (Wolffian) and
paramesonephric (mllerian) ducts has important clinical relevance
because developmental insult to either system is often associated
with anomalies that involve the kidney, ureter, and reproductive
tract. For example, Kenney and colleagues (1984) showed that up to
50 percent of females with uterovaginal malformations have
associated urinary tract anomalies.
Gonadal Differentiation
Mammalian sex is determined genetically. Individuals with X and Ychromosomes normally develop as males, whereas those with two X
chromosomes develop as females. Before 7 weeks of embryonic
development, embryos of male or female sex are indistinguishable.
During this indeterminate time, the genital ridge begins as coelomic
epithelium with underlying mesenchyme. The epithelium
proliferates, and cords of epithelium invaginate into the
mesenchyme to create primitive sex cords. In both 46,XX and 46,XY
embryos, the primordial germ cells are first identified as large
polyhedral cells in the yolk sac. As noted earlier, these germ cells
migrate by amoeboid motion along the hindgut dorsal mesentery to
populate the undifferentiated genital ridge. Thus, the major cellular
components of the early genital ridge include primordial germ cells
and somatic cells.
At this point, the presence or absence of gonadal determinant genes
determines fetal gender development (Fig. 18-3) (Taylor, 2000).
Sexual differentiation is dependent upon the genetic sex that is
determined at fertilization of the X-bearing oocyte by either an X- or
Y-chromosome bearing sperm. In humans, the gene, named the sexdetermining region of the Y (SRY), is the testis-determining factor. In
the presence of SRY, gonads develop as testes. Other important
gonadal developmental genes include SF1, SOX9, WT1, WNT4, and
DAX1 (Viger, 2005).
In males, cells in the medullary region of the primitive sex cords
differentiate into Sertoli cells, and these cells organize to form the
testicular cords (Fig. 18-3A). Testicular cords are identifiable at 6
weeks and consist of these Sertoli cells and tightly packed germ
cells. Early in the second trimester, the cords develop a lumen and
become seminiferous tubules. Development of a testis-specific

vasculature is crucial for normal testicular development (Ross,

2005).
The developing Sertoli cells begin to secrete antimllerian hormone
(AMH) (also called mllerian inhibitory substanceMIS) during
developmental weeks 7 to 8. This gonadal hormone causes
regression of the ipsilateral paramesonephric (mllerian duct)
system, and this involution is completed by 9 to 10 weeks gestation
(Marshall, 1978). AMH also controls the rapid gubernacular growth
necessary for the transabdominal descent of the testis. Serum AMH
levels remain elevated in boys during childhood and then decline at
puberty to the low levels seen in adult men. In contrast, girls have
undetectable AMH levels until puberty, when serum levels become
measurable. Clinically, AMH levels can be used to measure ovarian
reserve and to predict the success of controlled ovarian hyperstimulation during assisted reproduction (Chap. 19, p. 515).
In the testes, Leydig cells arise from the original mesenchyme of the
gonadal ridge and lie between the testicular cords. Their
differentiation begins approximately 1 week after Sertoli cell
development. The Leydig cells begin to secrete testosterone by 8
weeks gestation. At weeks 15 to 18, testosterone production peaks
as a result of stimulation of the testes by human chorionic
gonadotropin (hCG). Testosterone acts in a paracrine manner on the
ipsilateral mesonephric (Wolffian) duct to promote virilization of the
duct into the epididymis, vas deferens, seminal vesicle, and
ejaculatory duct. The androgens testosterone and
dihydrotestosterone are essential for male phenotype development.
These androgens control differentiation and growth of the internal
and external genitalia and also prime male differentiation of the
brain.
In the female embryo, without the influence of the SRY gene, the
bipotential gonad develops into the ovary. Compared with testicular
development, ovarian differentiation is delayed by approximately 2
weeks. Development is first characterized by the absence of
testicular cords in the gonad. The primitive sex cords degenerate,
and the mesothelium of the genital ridge forms secondary sex cords
(Fig. 18-3B). These secondary cords become the granulosa cells that
band together to form the follicular structures that surround the
germ cells. Oocytes and the surrounding granulosa cells begin
communication when the resting primordial follicles are stimulated
to grow under the influence of follicle-stimulating hormone (FSH) at
puberty. The medullary portion of the gonad regresses and forms
the rete ovarii within the ovarian hilum.
Germ cells that carry two X chromosomes undergo mitosis during
their initial migration to the female genital ridge. They reach a peak
number of 6 to 7 million by 20 weeks gestation. At this time, the
fetal ovary demonstrates mature organization, with the presence of
stroma and primordial follicles containing oocytes. During the third

trimester, oocytes begin meiosis but arrest during meiosis I until the
oocyte undergoes ovulation after menarche. Atresia of the oocytes
starts in utero, leading to a reduced number of germ cells at birth
(Fig. 14-1, p. 383).
Ductal System Development
Sexual differentiation of the reproductive ducts begins in week 7
due to the influence of gonadal hormones (testosterone and AMH)
and other factors on the mesonephric (Wolffian) and
paramesonephric (mllerian) ducts.
In the female, the lack of AMH allows mllerian ducts to persist.
These ducts grow caudally along with the mesonephric ducts.
During their elongation, both duct systems become enclosed in
peritoneal folds that later give rise to the broad ligaments of the
uterus (Fig. 18-4). At approximately 10 weeks gestation and during
their caudal migration, the two distal portions of the mllerian ducts
approach each other in the midline and fuse even before they reach
the urogenital sinus. The fused ducts form a tube called the
uterovaginal canal. This tube then inserts into the urogenital sinus
at Mller tubercle.
By 12 weeks, the uterine corpus and cervix differentiate, and the
uterine wall thickens. Initially, the upper pole of the uterus contains
a thick midline septum that undergoes dissolution to create the
uterine cavity. Dissolution of the uterine septum is usually
completed by 20 weeks. The unfused cephalad portions of the
mllerian ducts become the fallopian tubes (Fig. 18-2F). Any failure
of lateral fusion of the two mllerian ducts or failure to reabsorb the
septum between them results in separate uterine horns or some
degree of persistent midline uterine septum.
Most investigators suggest that the vagina develops under the
influence of the mllerian ducts and estrogenic stimulation. The
vagina forms partly from the mllerian ducts and partly from the
urogenital sinus (Masse, 2009). Specifically, the upper vagina
derives from the fused mllerian ducts. The distal vagina develops
from the bilateral sinovaginal bulbs, which are cranial evagination of
the urogenital sinus.
During vaginal development, the mllerian ducts reach the
urogenital sinus at Mller tubercle (Fig. 18-5A). Here, cells in the
sinovaginal bulbs proliferate cranially to lengthen the vagina and
create a solid vaginal plate (Fig. 18-5B). During the second
trimester, these cells desquamate, allowing full canalization of the
vaginal lumen (Fig. 18-5C). The hymen is the partition that remains
to a varying degree between the dilated, canalized, fused
sinovaginal bulbs and the urogenital sinus (Fig. 18-5B,C). The hymen
usually becomes perforated shortly before or after birth. An
imperforate hymen represents persistence of this membrane.
External Genitalia

Early development of the external genitalia is similar in both sexes.

By 6 weeks gestation, three external protuberances have
developed surrounding the cloacal membrane. These are the left
and right genital swellings, which meet ventrally to form the third
protuberance, the genital tubercle (Fig. 18-6A). The genital swellings
become the labioscrotal folds. The urogenital sinus extends onto the
surface of the enlarging genital tubercle to form the urethral groove,
which is flanked on either side by the urethral folds, which lie within
the labioscrotal folds. By week 7 of gestation, the urogenital
membrane ruptures, exposing the cavity of the urogenital sinus to
amnionic fluid. The genital tubercle elongates to form the phallus in
males and the clitoris in females.
It is not until week 12 of gestation that one is able to visually
differentiate between male and female external genitalia (Fig. 18-7).
In the male fetus, dihydrotestosterone (DHT), formed locally by the
5- reduction of testosterone, prompts the anogenital distance to
lengthen, the phallus to enlarge, the labioscrotal folds to fuse and
form the scrotum, and subsequently, the urethral folds to merge and
enclose the penile urethra (Fig. 18-6B). In the female fetus, in the
absence of DHT, the anogenital distance does not lengthen, and the
labioscrotal and urethral folds do not fuse (Fig. 18-6C). The genital
tubercle bends caudally to become the clitoris, and the urogenital
sinus becomes the vestibule of the vagina. The labioscrotal folds
create the labia majora, whereas the urethral folds persist as the
labia minora.