Fiona M. Lewis A basic knowledge of the normal embryogenesis and organogenesis of the female genital tract is important in order to understand the developmental abnormalities that may arise. The embryogenesis of the female genital tract is closely linked to that of the urinary tract and the terminal portion of the gastrointestinal tract, which explains why developmental abnormalities of the female genital tract are often seen in association with anomalies of these systems. Sexual determination is the process whereby cells commit to a certain course of development. The genetic sex of an individual is established at fertilisation, and so can be regarded as the point of determination. However, the gonads and external genitalia remain sexually indeterminate for the first 6 weeks. Sexual differentiation describes how the cells achieve sexual development as determined at fertilisation. The differentiating processes are regulated by at least 30 specific genes located on sex chromosomes or autosomes that act through a variety of mechanisms. The presence of the Y chromosome determines whether the undifferentiated gonad will develop into a testis or ovary and is an extremely important factor in testicular differentiation. It contains a region known as SRY (sex‐determining region of the Y chromosome). The testis‐determining factor is a 3.5 kilobase pair sequence located on the Yp11.31 sub‐band. If the SRY is absent or altered, the undifferentiated gonad will develop into an ovary. However, the SRY gene has been detected in some cases of Turner’s syndrome where there is no Y chromosome in their karyotype. This finding demonstrates that the presence of a single dominant Y chromosomal gene alone is not enough to determine testicular differentiation [1], and other genes are involved. These include WT1 Wilms’ tumour suppressor gene, which regulates SRY expression, DAX1 on the X chromosome, SF1 on chromosome 9, SOX9 on chromosome 17, and AMH on chromosome 19. The WnT4 gene is also an important gene which induces the female phenotype [2]. Ovarian differentiation is determined by the presence of two X chromosomes, and the DAX1 gene on the short arm of the X chromosome is felt to be the gene that triggers ovarian development from the undifferentiated gonad. The absence of this short arm results in ovarian agenesis. Other genes, including some that are autosomal recessive, may also be involved in ovarian and mesonephric duct development [3,4]. Sexual differentiation is also under hormonal influence. The development of the internal ducts is the result of a paracrine effect from the ipsilateral gonad. Further organ development depends primarily on the presence of a testis. If absent, female organs will develop, irrespective of whether ovaries are present. A female phenotype develops in the absence of the androgens testosterone, dihydrotestosterone (DHT), anti‐Müllerian hormone (AMH), and Müllerian‐inhibiting substance hormone. AMH is a member of the TGFβ family, which induces regression of the paramesonephric ducts. In the female, this is not produced as there are no Sertoli cells, and so the paramesonephric ducts persist [5]. Incomplete masculinisation can occur when testosterone fails to convert to DHT or when DHT fails to act within the cytoplasm or nucleus of the cells of the external genitalia and urogenital sinus. This can occur even if testes are present. High local levels of testosterone are needed for Wolffian mesonephric duct development. This is demonstrated as maternal ingestion of androgens does not result in male internal differentiation in a female foetus, nor does this differentiation occur in females with congenital adrenal hyperplasia (CAH). Conversely, high levels of oestrogens can sometimes reduce Müllerian‐inhibiting substance action, resulting in some paramesonephric (Müllerian) duct development. In summary, the genetic sex determines gonadal sex, which then determines the differentiation/regression of the internal ducts (i.e. Müllerian and Wolffian ducts) and the ultimate phenotypic sex. However, the final sexual identity of an individual depends not only on the phenotypic appearance but also on the brain’s prenatal and postnatal development. In the first 8 weeks of development after ovulation, a system known as Carnegie staging is used to describe the apparent maturity of the embryo. There are 23 Carnegie stages, and each is based on external physical features and crown‐rump length (Table 1.1) [6]. The point of fertilisation occurs on the first post‐ovulatory day in which the human zygote, with its XX sex chromosome constitution, is conceived in the distal third of the uterine tube. An acellular envelope, the zona pellucida, encases the zygote. The first cleavage division occurs 24–30 hours after fertilisation, and the two‐cell zygote increases to 8–16 blastomeres. A blastocyst then develops with a fluid‐filled cavity. There are 16–32 blastomeres which start to form an inner cell mass (embryonic pole) and outer cell mass (mural and polar trophoblast). The blastocyst eventually comes to lie free within the reproductive tract as the surrounding zona pellucida degenerates (Figure 1.1). The blastocyst penetrates and embeds in the uterine endometrium. The outer envelope of cytotrophoblast, forming the wall of the blastocyst, generates the syncytiotrophoblast on its external surface [7] and the extraembryonic mesoderm on its internal surface. This structure is termed the chorion (Figure 1.2a). The primitive amniotic cavity develops at approximately 7–9 days post ovulation, and its floor forms the primary ectoderm (Figure 1.2b). The primary endoderm is probably formed from cells originating from the ectoderm that migrate around the blastocoelic cavity and enclose the yolk sac. The ectoderm covering the floor of the amniotic cavity and the endoderm forming the roof of the yolk sac are in apposition, and therefore establish the bilaminar embryonic disc (Figure 1.2c). A projection of the yolk sac endoderm into the extraembryonic mesoderm forms the allantoic diverticulum which identifies the caudal end of the bilaminar embryonic disc and the site of the body stalk (Figure 1.2d). The primitive streak (Figure 1.3a) is formed and lies caudally in the midline of the embryonic disc. The primitive streak subsequently generates the intraembryonic mesoderm, which migrates through the bilaminar embryonic disc, in the plane between ectoderm and endoderm (Figure 1.3b), converting it into a trilaminar disc. The disc remains bilaminar at the caudal and rostral ends. The caudal end forms the cloacal membrane. Table 1.1 Carnegie stages in early embryogenesis. Figure 1.1 The conceptus is enclosed within an acellular envelope, the zona pellucida. After the formation of the blastocyst and dissolution of the zona pellucida, the characteristic fluid‐filled cavity, the embryonic pole or inner cell mass, and the mural trophoblast can be identified. Figure 1.2 The conceptus continues to differentiate forming (a) the chorion, (b) the amniotic cavity, and (c) the yolk sac. The area of contact between the amniotic cavity and the yolk sac is the bilaminar embryonic disc. (d) Projection of the yolk sac endoderm into the mesoderm to form the allantoic diverticulum. The primordial germ cells, which are the antecedents of the male and female gametes, are present in the endoderm around the allantoic diverticulum (now a ventral outpouching of the hind gut) and are usually seen in the 17–20 day embryo, although possible primordial germ cells have been identified at 13 days [8]. The primordial germ cells are ectodermal in origin, having migrated to the allantoic diverticulum from the epiblast, and they retain two functional X chromosomes in contrast to the somatic cells, which possess only one functional X chromosome [9]. From here, they migrate through the mesoderm surrounding the hindgut and into the dorsal mesentery. The final destination is the gonadal ridge, which they reach at about 35 days (Figure 1.4). The neural plate and the longitudinal neural ridges develop. The embryo flexes to accommodate the neural tube (Figures 1.5a–c) and in so doing reorients the primitive embryonic tissues and their relationship to each other. The endoderm of the dorsal part of the yolk sac is drawn into the ventral concavity of the embryo and is subdivided into foregut, midgut, and hindgut (Figure 1.6a,b). The hindgut appears about day 20 and is enclosed within the tail fold of the embryo. In this situation, the hindgut lies caudal to the rostral limit of the allantoic diverticulum and dorsal to the cloacal membrane. The mesoderm in the mid‐embryo region is divided into paraxial (surrounding the neural tube), lateral, and intermediate mesoderm. The intermediate mesoderm lies ventrally and lateral to the paraxial mesoderm, and differentiates medially into the gonadal ridge and laterally into the mesonephric region. The intermediate mesoderm at the rostral limit of the allantoic diverticulum extends dorsally and then caudally, in line with the curvature of the tail fold, dividing the hindgut into ventral and dorsal parts. As this division proceeds, the two parts of the hindgut remain in continuity with each other caudal to the advancing mesoderm of the urorectal septum. The caudal end of the hindgut is lined with endoderm and is known as the cloaca. On the ventral aspect of the cloaca there is a membrane which separates the endoderm from the surface ectoderm, the cloacal membrane. As development continues, a mesenchymal septum, the urogenital septum, migrates caudally (Figures 1.7a–c). Figure 1.3 (a) The floor of the amniotic cavity, the dorsal surface of the bilaminar embryonic disc, revealing the primitive streak and notochord. (b) Intraembryonic mesoderm, generated by the primitive streak and interposed between the floor of the amniotic cavity and roof of the yolk sac, converts the bilaminar embryonic disc into a trilaminar disc. The buccopharyngeal and cloacal membranes remain bilaminar. Figure 1.4 Migration of primordial germ cells into the genital ridge from the body stalk. Figure 1.5 (a) As the neural tube is enclosed within the intraembryonic mesoderm, it lengthens and expands rostrally, causing a dorsal convexity and ventral concavity. (b) Further growth of the neural tube increases this curvature in the longitudinal plane (c) with the eventual formation of the head and tail folds. Figure 1.6 (a) Midline section of the embryo after formation of the head and tail folds. (b) A transverse section of the mid‐embryo region after formation of the lateral folds. When embryo flexion has been completed (day 24), the anterior limit of the cloacal membrane abuts on the base of the umbilical cord. On either side of the cloaca are the paired primordia of the genital tubercle (Figure 1.8a) which fuse as the cloaca retracts from the umbilical cord to form an anterior wall. Posterior to the tubercle and running laterally by the sides of the cloacal membrane are the cloacal folds, and lateral to these the genital swellings (Figure 1.8b). The urogenital septum reaches the cloacal membrane at 30–32 days and fuses with the cloacal membrane, dividing the embryonic hindgut into the ventral (anterior) urogenital sinus and dorsal (posterior) rectum. The cloacal membrane is also divided, the ventral part forming the urogenital membrane and the dorsal part forming the anal membrane. It eventually ruptures to form the urogenital and anal orifices. The genital folds develop from the anterior part of the cloacal folds, and the anal folds form the posterior component. (Figure 1.8c). The two primitive gonadal streaks proliferate to form a genital tubercle at the ventral tip of the cloacal membrane. These two genital tubercles grow further and must reach a critical mass, or only rudimentary structures will be formed. They then fuse to form the glans of the clitoris. Labioscrotal swellings and urogenital folds develop on each side of the cloacal membrane. As the urogenital septum reaches the cloacal membrane, the labioscrotal folds fuse posteriorly forming the perineal body, which separates the urogenital membrane from the anal membrane, but sexual differentiation at this stage is still indeterminate. Cells from cephalic mesonephric vesicles invade the coelomic epithelium on the medial aspect of the adjacent intermediate mesoderm to induce the formation of the indifferent gonad at 30–32 days [10]. The indifferent gonad begins to develop (day 35) on the medial aspect of the mesonephros by the invasion of three other cell types: the primordial germ cells, cells from the overlying coelomic epithelium, and the cells from the adjacent mesonephros. All cell types are probably essential to the proper differentiation of the gonad. The paramesonephric ducts (Müllerian ducts) appear at about 40 days. The precursor of each duct extends caudally as a solid rod of cells in the intermediate mesoderm, in close association with, and initially lateral to, the mesonephric (Wolffian) duct. The mesonephric duct has been shown experimentally both to induce the paramesonephric duct [11] and to guide its descent [12]. The growing caudal tip of the paramesonephric duct lies within the basement membrane of the mesonephric duct.
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Vulval Embryology and Developmental Abnormalities
Vulval embryology
Sexual determination and differentiation
Early female embryogenesis (weeks 1–8)
Carnegie stage 1–3
Carnegie stages 4–6
Carnegie stage
Days – post ovulation
Approximate size (mm)
Important events in genital & urological tract embryogenesis
1
1 (week 1)
0.1–0.15
Point of fertilisation
2
2–3
0.1–0.2
3
4–5
0.1–0.2
Blastocyst forms
4
5–6
0.1–0.2
Embeds in endometrium
5
7–12 (week 2)
0.1–0.2
Allantoic diverticulum formed
6
13–15
0.2
Cloacal membrane formed
7
15–17 (week 3)
0.4
8
17–19
1–1.5
Primordial germ cells present
9
19–21
1.5–2.5
Hindgut formed and urogenital septum migrates caudally
10
22–23 (week 4)
2–3.5
11
23–26
2.5–4.5
Genital tubercle, cloacal folds, and genital swellings form
12
26–30
3–5
13
28–32 (week 5)
4–6
Urogenital septum divides hindgut into urogenital sinus and rectum
14
31–35
5–7
Labioscrotal folds fuse to form perineal body
15
35–42
7–9
Indifferent gonad
16
37–42 (week 6)
8–11
Paramesonephric ducts appear. Trigone of bladder and posterior urethra formed
17
42–44
11–14
18
44–48 (week 7)
13–17
Embryonic testis develops in male
19
48–51
16–18
Bladder and urethra formed
20
51–53 (week 8)
18–22
Ovary develops
21
56–60
27–31
22
54–56
23–28
23
56–60
27–31
External genital primordium developed, but still indeterminate sex 
Carnegie stage 8
Carnegie stage 9
Carnegie stage 11
Carnegie stages 13 and 14
Carnegie stages 15 and 16
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