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.
Early female embryogenesis (weeks 1–8)
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].
Carnegie stage 1–3
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).
Carnegie stages 4–6
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.
| 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
|
