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46,XX DSD Foetal androgen excess Maternal androgen excess Exogenous androgen excess 46,XY DSD Disorders of gonadal development Complete or partial gonadal dysgenesis Ovotesticular disorder

        Structural developmental defects Vagina Vaginal agenesis (Müllerian agenesis) Vaginal atresia Vaginal septa Imperforate hymen Vaginal cysts

        External genitalia

        Vulval and urinary system abnormalities Kidney Ureter Bladder Urethra

        Vulval and intestinal abnormalities

        Patient Support Groups

        References

      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.

Vulval embryology

      Sexual determination and differentiation

      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.

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 ( Скачать книгу