Ridley's The Vulva

The staff at Wiley have provided great support, especially Rajalaxmi Rajendra Singh, who took on the administration of this edition with great skill. Jennifer Seward, the Managing Editor at Wiley, has been a constant help and guide and has tolerated my many queries with great patience. For this, I thank her.

Lastly, enormous thanks to my brother, Jeff Lewis, for ongoing help with grammar and spelling, and for being a good opinion in my attempts to make things understandable!

This book is accompanied by a companion website.

www.wiley.com/go/thevulva4e

This website includes:

Downloadable PDFs of the complete reference lists from the book.

Downloadable PowerPoint slides of over 100 extra figures.

Fiona M. Lewis

Vulval embryologySexual determination and differentiation Early female embryogenesis (weeks 1–8) Carnegie stage 1–3 Carnegie stages 4–6 Carnegie stage 8 Carnegie stage 9 Carnegie stage 11 Carnegie stages 13 and 14 Carnegie stages 15 and 16 Carnegie stage 19 Carnegie stages 20–23 End of the female embryonic period and further development (week 8 onwards) Development of the epithelia

Disorders of Sexual Development Sex Chromosome DSDTurner’s syndrome Mosaicism 46,XX DSD Foetal androgen excess Maternal androgen excess Exogenous androgen excess 46,XY DSD Disorders of gonadal developmentComplete or partial gonadal dysgenesis Ovotesticular disorder

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

External genitalia

Vulval and urinary system abnormalitiesKidney 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.

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).