Chapter 1 continued
3. Embryological Origins Of Hypospadias
Hypospadias may be considered as a relatively common malformation of the male genito-urinary organs (Hencha-Razavi & Escudier, 2000).
It is caused by arrested development of the urethra during the period of embryological sexual differentiation (Larsen, 1996). To better understand this, I shall review some principles of embryonic sexual differentiation [1], the process which leads to development of the genito-urinary tract in humans.
I will pay particular attention to this development in the male. To do so, I will refer to Hugues (2001, p. 3281), for whom the process of sexual differentiation can be defined as ‘phenotypic development of the internal and external genital structures, under the action of hormones which have been produced following the determination of the gonad’.
3.1. Normal sexual determination and differentiation: a recap
The differentiation of the gonad (which at the beginning of the process is the same in both sexes [2]) into a testicle or an ovary is a genetic process known as sexual determination (Hugues, 2001).
The factors responsible for sexual determination are partly chromosomal and partly at the level of the gene (Hencha- Razavi & Escudier, 2000). At the moment of conception the sex of the embryo is determined by the combination of sexual chromosomes: in males, the chromosomal sex is most often 46 XY, in females 46 XX.
In addition, there is a specific gene sequence responsible for testicular development. It appears that the gene SRY [3], carried by the Y chromosome, is the principal initiator of the cascade of genetic interactions which determine the development of the undifferentiated gonad into a testicle [4].
As for the term gonadic sex, this is used to describe the status of the gonads: whether they comprise testicular tissue, or ovarian tissue.
Following the gonad’s determination as a testicle, masculine sexual differentiation is dependent on the production and action of androgens – hormones of gonadic origin (Hugues, 2001).
Until the sixth week, whatever the sex of the embryo, the internal genital passages are represented by two pairs of genital canals: the Wolferian and Müllerian ducts. These ducts take one or other direction according to the hormones produced by the gonads (Hencha-Razavi & Escudier, 2000).
In male embryos (46 XY), the internal male phenotype is achieved thanks to the secretion and action of two androgens. One is the anti-Müllerian hormone (AMH) which permits a regression of the Müllerian ducts. The other is testosterone, which contributes to the maintenance and development of the Wolferian ducts (epididymis, vas deferens, seminal vesicles and ejaculatory ducts [5].)
The constitution of the external male phenotype sex (external genital organs and genito-urinary sinus) needs the conversion of testosterone into a more powerful hormonal derivative – dihydrotestosterone or DHT – which happens with the help of a specific enzyme, type 2 5-alpha-reductase (Hugues, 2001).
To recap, the external genital structures develop in both sexes (46 XY or 46 XX), from the same original tissues. In the state known as undifferentiated (Hencha-Razavi & Escudier; Larsen, 1996), these tissues are identical and comprise a pair of labio-scrotal folds, a pair of genito-urinary folds and a genital tubercule (see Figure 1).
FIGURE 1 Source : Larsen (1996)
Normally, in an individual of male genetic sex (46 XY), between the 8th and 14th week the genital outlines change under the influence of DHT which fixes itself on special cell receptors (Larsen, 1996). On one side the pads of genital tissue knit together to form the scrotum. On the other, the genital tubercule elongates to form the shaft and glans of the penis.
As the penis grows, the genital folds are drawn forward, then knit together under the penis. During this process of knitting together the genito-urinary membrane forms the urethral canal, which, in fusing, forms a tube the whole length of the penis, comprising the penile urethra.
This process continues forward and draws nearer the glans: this is the glanular urethra. The extremity of the glans, containing the most distal part of the urethra, is formed through an invagination of epithelial cells hollowing out the centre of the glans.
Finally, the urethra opens at the extremity (or apex) of the glans in a vertically oriented slit (see Figure 2). The formation of a complete prepuce (foreskin), with its final cutaneous fold surrounding the glans on its ventro-dorsal part, signals the successful end of this process.
FIGURE 2 Source: Larsen (1996)
In the absence of androgens and DHT, the external sex organs differentiate in the female way (Larsen, 1996). The genital tubercule inclines towards the base to form the clitoris, the genito-urinary folds remain separated to form the small lips (labia minora) of the vulva, and the labio-scrotal folds do not knit together and consequently form the large lips (labia majora).
3.2. Hypospadias: embryogenesis
Different manifestations of hypospadias can appear, depending on the moment when, during the embryonic development of the phenotypic masculine sex, the different fusion processes which form the urethra are disrupted (Larsen, 1996).
According to Frisén (2002), the severity of hypospadias can be seen as a continuum. The earlier the fusion process is interrupted, the hypospadias will be classified as ‘severe’ or ‘complex’. Conversely, ‘simple’ cases of hypospadias will arise from failures during the terminal phases of urethral development.
The degree of hypospadias depends on the location and the length of the urethral orifice (Larsen, 1996). The most severe cases of hypospadias arise when the pads of genital tissue do not fuse at all. The urethra opens in the perineum and the hypospadias is called ‘perineal’ [6].
In the case where the genital pads fuse only partially, and the urethral orifice opens between the base of the penis and the root of the scrotum, the hypospadias is classified as ‘peno-scrotal’ (see Figure 3).
FIGURE 3 Source: Larsen (1996)
An incomplete fusion of the genital folds produces an opening of the urethra at a point along the ventral side of the penis, which is ‘penile’ hypospadias (see Figure 4).
FIGURE 4 Source: Larsen (1996)
Finally, when the epithelial invagination of the glans is defective, the urethral opening is located under the glans, and this is known as ‘glanular’ hypospadias (see Figure 5).
FIGURE 5 Source: Larsen (1996).
The conditions described (Larsen, 1996), represent the four major forms of hypospadias likely to be encountered. However, as we shall see, numerous anatomical varieties of this condition are possible.