Chapter 1 continued
6. Etiological hypotheses of hypospadias
Because of its frequency in the male population, there have been many investigations into the etiology of hypospadias (Baskin, 2000). It’s now recognized that the etiology of hypospadias comprises hereditary, genetic, endocrinal and environmental factors (Silver, 2000)
6.1. Hereditary factors
The existence of a hereditary causal factor for hypospadias has been demonstrated by certain studies which show the presence of several affected people in the same family. In one relatively old study (Bauer, Bull et Retik 1979; quoted in De Sy & Hoebeke, 1996), the authors concluded that if the father of a family has hypospadias, the probability that one of his sons will carry it is increased to around 8 percent, and the likelihood that one of his brothers will also be affected reaches 12 percent. Moreover, the risk for the next generation increases to around 26 percent if two members of the same family are carriers of hypospadias (e.g., when the father and one of the sons are affected).
According to a more recent study concerning the heredity of hypospadias (Fredell, Kockum, Hansson et al., 2002), almost 7 percent of the families interviewed – in which a child presented one or other form of hypospadias at birth – reported knowing of the existence of another affected family member.
6.2. Genetic factors
The pathogenesis of hypospadias equally comprises factors of a genetic order. Earlier molecular analyses have revealed that there might be, among certain boys presenting an isolated case of hypospadias, mutations of the gene responsible for the enzyme activity of 5-alpha-reductase, leading to disturbance of the production of dihydrotestosterone which is necessary for development of the male genito-urinary tract (Silver & Russel, 1999).
Recent genetic studies carried out on humans (Frisén, 2002), and on animals (Morgan, Nguyen, Scott & Stadler, 2003), have shown that alterations affecting certain genes – such as gene HOXA13 – are susceptible to change the response of the receptor to androgens (located at the level of the genital tubercule) and to lead to the phenotypic expression of hypospadias.
6.3. Endocrinal factors
The presence of hypospadias may also be explained through certain endocrinal factors. Nowadays, it is widely accepted that androgens play a crucial role in the development of the male external genital organs (Hugues, 2001). More precisely, recent anatomical studies support the hypothesis that androgens are essential for the formation of the ventral portion of the human urethra (Liu, Cunha, Russel et al., 2002).
This type of research supports even more strongly the possibility that hypospadias can appear following deficiencies during the biosynthesis of 5-alpha-reductase or via a defect in the androgen receptors.
It is notable also that other hormone deficiencies, such as an excessive production of the anti-Müllerian hormone (AMH) (Austin, Siow, Fallat et al., 2002), may equally play a role in the etiology of hypospadias by interfering with the biosynthesis of testosterone.
6.4. Environmental factors
In recent years a debate has begun in the scientific community about the negative impact of environmental factors on male reproduction in humans (Weber, Pierik, Dohle & Burdof, 2002).
This debate has mostly centered on the hypothesis that certain substances of exogenous origin, known as endocrine disruptors , could be responsible for the appearance of disorders of sexual differentation (Toppari, 2002). More precisely, disturbances in masculine sexual differentiation may be induced by two categories of products: the xenoestrogens and the anti-androgens (Sultan, Balaguer, Terouanne et al., 2001).
Endocrine disruptors will affect in particular the normal development of the urethra, but will equally influence the physiology of testicular descent and spermatogenesis in the male (Rittler & Castilla, 2002 ; Toppari, Haavisto and Alanen, 2002).
The list of products incriminated as endocrine disruptors is a long one. According to Sultan et al. (2001), this list comprises diverse synthetic products such as insecticides, pesticides, fungicides, industrial chemical products, substances used in the pharmaceutical industry, detergents and materials used in the fabrication of plastics.
Certain natural substances of vegetable origin but having similar properties to hormones naturally produced in the body (animal and human), known as phyto-estrogens, have also been classified as potential endocrine disruptors (Santti, Makela, Strauss et al., 1998). It is now almost ten years since researchers alerted the scientific community to the possible links between the presence of these substances in our environment and the incidence of demasculinization phenomena  in diverse animal species living in the natural environment (Hose & Guillette, 1995).
A number of experiments, some carried out on animals, have drawn attention to how substances with xenoestrogenic or anti-androgenic effects may exert their influence on the development of the male reproductive and genito-urinary system (Gray, 1998; Gray, Wolf, Lambright et al., 1999; Hayes, Collins, Lee et al., 2002).
The injection of certain potentially anti-androgenic substances have induced hypospadias in rodents, as has finisteride (an inhibitor of 5-alpha-reductase type 2) in rabbits (Kurzrock, Jegatheesan, Cunha et al., 2000), and flutamide (an inhibitor of testosterone fixation on the special receptors) in mice (Kojima, Hayashi, Mizuno et al., 2002).
Note that these experiments using animals do not exactly mirror the situations which could be encountered by humans, but nevertheless they provide valuable information about the stages of normal genito-urinary development, as well as throwing light on the biochemical activities leading to the appearance of hypospadias.
Scientists have recently proposed the hypothesis that endocrine disruptors may be partly responsible for hypospadias in humans (Baskin, Himes, & Colborn, 2001). But only a limited number of studies on this subject exist. Klip, Verloop, van Goel et al. (2002) showed that boys born to mothers who had been exposed to diethylstilbestrol  (DES) in utero had a higher risk of hypospadias.
Another study (North & Golding, 2000), suggested that a potentially excessive consumption of phyto-estrogens (via a strictly vegetarian diet in the mother) could disrupt genito-urinary development in the male fetus. Some studies, however, have found no accumulated risks in certain target populations. Vrijheid, Amstrong, Dolk et al. (2003) recently reported that mothers exposed (through their professional occupation) to products classed as endocrine disruptors have no increased risk of giving birth to a child with hypospadias (Vrijheid, Armstrong, Dolk et al., 2003).
Current knowledge notwithstanding, the absence of an exact causal agent for hypospadias in humans continues to pose a problem (Baskin et al., 2001). Even today, the etiology of the majority of observed cases remains, unexplained (Boehmer, Nijman, Lammers et al., 2001 ; Sharpe, 2003).