Category Archives: Hypospadias research

Physical and Psychological Effects Of Hypospadias (Chapter 1 part 5)

Chapter 1 continued

7. Epidemiology
7.1. Frequency of Hypospadias

In the specialist field of pediatric urology, it is reported that hypospadias is a common congenital malformation. The estimations of frequency are placed between 1 in 300 (0.3 %) and 1 in 250 (0.4%) of male births (Baskin, 2000 ; Sheldon & Duckett, 1987 ; Paparel et al., 2001).

7.2. Incidence of hypospadias

However, certain scientific studies published towards the end of the 1990s reported an increasing incidence of hypospadias in several western countries. Based upon the analysis of American and European surveys of congenital malformations and earlier epidemiological reports, Paulozzi, Erickson et Jackson (1997) observed that the rate of hypospadias almost doubled [18] between 1970 and 1990 in the United States. Paulozzi (1999) also stated that similar increases in hypospadias had been reported in several European countries [19].

A series of recent publications, based upon hospital birth registers, have reported an increase in hypospadias. One study carried out by Pierik, Burdof, Nijman et al. (2002) produced evidence that the frequency of hypospadias rose to 0.7 percent in child health centers situated in the south west region of the Netherlands; this represented a rate 6 times higher than that generally reported in the region by national registers.

Another study by Hussain, Chagtai, Herndon et al. (2001) showed an incidence 10 times higher (4.0% vs 0.4 %) of hypospadias in 2000 compared to 13 years previously (1987) in neo-natal intensive care units in the USA (Connecticut) [20]..

Other studies using different registers have discovered a higher frequency of hypospadias than is generally recognized. After an analysis of American national military registers, Gallentine, Morey and Tompson (2001) estimated a frequency of hypospadias rising to 0.7% (709 cases of hypospadias counted in 99210 males). By contrast, this frequency (0.7%) is almost double that calculated by other researchers in Italy, in a male population over 18 years of age who were examined during enrolment for military service, which reached 0.36% (42 cases per 11649 males) (Mondaini, Ponchietti, Bonafè et al., 2001).

What explanations does the scientific community give regarding these rises?

The concept of endocrinal disruption, as discussed above, has been increasingly accepted and proposed as a way of accounting for the increased incidence of hypospadias observed in more industrialized nations (Dolk, 1998 ; Harrison, Holmes & Humfrey, 1997 ; Wakefield, 2001).

However, a number of authors agree that new epidemiological research of a multi-disciplinary nature must be carried out, in order to clarify the part played by chemical substances disrupting endocrine function in the reported increased frequency of hypospadias (Baskin et al., 2001; Rittler & Castilla, 2002; Sultan et al., 2001; Toppari et al. 2002; Weber et al., 2002).

Taken together, the published studies draw attention to the fact that nowadays hypospadias is a congenital condition far more common than is normally supposed (Sharpe, 2003).

8. Conclusion

Hypospadias benefits from a vast literature concerning the investigation of its physical aspects. Currently, different medical disciplines are working together to understand better the etiology of this condition. The data currently available on this subject stem from endocrinology, molecular biology, epidemiology and even eco-toxology. Although some considerable progress has been made in these fields, supplementary research is required to better understand the factors combining to produce this condition.

This review of the relevant literature shows that hypospadias is a much more common condition than is generally supposed, that it is becoming increasingly common, and indeed that it is more common now than ever before.

Footnotes to Chapter 1

[1] The mechanisms of prenatal sexual differentiation have been to a large part elucidated by the many experiments carried out, some 50 years ago, on different animal species (batrachians, mammals and birds) (for a review see Aron, 1973, pp. 109-121).
[2] The gonadic outline is called undifferentiated when it contains both ovarian and testicular tissue.
[3] SRY : Sex determining Region Y gene. Only a tiny region (known as the ‘short arm’ of the Y chromosome contains the gene(s) of sexual determination (see Haqq & Donahoe, 1998, pp. 2-5).
[4] In the absence of SRY, the undifferentiated gonad develops as an ovary.
[5] In the absence of AMH (anti-Müllerian hormone) and testosterone, sexual differentiation follows a fixed pattern, characterized by the regression of the Wolfian ducts and the development of Müllerian ducts (the upper third of the vagina and uterus).
[6] This severity of hypospadias is also classified as vulviform; the external genital organs of the newborn male (46XY) can appear as the phenotypic feminine.
[7] The prepuce is known as a dorsal hooded foreskin.
[8] In fact, certain varieties of hypospadias with a complete prepuce have been reported in the literature (see, for example, Cold & Taylor, 1999).
[9] A penis of under-developed size, sometimes observable in hypospadias, is not to be confused with what has been called a micropenis or microphallus: here the penis is morphologically normal and the urethra’s outlet is well positioned at the end of the glans, but the size is very much reduced in comparison to the available norms (Bourgeois, 2003).
[10] The non-descent of testicles (without the association of hypospadias) is a condition frequently encountered in newborns of the masculine sex, its incidence being estimated at around 3 percent of full-term newborns (Leissner, Filipas, Wolf & Fish, 1999).
[11] Impacting of the penis in the scrotum is defined by the presence of scrotal skin, either low or high on the body of the penis. Total impacting is rare, but if this is the case only the dorsal face is visible, the ventral side remains stuck in the scrotum.
[12] The notion of sexual ambiguity relates to an undifferentiated or badly differentiated appearance of the external genital organs, or to a state of discordance between the internal and external genital organs (Encha-Razavi & Escudier, 2000). The notion of intersexuality refers to a variation of normal development whereby the appearance of the external genitals makes it difficult to assign a sex to the child at birth (Hugues, 2002).
[13] The balano-preputial ridge is the anatomical transition between the glans and the shaft of the penis.
[14] The explanation of such a classification is relatively easy to explain: the position of the urethral meatus is considered an untrustworthy criterion for judging the severity of hypospadias as, in general, the meatus moves backwards after surgical repair of the chordee (orthoplasty), worsening to some extent the degree of hypospadias confirmed initially (De Sy & Hoebeke, 1996).
[15] The concept of endocrinal disturbance refers to the molecules capable of imitating sexual hormones naturally produced by the body (xenoestrogens) or of blocking certain hormones (anti-androgens) at the stage crucial for sexual development in utero (Toppari, 2002).
[16] I cite as an example the research of Facemire, Gross and Guillette (1995) and that of Guillette (2000) (in Florida, USA). In a first study, the researchers clearly gave evidence that the abnormally high presence of cryptorchidism, observed in a population of panthers, could be explained by the fact that these felines lived very close to an agricultural area where pesticides were widely distributed. (Facemire et al., 1995). In a second series of studies, the researchers noticed a notable diminishing of the penis size of alligators born in a polluted lake (Lake Apopka) following a leakage of toxic substances (Guillette, 2000; see also Semenza, Tolbert, Rubin et al., 1997).
[17] Diethylstilbestrol (DES) is a synthetic estrogen which was widely prescribed to pregnant women between 1938 and 1975 to prevent miscarriage. The effects of DES as evidenced are avowed to be transgenerational. In the article by Klip et al. (2002), the hypothesis is that DES would be associated with a disturbed function of the placenta, resulting in a diminishing of placental and fetal hormones which could disrupt fetal development; this would predispose a likelihood of hypospadias.
[18] The rate has gone from 20/10000 in 1970 to 40/10000 in 1993 in USA (Paulozzi et al., 1997).
[19] Norway, Sweden, United Kingdom, Denmark, Italy and France (for details see Paulozzi, 1999).
[20] Other American researchers have reported an incidence, also in neonatal intensive care units (in the Atlanta region), ten times higher than normally estimated in that particular population (11% vs 1%) (Gatti, Kirsch, Troyer et al., 2002).

Continued here: Chapter 2. (The rest of this material will be added as soon as possible…. please call back or email to check)

Physical and Psychological Effects Of Hypospadias (Chapter 1 part 4)

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 [15], 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 [16] 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 [17] (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).

Continued here.