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Review |
From the UCSF Children's Hospital, Department of Urology, University of California, San Francisco, California.
| Correspondence to: Laurence S. Baskin, MD, Chief, Pediatric Urology, Professor Urology and Pediatrics, UCSF Children's Hospital, University of California, San Francisco, 400 Parnassus Avenue A640, San Francisco, CA 94143 (e-mail: lbaskin{at}urology.ucsf.edu). |
| Received for publication January 14, 2008; accepted for publication March 25, 2008. |
Hypospadias is one of the most common congenital anomalies in the United
States, occurring in approximately 1 in 125 live male births. Embryological
studies have demonstrated that, depending on where the urethral development
arrests, the meatal opening can be anywhere along the shaft of the penis or,
in more severe forms, within the scrotum or in the perineum. Currently, the
only available treatment is surgery. If left uncorrected, especially in its
severe form, there is risk of infertility and psychological effects, such as
avoidance of intimate relationships. The cause of hypospadias is largely
unknown; however, current epidemiology and laboratory studies have shed new
light into the etiology of hypospadias. With recent advancements in molecular
biology and microarray technology, it appears that hypospadias is potentially
related to disrupted gene expression. Specifically, some of the environmental
chemicals are acting as antiandrogens and interfere directly with the action
of testosterone-related gene expression. In this paper, we briefly review the
normal development of male external genitalia and the prevalence and
environmental risk factors related to hypospadias. In addition, we discuss
some of the recent laboratory findings that contribute to our current
understanding of this disease.
Multiple animal studies have linked endocrine disruptors to adverse biological effects, raising concerns that low-level exposure might cause similar effects in humans (Giesy et al, 1994; Guillette et al, 1994, 1995; Fry 1995; Sumpter and Jobling, 1995; de Solla et al, 1998). Within the last decade, several epidemiologic studies have suggested environmental factors as a possible cause for the observed increased incidence of abnormalities in male reproductive health. Some examples include the increased incidence of testicular cancer, a decline in semen quality, an increase in the frequency of undescended testes and hypospadias, and a growing demand for assisted reproduction (Chilvers et al, 1984; Matlai and Beral, 1985; Campbell et al, 1987; Carlsen et al, 1992; Adami et al, 1994; Auger et al, 1995; Irvine et al, 1996; Swan et al, 1997; Moller, 1998; Andersen et al, 2000). However, some of the recent studies both in Greenland and Denmark showed a stabilization or even decline in the incidence of hypospadias (Giwercman et al, 2006, Cortes et al, 2008).
In 2001, Skakkebæk and others published a paper suggesting that these observations are in fact related and indicate a common cause. His conclusions were based on the number of male reproductive abnormalities that have risen sharply over the past 50 years, concurrent with the swift growth of the chemical industry and its associated release of chemicals into the environment. He coined the term "testicular dysgenesis syndromes" (TDS), which encompasses cryptorchidism, in situ germ cell carcinoma of the testis/overt testicular cancer, reduced semen quality, and hypospadias. Additional signs include presence of microliths in the testes, Sertoli cell–only seminiferous tubules, or immature tubules with undifferentiated Sertoli cells (Skakkebæk et al, 2001, Skakkebæk, 2004).
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Development of the Male External Urogenital System
Formation of the external male genitalia is a complex process starting with
genetic programming (ie, the presence of the Y chromosome and its associated
sex-determining region Y [SRY] and its protein product, testis-determining
factor [TDF], which are necessary for cell differentiation), hormonal
signaling, enzyme activities, and tissue remodeling. At 3.5 weeks of
gestation, the wolffian system appears as 2 longitudinal ducts connecting
cranially to the mesonephros and caudally draining into the urogenital sinus.
Meanwhile, the müllerian duct develops as an evagination in the coelomic
epithelium just lateral to the wolffian duct at approximately the sixth week
of gestation (Figure 1). In
addition, by the end of the fourth week of gestation, both the hindgut and
future urogenital system have reached the cloacal membrane on the ventral
surface of the developing embryo. From this indifferent stage until the end of
the eighth week of gestation, the urorectal septum continues to develop and
divides the cloacal membrane into anterior and posterior segments; with the
anterior aspect destined to be the urogenital membrane and the posterior
segment the future rectum. Up to this point, the male and female genitalia are
essentially indistinguishable. With the surge in luteinizing hormone, coupled
with the influence of testosterone and 5[alpha]-dihydrotestosterone (DHT),
masculinization of the external genitalia occurs. One of the first signs of
masculinization is an increase in the distance between the anus and the
genital structures, followed by elongation of the phallus, formation of the
penile urethra from the urethral groove, and the development of the prepuce.
By 11–12 weeks, the coronal sulcus has separated the glans from the
shaft of the penis. At 16–17 weeks of gestation, the urethral folds have
completely fused in the midline on the ventrum of the penile shaft with medial
fusion of the endodermal urethra and fusion of the ectodermal edges
(Figure 2;
Hinman, 1993;
Moore and Persaud, 1998).
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The glandular urethra, which consists of the squamous epithelium, also completes its formation during this period. The mechanism of the glandular urethral formation remains controversial. Two theories have been proposed: endodermal cellular differentiation, wherein the glandular urethra formed by an extension of urogenital sinus epithelium undergoes transdifferentiation, and primary intrusion of the ectodermal tissue from the skin of the glans penis (Figure 3). Anatomical and immunohistochemical studies support the new hypothesis of endodermal differentiation, which shows that the epithelium of the entire urethra is of urogenital sinus origin. The entire male urethra, including the glandular urethra, is formed by dorsal growth of the urethral plate into the genital tubercle and ventral growth and fusion of the urethral folds. Under proper mesenchymal induction, the urothelium has the ability to differentiate into a stratified squamous phenotype with characteristic keratin staining, thereby explaining the cell type of the glans penis (Yamada et al, 2003).
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The future prepuce is formed at the same time as the urethra and is dependent on normal urethral development. At about the eighth week of gestation, low preputial folds appear on both sides of the penile shaft, which join dorsally to form a flat ridge at the proximal edge of the corona. The ridge does not entirely encircle the glans because it is blocked on the ventrum by the incomplete developed glandular urethra. The process of preputial formation continues until it covers all of the glans, forming a midline seam. If the genital folds fail to fuse (ie, if there is a defect in the formation of the urethra), the preputial tissues do not form ventrally (Figure 4).
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In 1999, the International Clearinghouse for Birth Defects Monitoring Systems, a nongovernmental organization of the World Health Organization, reported an increased rate of hypospadias in 7 European countries, including Norway, Sweden, England and Wales, Hungary, Denmark, Italy, and France in the 1960s, 1970s, and 1980s (Paulozzi, 1999). Independently, the Centers for Disease Control and Prevention (CDC) reported their findings of a doubling of hypospadias from 1968 to 1993 in the United States (Paulozzi et al, 1997). The data were based on collective analysis from 2 independent surveillance systems. Specifically, data from the Metropolitan Atlanta Congenital Defects Program (MoD/MACDP/CBDMP, 2001), a population-based registry that uses active case studies in 22 hospitals and clinics in the Atlanta, Georgia, area, indicate that the rate of total hypospadias almost doubled from 1968 to 1993 at an annual rate of 2.9%. Concurrently, the Birth Defects Monitoring Program, a program that gathered discharge diagnoses of newborns across the country, also reports an increase in hypospadias: from 20.2 per 10 000 live births in 1970 to 39.7 per 10 000 live births in 1993. Overall, these longitudinal studies suggest an almost doubling of hypospadias in the United States over a 14-year period.
Environmental Factors
In the past, environmental effects were generally ruled out as causes for
hypospadias. However, in light of the growing number of endocrine disruptors
reported in human tissue and the probability of shared exposure, environmental
contaminants are now being evaluated in familial cluster studies. Reports of
increase rates of hypospadias have paralleled reports of other adverse effects
observed in male reproductive health, include increased rates of testicular
cancer, cryptorchidism, and decreasing semen and sperm quality
(Bergstrom et al, 1995;
Carlsen et al, 1995). Cheng et
al (1996) found that 8% of
patients (n = 252) with undescended testes also had other urogenital
anomalies, including hypospadias. A separate study reports an increase in
testicular cancer risk with undescended testicles and hypospadias
(Prener et al, 1996).
To understand the biology of antiandrogens, and their roles as endocrine disruptors in the development of the external genitalia and urethra, we must first look at testosterone. Under normal conditions, testosterone dissociates from its carrier proteins in the plasma and enters the cells via passive diffusion. Once intracellular, testosterone binds to the androgen receptor (AR) and forms a complex that can subsequently bind to the androgen response element on DNA. With this binding, multiple downstream androgen-responsive activities are initiated, one of which is the development of male external genitalia. Antiandrogens can directly interfere with the proper functioning of testosterone in multiple ways. Examples include inducing a conformational change within AR, increasing AR degradation, or blocking the release of heat shock proteins from AR. A well-known example of an antiandrogen is DDT (dichlorodiphenyltrichloroethane). DDT was widely used to combat mosquitoes spreading malaria, typhus, and other insectborne diseases. In 1962, Rachel Carson published the book Silent Spring, questioning the environmental effects of the indiscriminate use of DDT and its effect on ecology and human health (Carson, 1962). A study in the male rat fetus found that in utero exposure to p,p'-DDE, a lipophilic metabolite of DDT, leads to feminization of the genital urinary tracts; reduced anogenital distance, hypospadias, and cryptorchidism (Kelce et al, 1995). Perhaps the most alarming aspect of the study is that the experimental dose used was within the range of human exposure.
Normal urogenital differentiation also relies on the interaction between testosterone and epidermal growth factors (EGFs). In vivo experiments show that EGF alone can induce partial virilization of the external genitalia and that sexual differentiation is inhibited when EGF is depleted (Gupta et al, 1996). Dioxin (TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin), a component of agent orange, a herbicide and defoliant used by the US Armed Forces in the Vietnam War, has gained popular attention because of its association with various cancers. It has been shown in rats to induce c-Src kinase activity and reduces EGF receptor binding during testicular development (El-Sabeawy et al, 1998). However, there are no definitive studies that have demonstrated an association between agent orange and human cancers. Chlorinated pesticides, such as dioxin, as well as furans and polychlorinated biphenyls are known cytochrome P450 (CYP450) agonists that interfere with the normal aromatization of androgens (Haake et al, 1987; Paolini et al, 1996; Sanderson et al, 1997).
Several synthetic chemicals have consistently been shown to induce hypospadias in laboratory animals. Vinclozolin, a commonly used fungicide, induces female-like AGD (anal-genital distance), retained nipples, reduced sperm count and fertility, and hypospadias in 100% of male offspring that were exposed to the chemical in utero (Gray et al, 1999a; Kelce et al, 1994). Procymidone, another antiandrogenic fungicide, induces hypospadias in all male rat offspring when mothers are exposed during gestation (Ostby et al, 1999). It has been shown that procymidone exerts its effects by inhibiting DHT-induced transcriptional activities (Gray et al, 1999b). Mice exposed to vinclozolin have less robust and atrophic urethras when compare with controls (Kim et al, 2004; Buckley et al, 2006). Phthalates, ubiquitous chemicals found in plastics, have gained attention because of their hormonal effects in laboratory animals. Male rodents exposed to dibutyl phthalate and diethylhexyl phthalate have reduced AGD, retained nipples, epididymal agenesis, undescended testes, and hypospadias (Gray, 1998).
As mentioned previously, DES provides an excellent model for studying interrupted genital development because of exogeneous hormones in humans. Longitudinal studies have shown that DES daughters have a 2.5-fold increase in breast cancer after age 40, in addition to an increased risk for vaginal and cervical cancers (Herbst et al, 1971). Sons of DES-exposed mothers are at an increased risk for feminization of the male fetus; a study noted a 20-fold increase in the development of hypospadias (Brouwers et al, 2006). A separate study confirmed this risk: 10 of 225 DES-exposed male offspring developed penile malformations, including strictures/stenoses and hypospadias, vs 0 in patients who were unexposed (Henderson et al, 1976).
Molecular Mechanism of Hypospadias and Endocrine Disruptors
The exact molecular events that lead to normal urethral development and
hypospadias remain largely unknown; however, recent studies have revealed
possible involvement of sonic hedgehog (SHH), fibroblast growth factors 8 and
10 (FGF8 and FGF10), and homeobox A13 and D13 (HOXA13 and HOXD13) genes in
early genital tubercle outgrowth and patterning
(Haraguchi et al, 2001;
Perriton et al, 2002;
Morgan et al, 2003). As
discussed earlier, antiandrogen might play a role in the development of
hypospadias. It has been shown that pregnant female mice exposed to synthetic
estrogen compounds gave birth to offspring with hypospadias
(Kim et al, 2004;
Willingham et al, 2006).
Microarray analysis of tissue samples from hypospadias have identified
additional genes that are both estrogen responsive and up-regulated
(Wang et al, 2007). One such
gene found in the tissues/foreskin of human hypospadias, which also
demonstrated significant up-regulation in the presence of estrogen, is
activating transcription factor-3 (ATF-3). A recently published study
utilizing human foreskin fibroblast treated with estrogen showed an increase
in staining for ATF-3 within 2 hours of treatment
(Liu et al, 2006). This was
further substantiated by an increase in protein expression, and ATF-3 promoter
activity (Liu et al, 2007).
Similar results were also noted in the mouse genital tubercle, where
quantitative reverse transcriptase polymerase chain reaction showed that ATF-3
mRNA is up-regulated in estrogen-exposed specimen compared with controls. A
study of human tissues from 28 children who underwent repair of hypospadias vs
20 tissue samples from children who underwent elective circumcision,
demonstrated a significant increase in immunohistochemical staining for ATF-3
in the hypospadias population (86% vs 13%),
(Liu et al, 2005). Studies
have shown that ATF-3 protein suppresses cellular growth, we can hypothesize
that its up-regulation induces an arrest in urethral development as a
potential cause of hypospadias. Further studies of ATF-3 and other
estrogen-related genes would perhaps provide a link between exogenous hormones
and the development of hypospadias.
With the increasing incidence of hypospadias paralleling the rate of increase in environmental pollutants, it is imperative that we consider endocrine disruptors as a potential cause for this anomaly. Additional molecular studies will help us elucidate the role of these exogenous hormones and offer insights into other male developmental disorders.
Footnotes
Supported by a grant from the National Institute of Health R01 DK058105.
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