HYPOSPADIAS

Laurence S. Baskin* M.D., FAAP

1. INTRODUCTION

Hypospadias is one of the most common congenital anomalies occurring in

approximately 1:250 newborns or roughly lout of 125 live male births
(Paulozzi et al., 1997). Hypospadias can be defined as an arrest in normal
development of the urethral, foreskin and ventral aspect of the penis. This
results in a wide range of abnormalities with the urethral opening being
anywhere along the shaft of the penis, within the scrotum or even in the
perineum (Figure 1).

Figure I.
Variations of hypospadias from mild to severe. A. Mild with the urethral opening on the glans. B.
Mild with the urethral opening at the coronal margin. C. Moderate with the urethral opening on the
distal penile shaft. D. Moderate with the urethral opening on the mid penile shaft E. Severe with
the urethral opening at the penoscrotal junction. F. Severe with the urethral opening in the scrotum.
(the arrows locate the opening of the hypospadiac urethra meatus) Note that in hypospadias the
foreskin is absent on the ventral surface of the penis and excessive on the dorsal aspect. The more
severe fonns of hypospadias are associated with penile curvature.

·Chief, Pediatric Urology, Associate Professor of Urology and Pediatrics, University of California,
San Francisco, San Francisco, CA, 94143-0738, (415) 476-1611, (415) 476-8849 (FAX),
Ibaskjnl@urol.ucsfedu

Hypospadias and Genital Development, edited by

L. Baskin, Kluwer AcademicIPlenum Publishers, 2004 3
4 Baskin

Hypospadias is also associated with penile curvature. Left uncorrected, patients

with severe hypospadias may need to sit down to void and tend to shun intimate
relationships because of the fears related to abnormal sexuality. Babies born
with severe hypospadias and penile curvature may have "ambiguous genitalia"
in the newborn period, making an immediate and accurate sex assignment
difficult.
Hypospadias is classified by the location of the urethral meatus (Figure 2).

Figure 2. Classification and Incidence of Hypospadias: Anterior, Middle and Posterior.

Anterior hypospadias is described as glandular (meatus on the ventral surface of

the glans penis); coronal (meatus in the balanopenile furrow); or distal (in the
distal third of the penile shaft). Middle hypospadias is along the middle third of
the penile shaft. Posterior hypospadias extends through the proximal third of the
penile shaft to the perineum and is described as posterior penile (at the base of
the shaft); penoscrotal (at the base of the shaft in front of the scrotum); scrotal
(on the scrotum or between the genital swellings): or perineal (behind the
scrotum or behind the genital swellings). As noted, chordee or penile curvature
is a downward curvature of the penis that typically accompanies the more severe
forms of hypospadias. Standard classification of hypospadias does not take into
account the associated penile curvature. In reality a patient with severe
Hypospadias 5

curvature and an anterior urethral meatus may in fact require a more extensive
surgery to correct both the curvature and the abnormal urethra.

2. Historical Notes

Throughout Greek culture, there was high appreciation for the goddess
Hermaphrodite, half man, half woman. Many statues reflect hypospadiac
genitalia, perhaps indicative of admiration for this condition. It is, therefore,
understandable why it was not until the first and second centuries A.D. that the
Alexandrian surgeons Heliodorus and Antyllus are given credit for the first
attempted correction of this anomaly by amputation of the distal curved portion
(Rogers, 1973). Sexually, the dystopia of the meatus may cause impotentia
generandi, which is illustrated from the following historic note concerning
Henry II of France. Henry II was known to have hypospadias, as recorded by
his physician Fernal. His marriage with Catherine the Medici was infertile until
Fenral "advised his patient that in such cases coitus more ferarum permitted him
to overcome the difficulty" (Ombredanne, as quoted by Van der Muelen, 1964).
Henry II then proceeded to sire three kings of France, along with seven other
children.

3. Embryology: Development of the Male External Urogenital System

Formation of the external male genitalia is a complex developmental process

involving genetic programming, cell differentiation, hormonal signaling,
enzyme activity, and tissue remodeling. By the end of the first month of
gestation, the hindgut and future urogenital system reach the ventral surface of
the embryo at the cloacal membrane. The cloacal membrane divides the
urorectal septum into a posterior, or anal half and an anterior half, the urogenital
membrane. Three protuberances appear around the latter. The most cephalad is
the genital tubercle. The other two, the genital swellings, flank the urogenital
membrane on each side. Up to this point, the male and female genitalia are
essentially indistinguishable. Under the influence of testosterone in response to
a surge of luteinizing hormone from the pituitary, masculinization of the
external genitalia takes place. One of the first signs of masculinization being 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 development of the prepuce (Jira'iek et aI., 1968; Hinman, 1993).
At eight weeks gestation the external genitalia remain in the indifferent
stage (Figure 3A).
6 Baskin

Figure 3.
Normal Male Genitalia Development: A. 10 weeks gestation. Note the open urethra. prominent
urethra folds (arrows) and the glandular epithelial skin tag. B. 16 weeks gestation. Note that penile
and urethra development are complete.

The urethral groove on the ventral surface of the phallus is between the paired
urethral folds (Baskin et ai, 2001). The penile urethral forms as a result of fusion
of the medial edges of the endodermal urethral folds. The ectodermal edges of
the urethral groove fuse to form the median raphe. By 12 weeks the coronal
sulcus separates the glans from the shaft of the penis. The urethral folds have
completely fused in the midline on the ventrum of the penile shaft. During the
16th week of gestation the glandular urethral appears. The mechanism of the
glandular urethral formation remains controversial. Evidence suggest two
possible explanations; 1) endodermal cellular differentiation (new theory) or 2)
primary intrusion of the ectodermal tissue from the glans (old theory) (Figure 4).
Anatomical and immunohistochemical studies advocate the new theory of
endodermal differentiation which shows that epithelium of the entire urethra is
of urogenital sinus origin (Kurzrock et aI., 1999). 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, urothelium has the ability to differentiate
into a stratified squamous phenotype with characteristic keratin staining thereby
explaining the cell type of the glans penis (Kurzrock et aI., 1999). There is no
evidence of an ectodermal ingrowth or a solid ectodermal cord filling the glans
as was historically proposed (old theory) (Glenister, 1954).
The future prepuce is forming at the same time as the urethra and is
dependent on normal urethral development. At about eight weeks 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 incomplete
Hypospadias 7

Ectodennal Ingrowth Theory Endodennal Differentiation Theory

Declodenn
ndo<lenn
~slratified
squamous

Figure 4.
Two theories of urethral development. The older theory of ectodermal intrusion and the newer
theory of endodermal differentiation. (Used with permission from Dr. Kurzrock)
8 Baskin

development of the glandular urethra. Thus, the preputial fold is transported

distally by active growth of the mesenchyme between it and the glanular
lamella. The process continues until the preputial fold (foreskin) covers all of
the glans. (Figure 3B) The fusion is usually present at birth, but subsequent
desquamation of the epithelial fusion allows the prepuce to retract. If the genital
folds fail to fuse, the preputial tissues do not form ventrally; consequently, in
hypospadias, preputial tissue is absent on the ventrum, and excessive dorsally
(Figure 1).
The chronology of penile differentiation commences when "passive", or
default, female differentiation is interrupted by androgenic hormones triggered
by male genes ( Conte and Grumbach, 1995). At the molecular level testosterone
must be converted to 5a-dihydrotestosterone (DHT) by the microsomal enzyme,
type 2 5a-reductase, for complete differentiation of the penis with a male-type
urethra and glans (Wilson et aI., 1993). Testosterone dissociates from its carrier
proteins in the plasma and enters cells via passive diffusion (Kelce and Wilson,
1997). Once in the cell, testosterone binds to the androgen receptor (AR) and
induces changes in conformation, protecting it from degradation by proteolytic
enzymes (Kelce and Wilson, 1997). This conformational change is also required
for AR dimerization, DNA binding, and transcriptional activation, all necessary
for testosterone to be expressed. Androgen binding also displaces heat shock
proteins, possibly relieving constraints on receptor dimerization or DNA
binding. After entering the nucleus the AR complex then binds androgen
response element DNA regulatory sequences within the androgen responsive
genes and activates them. DHT also binds the AR, with enhanced androgenic
activity, in part because of its slow dissociation rate from the AR (Griffin et aI.,
1995).

4. Incidence of Hypospadias

Seven European countries, including Norway, Sweden, England and Wales,

Hungary, Denmark, Italy, and France, as well as the United States published
independent reports of increasing rates of hypospadias during the 1960s, 1970s,
and 1980s (Paulozzi, 1999). Recently, data from the International Clearinghouse
for Birth Defects Monitoring Systems (ICBDMS) was analyzed to determine if
these increases were worldwide, continuing, and whether they revealed any
geographic patterns. The data from ICBDM suggest that increases in
hypospadias are not a worldwide trend. Increases were most notable in the
United States, Norway, and Denmark (Paulozzi, 1999). Also, it was determined
that increases were not seen in the less affluent and less industrialized nations
(gross domestic product, GDP, was used as a marker of affluence and
industrialization) for which data were available. Increasing trends in England,
Canada, and Northern Netherlands appeared to be leveling off since 1985
(Paulozzi" 1999).
It is difficult to draw conclusions from international monitoring of birth
defects. Different registries have different reporting methodologies and
diagnostic criteria as well as varying degrees of physician compliance with
Hypospadias 9

reporting. However, as noted above, two independent surveillance systems in

the United States with consistent and unchanging diagnostic criteria have also
reported significant increases in hypospadias. While these surveillance programs
are not flawless the data warrant particular mention (Paulozzi et al., 1997).
Data from the Metropolitan Atlanta Congenital Defects Program (MACDP),
a population-based registry that uses active case ascertainment in 22 hospitals
and clinics in the Atlanta, Georgia area, indicated that the total hypospadias rate
almost doubled from 1968 to 1993 (p < 10'°) at an annual rate of increase of
2.9% (Paulozzi et al., 1997). No one hospital in the Atlanta metropolitan region
was responsible for the observed increases. Of particular significance, is that the
incidence of severe hypospadias increased. Severe cases involve the urethral
opening on the shaft of the penis or on the scrotum or perineum. Between 1968
and 1990 the severe cases increased from l.l to 2.7 per 10,000 live births and by
1993 to 5.5 per 10,000 births per year (p < 10.6) (Paulozzi et al., 1997).
The Birth Defects Monitoring Program (BDMP), a program which gathers
diagnoses recorded on newborn discharge summaries from hospitals nationwide,
also reported an increase in hypospadias. Incidences increased from 20.2 per
10,000 live births (includes both male and female births) in 1970 to 39.7 per
10,000 live births in 1993 (p < 10-6) (Paulozzi et al., 1997).
Both independent surveillance programs indicate a near doubling in reported
rates of hypospadias. It is unlikely that this increase is due to flaws in the
surveillance programs. For example, if increased sensitivity were to account for
the observed increases, the surveillance programs would initially have had to
record fewer than half of all defects. This is unlikely as no major changes in case
ascertainment has occurred in the MACDP or the BDMP during that time
period. It is possible that physicians' reporting habits of hypospadias have
changed over time-particularly an increased reporting of mild hypospadias.
This is not consistent, however, with reports from the MACDP that indicate that
the ratio of mild to severe hypospadias decreased from 4.2 from 1968 to 1982 to
2.6 from 1983 to 1993 (Paulozzi et al., 1997). It is important to note, however,
that as the ratio of mild to severe hypospadias decreased, the number of
unclassified hypospadias also decreased making this data more difficult to
interpret. This raises the question whether the mild cases are under-reported.
Nonetheless, these longitudinal studies support an increasing incidence of
hypospadias in the United States.

5. Associated Anomalies

Undescended testis and inguinal hernia are the most common associated
anomalies with hypospadias. In one series, 9.3% of hypospadias patients had an
undescended testis (Khuri et al., 1981). Posterior hypospadias had a 32%
incidence, middle 6%, and anterior 5%. Khuri and associates also found the
overall incidence of inguinal hernia to be 9%, with 17% associated with
posterior hypospadias. Ross and colleagues (Ross et al., 1959) reported a
similar incidence of either cryptorchidism or hernia in 16%, and Cerasaro and
co-workers (Cesasaro et al., 1986) found 18% of 301 patients had these
10 Baskin

anomalies. A utriculus masculinus (utricle) is found in a high percentage of the

more severe cases. For example, Devine and associates (Devine et aI., 1980)
found that of 44 patients whose meatus was posterior, 6 (14%) had a utricle. Of
seven with perineal hypospadias, four (57%) had a utricle, compared with 2 of
20 (10%) with a penoscrotal meatus. None of the 17 patients with penile
hypospadias had a utricle. Shima and colleagues (Shima et aI., 1979) found a
utricle in 1 of29 glandular, 3 of74 penile, 11 of 122 penoscrotal, and 10 of29
scrotal-perineal hypospadias cases. Thus the incidence is 14% in 151
penoscrotal or perineal hypospadias cases. If both studies are combined, there is
an 11 % incidence of a utricle in severe hypospadias. Usually there are no
complications from the presence of a utricle except for infection and difficulty
passing a catheter (Ritchey et aI., 1988).
It is not surprising that urinary tract anomalies are infrequent, because the
external genitalia are formed much later than the supravesical portion of the
urinary tract. McArdle and Lebowitz found only 6 genitourinary anomalies
among 200 patients with hypospadias (3%) (McArdle and Lebowitz, 1975).
Cerasaro and associates found 1.7% (4 of 233) patients with significant
anomalies (Cerasaro et aI., 1986). Avellan found only 1% renal anomalies in his
Swedish patients with hypospadias, whereas he found 7% of patients with other
systems involved (Avellan, 1975). In a review of 169 patients, Shelton and Noe
do not recommend routine urinary tract evaluation (Shelton and Noe, 1985).
Khuri and co-workers reviewed 1076 patients. Urinary tract anomalies
considered to be significant were ureteropelvic junction obstruction, severe
reflux, renal agenesis, Wilms' tumor, pelvic kidney, crossed renal ectopia, and
horseshoe kidney. They conclude that patients with hypospadias and an
associated inguinal hernia or undescended testis need not have further urinary
tract evaluation. However, patients who have hypospadias in association with
other organ system anomalies should undergo an upper urinary tract screening
with an abdominal ultrasound.
Henderson and associates (1976) studied urogenital abnormalities in 500
sons of women treated with diethylstilbestrol (DES). He found 2% had
hypospadias, and 4.4% had abnormalities of the penile urethra (Goldman, 1977).
Gupta and Goldman (1986) implicated metabolic disturbances of the
arachidonic acid cascade in midline fusion defects, such as cleft palate and
hypospadias (Gupta and Goldman, 1986). Hypospadias occurs in association
with a number of well-known syndromes as well as with Wilms' tumor.

6. Etiology of Hypospadias

Reports of increasing incidences of hypospadias have raised questions

concerning etiology, treatment, and prevention. To date there is no sound
understanding of the etiology of hypospadias that can inform primary prevention
efforts and improve therapeutics. For example, in a recent study, 33 patients
with severe (scrotal or penoscrotal) hypospadias were evaluated with a range of
diagnostic techniques including clinical assessment, ultrasonography,
Hypospadias 11

karyotyping, endocrine evaluation, and molecular genetic analysis of the AR

gene and the Sa-reductase gene to classify and determine the cause of the
hypospadias. In 12 patients, diagnoses were determined. The remaining 64% of
patients were classified as hypospadias of unknown etiology (Albers et a\.,
1997). Other investigators have also attempted to link abnormalities in androgen
metobolism and/or receptor to hypospadias. For example, Gearheart and
associates could not find any deficiencies in either androgen receptor levels or 5-
_ reductase in their study of preputial skin from hypospadias boys (Gearhart et
aI., 1988). Allera et al. analyzed 9 patients with severe hypospadias and found a
defect in open-reading frame of the androgen receptor in only one patient
(Allera et aI., 1995). Sutherland et al. also concluded that the mutations in the
androgen receptor gene are rarely associated with hypospadias (Sutherland et a\.,
1996). Using single strand conformational polymorphism analysis they found a
missense mutation of exon 2 of the androgen receptor gene in 1 of 40 patients
with distal hypospadias. Molecular biology techniques have demonstrated that
defects in the androgen receptor gene are definitely associated with isolated
hypospadias. However, the frequency of these genetic defects accounts for an
extremely small subset of cases implying that other factors are responsible for
hypospadias.

7. Genetic Impairment

Uncertainty about the etiology of hypospadias is in part a reflection of the

complicated and incompletely understood molecular and cellular basis for
normal phallus and urethral development (Wilson et aI., 1981). It is well
established that the urethral folds fuse during the formation of the penile urethra
in the seventh to twelfth week after' ovulation. Fusion of the folds eventually
leads to a fully formed penis that is dependent on the synthesis of testosterone
by the fetal testis. Adequate virilization of the urogenital sinus and external
genitalia during embryogenesis is dependent on the conversion of testosterone to
DHT by Sa-reductase. Genetic defects anywhere along this pathway can
interfere with proper fusion of the urethral folds and result in hypospadias
(Aaronson et aI., 1997).
Increasingly, researchers art: examining the role of cellular signals other
than testosterone and DHT in the morphogenesis of the phallus and the etiology
of hypospadias. Normal embryogenesis of the urogenital system depends on
epithelial-mesenchymal interactions and it has been hypothesized that aberrant
signaling between epithelium and mesenchyme could lead to hypospadias
(Kurzrock et a\., 1999). For example, prostate development requires
"testosterone-dependent Sonic hedgehog (Shh) expression in the epithelium of
the urogenital sinus" (Podlasek et aI., 1999). It is likely that researchers may find
similar genetic, signaling molecules involved in epithelial-mesenchymal
interactions in the phallus that playa role in its development.
Another area of investigation with respect to the etiology of hypospadias is
the expression and regulation of homeobox (Hox) genes. These genes are
transcriptional regulators that play an essential role in directing embryonic
development. Genes of the Hox A and Hox D clusters are expressed in
12 Baskin

regionalized domains along the axis of the urogenital tract. Transgenic mice
with loss of function of single Hox A or Hox D genes exhibit homeotic
transformations and impaired morphogenesis of the urogenital tract (Dolle et aI.,
1991; Benson et aI., 1996; Hsieh-Li et aI., 1995; Podlasek et aI., 1997). Human
males with hand-foot-genital (HFG) syndrome, an autosomal dominant disorder
characterized by a mutation in HOXA13, exhibit hypospadias of variable
severity, suggesting that HOXA13 may be important in the normal patterning of
the penis (Mortlock and Innis, 1997; Donnenfeld et aI., 1992; Fryns et aI., 1993).
Furthermore, recent research has shown that the embryonic expression of certain
Hox genes is regulated by hormonal factors (Ma et aI., 1998). Estrogen and the
'synthetic estrogen diethylstilbestrol (DES) for example, inhibit Hoxa-9, Hoxa-
10, Hoxa-ll, and Hoxa-13 genes in mice. Thus, in addition to defects in Hox
genes, it is possible that improper regulation or expression of hormonal factors
during embryogenesis could disrupt normal expression of Hox genes and lead to
reproductive tract anomalies.

8. Hormone Receptor Impairment

As noted above, studies examining the androgen receptor (AR) have yielded
even less insight into the etiology of hypospadias. In fact, a number of studies
have concluded that defects in the androgen receptor or mutations in the
androgen receptor coding sequence are rare in patients with hypospadias
(McPhaul et aI., 1993; Hiort et aI., 1994). In addition, Bentvelsen et at. measured
AR expression in the foreskins of boys with hypospadias and age-matched
controls and found no significant difference in mean AR content (Bentvelsen et
aI., 1995). However, Bentvelsen et al. did not measure the mean AR content in
the foreskin during gestational development.

9. Enzyme Impairment

Despite the central role that testosterone plays, attempts to ascribe all
hypospadias to an underlying genetic defect in this pathway have been only
partly successful. Aaronson et al. determined the incidence of defects in three
major enzymes in the biosynthetic pathway of testosterone-3~-hydroxysteroid
dehydrogenase, 17a-hydroxylase, and 17,20-lyase-in 30 boys with fully
descended testes but with penoscrotal or proximal shaft hypospadias (Aaronson
et aI., 1997). A total of 15 boys had evidence of impaired function of one or
more of these enzymes suggesting that half the boys had an underlying defect in
the biosynthesis of testosterone. This still left 50% of the cases unexplained
(Aaronson et aI., 1997).

10. Environmental Factors and Endocrine Disruptors

In the past, environmental factors were generally ruled out as causes for
hypospadias (Harris, 1990; Stoll et aI., 1990). More recently, multi-causality
models include environmental contaminants to determine the risk of developing
Hypospadias 13

a given phenotype. For example, familial clustering of hypospadias among first-

degree relatives has been perceived as under the influence of a strong genetic
and heritable component, but there have been many exceptions where genetics
were ruled out. More recently it has been suggested that environmental
influences should be considered as well, taking into consideration that families
share similar exposure. And, especially, in those cases where the effects are the
most profound, genetic predisposition exacerbated by environmental exposure
should be considered (Fritz and Czeizel, 1996).
Attempts to determine risk factors for hypospadias have yielded a number of
maternal and paternal risk factors. Among traditional studies of maternal risk
factors for congenital anomalies, maternal age and primiparity are significantly
associated with hypospadias, although some studies have contested the maternal
age effect (Harris, 1990). Paternal risk factors associated with hypospadias
include abnormalities of the fathers' scrotum or testes (Sweet et aI., 1974) and
low spermatozoa motility and abnormal sperm morphology (Fritz and Czeizel,
1996). It has been suggested that the recent increase in hypospadias reflects the
improvement in fertility treatment, contributing to more subfertile men fathering
children. As the authors state, this " .. relaxed-selection hypothesis, which states
that there is a redistribution in the number of children born to fertile and infertile
(subfertile) couples, may account for the increasing number of other defects and
cancers of male genitalia observed today and the fall in sperm counts" (Fritz and
Czeizel, 1996).
In addition to parental risk factors there is strong consensus in the literature
that boys with hypospadias have lower birth weight (Fredell et aI., 1998).
Fredell et al. examined hypospadias in discordant monozygotic twins and found
that the twin with hypospadias weighed 78% of the twin without hypospadias.
The birth weight difference was still significant when compared with birth
weight difference between healthy monozygotic twins. Another study found that
boys with hypospadias have a lower placental weight than control boys (Stoll et
aI., 1990). A 1995 meta-analysis of first trimester exposure to progestins and
oral contraceptives, did not indicate an increased risk of hypospadias (Raman-
Wilms et aI., 1995). Exposure to DES was excluded in this study. However, a
number of studies do list gestational exposure to progestins as a causal agent.
Another recent study links a maternal vegetarian diet in pregnancy with an
increase in the incidence of hypospadias (North and Golding, 2000). This study
looked at 51 boys with hypospadias from a group of 7928 boys born to mothers
taking part in the Avon Longitudinal Study of Pregnancy and Childhood. The
authors hypothesize that vegetarians have a greater exposure to phytoestrogens
than omnivores. The phytoestrogens may come in the from of soya which is
high in isoflavones or related to endocrine disrupters in pesticides and fertilizers
(Price and Fenwick, 1985).
While these risk factors do not reveal direct infonnation about the etiology
of hypospadias, they provide additional information that may reveal a common
developmental pathway and can inform future research. For example, there is
growing evidence that androgens playa central role in the lower birth weight of
girls compared to boys (de Zegher et aI., 1998). Androgens are also crucial to
14 Baskin

the development of the male reproductive tract. Thus, perhaps exposure to an

agent that compromises the weight-gaining advantage of androgen during
gestation could playa role in the development of hypospadias and lowered birth
weight.
Increasing rates of hypospadias have paralleled reports of other untoward
endpoints related to male reproductive health, including increases in testicular
cancer, (Bergstrom et aI., 1996) increasing incidences of cryptorchidism, and
decreasing semen and sperm quality.[54] In another study, 8% of patients
diagnosed (n = 252) with undescended testes had urogenital anomalies and over
50% of those had hypospadias (Cheng et aI., 1996). The increasing incidence
over the past 50 years of multiple endpoints co-occurring with increasing
production and use of synthetic chemicals has raised concerns that
environmental factors may playa role in the etiology of these problems (Toppari
et aI., 1996). It is now well documented from wildlife studies and accompanying
laboratory data, that a number of synthetic and natural chemicals commonly
found in the environment can mimic or antagonize hormones or otherwise

A
.. \.

Figure 5A-D. Normal Human fetal penis. 25 weeks. A-H Transverse sections distal to proximal
immunostained with neuronal marker S-IOO (25X). Note localization of S-I00 nerve marker in
brown completely surrounding the cavernous bodies up to the junction with the urethral spongiosum
along the penile shaft except at the 12 o'clock position (A-D).
Hypospadias 15

Figure 5E-H. On the proximal penis at the point where the corporal bodies split into two (E) and
continue in a lateral fashion inferior an adjacent to the pubic rami the nerves localize to an imaginary
triangular area at the II and I o'clock position. At this point (E) the nerves reach there furthest
vertical distance from the corporeal body (- one half the diameter of the corporeal body) and
continue (F-G) in a tighter formation at the II and I o'clock position well away from the urethra.
16 Baskin

Figure 6.
Normal Human fetal penis, 25 weeks' gestation
Four views of a computer-generated three-dimensional reconstruction (A, Side; B, Front; C, Side; D,
Back E, Front (without urethral); F, Side (without urethral». Note the nerves in red and their
absence at the 12 o'clock position. The tunica is represented in blue, the urethral lumen in yellow
and the urethral spongiosum and prepuce in lime.

interfere with the development and function of the endocrine and reprvductive
systems (Rolland et a!., 1995; Colborn et a!., 1999). Whether endocrine
disruptors are having an impact on male reproductive health and on hypospadias
in particular, is difficult to determine (Shakkebaek et aI., 1998). Regardless,
public health agencies world-wide are increasingly concerned about endocrine
disruption and it remains an active area of research (Jensen, 1998; Groshart et
aI., 1999; EPA, 1998; Baskin et aI., 2001).

11. Penile Anatomy

Surgical repair of hypospadias requires an expert understanding of the

normal anatomy of the penis, as well as an understanding of the anatomy of the
hypospadiac penis. The human penis consists of paired corpora cavernosa
covered by a thick, elastic tunica albuginea, with a midline septum (Figure 5)
(Hinman, 1993).
The urethral spongiosum lies in a ventral position, intimately engaged between
the two corporal bodies. Buck's fascia surrounds the corporal cavernosa and
splits to contain the corpus spongiosum in a separate compartment. Recent
work has shown that the neurovascular bundle lies deep to Buck's fascia and
where the two crural bodies join to form the corporal bodies, the neurovascular
bundle completely fans out around the corporal cavernosa, all the way to the
junction of the corporal spongiosum (Figure 5 and 6).
Hypospadias 17

Figure 7.
Hypospadiac Penis, 33 weeks' gestation A-H Transverse sections distal to proximal irnrnunostained
with neuronal marker S-l ()() (20X). Note the anatomy of the hypospadias penis is the same as the
normal penis except for the abnormal formation of the distal urethra and glans (A-C). The nerves
are black staining in Figures A-D and brown staining in E and F.
18 Baskin

(Baskin et aI., 1997). This concept disagrees with the classic dogma that the
neurovascular bundle lies in the 11 and 1 o'clock position. Superior to Buck's
fascia is the dartos fascia which lies immediately beneath the skin. This fascia
contains the blood supply to the prepuce. The prepuce is supplied by two
branches of the inferior external pudendal arteries, the superficial penile arteries
(Hinman, 1991). These arteries divide into the anterolateral and posterolateral
branches. The island flap is typically based on the anterolateral superficial
vessels. The onlay island flap and tubularized island flap are dependent on
careful preservation of these blood vessels. In hypospadias surgery, the outer
skin survives from remaining subcutaneous vessels.

12. Neuro and Vascular Anatomy of Hypospadias

The normal anatomy of the penis is to be compared to the anatomy of the·

hypospadiac penis (Figure 7)
(Baskin et aI., 1998). Except at the region of the abnormal urethral spongiosum
and glans, the hypospadiac and normal penises show no difference in neuronal
innervation, corporal cavernosa and tunica albuginea architecture and blood
supply. The nerves in both the normal and hypospadiac penises start as two
well-defined bundles superior and slightly lateral to the urethra. As the two
crural bodies converge into the corporal cavernosal bodies, the nerves diverge
spreading around the cavernosal bodies up to the junction with the urethral
spongiosum, not limiting themselves to the 11 and 1 o'clock position (Figure 7
and 8). The 12 o'clock position in the hypospadiac penis is spared of any
neuronal structures just as in a normal penis. The most striking difference
between the normal penis and the hypospadiac penis is a difference in
vascularity (Figure 7). The hypospadiac penis has huge endothelial-lined
vascular channels filled with red blood cells. In contrast, the normal penis has
well defined, small capillaries around the urethra, fanning into the glans.
Anatomical studies of the urethral plate do not show any evidence of fibrosis
or scarring (Erol et aI., 2000). The urethral plate is well vascularized, has a rich
nerve supply and an extensive muscular and connective tissue backing (Figure
9). These features may explain the successful use of incorporating the urethral
plate into hypospadias reconstruction.

13. Surgical Techniques

The goal of hypospadias surgery is to correct the penile curvature, reposition

the meatus to allow for intercourse and proper delivery of semen and to
reconstruct a forward directed stream. Each hypospadiac penis is different and
therefore one operation will not solve all the reconstructive problems. When
planning hypospadias surgery, the issues at hand are reconstruction of a new
urethra, correction of penile curvature, creation of a new meatus, skin coverage,
and finally correction of any penile scrotal transposition and/or bifid scrotum.
Hypospadias 19

Figure 8.
Hypospadiac Penis, 33 weeks' gestation Four views of a computer-generated three-dimensional
reconstruction. (A, Side; B, Back; C, Front; D, Side). Note the nerves in red and their absence at the
12 o'clock position. The tunica of the corporal bodies is represented in blue in A and B and blue and
yellow in C and D, the urethral lumen in orange and the urethral spongiosum in lime. The
hypospadiac penis has the same innervation and anatomy as the normal penis except the abnormal
urethral spongiosum.

Figure 9.
The urethral plate in a newborn human penis with proximal hypospadias, (25x, a-actin
immunostaining) The urethral plate is well vascularized, without any evidence of fibrosis or
scarring. Glans or the abortive attempt at the formation of the urethra are seen within the plate (see
insert).
20 Baskin

These issues must be assessed prior to surgery, but flexibility needs to be

maintained in that the quality of the hypospadiac urethra may be difficult to
assess until the patient is under anesthesia. An anterior hypospadias may
therefore turn into a proximal hypospadias, especially after the correction of
penile curvature and resection of abortive or inadequate urethral tissue. A
surgeon's approach to hypospadias depends on his personal preference, skill and
experience. The father of modern hypospadias surgery, Dr. John W. Duckett,
coined the term "hypospadiology" building his knowledge and technique on an
extensive familiarity with those who have come before him. The reader is
refered to multiple chapters and articles on specific surgical techniques (Baskin,
2001; Baskin et aI., 1996; Duckett and Baskin, 1996; Snodgrass et aI., 1996;
Baskin and Duckett, 1998).

REFERENCES

Aaronson, LA., Cakmak, M.A. and Key, L.L., 1997,.Defects of the testosterone biosynthetic
pathway in boys with hypospadias, JUral. 157(5): p. 1884-8.
Albers, N., et aI., 1997, Etiologic classification of severe hypospadias: implications for prognosis
and management [see comments]. J Pediatr. 131(3): p. 386-92.
Allera, A., et aI., 1995, Mutations of the androgen receptor coding sequence are infrequent in
patients with isolated hypospadias, J Clin Endacrinal Metab. 80(9): p. 2697-9.
Avellan, L., 1975, The incidence of hypospadias in Sweden, Scand J Pfast Reconstr Surg. 9: p. 129-
138.
Baskin, L.S., Duckett, 1.W. and Lue, T.F., 1996, Penile curvature, Urology. 48(3): p. 347-56.
Baskin, L.S., Lee, Y.T. and Cunha, G.R., 1997, Neuroanatomical ontogeny of the human fetal penis,
Br J Urol. 79(4): p. 628-40.
Baskin, L. and Duckett, J., 1998, Hypospadias: Long-Term Outcomes, in Pediatric Surgery and
Urology: Long-Term Outcome, M. Pierre D.E. Mouriquand, Editor. W.B. Saunders: London.
p.559-567.
Baskin, L.S., et aI., 1998, Anatomical studies of hypospadias. J Urol. 160(3 Pt 2): p. 1108-15;
discussion 1137.
Baskin, L.S., Colborn, T. and Himes, K., 2001, Hypospadias and endocrine disruption: is there a
connection? Environmental Health Perspectives. 109: p. 1175-1183.
Baskin, L.S., et aI., 2001, Urethral Seam Formation and Hypospadias, Cell Tissue Res. 305: p. 379-
387.
Baskin, L.S., 2001, in press., Hypospadias: a critical analysis of cosmetic outcomes using
photography, British Journal ofUrology.
Benson, G.V., et aI., 1996, Mechanisms of reduced fertility in Hoxa-IO mutant mice: uterine
homeosis and loss of matemal Hoxa-IO expression, Development. 122(9): p. 2687-96.
Bentvelsen, F.M., et aI., 1995, Decreased immunoreactive androgen receptor levels are not the cause
of isolated hypospadias. Br J Urol. 76(3): p. 384-8.
Bergstrom, R., et aI., 1996, Increase in testicular cancer incidence in six European countries: a birth
cohort phenomenon, J Natl Cancer [nst. 88(11): p. 727-33.
Carlsen, E., et aI., 1995, Declining semen quality and increasing incidence of testicular cancer: is
there a common cause? Environ Health Perspect. 103 Suppl 7: p. 137-9.
Cerasaro, T.S., Brock, W.A. and Kaplan, G.W., 1986, Upper urinary tract anomalies associated with
congenital hypospadias: is screening necessary? JUral. 135(3): p. 537-8.
Cheng, W., Mya, G.H. and Saing, H., 1996, Associated anomalies in patients with undescended
testes, J Trop Pediatr. 42(4): p. 204-6.
Hypospadias 21

Colborn, T., Short, P. and Gilbertson, M., 1999, Health effects of contemporary-use pesticides: The
wildlife/human connection, in Toxicology and Industrial Health.
Conte, F. and Grumbach, M., 1995, Pathogen isis, classification, diagnosis and treatment of
anomalies of sex, in Endocrinology. DeGroot, Editor. Saunders.
Devine, C., et al., 1980, Utricular configuration in hypospadias and intersex, J Urol. 123: p. 407-
411.
de Zegher, F., et aI., 1998, Androgens and fetal growth, Horm Res. 50(4): p. 243-4.
Dolle, P., et aI., 1991, HOX-4 genes and the morphogenesis of mammalian genitalia. Genes Dev.
5(10): p. 1767-7.
Donnenfeld, A.E., Schrager, D.S. and Corson, S.L., 1992, Update on a family with hand-foot-genital
syndrome: hypospadias and urinary tract abnormalities in two boys from the fourth generation,
Am J Med Genet. 44(4): p. 482-4.
Duckett, J. and Baskin, L., 1996, Hypospadias, in Adult and Pediatric Urology, J. Gillenwater, et
aI., Editors. Mosby: St. Louis.
EPA, 1998, Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC). Final
Report. United States Environemental Protection Agency.
Erol, A., et aI., 2000, Anatomical studies of the urethral plate: why preservation of the urethral plate
is important in hypospadias repair, BJU Int. 85(6): p. 728-34.
Fredell, L., et aI., 1998, Hypospadias is related to birth weight in discordant monozygotic twins, J
Urol. 160(6 Pt I): p. 2197-9.
Fritz, G. and Czeizel, A.E., 1996, Abnormal sperm morphology and function in the fathers of
hypospadiacs, J Reprod Ferti/. 106(1): p. 63-6.
Fryns, J.P., et aI., 1993, The hand-foot-genital syndrome: on the variable expression in affected
males, C/in Genet. 43(5): p. 232-4.
Gearhart, J.P., et aI., 1988, Androgen receptor levels and 5 alpha-reductase activities in preputial
skin and chordee tissue of boys with isolated hypospadias, J Urol. 140: p. 1243-6.
Glenister, T., 1954, The origin and fate of the urethral plate in man, J Anat. 288: p. 413-418.
Griffin, J., et aI., 1995, The Androgen Resistance Sydromes: Steroid 5 alpha-Reductase Deficiency,
Testicular Feminization and Related Disorders, in The Metabolic and Molecular Bases of
Inherited Disease., C. Scriver, Editor., McGraw-Hill,: Philadelphia. p. 2967-2998.
Goldman, A., 1977, Abnormal organogenesis in the reproductive system, in Handbook of
Teratology, J. Wilson and F. Fraser, Editors., Plenum Press: New York. p. 391-419.
Groshart, C., Okkerman, P. and Folkers, G., 1999, Report to the European Commission:
Identification of Endocrine Disruptors, First Draft Interim Report, Delft, The Netherlands:
BKH Consulting Engineers.
Gupta, C. and Goldman, A., 1986, Arachidonic acid cascade is involved in the masculinization of
embryonic external genitalia in mice, Proc Natl Acad Sci. 83: p. 4346-4349.
Harris, E.L., 1990, Genetic epidemiology of hypospadias, Epidemiol Rev. 12(29): p. 29-40.
Hinman, F., Jr., 1991, The blood supply to preputial island flaps, J Urol. 145(6): p. 1232-5.
Hinman, FJ., 1993, Penis and male urethra, in UroSurgical Anatomy, FJ. Hinman, Editor. WB
Saunders Co.: Philadelphia. p. 418-470.
Hiort, 0., et aI., 1994, Molecular characterization of the androgen receptor gene in boys with
hypospadias, Eur J Pediatr. 153(5): p. 317-21.
Hsieh-Li, H.M., et aI., 1995, Hoxa II structure, extensive antisense transcription, and function in
male and female fertility, Development. 121(5): p. 1373-85.
Jensen, K., 1998, European Parliament's Committee on the Environment, Public Health and
Consumer Protection. Report on Endocrine Disrupting Chemicals. Rapporteur.
Jirasek, J., Raboch, J. and Uher, J., 1968, The relationship between the development of gonads and
external genitals in human fetuses, Am J Obstet Gynecol. 101: p. 830.
Kelce, W.R. and Wilson, E.M., 1997, Environmental antiandrogens: developmental effects,
molecular mechanisms, and clinical implications. J Mol Med. 75(3): p. 198-207.
Khuri, F., Hardy, B. and Churchill, 8., 1981, Urologic anomalies associated with hypospadias, Urol
C/in North Am. 8: p. 565-571.
Kurzrock, E., Baskin, L. and Cunha, G., 1999, Ontogeny of the Male Urethra: Theory of endodermal
differentiation, Dijferentation. 64: p. 115-122.
Kurzrock, E., et al., 1999, Epithelial-mesenchymal interactions in development of the mouse fetal
genital tubercle, Cells Tissues and Organs. 164: p. 1015-1020.
22 Baskin

Ma, L., et aI., 1998, Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and
progesterone and repression in mullerian duct by the synthetic estrogen diethylstilbestrol
(DES). Dev Bioi. 197(2): p. 141-54.
McArdle, F. and Lebowitz, R., 1975, Uncomplicated hypospadias and anomalies of upper urinary
tract. Need for screening? Urology. 5: p. 712-716.
McPhaul, MJ., et aI., 1993, Genetic basis of endocrine disease. 4. The spectrum of mutations in the
androgen receptor gene that causes androgen resistance, J C/in Em/ocrinol Metab. 76(1): p.17-
23.
Mortlock, D.P. and Innis, J.W., 1997, Mutation of HOXAI3 in hand-foot-genital syndrome [see
comments], Nat Genet. 15(2): p. 179-80.
North, K. and Golding, J. 2000, A maternal vegetarian diet in pregnancy is associated with
hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and
Childhood. BJU Int. 85(1): p. 107-13.
Paulozzi, L., Erickson, D. and Jackson, R., 1997, Hypospadias Trends in Two US Surveillance
Systems, Pediatrics. 100(5): p. 831-834.
Paulozzi, LJ., 1999, International trends in rates of hypospadias and cryptorchidism, Environ Health
Perspect. 107(4): p. 297-302.
Podlasek, C.A., Duboule, D. and Bushman, W., 1997, Male accessory sex organ morphogenesis is
altered by loss of function of Hoxd-13, Dev Dyn. 208(4): p. 454-65.
Podlasek, C.A., et aI., 1999, Prostate development requires Sonic hedgehog expressed by the
urogenital sinus epithelium, Dev Bioi. 209(1): p. 28-39.
Price, K. and Fenwick, G., 1985, Naturally occuring oestrogens in foods- a review, Food Add
Contam,. 2: p. 73-106.
Raman-Wilms, L., et aI., 1995, Fetal genital effects of first-trimester sex hormone exposure: a meta-
analysis, Obstet Gynecol. 85(1): p. 141-9.
Ritchey, M.L., et aI., 1988, Management of mullerian duct remnants in the male patient, J Urol.
140(4): p. 795-9.
Rogers, B., 1973, History of external genital surgery, in Plastic and Reconstructive Surgery of the
Genital Area, C. Horton, Editor., Little, Brown & Co. Boston. p. 3-47.
Rolland, R., Gilbertson, M. and Colborn, T., 1995, Environmentally induced alternations in
development: A focus on wildlife, Environ Health Perspect. 103(suppI4).
Ross, F., Farmer, A. and. Lindsay, W., 1959, Hypospadias--a review of230 cases, Plast Reconstr
Surg. 24: p. 357-368.
Shelton, T.B. and Noe, H.N., 1985, The role of excretory urography in patients with hypospadias, J
Urol. 134(1): p. 97-9.
Shima, H., et aI., 1979, Developmental anomalies associated with hypospadias, J Urol. 122: p. 619-
621.
Skakkebaek, N.E., et aI., 1998, Germ cell cancer and disorders of spermatogenesis: an environmental
connection? Apmis. 106(1): p. 3-11; discussion 12.
Snodgrass, W., et aI., 1996, Tubularized incised plate hypospadias repair: results of a multicenter
experience, J Urol. 156(2 Pt 2): p. 839-41.
Stoll, C., et aI., 1990, Genetic and environmental factors in hypospadias, J Med Genet. 27(9): p. 559-
63.
Sutherland, R. W., et aI., 1996, Androgen receptor gene mutations are rarely associated with isolated
penile hypospadias, J Urol. 156(2 Pt 2): p. 828-31.
Sweet, R., et al., 1974, Study of the incidence of hypospadias in Rochester, Minnesota 1940-1970,
and a case-control comparison of possible etiologic factors, Mayo C/in Proc. 49: p. 52-58.
Toppari, J., et aI., 1996, Male reproductive health and environmental xenoestrogens [see comments],
Environ Health Perspect. 104 Suppl4: p. 741-803.
Van der Meulen, J., 1964, in Hypospadias Monograph .. Leiden, The Netherlands: AG Stenfert,
Kroese, NY.
Wilson, J.D., George, F.W. and Griffin, J.E., 1981, The hormonal control of sexual development,
Science. 211(4488): p. 1278-84.
Wilson, J.D., Griffin, J.E. and Russell, DW., 1993, Steroid 5 alpha-reductase 2 deficiency, Em/ocr
Rev. 14(5): p. 577-93.