Hypospadias

Updated: May 15, 2017

Author: John M Gatti, MD; Chief Editor: Marc Cendron, MD more...

OVERVIEW

Background
Hypospadias is an abnormality of anterior urethral and penile development in which the
urethral opening is ectopically located on the ventral aspect of the penis proximal to the
tip of the glans penis, which, in this condition, is splayed open. [1] The urethral opening
may be located as far down as in the scrotum or perineum. The penis is more likely to
have associated ventral shortening and curvature, called chordee, with more proximal
urethral defects.

The earliest medical text describing hypospadias dates back to the second century CE
and was the work of Galen, the first to use the term. During the first millennium, the
primary treatment for hypospadias was amputation of the penis distal to the meatus.
Since that time, many have contributed to development of modern hypospadias repair.
More than 300 different types of repairs have been described in the medical literature.
Although most reports have been in the past 60 years, most basic techniques were
described more than a century ago.

Modern anesthetic techniques, fine instrumentation, sutures, dressing materials, and

antibiotics have improved clinical outcomes and have, in most cases, allowed surgical
treatment with a single-stage repair within the first year of life on an outpatient basis.

Pathophysiology
Hypospadias is a congenital defect that is thought to occur embryologically during
urethral development, between 8 and 20 weeks' gestation. The external genital structures
are identical in males and females until 8 weeks' gestation; the genitals develop a
masculine phenotype in males primarily under the influence of testosterone. As the
phallus grows, the open urethral groove extends from its base to the level of the corona.

The classic theory is that the urethral folds coalesce in the midline from base to tip,
forming a tubularized penile urethra and median scrotal raphe. This accounts for the
posterior and middle urethra. The anterior or glanular urethra is thought to develop in a
proximal direction, with an ectodermal core forming at the tip of the glans penis, which
canalizes to join with the more proximal urethra at the level of the corona. The higher
incidence of subcoronal hypospadias supports the vulnerable final step in this theory of
development.

In 2000, Baskin proposed a modification of this theory in which the urethral folds fuse to
form a seam of epithelium, which is then transformed into mesenchyme and
subsequently canalizes by apoptosis or programmed cell resorption. [2] Similarly, this
seam theoretically also develops at the glanular level, and the endoderm differentiates to
ectoderm with subsequent canalization by apoptosis.

The prepuce normally forms as a ridge of skin from the corona that grows
circumferentially, fusing with the glans. Failure of fusion of the urethral folds in
hypospadias impedes this process, and a dorsal hooded prepuce results. On rare
occasions, a glanular cleft with intact prepuce may occur, which is termed the
megameatus intact prepuce (MIP) variant.

Chordee (ventral curvature of the penis) is often associated with hypospadias, especially
more severe forms. This is thought to result from a growth disparity between the normal
dorsal tissue of the corporal bodies and the attenuated ventral urethra and associated
tissues. Rarely, the abortive spongiosal tissue and fascia distal to the urethral meatus
forms a tethering fibrous band that contributes to the chordee. (See the image below.)

Severe penile chordee. Note extreme ventral curvature of penile shaft.

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The location of the abnormal urethral meatus classifies the hypospadias. Although
several different classifications have been described, most physicians use the one
proposed by Barcat and modified by Duckett, which describes the location of the meatus
after correction of any associated chordee. [3, 4] Descriptive locations described include
the following:

Anterior (glanular and subcoronal)

Middle (distal penile, midshaft, and proximal penile)
Posterior (penoscrotal, scrotal, and perineal)

The location is anterior in 50% of cases, middle in 20%, and posterior in 30%; the
subcoronal position is the most common overall. (See the images below.)
Proximal shaft hypospadias. Note deficient ventral foreskin, blind urethral pit at glanular level, and
lighter pigmented urethral plate extending to true meatus at proximal shaft level.
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Proximal shaft hypospadias. Note typical dorsal hood of foreskin and ventral penile skin deficiency.
View Media Gallery
Penoscrotal hypospadias. Note associated ventral chordee and true urethral meatus located at
scrotal level.
View Media Gallery

Etiology
Several etiologies for hypospadias have been suggested, including genetic, endocrine,
and environmental factors.

Genetic factors

A genetic predisposition has been suggested by the eightfold increase in incidence of

hypospadias among monozygotic twins as compared with singletons. This finding may
relate to the demand of two fetuses for human chorionic gonadotropin (HCG) produced
by a single placenta, with an inadequate supply during critical periods of urethral
development.

A familial trend has been noted with hypospadias. The prevalence of hypospadias in
male children of fathers with hypospadias has been reported as 8%, and 14% of brothers
of children with hypospadias are also affected. The inheritance is likely polygenic.

Endocrine factors

A decrease in available androgen or an inability to use available androgen appropriately

may result in hypospadias. In a 1997 report by Aaronson et al, 66% of boys with mild
hypospadias and 40% with severe hypospadias were found to have a defect in testicular
testosterone biosynthesis. [5]

Mutations in the 5-alpha reductase enzyme, which converts testosterone (T) to the more
potent dihydrotestosterone (DHT), have been associated with hypospadias. A 1999
report by Silver et al found that nearly 10% of boys with isolated hypospadias had at least
one affected allele with a 5-alpha reductase mutation. [6] Although androgen receptor
deficits, quantitative or qualitative, have been shown to result in hypospadias, this is
thought to be relatively uncommon, and other factors are more commonly implicated.

A higher incidence of hypospadias in winter conceptions has also been proposed.

Theoretically, this may be related to the effect of daylight on pituitary function, which, in
turn, affects the maternal and fetal hormonal milieu; however, other authors have not
noticed this association.

A fivefold increased risk of hypospadias appears to exist in males born through in-vitro
fertilization (IVF) in comparison with a control group. This may reflect maternal exposure
to progesterone, which is commonly administered in IVF protocols. Progesterone is a
substrate for 5-alpha reductase and acts as a competitive inhibitor of the T-to-DHT
conversion.

Other factors that contribute to infertility, such as underlying endocrinopathies or fetal

endocrine abnormalities, may play a role.
Environmental factors

Endocrine disruption by environmental agents is gaining popularity as a possible etiology

for hypospadias and as an explanation for its increasing incidence.

Estrogens have been implicated in abnormal penile development in many animal models.
Environmental substances with significant estrogenic activity are ubiquitous in
industrialized society and are ingested as pesticides on fruits and vegetables,
endogenous plant estrogens, in milk from lactating pregnant dairy cows, from plastic
linings in metal cans, and in pharmaceuticals.

A study by Hadziselimovic reported increased estradiol concentration in placental basal

syncytiotrophoblasts of boys with undescended testes as compared with a control
population. [7] Undescended testes and hypospadias have been associated, but
increased estradiol concentration has not been implicated in hypospadias per se. This
may support the association of hypospadias with increasing parity, increasing maternal
age, and low birth weight noted in some studies in relation to lifelong exposure to
environmental disruptors and a possible cumulative effect.

Combination theory

A growing body of evidence suggests that the development of hypospadias has a two-hit
etiology involving a genetic predisposition coupled with fetal exposure to an
environmental disruptor. [8, 9]

Epidemiology
United States statistics

Hypospadias occurs in approximately 1 in every 250 male births in the United States.
The incidence doubled from 1970 to 1993. Although some have suggested that this
doubling actually reflects increased reporting of minor grades of hypospadias, increases
in severe hypospadias have also been noted. Increasing sensitivity of surveillance
systems alone cannot explain this twofold increase. However, some reports have linked
the increased rate of hypospadias in boys born prematurely and small for gestational age
and boys with low birth weight.

International statistics

In several countries, the incidence of hypospadias may be rising. In general, the

frequency seems rather constant, at 0.26 per 1000 live births in Mexico and Scandinavia
and 2.11 per 1000 live births in Hungary. [10]

Race-related demographics

The incidence of hypospadias is higher in whites than in blacks, and the condition is
more common in those of Jewish and Italian descent. A genetic component may be
present in certain families; the familial rate of hypospadias is about 7%.
Prognosis
With modern anesthetics, instruments, sutures, dressing materials, and antibiotics,
hypospadias repair has become quite successful. Long-term studies on the outcomes of
hypospadias using current practices are limited. Although some earlier studies have been
discouraging, these reflect an era with poorer technical outcomes, increased number of
operations, and a lack of appreciation for the psychological morbidity associated with
intervention at an older age.

Subsequent long-term studies have suggested that despite having decreased satisfaction
with their genital appearance, patients having undergone hypospadias repair are more
satisfied with their sex lives compared to healthy controls. [11] Newer scoring systems to
lend an objective measure to long-term outcomes are becoming more popular. [12, 13]

Although the techniques of hypospadias repair continue to evolve, the broader future of
hypospadias treatment is truly promising. Nontraditional tissue adherence techniques are
being developed, including tissue glues and laser-activated soldering techniques that
have been shown to improve wound healing and to reduce fistula formation.

Urethral substitutes, which may obviate the difficulties associated with severe
hypospadias and poor tissue availability, are currently under investigation. These
substitutes are generally acellular synthetic or natural matrices that can incorporate the
patient's normal urethral cellular components.

The embryology of hypospadias is being elucidated, and the understanding of its causes
is improving; with new information, an exciting new paradigm shift to hypospadias
prevention or antenatal intervention may occur.

Patient Education
Because most patients with hypospadias are surgically treated at a very young age,
parental teaching and reassurance is very important to ensure a satisfactory experience
for the families of these patients . Evidence suggests that online support groups can play
an important role in how parents and patients cope with hypospadias. [14]

Clinical Presentation