ANATOMY, EMBRYOLOGY, AND RECONSTRUCTIVE TECHNIQUES
LAURENCE S. BASKIN
Urology, University of California, San Francisco, California, USA
is one of the most common congenital anomalies that can be treated with
surgical reconstruction. The etiology in the majority of cases of hypospadias
remains elusive. Androgens are clearly critical for penile development;
however, defects in androgen metabolism and/or the androgen receptor explain
only a small subset of patients with hypospadias. This paper reviews the
present strategies to understanding the etiology of hypospadias. This
is followed by a review of the anatomy of the male and female genitalia
with an emphasis on reconstructive implications. Finally, current techniques
for hypospadias repair are reviewed.
hypospadias; anatomy; embryology; surgical technique; congenital anomalies
Braz J Urol, 26: 621-629, 2000
is one of the most common congenital anomalies occurring in approximately
1:250 to 1:300 live births. In patients with severe hypospadias the genitalia
may look ambiguous at birth resulting in emotional and psychological stress
for parents in that the gender assignment of their baby immediately comes
into question. Left-uncorrected patients with hypospadias may need to
sit down to void and tend to shun intimate relationships because of the
fears related to normal sexuality.
Europe the prevalence of hypospadias in the 1970s and 1980s
has been increasing with no obvious explanation. In the United States
data from two birth defects surveillance systems has also shown an unexplained
doubling in the incidence of hypospadias (1). The U.S. study from the
Center of Disease Control is particularly intriguing in that the incidence
of severe hypospadias, not just mild forms, is increasing implying that
the increase in hypospadias is not secondary to an increase in surveillance
sexual differentiation is dependent on testosterone and its metabolites
along with the presence of a functional androgen receptor. Genetic defects
in the androgen metabolism pathway (i.e. 5-alfa-II reductase defects or
androgen receptor defects) are known to result in hypospadias. Although
abnormalities in androgen metabolism can result in severe hypospadias
this does not explain the etiology of moderate and mild forms of hypospadias
propose an alternative hypothesis whereby hypospadias occurs by abnormal
cellular signaling between tissues of the phallus during development.
This hypothesis has been pursued by first defining the ontogeny of epithelial
and smooth muscle differentiation markers in the developing male and female
genitalia (6). The original work has been extended to anatomical studies
of hypospadias and the anatomy of the clitoris (see below). Specifically,
emphasis has been given to reconstructive strategies for penile curvature
and feminizing genitoplasty surgery based on the anatomical studies (7,8).
We have also focused on penile growth and
differentiation. A number of important questions concerning penile growth
remain unanswered. For example, the testosterone pathway and specifically
DHT are critical for penile growth and differentiation. However, what
about other non-androgen independent growth factors such as the insulin
growth factor family. A model to study human penile growth has been designed
to begin to answer some of these questions (9).
To test the hypothesis that epithelia-mesenchymal
interactions are critical for normal penile growth and differentiation
an extensive study was performed using the mouse genital tubercle (10).
Various epithelial mesenchymal separation experiments were performed so
show the importance of epithelial-mesenchymal signaling. When normal signaling
was present the growth of the genital tubercle exhibited normal growth
and differentiation (defined by the presence of cartilage). In contrast,
removal of the developing epithelium [epidermis (skin) and endoderm (urethra)]
greatly stunted the growth of the genital tubercle.
Basic work on penile growth has leaded us
to reexamine the embryology of the urethral development (11). The most
widely accepted mechanism of male urethral development proposes that the
urethral plate is elevated by urethral folds, which fuse ventrally in
a proximal to distal sequence. Unlike its proximal counterpart, the urethra,
which forms within the glans, is lined by a stratified squamous epithelium
and has a more controversial development. One theory supports the idea
that fusion of the urethral folds extends all the way to the tip of the
glans. Another theory suggests that a solid ectodermal ingrowth of epidermis
canalizes the glandular urethra. With newer immunohistochemical techniques
and tissue separation and recombination experiments we proposed a new
theory to explain the formation of the male distal urethra. Thirty-six
human fetal phallic specimens, gestational ages 5-22 weeks, were sectioned
and stained immunohistochemically with antibodies raised against different
cytokeratins. Evaluation of the sections showed that the urethral plate,
an extension of the urogenital sinus, extended to the tip of the phallus
and maintained patency and continuity throughout the process of urethral
development. The entire urethra, including the glans portion, was formed
by dorsal extension and disintegration of the urethral plate combined
with ventral growth and fusion of the urethral folds. Sections of the
distal glandular urethra showed no evidence of a solid ectodermal ingrowth.
Rather, immunostaining results at different ages suggested differentiation
of the endodermal urethral plate into a stratified squamous epithelium
(11). To determine whether urothelium could be induced to express a stratified
squamous phenotype, mouse fetal bladder epithelium was combined with rat
fetal genital tubercle mesenchyme and grown under the kidney capsule of
athymic mice. The bladder epithelium differentiated into a stratified
squamous epithelium. Thus, proper mesenchymal signaling may induce differentiation
of urothelium into a stratified squamous epithelium, such as during development
of the urethra of the glans penis. Figure-1 is a schematic of the classic
theory of ectodermal intrusion contrasted with the new theory of endodermal
differentiation supported by our experiments. If we are going to understand
the etiology of hypospadias it is critical that we understand normal penile
and urethral development.
possible explanation for the worldwide increase in the incidence of hypospadias
may be environmental contamination, which could interfere with the normal
androgen pathways and normal cellular signaling. In this regard it is
well established that humans continually ingest substances with known
estrogenic activity such as insecticides utilized in crop production,
natural plant estrogens, by-products of plastic production and pharmaceuticals.
Indeed, the metal cans used in the food industry are coated internally
with plastic known to contain estrogenic substances. Many of these estrogenic
substances find their way ultimately into fresh and seawater in trace
amounts, but are bio-accumulated and concentrated in higher organisms
of the food chain. For this reason predators at the top of the food chain
(large fish, birds, sea mammals and humans) accumulate high levels of
estrogenic environmental contaminants. For many species of wild life the
consequences for reproduction and health are devastating. For example,
the thinning of eggshells in a variety of birds was ultimately traced
to the estrogenic activity of insecticides to which the birds were exposed
through their diet. Thus, humans and wild animals are constantly exposed
to estrogenic compounds known for their ability to disrupt reproduction,
so called endocrine disrupters.
Estrogenic contaminants are known to impair
penile development in the American alligator (12). Moreover, the potent
estrogen, estradiol 17-beta, is known to disrupt penile development in
mice even through very little is known about the molecular mechanisms
whereby exogenous estrogens perturb penile development (13). In a general
sense the normal process of penile development is poorly understood at
the cellular and molecular levels. Thus, it is paramount to initiate basic
research into the mechanism of normal penile development in concert with
studies designed to test the hypothesis that estrogenic compounds can
perturb penile development. If it can be established that estrogenic endocrine
disrupters are responsible for the increased incidence of hypospadias,
preventive steps can be taken to minimize contact with such agents. In
the final analysis prevention is the best strategy for this serious medical
the last three years, we have preformed careful anatomical studies on
genital specimens between the ages of 8 and 33 weeks. In short, specimens
were serially sectioned and stained for epithelial, smooth muscle and
nerve structures using immunocytochemical techniques. Select specimens
were reconstructed in 3 dimensions to better understand the relationship
between the nerves, corporal bodies and urethral spongiosum using the
computer software NIH imaging and Adobe Photoshop® (6). Careful analysis
of the male specimens revealed localization of the nerves dorsally not
only at the 11 and 1 oclock position but extending around the tunica
to the junction of the corpus spongiosum and corpora cavernosa suggesting
that we may be injuring these structures in penile straightening procedures
The tunica albuginea showed consistent variations
in thickness, with the mid dorsal 12 oclock position being the thickest
followed by the 5 and 7 oclock periurethral positions. The lack
of nerves and the thickness of the tunica at the 12 oclock position
have lead to the design of penile straightening procedures by the placement
of plication sutures (Figure-2) (6,8).
Analysis of female specimens showed that
the normal fetal clitoris consists of two corporal bodies with a midline
septum. The ultrastructure of the female corporal bodies is analogous
to the male counterpart. The glans clitoris forms a cap on top of the
distal end of the corporal bodies. Large bundles of nerves course along
the corporal bodies with the greatest density on the dorsal aspect. These
anatomical relationships are useful when preserving nerves during feminizing
genitoplasty surgery (Figure-3) (7).
Finally, the ultrastructure of hypospadias
has revealed that the nerves and corporal bodies have the same anatomical
relationship as the normal penis. The most striking difference between
the normal penis and the hypospadiac penis is the difference in vascularity.
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 and fanning into the glans (8,14). The
anatomy of the normal and hypospadiac penis is relevant to the surgical
techniques in respect nerve and vascular preservation.
only treatment for hypospadias is surgical repair of the anatomical defect
(15-18). In experienced hands the surgery is typically performed as an
outpatient procedure with 80-90% of children requiring one operation.
Since the surgery is elective, the optimum time as recommended by the
American Academy of Pediatric Consensus Panel on genital surgery is between
6 months and 18 months (19).
technique chosen for the repair of anterior hypospadias will depend on
the anatomy of the hypospadiac penis. The most common accepted procedures
are the MAGPI (meatal advancement glansplasty), the GAP (glans approximation
procedure), the Mathieu or flip-flap and the tubularized incised plate
urethroplasty (20-33). We have been most pleased with the results from
the MAGPI and GAP procedure, which we present in more detail below. The
Mathieu is based on a random flap, which is not as reliable as a vascularized
pedicle graft. Long-term complications from meatal stenosis secondary
to ischemia have been more common (17).
MAGPI technique was devised by Duckett in 1981 (20). This technique will
provide outstanding results if appropriate patient selection is followed.
The hypospadiac penis that is amenable to the MAGPI is characterized by
a dorsal web of tissue within the glans that deflects the urine from either
a coronal or a slightly subcoronal meatus. Once the patient is asleep,
the urethra itself must have a normal ventral wall, without any thin or
atretic urethral spongiosum. The urethra also must be mobile so it can
be advanced into the glans (Figure-4).
GAP procedure is applicable in a small sub-set of patients with anterior
hypospadias who have a wide and deep glandular groove (21). These patients
do not have a bridge of glandular tissue that typically deflects the urinary
stream, as seen in patients who would be more appropriately treated with
the MAGPI procedure. In the GAP procedure, the wide mouth urethra is tubularized
primarily over a stent (Figure-5).
if the urethral groove was not wide enough for tubularization in situ,
such as in the GAP or Thiersch Duplay procedure (21,24) then an alternative
approach such as the Mathieu or for more severe hypospadias, a vascularized
pedicle flap was performed. Recently the concept of the incision in the
urethral plate with subsequent tubularization and secondary healing has
been introduced by Snodgrass (Figure-6) (22). Short-term results have
been excellent and this procedure is enjoying extensive popularity (25).
One appealing aspect is the slit-like meatus, which is created with the
dorsal mid-line incision. More recently, this technique has been applied
to more posterior forms of hypospadias. Theoretically, there is concern
about the possibility of meatal stenosis from scarring as occurs in patients
with urethral stricture disease where direct vision internal urethrotomy
often leads to recurrent stricture. In hypospadias, the native virgin
tissue with excellent blood supply and large vascular sinuses seems to
respond to primary incision and secondary healing without scar (8,14).
have been quite satisfied with the onlay island flap hypospadias technique
for the majority of penile shaft and more severe cases of hypospadias
(Figure-7). The onlay island flap has withstood the test of time with
excellent long-term results (15,17). Preservation of the urethral plate
in the onlay island flap has essentially eliminated proximal anastomotic
strictures and has reduced the incidence of fistula formation. When necessary
penile curvature is corrected by dorsal plication (Figure-2)(8).
Recent reports have summarized standard
techniques and introduced subtle variations (26-29). Occasionally extensive
surgery is necessary and in some cases multiple operations leave the unfortunate
child with a suboptimal result, the patient then being classified as a
hypospadias cripple. For very severe hypospadias, the prepuce
can be designed as a horseshoe style to bridge extensive gaps (30).
summary, in the last twenty years there has been an incredible evolution
in the surgical treatment of hypospadias. Optical magnification, delicate
tissue handling and fine sutures have greatly benefited patients and families
with this congenital anomaly. The next step is to begin to understand
the etiology of hypospadias. This is especially germane if the incidence
of hypospadias is truly doubling. A multidisciplinary effort is warranted
in the areas of androgen metabolism and epithelial-mesenchymal signaling
based on the hypothesis that endocrine disrupters may account for the
documented increase incidence of hypospadias. Through a better understanding
of normal penile growth and urethral differentiation new strategies of
prevention and treatment can be developed.
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Received: August 12, 2000
Accepted: September 20, 2000
Dr. Laurence S. Baskin
Chief, Pediatric Urology
University of California San Francisco
San Francisco, California, 94143, USA
Fax: + + (1) (415) 476-8849