CHAPTER 1

General
Considerations
 Chapter Outline
¾¾ Introduction

¾¾ Embryology

¾¾ Etiology of Hypospadias

¾¾ Incidence

¾¾ Severity and Classification

¾¾ Presentation and Initial Evaluation

¾¾ Associated Anomalies

Introduction
Hypospadias is a common congenital anomaly of the penis. The term
“hypospadias” refers to a urinary opening situated on the undersurface of
the penis, instead of the tip of the penis. This abnormality of the urethral
opening is usually associated with other abnormalities like penile
curvature/bend (chordee), foreskin abnormalities, and poor tissue devel-
opment in the penis, and may be associated with a small-sized penis and
anomalies in the testis. The extent to which these anomalies are present
determines the severity of the condition, which in turn determines the
plan of surgical treatment and the outcome.

Embryology
The complete embryology of the development of external genitalia
is beyond the scope of this book. Only a brief insight into the possible
embryology of hypospadias formation is presented here.

Development of External Genitalia

The external genitalia of the developing fetus are initially indifferent and
can develop into either the male or female phenotype. Unless proper
 General Considerations 3

androgenic stimulation occurs between the 9th and 12th weeks of gesta-
tion, these primordia of the external genitalia would become a female
phenotype. When appropriate hormone stimulation occurs at the appro-
priate gestation, it causes the genital tubercle to elongate, causes fusion
of the urethral folds, and tubularizes the urethral groove beginning prox-
imally and continuing to the level of the glans. It is generally believed
that the spongy urethra and the glanular urethra have different embry-
ological origins. The epithelium of most of the male urethra is derived
from the endoderm of the urogenital sinus. The distal part of the urethra
in the glans penis is derived from a solid cord of ectodermal cells that
grows from the tip of the glans and joins the rest of the spongy urethra.
Thus, the epithelium of the terminal part of the urethra is derived from
the surface ectoderm. The connective tissue and smooth muscle of the
urethra are derived from splanchnic mesenchyme.
The currently accepted theories are fusion theory for the development
of the spongy urethra and ectodermal ingrowth or endodermal transfor-
mation theories for the development of the glanular urethra. Although
Hadidi et al recently questioned these concepts, they still remain the
most widely accepted theories for the development of the human
urethra. Masculinization of the indifferent external genitalia is induced
by dihydrotestosterone that is produced peripherally by 5α-reductase
conversion of testosterone from the testicular Leydig cells. As the primor-
dial phallus enlarges and elongates to become the penis, the urogenital
folds form the lateral walls of the urethral groove on the ventral surface
of the penis. This groove is lined by a proliferation of endodermal cells,
the urethral plate, which extends from the phallic portion of the urogen-
ital sinus. The urethral folds fuse with each other along the ventral
surface of the penis to form the spongy urethra. The surface ectoderm
fuses in the median plane of the penis, forming the penile raphe and
enclosing the spongy urethra within the penis. The exact formation of
the human urethra within the glans penis is unclear, but examination of
human embryos suggests that the solid glans plate canalizes and joins
the developing penile urethra to form the glans urethra and external
 4 Chapter 1

urethral meatus. At the tip of the glans penis, an ectodermal ingrowth

forms a cellular ectodermal cord that extends toward the root of the
penis to meet the spongy urethra. This cord canalizes and joins the previ-
ously formed spongy urethra. This juncture completes the terminal
part of the urethra and moves the external urethral orifice to the tip of
the glans penis. During the 12th week, a circular ingrowth of ectoderm
occurs at the periphery of the glans penis. When this ingrowth breaks
down, it forms the prepuce (foreskin). The corpora cavernosa and corpus
spongiosum develop from mesenchyme in the phallus. The labioscrotal
swellings grow toward each other and fuse to form the scrotum. The line
of fusion of these folds is clearly visible as the scrotal raphe.
To summarize, the genital tubercle develops during the fourth week
of gestation as the precursor of the phallus. Endodermal cells migrate
from the cloaca along its ventral midline to form the urethral plate and
on either side proliferating mesenchyme form the urogenital folds. From
the 9th to the 12th week, androgenic stimulation causes phallic devel-
opment. Elongation of genital tubercle occurs, and the urogenital folds
migrate to the midline and fuse enclosing the urethral groove. This
process moves proximal to distal creating the urethra. As the plate tubu-
larizes, mesoderm within the urethral folds differentiates into the corpus
spongiosum, which then fuses distally to the glans. Mesoderm also forms
the corpora cavernosa. Development of the penis proceeds at different
rates along the ventral and dorsal surfaces resulting in temporary ventral
curvature. Similarly, the dorsal prepuce extends beyond the glans before
the ventral aspect, which follows closure of the urethral groove. Midline
fusion of the ventral prepuce results in the frenulum.
There have been efforts to develop an animal model similar to human
external genitalia development. The most important step in sex differ-
entiation of external genitalia is urethral tubularization in males. In
humans, this process is described as double zipper model in males. This
distal-opening-proximal-closing process of tubular urethra formation
has never been clearly shown in any published animal models.
 General Considerations 5

Recently, some authors reported that urethral groove formation and

urethral tube closure process of guinea pigs are more similar to humans,
making this a more suitable model to study closure of the tubular urethra.
Further, in their guinea pig model, hypospadias could be induced by
prenatal anti-AR bicalutamide in males, and additional androgen methyl­
testosterone in utero exposure resulted in tubular urethra formation
in females. Thus, the use of this animal model may allow further study
of cellular and molecular mechanisms involved in the tubular urethra
formation and the evaluation of the pathophysiological processes of
hypospadias.

Embryological Basis of Hypospadias

Hypospadias appears to represent an arrest of penile development,

more specifically an arrest of urethral formation. The formation of glan-
ular hypospadias may be influenced by multiple factors, but its direct
cause is probably defective canalization of the distal glans plate. The
arrest or nonfusion of urethral folds causes other (more severe) types of
hypospadias. Thus, the urethral opening may be found anywhere along
the ventral midline from the perineum to the glans depending on the
time at which fusion of the urethral folds was arrested. The nontubu-
larized, flat residual tissue in the midline represents the urethral plate,
extending from the meatus to the glans. In severe forms of hypospadias
(penoscrotal, scrotal, and perineal forms), apart for an arrest of fusion of
the urethral folds, there is also an arrest of fusion of labioscrotal folds.
If the labioscrotal folds fuse partially, scrotal hypospadias may result;
when the labioscrotal folds do not fuse at all, a completely bifid scrotum
with perineal hypospadias will result (Fig. 1.1).
Along with these changes, there is arrested or poor development of
ventral tissues of the penis to a varying degree. Thus, these defects can
be seen as a distal urethral plate of variable quality, open glans wings
(split glans penis open like a book, instead of being closed like a cone);
 6 Chapter 1

Fig. 1.1 Perineal hypospadias with completely bifid scrotum. In this

extreme case, the blind-ending vagina can also be seen opening
onto the perineum behind the urethral opening. Both the testes
can be seen in the labioscrotal folds. Karyotype was 46XY.

an abnormal, splayed corpus spongiosum; and an absent ventral prepuce

(except in some special cases). Most often, apart from the abnormalities
discussed above, an abnormal ventral or downward bending/angulation
of the penis, called “chordee” may be present.

Etiology of Hypospadias
The etiology of hypospadias has been a subject of much speculation and
research, but the exact cause is still unknown. The various causes that
have been proposed are genetic, endocrine (hormone) related issues, or
environmental agents.
 General Considerations 7

Genetic

In most boys, particularly those with mild or moderate defects (distal

or midshaft forms), genetic factors may not play a major role. However,
genetic factors (with multifactorial inheritance) may play a role in severe
forms of hypospadias, with a 10 to 20% risk of recurrence in the siblings.
Heritability of hypospadias is definitely high; there is no doubt that
genetic abnormalities are involved, and many different candidate genes
and polymorphisms have been suggested for hypospadias. Although
some associations with hypospadias were found, none of these associa-
tions have been replicated consistently in all studies. Each mutation may
explain selective pathogenic factors in only a few percent of hypospadias
cases. It is most likely that the majority of isolated hypospadias cases are
a result of several additive low-grade genetic risk factors.

Endocrine

The role of maternal endocrine factors leading to hypospadias in the

baby has been investigated. Some studies have found a small but signifi-
cant increase in the incidence of hypospadias in the offspring of women
receiving estrogen treatment in pregnancy. Defects in testosterone
synthesis have been found in some boys with hypospadias, but the find-
ings have not been consistent. However, a subgroup of boys with severe
hypospadias may have 5α-reductase enzyme deficiency, which may
present as 45XY disorder of sexual differentiation (DSD). Mutations that
reduce or disable this enzyme have little consequence in females, but in
males the resulting loss of dihydrotestosterone results in severe peno-
scrotal hypospadias and genitalia that seem to be female at birth. These
individuals have normal testes located in the inguinal region or inside the
labioscrotal folds. The testes produce antimullerian hormone (AMH) and
testosterone at appropriate times, so paramesonephric duct derivatives
are absent, and the mesonephric ducts differentiate into vasa deferentia.
In 46XY DSDs of this type, the sudden rise of testosterone at puberty may
 8 Chapter 1

cause dramatic differentiation of the external genitalia and accessory

glands into typically male structures. The urethral folds and labioscrotal
swellings may fuse completely, and the genital tubercle may differentiate
into a penis. The normal testosterone levels during fetal life and after
puberty are thought to result in normal male differentiation of the brain
and, hence, a sense of male gender identity. Thus, these children may
present as adolescents for hypospadias repair.
Another endocrine-related cause of hypospadias is androgen insensi-
tivity syndrome (AIS), where androgen receptors are reduced or absent.
The male fetus may have normal or high levels of male steroid hormones,
but the target tissues do not respond, and development proceeds as
though androgens were absent. AIS may be partial or complete: Partial
AIS presents with severe hypospadias, small phallus, penoscrotal trans-
position, and bifid scrotum with usually descended gonads (testes). These
children are usually reared as males and come for hypospadias repair.
Because of the small phallus, they may require preoperative testosterone
injections; however, because of androgen resistance, they require higher
doses of hormones. As in cases of primary testosterone deficiency, testes
are present and AMH is produced, so the paramesonephric ducts regress,
although a blind-ending vagina (enlarged prostatic utricle) may form;
these cases, in particular, may pose difficulty in catheterization during
hypospadias repair. The complete form of AIS presents a phenotypic
female and is referred to as testicular feminization syndrome.

Environmental

Apart from genetic and hormonal defects, a variety of dietary (soya,

nonorganic diet) and environmental agents (oral contraceptive pills,
pesticides, detergent agents, compounds used in the manufacture of plas-
tics, and some medications) have been shown to have mild hormonal
activity and have been implicated in the causation of hypospadias. Most
of these agents have only weak estrogen activity and usually occur in low
concentrations; hence, at low concentrations they are unlikely to exert
 General Considerations 9

a significant direct estrogenic effect on the fetus. However, even low

concentrations of these agents may interfere with androgen biosynthesis
and block androgen receptor expression. Thus, the role of these environ-
mental agents in hypospadias causation may be mediated via disruption
of androgen pathways rather than a direct estrogenic hormonal effect on
the fetus. Although strong evidence supports an association of valproic
acid, which has gonadotropin-releasing hormone-agonist properties and
thus results in antiandrogenic effects, and in utero exposure of mothers
of male babies to diethylstilbestrol (DES) with hypospadias, many
other medications including iron, loperamide, antiretroviral agents,
nystatin, loratadine, and corticosteroids, along with fertility treatments
and maternal cocaine usage, require further investigation to determine
whether these are connected with hypospadias development.
Some investigators have found a 50% higher incidence of hypospadias
in the offspring of women aged 35 years or older than in the offspring of
mothers aged younger than 20 years. In addition, low birth weight is asso-
ciated with an increased risk, which is independent of gestational age,
and some (but not all) studies have reported a significantly greater risk of
hypospadias after in vitro fertilization. Further, maternal factors such as
obesity, advanced maternal age, age at menarche, parity, diet, ethnicity,
and underlying conditions like diabetes and thyroid disease need to
be confirmed by further research in regard to their association with
hypospadias. Endocrine disruptors also remain controversial as to their
relationship with hypospadias, necessitating additional investigation.
Factors most likely associated with hypospadias in most studies
are placental insufficiency, low birth weight/small for gestational age,
maternal hypertension and preeclampsia, maternal intrauterine DES
exposure, and maternal use of antiepileptics. The consistent association
of hypospadias with intrauterine growth retardation, low birth weight,
maternal hypertension, and preeclampsia suggests that placental insuffi-
ciency is a major risk factor for hypospadias, possibly through inadequate
provision of human chorionic gonadotrophin to stimulate fetal androgen
production. Male infants conceived with the aid of intracytoplasmic
 10 Chapter 1

sperm injection may have an increased risk of being born with hypospa-
dias. A study from China found that the risk of hypospadias was higher
for children of mothers older than 35 and younger than 18 years of age
and in mothers who had consumed alcohol, used drugs, and had an infec-
tion during pregnancy. The risk of hypospadias was also higher when
mothers and fathers were engaged in agriculture.
In addition to all this information, a recent study has identified an
increased risk of neurodevelopmental disorders in patients with hypo-
spadias, as well as an increased risk for autism spectrum disorders in
their brothers, suggesting a common familial (genetic and/or environ-
mental) liability.
To summarize, current available evidence suggests that hypospadias
is a complex disorder because both genetic and environmental contrib-
utors are involved. Hypothetically, a genetic predisposition in combi-
nation with placental insufficiency may indicate a strong two-hit risk
factor model necessary for a hypospadias phenotype. It has also been
hypothesized that in most cases, hypospadias develops because of gene–
environment interactions, and both these must coexist for hypospadias
formation. Furthermore, it has been shown that interactions between
genetic and environmental factors may help to explain nonreplication in
genetic studies of hypospadias.

Incidence
Although highly variable, the incidence of hypospadias is about 0.3 to
0.6% boys (1 in 150 to 1 in 300 boys). There is some evidence that the inci-
dence of hypospadias is increasing, presumably due to dietary and envi-
ronmental agents. One study from Sweden demonstrated an increased
incidence of hypospadias diagnoses in Sweden from 1990 to 1999 that
was not attributable to previously known risk factors. This increase
included both mild and severe types of hypospadias, suggesting that this
reflected an actual increase in the incidence of hypospadias. In India, it
 General Considerations 11

is roughly estimated that about 70,000 to 75,000 boys may be born with
hypospadias every year.

Severity and Classification

The severity of hypospadias is traditionally determined by the position of
the urethral meatus and the extent of ventral penile angulation (chordee).
However, the location of the urethral opening may be misleading in some
cases, when a length of distal urethra may be thin without corpus spon-
giosum cover. A more accurate estimate of severity may be used to iden-
tify the level of division of corpus spongiosum. Similarly, after correction
of chordee, the urethral opening may be moved downward. Many a time,
these variations can only be identified during the surgery by assessing
the quality of tissues. Thus, preoperative assessment in the clinic may
underestimate the true severity of the hypospadias, and this has to be
kept in mind when counseling the parents in the clinic. An important
practical lesson is not to decide on the technique of operation until the
true severity of the defect and the quality of tissues available for recon-
struction are correctly assessed during surgery.
Although there are many ways to classify hypospadias, a simple way is
to classify it as distal, mid, and proximal. Another practical method used
to classify hypospadias is based on the presence and severity of chordee.
The practical implication of such a classification is obvious; the cases
with no chordee or only mild chordee may be mostly corrected in a single
operation, whereas those cases with severe chordee usually require two
operations to correct them.
According to Mouriquand, a more practical method is to classify hypo-
spadias on the basis of the level of division of corpus spongiosum. The
hypospadiac penis has hypoplastic ventral tissues distal to the division
of the corpus spongiosum. This is seen as a ventral triangular defect
whose summit is the division of the corpus spongiosum, whose sides are
represented by the two pillars of atretic spongiosum, and whose base is
 12 Chapter 1

the glans itself. This triangle in some cases contains a segment of vari-
able length of atretic urethra (not surrounded by any spongiosum) which
starts where the corpus spongiosum divides. Therefore, it is possible to
distinguish two main types of hypospadias: one with a distal division
of the corpus spongiosum with little or no chordee and another with a
proximal division of the corpus spongiosum with a marked degree of
hypoplasia of the tissues of the ventral penis, with a significant degree
of chordee. Besides these two main types, there is also hypospadias for
which several procedures have failed (hypospadias cripple). In author’s
experience, the identification of the level of division of corpus spon-
giosum is a much better indicator of the severity of hypospadias than the
location of urethral meatus (Fig. 1.2).

Fig. 1.2 Hypospadias with apparently midpenile opening but

severely hypoplastic urethra (lacking spongiosum cover) till the
perineum.
 General Considerations 13

Presentation and Initial Evaluation

Hypospadias is usually recognized during initial physical examination
of a newborn baby. Typically, the abnormal prepuce (dorsal hood with
absent ventral foreskin) gives a clue to the anomaly; further clinical
examination often finds the glans tilted downward and the penile raphe
displaced from the midline. The meatus will be seen to be on the under-
surface of the penis (Fig. 1.3).
The meatus may appear small in size (the so-called “pinhole” meatus),
but surprisingly, even such small meatus is quite pliable and does not
usually cause significant obstruction to urine flow. Ventral curvature of
the penile shaft may be noted during erection.

Fig. 1.3 Hypospadias with penile torsion. Note

that the torsion is to the left, while the midline
raphe is deviated to the right side.
 14 Chapter 1

These characteristics, the dorsal hood, altered glans shape, and

penile curvature, also can now be identified prenatally by fetal
ultrasonography. Observation of micturition from the misplaced meatus
confirms the diagnosis. However, the law in India forbids the reporting
of external genitalia of the fetus and fetal sex determination; hence, the
diagnosis of hypospadias is always made after birth.
When a baby with hypospadias is seen, it is important to examine
the testes also. In case of hypospadias with undescended testis (UDT) or
severe hypospadias, it may be necessary to obtain a karyotype for associ-
ated DSD. It is not generally necessary to get an ultrasound of the kidneys
in all children with hypospadias because the association of upper urinary
tract abnormalities is low. However, in severe hypospadias, in a child
with history of urinary infection or a child with multiple anomalies, an
ultrasound examination of the kidneys and bladder may be obtained.

Associated Anomalies
Undescended Testis

Since both hypospadias and UDT may result from male hormone defi-
ciencies, it is possible for the two conditions to coexist in the same child.
Some studies report that approximately 8% of boys with hypospadias also
have a UDT. The more severe the hypospadias, more are the chance of
having associated UDT; studies show that about 5% of distal hypospadias
may have UDT, while up to 32% of severe hypospadias are associated with
UDT. Fig. 1.4a, b and Fig. 1.5 show distal and midpenile hyposapdias. Fig.
1.6 and Fig. 1.7a, b show severe hyposapdias with bilateral descended
gonads. Fig. 1.8 shows severe hyposapdias with unilateral nonpalpable
gonad, to be investigated for DSD.

Prostatic Utricle

Prostatic utricle or vaginal pouch is a homolog of the vagina in males.

Enlargement of the utricle has been noted in boys with hypospadias, and
 General Considerations 15

a b

Fig. 1.4 (a) Distal hypospadias. Note the meatus at the corona, with well-developed ventral
penile tissues. There is no significant chordee. (b) Distal hypospadias in 17-year-old adolescent
boy. Note the significant ventral curvature.

Fig. 1.5 Midpenile hypospadias. Note the poor

urethral plate.
 16 Chapter 1

Fig. 1.6 Severe hypospadias. Note the scrotal opening,

small phallus, severe chordee, and a generalized
hypoplasia of ventral penile tissues.

a b

Fig. 1.7 (a) Severe hypospadias with severe penoscrotal transposition giving a female
phenotype appearance. (b) Separating the labioscrotal folds reveals a small phallus, severe
hypospadias, and bilateral gonads in labioscrotal folds.
 General Considerations 17

Fig. 1.8 Mixed gonadal dysgenesis presenting with severe

hypospadias, right descended gonad, and nonpalpable left gonad.
The karyotype was mosaic (46XY/45XO).

may be because of deficient action of mullerian inhibiting factor. Most of

the enlarged prostatic utricles are found in proximal and severe hypo-
spadias, occurring in about 11% of such severe cases. In the most severe
cases, it may even open onto the surface on the perineum (Fig. 1.1).
Enlarged utricles may result in urinary tract infection, and a large utricle
may compress the urethra and result in difficulty in voiding or urinary
retention. In addition, a common practical problem during operation for
severe hypospadias is that an enlarged utricle may cause difficulty in
passing the catheter into the bladder.

Disorders of Sex Development

Hypospadias and DSD may occur as a spectrum. In general, the chance

of a child with hypospadias having a DSD increases with an increased
severity of hypospadias especially with scrotal or perineal hypospadias.
 18 Chapter 1

Thus, in a child with hypospadias, the possibility of associated DSD should

be considered in the following cases:
a. Severe hypospadias or hypospadias with small phallus (micropenis).
b. Hypospadias with associated UDT, especially if the UDT is nonpal-
pable, the risk of DSD may be as high as 50%. The most common
diagnosis is mixed gonadal dysgenesis (MGD; Fig. 1.8), followed
by ovotesticular DSD (which is much less common). The diagnosis
of MGD is suspected clinically when there is severe hypospadias
with unilateral nonpalpable UDT. Karyotype showing 46XY/45XO
mosaic pattern confirms the diagnosis. The management depends
on the age at diagnosis, if sex of rearing has already been
established. It is recommended to remove the dysgenetic (streak)
ovary present in the abdomen by laparoscopy. The need to remove
mullerian remnants (usually seen as a hemiuterus-like structure) is
not clear, although malignant transformation of retained mullerian
structures has been reported in other conditions.
Any child with above features should be investigated for DSD, using a
karyotype and other investigations.

Malformation Syndromes

Over 90% of cases of hypospadias occur as an isolated anomaly. However,

a number of syndromes may be associated with hypospadias. Syndromic
hypospadias is suspected with dysmorphic facies, developmental delay,
microcephaly, and/or anorectal malformation. A few examples are
given below:

Smith-Lemli-Opitz Syndrome
This results from an autosomal recessive mutation of the DHCR7 gene on
chromosome 11q13 coding for 7-dehydrocholesterol reductase; multiple
congenital anomalies are attributed to this single metabolic defect. This
autosomal recessive condition occurs in 1:20,000 births, ranking it third
in prevalence among whites, behind cystic fibrosis and phenylketonuria.
Affected individuals have impaired cholesterol synthesis because of
 General Considerations 19

deficiency of 7-dehydrocholesterol reductase, resulting in mental retar-

dation, facial deformities, microcephaly, syndactyly, and genital anom-
alies. The spectrum of external genital findings in males ranges from a
female phenotype to hypospadias with cryptorchidism.

G Syndrome (Opitz G/BBB Syndrome)

This includes both X-linked and autosomal dominant forms: X-linked
mutations in the midline-1 gene or autosomal dominant deletions in
chromosome 22q11. The resultant phenotype includes hypertelorism,
tracheoesophageal defects, cleft lip/palate, and mild mental retardation.
Mild-to-moderate mental retardation and swallowing problems causing
aspiration may also occur.

WAGR Syndrome
WAGR syndrome (Wilms’ tumor, aniridia, genital anomalies, mental
retardation) results from a deletion in chromosome 11p13.

13q Deletion Syndrome

It is characterized by mental retardation, facial dysmorphia, imperforate
anus, penoscrotal transposition, and hypospadias (Fig. 1.9a, b).

a b

Fig. 1.9 Megameatus intact prepuce (MIP) variant of hypospadias. (a) The normal prepuce
and (b) the coronal hypospadias are seen on preputial retraction.
 20 Chapter 1

Hand-Foot-Uterus Syndrome
This is an autosomal dominant condition due to mutations in the HOXA13
gene on chromosome 7p14-15 resulting in bilateral thumb and great toe
hypoplasia.

Wolf–Hirschhorn Syndrome (Pitt’s Syndrome)

This is a microdeletion syndrome due to deletion on the short arm of
chromosome 4. The characteristic features are craniofacial anomalies
(microcephaly, micrognathia, hypertelorism, and periauricular tags),
growth retardation, intellectual disability, hypotonia, seizures, congenital
heart defects, hypospadias, and other anomalies. Antibody deficiencies
are also common.

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 General Considerations 21

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