Review
Review
Urol Int 2005;75:291–297
DOI: 10.1159/000089160
Dominic Frimberger
John P. Gearhart Ambiguous Genitalia and
The Brady Urological Institute, Intersex
The Johns Hopkins University School
of Medicine, Baltimore, Md., USA
Abstract
Intersex disorders are rare congenital malformations
with over 80% being diagnosed with congenital adrenal
hyperplasia (CAH). It can be challenging to determine the
correct gender at birth and a detailed understanding of
the embryology and anatomy is crucial. The birth of a
child with intersex is a true emergency situation and an
immediate transfer to a medical center familiar with the
diagnosis and management of intersex conditions should
occur. In children with palpable gonads the presence of
a Y chromosome is almost certain, since ovotestes or
ovaries usually do not descend. Almost all those patients
with male pseudohermaphroditism lack Mullerian struc-
tures due to MIS production from the Sertoli cells, but
the insufficient testosterone stimulation leads to an in-
adequate male phenotype. The clinical manifestation of
all CAH forms is characterized by the virilization of the
outer genitalia. Surgical correction techniques have
been developed and can provide satisfactory cosmetic
and functional results. The discussion of the manage-
ment of patients with intersex disorders continues. Cur-
rent data challenge the past practice of sex reassign-
ment. Further data are necessary to formulate guidelines
and recommendations fitting for the individual situation
of each patient. Until then the parents have to be sup-
plied with the current data and outcome studies to make
the correct choice for their child.
Copyright © 2005 S. Karger AG, Basel
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Introduction
Intersex disorders are rare congenital malformations
and the reported incidences of the different malforma-
tions are mostly based on small series. Bertrand et al. [1]
and David et al. [2] reported about their 25 years’ experi-
ence of 325 infants with intersexuality. Altogether 167
patients were diagnosed with female pseudohermaphro-
ditism, of which 80% were found to have congenital ad-
renal hyperplasia (CAH). Hyperandrogenism due to
overproduction by the mother was found in 3% only. Ab-
normal male sex differentiation was diagnosed in 150
children, 27% of those with either gonadal dysgenesis or
male pseudohermaphroditism. Hormonal problems like
testicular deficiencies were found in 13% and androgen
insensitivity syndrome in 16% [1, 2]. It can be challeng-
ing to determine the correct gender at birth and even
more difficult to establish the right diagnosis inside the
various intersex disorders.
In order to understand the wide variety of genital am-
biguity it is crucial to be aware of the regular sexual dif-
ferentiation process. Appreciating the embryologic devel-
opment and the hormonal influence on the development
of the fetus in utero is essential to counsel the parents ap-
propriately about sex assignment, necessary treatments
and the surgical possibilities [3]. Sexual differentiation of
the embryo starts after the 7th week of gestation. Before
that time point the urogenital ridge in both sexes holds
John P. Gearhart, MD
Department of Urology, Division of Pediatric Urology
Brady Urological Institute, The Johns Hopkins Hospital
600 North Wolf Street, Marburg 146, Baltimore, MD 21287-2101 (USA)
E-Mail jgearhart@jhmi.edu
Review
mesonephric (Wolffian) and paramesonephric (Mulleri-
an) duct structures. The differentiation into each gender
is dependent on the exact sequence of events occurring at
specific time points, dependent on chromosomal, hor-
monal and hormonal receptor function. While the genet-
ic sex and the gonadal differentiation are determined by
the sex chromosomes, the phenotype is dependent on the
influence of the hormonal secretions from the testes. The
sex-determining region on the Y chromosome (SRY) is
the main gene required to differentiate the bipotential
gonad into a testis [4, 5] which than give raise to the Ser-
toli cells. In the absence of male Mullerian-inhibiting sub-
stance (MIS) from the Sertoli cells and testosterone from
the Leydig cells a female phenotype will develop. In males
the Wolffian ducts develop under testosterone production
while the Mullerian ducts regress under the influence of
MIS. In females on the other hand the lack of testosterone
and MIS cause the Wolffian ducts to regress and the Mul-
lerian ducts to develop, respectively. The differentiation
of the external genitalia is under the control of dihydrotes-
tosterone (DHT), a metabolite of testosterone under the
enzymatic control of 5␣-reductase. Much like the gonads,
the external genitalia have bipotential in the fetus and
develop into a male phenotype only under the influence
of DHT, while a lack of DHT will irreversibly lead to a
female external phenotype in both chromosomal sexes
[6]. The complexity of the physiologic sexual differentia-
tion explains the wide range of intersex disorders and the
variety of presentation among the subgroups. The most
definite and undisputable factor is the genetic sex, deter-
mined by the karyotype. Therefore, it seems logic to clas-
sify the intersex disorders into female pseudohermaphro-
dites (FPH) with a female karyotype (46,XX) and mas-
culine features caused by an excess amount of androgens
in utero (e.g. CAH) and male pseudohermaphrodites
(MPH) with a male karyotype (46,XY) and female fea-
tures due to a lack of testosterone or androgen receptors
[7]. Some patients cannot be placed into these two catego-
ries, e.g. those with chromosomal abnormalities like
Klinefelter’s (47,XXY) or Turner syndrome (45,X0). Ad-
ditional groups, which are not considered to be ambigu-
ous, include phenotypical females with vaginal atresia
(Mayer-Rokitansky-Küster-Hauser syndrome), pheno-
typic males with additional female internal structures due
to lack of MIS, or males with a micropenis.
The birth of a child with intersex is a true emergency
situation. Acute life-threatening situations can arise in
children with CAH from electrolyte disturbances caused
by salt-wasting 21-hydroxylase deficiencies. But besides
the medical emergencies, it is of utmost importance to
292 Urol Int 2005;75:291–297
identify the correct diagnosis as early as possible in order
to counsel the anxious parents appropriately towards the
sex of rearing.
Evaluation and Diagnostic Pathway of the
Newborn with Ambiguous Genitalia
The birth of a newborn with ambiguous genitalia often
comes as a surprise for the parents, treating physicians
and nursing staff. Although some authors report that 60%
of affected children are diagnosed prenatally [8], many
parents are faced with the situation at birth.
The child should immediately be transferred to a med-
ical center familiar with the diagnosis and management
of intersex conditions. Not only life-threatening situation
as in salt-wasting CAH have to be addressed immediate-
ly, but also the psychological devastation of the parents.
For the referring inexperienced physician, it is often best
not to confuse the situation by discussing the issue with
the parents but rather transfer the child to a center. Until
a diagnosis is made and a sex of rearing has been decided,
the parents should be encouraged not to name the child
or register the birth to prevent later changes and explana-
tions to their social surroundings [9].
The evaluation should begin with a detailed history
from the parents towards ambiguity, hirsutism or unex-
plained sudden infant death in the family. Additionally
the maternal exposure to hormonal medications or corti-
sone during the pregnancy has to be evaluated.
Serum studies should be initiated, including electro-
lytes to rule out salt-wasting CAH, testosterone, DHT,
17-hydroxyprogesterone and certainly a karyotype to de-
termine the chromosomal sex. The testosterone level can
help to determine if the intersex condition is due to a lack
of androgen or cortisone synthesis or rather due to a re-
ceptor defect. Key to the physical examination is the pal-
pation of the groin and scrotal or labial folds to determine
the presence of the gonads. The outer genitals are inspect-
ed and presence and length of the phallus noted. A rectal
exam can confirm the presence of a uterus and cervix and
should always be performed. The examination should be
done in the presence of the parents to familiarize them
with the situation.
Further evaluations include a pelvic and abdominal
ultrasound for the evaluation of female internal organs
and to rule out possible accompanying urological or ad-
renal anomalies. The urogenital sinus can be anatomi-
cally defined by a retrograde genitogram, localizing the
position and entrance of the urethra and vagina into the
Frimberger/Gearhart

sinus. It is important that the surgeon planning to do the
reconstructive procedure is present to assist the radiolo-
gist with the genitogramm. In rare cases where a definite
diagnosis cannot be determined an exploratory laparos-
copy with possible biopsy of the gonads can become nec-
essary.
Male Pseudohermaphroditism
If gonads are palpable, the presence of a Y chromo-
some is almost certain, since ovotestes or ovaries usually
do not descend. Consequently FPH can be excluded and
the differential diagnosis shifts towards inadequate pro-
duction of testosterone or androgen receptor deficiencies
in a genetically male. Almost all MPH lack Mullerian
structures due to MIS production from the Sertoli cells,
but the insufficient testosterone stimulation leads to an
inadequate male phenotype. Testosterone is responsible
for the formation of the epididymis, vas and seminal ves-
icles while the external masculinization is dependent on
DHT metabolized from testosterone via 5␣-reductase.
Therefore patients with 5␣-reductase deficiency present
with female external genitalia but regular male internal
genital structures, while individuals with complete an-
drogen receptor defects block the external and internal
masculinization completely. These patients are also de-
scribed as a complete form of androgen insensitivity syn-
drome (CAIS) and have normal or elevated levels of tes-
tosterone, a regular female phenotype with normal breast
development and a short blind-ending vagina. But they
have no internal female genitalia due to intact MIS pro-
duction from the Sertoli cells and they usually do not be-
come apparent until puberty when they are evaluated for
primary amenorrhea.
Incomplete forms of AIS (PAIS) on the other hand
rather present with an incomplete masculinization than
a female phenotype and can have a varying range of in-
ternal male structures. Frequent features include pheno-
typic males with a penoscrotal hypospadias and a bifid
scrotum, often containing small testes. Additionally a
small, blind-ending vaginal pouch without evidence of
other female structures can be found.
A very rare condition, persistent Mullerian duct syn-
drome, is found in genetically and phenotypically normal
males. They have a deficiency of MIS and form complete
internal female genitalia but usually are not detected un-
til undergoing surgery for a hernia or an undescended
testis.
Ambiguous Genitalia and Intersex
Review
Children with complete gonadal dysgenesis (Swyers
syndrome) [10] can only be identified by their XY karyo-
type, since the complete absence of Sertoli and Leydig
cells in the bilateral streak gonads leads to a complete fe-
male phenotype with normal internal and external female
genitalia. But since they lack ovaries they do not produce
sufficient estrogens and therefore become apparent at pu-
berty due to primary amenorrhea, missing breast devel-
opment and elevated serum gonadotropins [11]. Interest-
ingly, pregnancies are possible after transfer of fertilized
eggs in the functioning uterus. The most important fact
in complete gonadal dysgenesis is the 30% risk of devel-
oping germ cell tumors, mostly gonadoblastomas [12].
Female Pseudohermaphroditism
The most common form of FPH in over 80% is caused
by the various enzymatic defects of CAH. The majority
of CAH cases (190%) are caused by 21-hydroxylase defi-
ciency and can clinically impress with a wide spectrum
of clinical variants. The enzymatic defect results in the
inability to produce cortisol, leading to an increase in
ACTH, stimulating the adrenal glands. The enzymatic
block together with the glandular stimulation results in
an increase of 17-hydroxyprogesterone, progestins and
androgen precursors. While the androgen excess is re-
sponsible for the masculinization of the fetus, the proges-
tins are accountable for the salt loss of the kidneys. In the
mild forms the loss can be compensated by increased pro-
duction of aldosterone, while the severe forms are com-
monly known as salt-wasting CAH, which can be fatal if
not compensated after birth. Less common are the 11-
hydroxylase (^5%) and the 3␤-hydroxysteroid deficien-
cies [7].
The clinical manifestation of all CAH forms is charac-
terized by the virilization of the outer genitalia. It can be
mild with a clitoral hypertrophy or a fusion of the poste-
rior labial folds only, but also as severe as a male pheno-
type with bilateral undescended testes. On further exam-
ination, all patients with a regular karyotype of 46,XX
have regular ovaries, Mullerian structures and regressed
Wolffian ducts, since the missing SRY prevented the de-
velopment of Sertoli cells and MIS, respectively.
Pure gonadal dysgenesis in genetic females is charac-
terized by bilateral streak gonads but regular female ex-
ternal and internal genitalia. However, affected females
usually present with sexual infantilism consisting of hy-
pergonadotropic hypogonadism, primary amenorrhea
and lack of breast development. They are closely related
Urol Int 2005;75:291–297 293
Review
in their sexual development to patients with Turner syn-
drome (45,X0) but lack the syndrome-typical features
[13].
True Hermaphroditism
The unique feature in true hermaphrodites is the co-
existence of regular testicular and ovarian tissue in the
same individual. The chromosomal distribution in about
65% of individuals is 46,XX, although 46,XY and mo-
saic forms like 45,XO/46,XY are possible. The patients
can either have a testis on one and an ovary on the other
side or they have a combination of both tissues in the
same gonad (ovotestis). The external phenotype is depen-
dent on the amount of androgens produced by the gonads,
but most patients are masculinized and about 75% are
raised as males [14]. Almost all patients have a uterus and
a urogenital sinus. On the side of the ovary, usually a fal-
lopian tube is found while the testis side always has a vas.
If an ovotestis is present, more than 65% will have a fal-
lopian tube only, while the rest either have only a vas or
both structures [15]. A cunning and interesting fact is the
existence of a testis in 46,XX patients, however the testis
part of the ovotestis is usually dysgenetic and even preg-
nancies are possible from follicles of the ovarian part of
the ovotestis [16].
Disorders of Gonadal Differentiation
Conditions in this category include seminiferous tu-
bule dysgenesis, like in Klinefelter‘s syndrome (47,XXY),
with small firm testes, gynecomastia, azoospermia, eu-
nuchoid statue and increased serum gonadotropins. Oth-
er chromosomal aberrations are seen in Turner syndrome
(45,X0) with short statue, lack of secondary sexual char-
acteristics, webbed neck, and coaractation of the aorta.
Mixed gonadal dysgenesis in most cases is character-
ized by a chromosomal distribution of 45,X0/46,XY.
They usually present with an intraabdominal testis on
one and a streak gonad on the other side [17]. Equivalent
to PAIS, patients present with a wide range of incomplete
masculinization, dependent on the degree of the gonadal
mal-development and the amount of androgens and MIS
secreted [15]. The Mullerian structures on the testis side
are usually regressed but can be in place on the streak go-
nad side.
294 Urol Int 2005;75:291–297
Management of Intersex Disorders and Sex
Assignment
The wide range of chromosomal, hormonal and clini-
cal presentations along with the expectations and cultur-
al circumstances of the family require an individualized
treatment of each patient. After the clinical diagnosis is
determined a careful evaluation of the situation with the
help of psychiatrists, endocrinologists and pediatric urol-
ogists has to be provided to the parents who ultimately
have to decide the appropriate gender for their child.
Since 70% of patients have FPH, the actual need for as-
signing a different sex of rearing from that of the karyo-
typical gonadal sex is quiet small.
Lately there has been an active discussion in the lit-
erature concerning sex assignment of children born with
intersex disorders or other anomalies involving the outer
genitalia like cloacal exstrophy or traumatic penile loss.
In the past it was believed that children without adequate
male genitals should be assigned to the female sex of rear-
ing [18, 19]. This common view was challenged by reports
of chromosomally male patients raised in the female sex
who, although they did not know about their previous sex
assignment, converted back to their chromosomal sex lat-
er in life [20–22]. Schober [23] reported about 10 inter-
sexuals who for the most part preferred sex partners that
had the same sex as their own assigned ones at birth. Ad-
ditionally the author concludes that the individuals are
successful in partnering and are satisfied with their sexu-
al function and that hormonal factors may influence the
behavior more than the correct anatomical situation. Mi-
geon et al. [24] followed 39 46,XY patients with sexual
ambiguity. Individuals assigned to the male gender had
significantly more surgeries and a worse surgical appear-
ance than females, but the majority was satisfied with
their body image in both groups. Although 23% were dis-
satisfied with their sex of rearing determined by their par-
ents, the majority of patients was exclusively heterosexu-
al and viewed themselves according to their assigned sex.
Adding to the controversy whether feminizing genitoplas-
ties should be performed is a recent study by Crouch et
al. [25]. Using questionnaires and functional assessments,
6 women who underwent genitoplasties in the past were
found to have severely impaired sensory and sexual func-
tion. But it has to be considered that most of these pa-
tients were operated upon years ago by children’s sur-
geons. These observations along with pressure from sup-
port groups question the practice of sex reassignment and
pose the question whether children with ambiguous gen-
italia should be raised in an intersex gender until they can
Frimberger/Gearhart

make a decision themselves which gender they choose
[26]. Nevertheless, in Migeon’s study [24], with many
years of follow-up, none of the affected individuals want-
ed a third gender and all agreed that surgery should be
completed in infancy or early childhood. Other groups
are concerned that the pressure and confusion of the in-
tersex condition could traumatize the child and the par-
ents more than the risk of choosing a gender for the child
[8, 27]. Until more data are available it will remain a con-
troversy and irreversible surgical procedures like remov-
al of the gonads or an underdeveloped phallus are cur-
rently rarely considered.
The Committee of Genetics and the sections of Endo-
crinology and Urology of the American Academy of Pe-
diatrics set up a number of considerations when deciding
the appropriate sex of rearing. According to the Commit-
tee, children with CAH or exposure to maternal andro-
gens should be raised in the female sex of rearing since
they are potentially fertile. The Committee acknowledges
the potential of testosterone imprinting in utero and the
well-known fact of more male-typical behavior of CAH
girls, but also points out that they generally do not dem-
onstrate sexual identity problems [9]. Other consider-
ations are the capacity for normal sexual and endocrine
function as well as the potential for malignant change of
the gonads.
More data and studies are needed before general guide-
lines and recommendations can be made. Until then the
parents have to be individually counseled and if desired,
a contact can be established with support groups or other
affected parents.
However, once a sex has been assigned, the treating
physicians should respect and support the decision and
carry out the necessary surgical and medical steps.
Surgical Management of Ambiguous Genitalia
The timing of the surgical procedures and the hormon-
al replacement is important from a surgical and social
point of view [28]. Surgical modifications usually concern
the gonads and the outer genitalia and often the presence
of a urogenital sinus. If a sex reassignment of a chromo-
somal male is decided, the gonads should be removed in
the first weeks of life. If a male sex of rearing is chosen,
hypospadias and undescended testes are corrected in the
first 18 months of life.
In CAH girls glucocorticoid and, if necessary, miner-
alcorticoid replacement is started after diagnosis and the
effectiveness controlled by routine serum 17-hyroxypro-
Ambiguous Genitalia and Intersex
Review
gesterone and androstenedione measurements [29]. Late-
ly the use of adrenalectomy as a treatment for CAH has
been proposed but has to be evaluated on higher numbers
and with longer follow-up to evaluate the long-term con-
sequences of removing the adrenal glands [30].
Feminizing Genitoplasty
Clitoroplasty. In the past clitoroplasties were per-
formed when the child was around 1 year of age [31].
However, advances in pediatric anesthesia and surgical
techniques cause most surgeons today to do the procedure
in the newborn period [32]. Formerly, the clitoris used to
be simply amputated if the surgery was performed by an
adult surgeon operating on an infant. Today, the surgery
is performed by pediatric surgeons and reconstructive
nerve sparing procedures are favored with the subtunical
excision of the erectile tissue [33]. Gearhart et al. [34] de-
scribed a nerve sparing procedure that protects the neu-
romuscular bundle and allows regular nerve conduction
and sensation and preserves later orgasmic function.
Vaginoplasty. Some authors prefer to correct the ex-
ternal genitalia in a single stage procedure in the newborn
period to take advantage of all native genital tissue and
avoid scarring [35]. Other groups advocate waiting with
the vaginal reconstruction until puberty when vaginal dil-
atations are more feasible to prevent vaginal stenosis
[36].
The technique used is dependent on the anatomical
findings. A simple cut-back vaginoplasty can be per-
formed when the vaginal orifice is separated from the
urethra and already reaches the perineum but is covered
by fused labia. If the vagina enters the urogenital sinus in
a low position, skin flaps can be created and placed into
the posteriorly opened urogenital sinus [37]. However, if
this procedure is performed in a high confluence sinus,
problems with hypospadias of the urethra and subsequent
vaginal voiding and incontinence can occur [38]. In va-
ginas with a high take off from the sinus, a pull-through
vaginoplasty [39] with complete separation of the vagina
from the urogenital sinus or a complete urogenital mobi-
lization without separation of the vagina can be per-
formed [40].
In patients with absent or rudimentary vaginas a com-
plete replacement is necessary. Progressive dilation using
dilators is a noninvasive method but requires continuous
dilatation and is not commonly used anymore [41]. Later
McIndoe [42] introduced a split-thickness skin graft sewn
over a vaginal mold to fit in the dissected rectovesical
space [43]. Initial results were favorable, but continuous
dilatations and stenosis remain problematic. The inter-
Urol Int 2005;75:291–297 295
Review
position of a sigmoid bowel loop as vaginal replacement
is commonly used today since it eliminates the need for
dilatation while the intestinal mucus provides lubrication
of the neovagina and allows excellent results [44, 45].
Labioplasty. The labioplasty is performed at the time
of the vaginoplasty and gives the external genitalia a nor-
mal female appearance. The dorsal hood of the foreskin
is incised and brought down to create labia minora, the
labia majora are moved inferiorly using a YV plasty
[28].
Phalloplasty. Testosterone stimulation in puberty can
increase the size of the phallus and should be substituted.
Radical mobilization at the time of hypospadias repair
can increase phallic length.
Phalloplasty using vascularized skin flaps with later
insertion of penile prosthesis can be applied after puber-
ty in patients with complete absence of penis.
However, currently there is no tissue available to in-
crease the size of an underdeveloped phallus in humans.
But several groups are investigating the possibilities in
tissue engineering to replace or create lost or mal-devel-
oped tissue or organs. Kropp et al. [46] used porcine in-
testinal submucosa for the repair of corporal deviations.
Kim et al. [47] seeded chondrocytes isolated from human
ears on rod-shaped biodegradable polymer scaffolds and
implanted them subcutaneously into athymic rats. The
same group successfully seeded human cavernosal smooth
muscle and endothelial cells on three-dimensional acel-
296 Urol Int 2005;75:291–297
lular collagen matrices derived from donor corpora. They
concluded that this might be useful techniques in the fu-
ture to replace lost erectile tissue for penile reconstruction
[48]. Currently human embryonic stem cells are under
investigation to regenerate the bladder in a rat model.
Therefore, with further research in tissue engineering it
might be possible in the future to replace and enhance
underdeveloped phalluses and vaginas [49].
Conclusion
The evaluation and diagnosis of the patient with geni-
tal ambiguity is challenging. Affected children should be
immediately transferred to a medical center familiar with
the management of these complex disorders. Accurate
diagnosis, close psychological support and information
are necessary to help the parents to deal with the situa-
tion. Surgical correction techniques have developed and
can provide satisfactory cosmetic and functional results.
The discussion of the management of patients with
intersex disorders continues. Current data challenge the
past practice of sex reassignment. Further data are neces-
sary to formulate guidelines and recommendations fitting
for the individual situation of each patient. Until then the
parents have to be supplied with the current data and
outcome studies to make the correct choice for their
child.
Frimberger/Gearhart

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