Congenital Anomalies of the

Female Genital Tract

?!

CONGENITAL ANOMALIES
Mllerian duct anomalies (MDAs)
Anomalies of the External Genitalia
Ambiguous genitalia/intersex anomalies

Chromosome: Why is
it important?

Sexual differentiation in the fetus

Adequate differentiation two fetal testicular
hormones, AMH or MRF and testosterone
AMH regression of MDs;
Testosterone - masculinization wolffian ducts
& urogenital sinus after reduction of
dihydrotestosterone (DHT)
autonomous in the
The MDs persist in the absence of AMH or
MRF
Wolffian ducts regress in the absence of
testosterone.

INTERMEDIATE MESODERM
BIPOTENTIAL GONAD

SRY

testis
sertoli

leydig

AMH

(-) MD

(-) uterus

ovary
granulosa

theca

(-) AMH
(-) T

DHT
follicles

MD

Estrogen
progesterone

Internal
Genitalia

Wolffian
Duct

Internal
Genitalia

External
Genitalia

Schematic diagram of testosterone biosynthesis in the Leydig cell of the testis and of th
mechanism of androgen action within target cells.
17HSD3, 17- hydroxysteroid dehydrogenase 3; 5aR2, 5a-reductase 2.

Indifferent Embryo
Genotype of embryo 46XX or 46XY is
established at fertilization
Weeks 1-6 sexually indifferent or
undifferentiated stage; that is genetically
female and male embryos are phenotypically
indistinguishable
Week 7 begins phenotypic sexual
differentiation
Week 12 female or male characteristics of
external genitalia can be recognized
Week 20 phenotypic differentiation is
complete.

ORMAL SEXUAL DEVELOPMENT IN EMBRYOGENESIS CONSISTS OF

THREE RELATED SEQUENTIAL PROCESSES
Establishment of chromosomal sex at fertilization, with
XY as male and XX as female. For the first two months of
gestation the two sexes develop in an identical fashion.

Determination of gonadal sex when the indifferent

gonad develops into an ovary or a testis, beginning at
week 8.

Development of sexual phenotypes as the result of

gonadal differentiation when the indifferent anlagen of the
internal and external genitalia develop into their
characteristic male or female structures

Indifferent Embryo
Components which form the adult
female and male reproductive systems
are:
1. Gonads
ovaries or testes
2. Genital Duct Systems
Paramesonephric and Mesonephric
Ducts
3. External Genitalia

 MD= mllerian ducts

(paramesonephric ducts)
WD= wolffian ducts (mesonephric
ducts)

Summary of differentiation
In females, the mllerian ducts give rise
to the fallopian tubes, uterus, and
upper vagina, and the wolffian ducts
persist in vestigial form.
In males, the wolffian ducts give rise
to the epididymides, vasa deferentia,
seminal vesicles, and ejaculatory ducts,
and the mllerian ducts regress.

Stage of Ductal differentiation (8 weeks):

Differentiation of male internal organs

- The Mullerian Inhibiting Hormone (MIH) (Sertoli cells ):

responsible for regression of the ipsilateral paramesonephric
ducts

- Testosterone (Leydig cells): responsible for developmen

of the mesonephric duct into the male internal genitalia

Differentiation of Female Internal Organs

In the absence of testes (MIF and testosterone) the
mesonephric system regress and the Mullerian duct
develop to give the fallopian tube, uterus, and upper
vagina.

PD: Paramesonephric duct

MD: Mesonephric Duct
US: Urogenital Sinus
MT: Mullerian Tubercle
UVP: Uterovaginal primordium
VP: Vaginal plate

I. EMBRYOLOGICAL DEVELOPMENT OF THE FEMALE

GENITAL TRACT
By the fifth to sixth week of gestation primordial germ
cells (endoderm) migrate from yolk sac to urogenital
ridge.
The mesoderm of the urogenital ridge becomes the
stroma and surface epithelium of the ovary.
At the sixth week the mullerian (paramesonephric) ducts
develops from the ceolomic epithelium. At their caudal
portion these paired ducts fuse medially and meet the
urogenital sinus located caudally.
External genitalia of male and female embryo
(23mm)

II. EMBRYOLOGIC ANLAGES OF THE

GYNECOLOGIC TRACT
Urogenital ridge + primordial germ cells =
ovary
Unfused portion of mullerian ducts = fallopian
tubes
Fused portion of mullerian ducts = uterus
and upper one third of vagina
Urogenital sinus = vestibule of external
genitalia

EMBRYOLOGIC DEVELOPMENT
OF THE UTERUS AND VAGINA

Wk 4

PronephrosDisappears

Wk 2-4

Mesonephros
Mesonephric duct forms at caudal end of
mesonephric tubule

Wk 5
WK 6

Ureteric bud appears, will form collecting

Mesonephros
ducts of kidney. KEY: kidneys start to form
early
Paramesone Forms under influence of mesonephros.
ph
Cranially they are lateral to the mesonephros
and open to the coelomic cavity, later formin
ros
fimbriated ends of the fallopian tube. As they
move caudally, they cross the mesonephros
and become medial to it. There they fuse
terminally at the urogenital septum or
mullerian tubercle.

Cranial portion degenerates in women but

Wk 10-16
Mesonephro remnants may persist and cause problems
1. Paroophoron and epophoron in the broad
s
ligament
2. Gartners cyst - in upper third of vagina,
cause dysparunia (pain with intercourse)
Wk 14

Dissolution of vertical septum between fused

ducts - development of single uterine fundus,
cervix and upper vagina
Paramesone
ros
ph

Embryology of Vagina
Derived paramesonephric ducts vs.
mesonephric ducts vs. urogenital sinus, or a
combination.
Most accepted, superior part derived fusion
paramesonephric , while inferior part arises
from urogenital sinus, BUT assumes the
inductor function of the mesonephric ducts
stimulate adequate
mullerian/paramesonephric development.

Theory of Mullerian Tubercle.

Mullerian tubercle cellular
condensation b/w inferior
part of fused
paramesonephric ducts and
urogenital sinus.
Sinovaginal bulbs develop,
constitute vaginal plate.
Cavity formed lined with
paramesonephric epithelium,
opens into the urogenital
sinus and the metaplastic
induction to polystratified
plain epiithelium would
produce the vagina.

Inductor role of mesonephric duct on vagina

Studies show sinovaginal
bulbs are caudal segments
of mesonephric ducts.
Between these bulbs and
caudally to the
paramesonephric ducts, a
solid epithelial structure is
located contacting the
dorsal wall of the urogenital
sinusthe mullerian
tubercle.

Mesonephric duct induction

Vagina derived from fused mesonephric
ducts and Mullerian tubercle.
Paramesonephric ducts form uterus to
external cervical os and adequate
formation is induced by mesonephric
ducts.
Mesonephric ducts regress cranially but
at cervical os, they enlarge and form
the sinovaginal bulbs.
The paramesonephric cellular
condensation (mullerian tubercle )
incorporates itself in the vaginal plate
formed by fusion of the two bulbs.
Cavitation allows the paramesonephric
cells to line the primitive vaginal cavity
with paramesonephric epithelium.

Agenesis of mesonephric duct

As ureteral bud sprouts from
the opening of the
mesonephric ducts in the
urogenital sinus, the absence
or distal agenesis of a
mesonephric duct would result
in an absence of its opening to
the sinus ( the origin of the
blind vagina) and in an
absence of the ureteral bud on
that side. Thus, the definitive
kidney would fail to develop
(ipsilateral renal agenesis)

Embryology of External Genitalia

Development external genitalia

Early, similar in both sexes
6th wk, three external protuberance surround
cloacal membrane, the left and right genital
swellings meet anteriorly to form the genital
tubercle.
12th wk identify difference.
Genital swelling
labioscrotal folds
scrotum or labia major
Genital tubercle
clitoris

phallus

penis or

Development of External Genitalia

Anlage

Male

Female

Genital
Tubercle

Glans and shaft Glans and shaft of

of penis
clitoris

Urogenital
Sinus

Penile urethra

Vestibule of
vagina

Urethral fold

Penis

Labia Minora

Labioscrotal
fold

Scrotum

Labia Major

Female and Male external genitalia

Role of Dihydrotestosterone
Differentiation depends indirectly on gonadal
secretion in male fetus.
Testosterone acts locally on the tubules but
not directly on the external genitalia.
Hormonal action is exerted by
dihydotestsoterone (DHT) formed from
testosterone by the 5 alpha reductase
enzyme.
DHT causes external genitalia to become a
penis and scrotum and induces development
of prostate

EMBRYOLOGIC DEVELOPMENT
OF THE UTERUS AND VAGINA
1. MDs (red area) fuse on the midline to form the
uterus
proximal part - duct gives rise to fallopian tube
wolffian ducts (green areas) regress
distal remnant of wolffian duct forms Gartner duct
mllerian ducts

wolffian ducts

EMBRYOLOGIC DEVELOPMENT
OF THE UTERUS AND VAGINA
2.

uterovaginal canal (red area) reaches urogenital sinus

(pink area)
(1). vaginal plate develops
(2), proliferates
(3), and undergoes canalization
(4). vagina is formed by both the MDs
and urogenital sinus (5).

UVC

UGS

Embryology
mllerian ducts

wolffian ducts

Vertical fusion
fusion of the ascending
sinovaginal bulb with the
descending mllerian
system
fusion of the lower one third
and upper two thirds of the
vagina
Complete vertical fusion
forms a normal patent
vagina
incomplete vertical fusion
results in an imperforate

hymen.

Remnants of the mesonephric (wolffian) ducts that may persist

the anterolateral vagina or adjacent to the uterus within the br
ligament or mesosalpinx.

Congenital abnormalities
Abnormalities of Mullerian duct
development:Absence/ incomplete
development of both
Abnormalities of Mullerian duct
development:Absence/ incomplete
development of one
Imperfect fusion

Overview: Mllerian Duct Anomalies

Background: Mllerian duct anomalies (MDAs)
uncommon often treatable cause of infertility higher incidence of infertility, repeated 1 st
trimester spontaneous abortions, fetal IUGR,
fetal malposition, preterm labor, & retained
placenta
Role of imaging -detect, diagnose, & distinguish
surgically correctable forms from inoperable
forms
In some correctable lesions, the surgical
approach is altered based on imaging findings.

Prevalence
Population - 5%
Infertile women - 3%
Recurrent miscarriages - 5-10%
Late abortions/ immature deliveries 25%

Prevalence
Race: No racial predilection
Age: Anomalies may be diagnosed in infancy,
adolescence, or young adulthood.
Infants: Obstructed mllerian system
(mucocolpos);
Adolescents: Primary amenorrhea, mass
(hematocolpos), or delayed onset of
menarche;
Adults: Fertility problems and/or carrying
pregnancy to term

Pathophysiology
2 paired MDs ~ female reproductive tract. fallopian
tubes, uterus, cervix, and upper 2/3 of vagina.
ovaries and lower 1/3 of vagina~separate embryologic origins
not derived from mllerian system.

Complete formation & differentiation of the MDs-3

phases of development as follows:
Organogenesis: One or both MDs may not develop fully
Fusion:
Lateral
vertical complete, incomplete

Septal resorption: After the lower MDs fuse, a central septum is

present, which subsequently must be resorbed to form a single
uterine cavity and cervix

Pathophysiology
Ovaries & lower vagina-not derived
from mllerian system
Ovaries - germ cells
lower vagina - arises from sinovaginal bulb

Morbidity / Mortality
MDA - not associated w/ significantly
increased mortality
Increased morbidity - obstructed or partially
obstructed mllerian systems: hematosalpinx,
hematocolpos, retrograde menses, &
endometriosis
Fairly high association - MDAs & renal
anomalies such as unilateral agenesis.
Anomalies are found only when dedicated
renal imaging is performed after the mllerian
abnormality is discovered; most commonly
seek medical attention because of infertility &
repeated pregnancy loss.

Complications
Menstruation: spasmodic
dysmenorrhoea, Menorrhagia
Coital: dyspareunia
Infertility: 1/4 reproductive problems
Obstetrical: abortions, preterm labour,
malpresentation, obstructed labour,
contractions poor

Anatomy
MDAs
PREVIOUSLY: categorized most commonly
into 7 classes according to the American
Fertility Society (AFS) Classification
Scheme (1988) as follows:

Normal Uterus

Classification based on Anatomy

Class I (hypoplasia/agenesis)
Class II (Unicornuate uterus)
Class III (Didelphys uterus)
Class IV (Bicornuate uterus)
Class V (Septate uterus)
Class VI (Arcuate uterus)
Class VII (Diethylstilberol associated
anomalies)

Based on similar
Classification into 3 groups:
embryonic development defects and clinical presentation

1. Agenesis of uterus/vagina:
Rokitansky-Kuster-Hauser Syndrome.
2. Defects in Vertical Fusion
(obstructive or non-obstructive)
3. Lateral Fusion defects (obstructive or
non-obstructive).

Revised Classification System

Acien proposed embryological classification.
1.Agenesis of urogential ridge absence kidney, ovary,
fallopian tube, hemiuterus, hemivagina.
2. Isolated Mullerian anomalies (probably also induced by
minor mesonephric defect) affect:
A. Paramesonephric uterine and/or tubal anomalies
B. Mullerian tubercle agenesis or atresia vagina.
C. All Paramesonephric derivatives RokitanskyKuster-Hauser syndrome.
3. Anomalies urogenital sinus urogenital membrane
(imperforate hymen).

Revised Classification System

4. Mesonephric anomalies, with absence
opening in urogenital sinus and forming
ureteral bud. Usually uterine anomaly,
b/c lack of inductor function of
mesonephric duct, as well as unilateral
renal agenesis and ipsilateral blind
vagina
5. Combination of above malformations

Anomalies of the internal genital tract

"Mllerian anomalies"
Obstructive Mullerian Anomalies
Longitudinal Fusion Anomalies
Agenesis/Hypoplasia And Other
Miscellaneous Anomalies

HYPOPLASIA/AGENESIS
includes entities - uterine/cervical agenesis or
hypoplasia
most common form: Mayer-RokitanskyKuster-Hauser syndrome (combined
agenesis of the uterus, cervix, and upper
portion of the vagina)
Vaginal anomalies-Cloaca malform, UG
sinus, Atresia
no reproductive potential

Mayer-Rokitansky-Kuster-Hauser Syndrome (uterovaginal agenesis)

15% of primary
amenorrhea

Normal secondary
development & external
female genitalia

Normal female range

testosterone level

Absent uterus and upper

vagina & normal ovaries

Karyotype 46-XX

15-30% renal, skeletal

and middle ear anomalies

RKH Syndrome: Diagnosis

Expected Menarche
Difficult to differentiate from
imperforate hymen
No uterus on exam, U/S, MRI,
Laparoscopy, IVP
Confused with Androgen Resistance
Syndrome with shallow pouch and no
uterus.
Determine karyotype.

RKH Syndrome: Etiology

Molecular mechanisms for differential
development:
Hox-9, 10, 11, 13 are expressed along
the length of mullerian ducts. Alteration
of HOX genes may give rise to mullerian
anomalies

RKH Syndrome: Treatment

Goal is to restore normal sexual function through creation

of neovagina.
Nonsurgical:
1. Frank technique: Pressure to perineal dimple.
2. Ingram method: Bicycle seat stool.
Surgical: Create neovagina
1. McIndoe operation: Skin graft between
rectum/bladder
2. Sigmoid vaginoplasty:
3. Vecchietti operation: transabdominal approach.

Obstructive Mllerian anomalies

Transverse vaginal septa:
Cervical agenesis
Imperforate hymen (embryo logically not of
mullerian origin)

Patients with this type of anomaly will usually

presents with amenorrhea or Cyclic pain due
to accumulated menstrual flow.

Potential sites of transverse vaginal septa.

A. High septum. B. Midvaginal septum. C.
Low septum.

Vaginal atresia

a, Isolated congenital cervical atresia with

normal vaginal development.

b, Congenital
cervical atresia
with complete
vaginal
agenesis

Hymen
originates from the embryonic vagina buds
from the urogenital sinus
a composite of vaginal epithelium and
epithelium of the urogenital sinus interposed
by mesoderm.
becomes perforated or forms a central
canal establishing a communication between
the upper vaginal tract and the vestibule of
the vagina

Imperforate Hymen:
The hymen represents the junction of the sinovaginal bulbs with the urogenital
sinus; hence it is formed form the endoderm of the urogenital sinus epithelium

Clinically:

May be discovered at birth ( "mucocolpos or

hydrocolpos"
More commonly at puberty: hematocolpos.

Vertical fusion
fusion of the ascending
sinovaginal bulb with the
descending mllerian
system
fusion of the lower one third
and upper two thirds of the
vagina
Complete vertical fusion
forms a normal patent
vagina
incomplete vertical fusion
results in an imperforate

hymen.

Imperforate hymen
solid membrane interposed between the
proximal uterovaginal tract and the
introitus
vertical fusion defect
most frequent cause of vaginal outflow
obstruction
0.1% of infant girls

Clinical Presentations
asymptomatic patient (incidental finding)

primary amenorrhea
Abdominal pain
back pain.

Physical Exam
Abdomen
Flat
soft
(+) hypogastric pain on deep palpation

Diagram of hematometra and

hematocolpos with imperforate
distal transverse vaginal septum

Physical Exam

Pelvic Exam
no vaginal opening

Rectal exam
good sphincteric tone
empty rectal vault
uterus cannot be
assessed due to
voluntary guarding

Imperforate Hymen

Hymenotomy

Treatment: SURGERY (Comprehensive

Gynecology 2nd edition)
Cruciate incision into
the hymen
extending to the 10,
2 and 6 o clock
position
In thick dense
hymen, triangular
section may be
excised
Hemostasis by fine
suture

Procedure
Y shape incision
2, 10 and 6 oclock
position

Menstrual blood
suctioned
500ml reddish brown
blood

 Packing with
vaselinized OS

Clinical Presentation

Adolescent (Nazir, 2006)

primary amenorrhea
cyclical lower abdominal or pelvic pain
back pain
urinary retention (37-60% of patients)
constipation
Palpable lower abdominal mass
Pelvic mass on bimanual rectal exam
distended, bluish membrane on introitus

Differential diagnosis
transverse vaginal septum
Rokitansky-Kster-Maier-Hauser syndrome

 Rokitansky-Kuster- Hauser syndrome

Diagnosis:
primary amenorrhea at the time of puberty
absence of a vaginal opening or presence of a
short vaginal pouch
failure to palpate a uterus on rectal examination
Ultrasound: presence of normal ovaries and
absence of uterus

 Transverse Vaginal Septum

Canalization of the mullerian tubercle and
sinovaginal bulb is not complete
Lies at the junction of the upper third and
lower two thirds of the vagina
Partial or Complete
Septum is thin <1cm
Partial reported in DES exposed females

 Transverse Vaginal Septum

primary amenorrhea
cyclic cramping
Incomplete septum
Vaginal bleeding
Hematocolpos distention of obstructed vagina
with blood and blood products
hematometrium
foul smelling discharge

Diagnostics
Ultrasonography
reliable
Rapidly diagnose hematocolpos or
hematometrocolpos

Transrectal ultrasonography
Delineates complex anatomy

MRI
If a complex mass is suspected

MRI and sonography

aid in excluding associated congenital anomalies of
the urinary tract.

Diagnostics
Other Tests:
Laparoscopy
recommended to evacuate pelvic and intraabdominal endometrial material generated
because of retrograde menstruation.
speculated to reduce the potential for
secondary endometriosis.

 Diagnostic Procedures:

Careful physical examination combined with

imaging is usually sufficient to establish
the diagnosis.

Complications
recurrent obstruction
ascending pelvic infection
Endometritis
Salpingitis
Tuboovarian abscess
2ndary endometriosis from retrograde
menstruation
advocate irrigation of the peritoneal cavity by
using a laparoscopic technique

Clinical Presentation
Neonate
bulging membrane between the
labia
membrane may be white distended
from trapped mucoid material
(maternal estrogen)
Severe cases, distention in the distal
vaginal tract extends proximally into
the uterus
A lower abdominal midline mass
Mucocolpos (collection of
secretion behind the hymen) lead to
UTI or bladder obstruction

Defects of Mullerian Duct fusion:

Unlike obstructive anomalies that usually

presents with primary amenorrhea, fusion
anomalies are often associated with
gynecological as well as obstetrics
complications e.g. infertility, recurrent pregnancy loss and
poor obstetrics outcome in pregnancy

Some case where there is partial obstruction

e.g. a unilateral rudimentary horn, may
present early in the years following puberty
usually with primary cyclic dysmenorrhea.

Anomalies of lateral fusion of the mullerian ducts: This may

be partial or complete failure of fusion.
Anomalies due to unilateral defects of Mullerian duct development:

Diethylstilbestrol Associated anomalies:

Uterine fusion anomalies

A. Normal uterus

Unicornuate
uterus

Septate uterus
Bicornuate
uterus

Arcuate uterus

Didelphic uterus with a

septate
vagina

UNICORNUATE UTERUS
complete, or almost complete,
arrest of development of 1
mllerian duct
If the arrest is incomplete, as in
90% of patients, a rudimentary
horn with or without functioning
endometrium is present.
If the rudimentary horn is
obstructed, it may come to
surgical attention when presenting
as an enlarging pelvic mass.
If the contralateral healthy horn is
almost fully developed, a full-term
pregnancy is believed to be
possible (see didelphys uterus).

DIDELPHYS UTERUS

complete nonfusion of both

mllerian ducts
The individual horns are fully
developed and almost normal in
size
Two cervices are inevitably
present
A longitudinal or transverse
vaginal septum may be noted
as well
Didelphys uteri have the
highest association with
transverse vaginal septa but
septa also may be observed in
other anomalies
Consider metroplasty; however,
since each horn is almost a fully
developed uterus, patients have
been known to carry
pregnancies to full term

BICORNUATE UTERUS
partial nonfusion of the
mllerian ducts
The central myometrium
extends to level of
internal os (bicornuate
unicollis) or external os
(bicornuate bicollis).
Distinguished from
didelphys uterus
because of some
degree of fusion b/w the
two horns-horns of
bicornuate uteri not fully
developed; typically,
smaller than those of
didelphys uteri.
Some patients are
surgical candidates for
metroplasty.

BICORNUATE UTERUS. The midline uterine external fundal

cleft
(superior
border) - depression of greater than 1 cm,

excluding
septate uterus from differential diagnosis. This image is of
bicornuate bicollis 2 cervices are present. Bicornuate
uterus is distinguished from didelphys uterus because
some degree of fusion has occurred b/w lower uterine
segments (ie, they are fused, but cavities are not
communicating).

BICORNUATE W/ pregnancy

SEPTATE UTERUS

Muscular

Fibrous

Failure of resorption of the septum b/w two uterine horns. Septum

partial or complete, in w/c case it extends to the internal cervical os

Histologically, septum composed of myometrium or fibrous tissue.
uterine fundus typically convex but may be flat or slightly concave (<1
fundal cleft).
with septate uterus -highest incidence of reproductive complications
Differentiation b/w a septate and a bicornuate uterus is important bec
septate uteri are treated using transvaginal hysteroscopic resection of
septum,
while if surgery is possible and/or indicated for the bicornuate uterus,
abdominal approach is required to perform metroplasty.

Bicornuate and Septate Uterus

Bicornuate and Septate Uteri

Bicornuate:
Fundus indented
Partial fusion of
mullerian ducts
Variable degree of
separation of uterine
horns that can be
complete, partial or
minimal
HSG wont dx, need
laparoscopy
Minimal reproductive
problems, however can
have pregnancy loss,
PTL, etc.

Septate:
Normal external surface,
need laparoscopy to dx
Defect in canalization or
resorption of midline
septum between mullerian
ducts.
Septum can cause
infertility, recurrent
midtrimester loss
Tx: resection of septum
hysteroscopically or
hysteroscopic metroplasty

Septate Uterus: Partial and Complete

Septate Uteri

Bicornuate Uterus

ARCUATE UTERUS

single cavity with convex or

flat uterine fundus
outer contour of uterusconvex or flat
endom cavity, shows
small fundal cleft or
impression (>1.5 cm)
normal variant not
significantly associated w/
increased risks of pregnancy
loss & other complications

DIETHYLSTILBEROL ASSOCIATED ANOMALIES (DES)

Several million
Treated with diethylstilbestrol (DES; an estrogen
analog used to prevent miscarriage) 1945-1971
The uterine anomaly in offspring of as many as
15% of exposed to DES during pregnancy
fetuses - variety of abnormal findings
uterine hypoplasia and a T-shaped uterine cavity
abnormal transverse ridges, hoods, stenoses of the
cervix, and adenosis of the vagina
risk of vaginal clear cell carcinoma
Imaging findings are pathognomonic for this anomaly

 T-SHAPED UTERUS
Classic configuration of the uterine cavity in a typical
diethylstilbestrol-exposed uterus
Uteri are typically hypoplastic.

Treatment
Vaginal septum
Uterine septum
Rudimentary uterine horn
Bicornuate uterus

Anomalies of the External Genitalia

Very troubling
parents
unconscious emotional
significance
impact of deformities on future
generations

Labial Adhesion
children
chronic inflammation - vulva
usually asymptomatic but
when introitus sealed
completely- Complications
Treatment topical 1%
estrogen cream (tid x 2 wk)

Ectopic labium and clitoral duplication

rare anomaly
homologous to ectopic scrotum
reported w/ renal agenesis or dysplasia
and the VATER (vertebral defects, anal
atresia, tracheoesophageal fistula,
esophageal atresia)
Clitoral duplication usually seen in
bladder exstrophy/epispadias complex
in

Clitoral hypertrophy
fetal exposure to androgens
result of congenital deficiencies of
adrenal enzymes -cortisol synthesis;
more rarely, idiopathic virilization or
exposure to progestational agents in
utero.
Although rare, by neurofibromas of the
clitoral corpora
TREATMENT:
degree of masculinization, Spence-Allen
technique- better results than technique
by Pelleren
Pelleren plication complicated by painful
engorgement of recessed corpora at
puberty

Interlabial masses

Urethral prolapse
Prolapsed ectopic ureterocele
Hydrocolpos or hydrometrocolpos
Sarcoma botryoides or rhabdomyosarcoma
Periurethral cyst

Interlabial masses
Vaginal Polyp

Hymenal Polyp

Persistent urogenital sinus & cloaca

Simple urogenital sinus
Persistent urogenital sinus

compatible w/ life
Mx: one of the greatest challenges of
pediatric surgery & urology
Devt of lower urinary tract, genital &
anorectal systems is correlated closely in
Consequently, abnormal embryological devt
can involve all 3 systems.

Persistent urogenital sinus & cloaca

Clinically, persistent urogenital sinus in

classified into the ff 3 categories:
Simple urogenital sinus w/ N anus &
rectum & w/o intersex condns
Urogenital sinus w/ intersex condns
Urogenital sinus associated w/ anorectal
malformation (ie, persistent cloaca, vaginal
anomalies)

Intersex Conditions
Ambiguous genitalia
External appearance

Ambiguous Genitalia and Intersexuality

Traditional intersex classifications
Based on the differentiation of the gonad:
1. TYPE I pseudohermaphrodite - Two ovaries
2. TYPE II pseudohermaphrodite - Two testes
3. TYPE IV True hermaphrodite - Ovary and/or testis
and/or ovotestis
4. TYPE III Mixed gonadal dysgenesis - Testis plus
streak gonad; Pure gonadal dysgenesis - Bilateral
streak gonads

(streak gonad is dysgenetic & resembles ovarian stroma.

Germ cells absent.)
The internal ducts & external genitalia may vary in
development

Diagnosis
History- Familial Hx detailed
Physical Examination- Very meticulous
Lab Studies:
Logical workup in infants w/ambiguous
genitalia includes the ff:

Chromosomal analysis
Endocrine screening
Serum chemistries/electrolyte tests
Androgen-receptor levels
5-alpha reductase type II levels

Physical Examination
External genitalia examination
size & degree of differentiation of structures
position of urethral meatus
Labioscrotal folds may be separated or folds may be fused
at the midline-giving scrotum-like appearance
Rugose scrotal or labioscrotal folds w/ pigmentation
possible corticotropin levels as part of adrenogenital
syndrome.
Gonadal examination
Palpation of gonads is important
inguinal gonads palpable, diagnoses is gonadal , Turner
syndrome, & pure gonadal dysgenesis can be eliminated.
Impalpable gonads possibility of a severely virilized
pseudohermaphrodite w/ CAH.
Rectal examination
Rectal examination ~ internal mllerian structures.
The uterus

Diagnosis
Imaging Studies:
Renal/bladder ultrasound: bedside in NICU
UTZ; visualization of a neonate's adrenal
glands, may be enlarged in infants w/ CAH;
low sensitivity
adrenal glands in CAH- glands cribriform
appearance
help identify mllerian structures
In a neonate, findings of ambiguous genitalia,
enlarged adrenal glands, and evidence of a
uterus are virtually pathognomonic for
CAH.

Diagnosis
Genitography: ductal anatomy
catheter inserted into distal urogenital sinus
(urethra)
Contrast outlines internal ductal anatomy.
Findings indicate N urethral anatomy, an
enlarged utricle, a mllerian remnant in , a
common urogenital sinus, or an area of
vaginal & urethral confluence in neonates.
CT scan & MRI-usually not indicated
may help identify internal anatomy

Diagnosis
Procedure
s:
1. EL/gonadal biopsy-many advocate
laparoscopy
2. Diagnostic laparoscopy/gonadal
biopsy: rapid identification and
delineation -Biopsy-gonads w/
additional trocars
3. Histologic Findings: Analysis - biopsy
specimens identify ovarian tissue,
testicular tissue, ovotestes, or streak
gonads

TYPE I

Pseudohermaphrodite

result of relative androgen excess in utero

- two ovaries & 46XX
level of androgen present-embryogenesis
results in genital ambiguity & may result --

phenotypic

Tumors, if they appear, are virtually

always benign.

TYPE I
Pseudohermaphrodite
Overall, CAH - most frequent cause in newborn~ 60% of intersex
cases

CAH produces PH, - a gonadal virilized phenotype

Basic biochemical defect - enzymatic block insufficient cortiso

production
Biofeedback via the pituitary gland causes the precursor to
accumulate above the block

Spectrum of abnormalities, including the degree of phallic

enlargement, the extent of urethral fold fusion, and the size and level
of entry of the vagina into the urogenital sinus

Although the degree of virilization seen in CAH can be extrem

internal mllerian structures are present consistently

TYPE I

Pseudohermaphrodite

In these children, endocrine stabilization must be

individualized, a process that usually takes several
weeks.
Clinical
CAH may result from the following:
manifestation depends on w/c enzymatic defect is present
21-Hydroxylase deficiency (CYP21)
11-Hydroxylase deficiency (CYP11B1)
3-Beta-hydroxysteroid dehydrogenase deficiency
Maternal androgens

CYP11A1, cholesterolm side-chain cleavage enzyme; desmolase; CYP17, 17a-hydroxylase/17,2

3b-HSD, 3b-hydroxysteroid dehydrogenase; CYP21A2, 21-hydroxylase; CYP11B1, 11b-hydroxy
CYP11B2, aldosterone synthase, corticosterone 18-methylcorticosterone oxidase/lyase

21-Hydroxylase deficiency
(CYP21)

90% of patients with CAH,

21-hydroxylation enzyme- mineralocorticoid deficiency - buildup of
androgenic byproducts, leads to masculinization fetus
result infant ~ varying degrees of virilization
75% have salt-wasting nephropathy
autosomal recessive trait
2 varieties, account for clinical heterogenicity seen w/ salt-wasting
nephropathy
Prenatal diagnosis - elevated AF level of 17-OHP: 2nd trimester or
HLA typing of amniotic cells
CAH is dxed - following birth given a 46, XX child w/ ambiguous
genitalia- rectal examination or retrograde genitogram - evidence
internal mllerian structure~cervix.
Diagnosis -elevated serum level of 17-OHP
newborn cord blood levels as high as 900-5000 ng/dL
rapidly decreases by 2nd or 3rd day of life
repeat elevated serum > 500 ng/dL - diagnosis highly likely
17-OHP levels may be markedly elevated in 11-hydroxylase form
CAH, also in child w/ 3-beta-hydroxysteroid dehydrogenase form o
CAH

21-hydroxylase deficiency
Mild virilization 46 XX
female
Despite the mild

clitoromegaly, this patient

has fusion of the labialscrotal folds and is a salt
waster.

Severe virilization 46 XX
female
This patient also has salt
wasting

11-Hydroxylase deficiency (CYP11B1)

11-hydroxylase block accumulate:

deoxycorticosterone (DOC) and 11deoxycortisol
salt retention and hypertension becau
DOC is a potent mineralocorticoid
Suspect this diagnosis in a 46, XX child
with ambiguous genitalia~mildly
elevated 17-OHP
The diagnosis can be confirmed by a
steroid screen of the serum

CYP11A1, cholesterolm side-chain cleavage enzyme; desmolase; CYP17, 17a-hydroxylase/17,2

3b-HSD, 3b-hydroxysteroid dehydrogenase; CYP21A2, 21-hydroxylase; CYP11B1, 11b-hydroxy
CYP11B2, aldosterone
synthase, corticosterone 18-methylcorticosterone oxidase/lyase

3-Beta-hydroxysteroid dehydrogenase deficiency

A less frequently seen version of CAH
less severe virilization of female infant than other
defects
buildup of pregnenolone~ hepatic conversion into
testosterone, produces virilization
Can present w/ salt-losing crisis caused by deficient
mineralocorticoid production, similar to 21hydroxylase deficiency
Diagnosis : elevated serum dehydroepiandrosterone
or its sulfate metabolite
ONLY 3-beta-hydroxysteroid dehydrogenase deficiency
the only common form of CAH causes ambiguity in the
genetic
ambiguity occurs because enzyme defect is present in
both the adrenal glands and the testes, leading to
inadequate production of testosterone in utero

CYP11A1, cholesterolm side-chain cleavage enzyme; desmolase; CYP17, 17a-hydroxylase/17,20-lya

3b-HSD, 3b-hydroxysteroid dehydrogenase; CYP21A2, 21-hydroxylase; CYP11B1, 11b-hydroxylase;
CYP11B2, aldosterone
synthase, corticosterone 18-methylcorticosterone oxidase/lyase

Maternal androgens

Rarely may be drug induced

Virilization may occur if progestational agents or androgen
used during 1st trimester
After the1st trimester ~ only phallic enlargement without
labioscrotal fusion
The incriminated drugs formerly administered to avoid
spontaneous miscarriages in patients who had a history of
habitual abortion

Endocrine abnormality in the mother as a source of virilizin

hormones is even rarer because these abnormalities, if ini
present, usually prevent development of a pregnancy

However, ovarian tumors (eg, arrhenoblastomas, Krukenbe

tumors, luteomas, lipoid tumors of the ovary, stromal cell
have produced virilization of fetus

TYPE II
Pseudohermaphrodite

heterogeneous group
characterized by intrauterine state of relative functional
androgen deficiency, an apparently normal 46 XY
karyotype
and either identifiable testes or evidence that testes were
present during fetal development
Ext genitalia usually female or ambiguous
in certain categories (e.g. testicular regression syndrome)
may appear as phenotypically male
The defect may be in
1. the gonad-leading to deficiency in androgens, MIS, or
both
2. end-organ -tissues unresponsive to androgens or MIS
lead to abnormal phenotype
Tumors, if they occur, are sometimes malignant

TYPE II
Pseudohermaphrodite

1. Isolated deficiency of MIS

2. Deficient testosterone biosynthesis
3. Androgen insensitivity (causing
testicular feminization)
4. 5-alpha-reductase deficiency

Isolated deficiency of MIS

RARE SYNDROME genitalia appear ~ w/undescended testes.

phenotypic findings 46, XY genetic and gonadal isolated defect i
testis is a complete failure to produce MIS
most common presentation - phenotypic w/ inguinal hernia on o
side & an impalpable contralateral gonad.
Herniorrhaphy -uterus & fallopian tube in hernia sac
testis
testosterone, a vas deferens presents bilaterally. At times
the vas deferens ends blindly.
surgical management - bring testes into scrotum ~ testis tumors m
occur later
malignancy is unknown. Removal - mllerian remnants unnecessa
since remnants rarely produce symptoms & have no reported hist
of subsequent malignancy.
pseudohermaphrodism occasionally occurs in families. Confined
s expressing the characteristic, inheritance may be either X-link
recessive or autosomal dominant.
Genetic counseling is important.

Deficient testosterone biosynthesis

Production of testosterone -5 enzymatic steps, defects identified at each s

3 enzymes shared with the adrenal glands
20-alpha hydroxylase, 3-beta-hydroxysteroid dehydrogenase,
17-alpha hydroxylase deficiency leads to ambiguous genitalia / sympt
CAH.
17, 20 desmolase and 17-ketosteroid reductase occur only as part of N
androgen synthesis, so their defects, while associated with genital
abnormalities, are not associated with CAH.
biochemical diagnosis of syndromes is possible, but impractical
newborn period- patients present as 46, XY gonadal w/ poor virilization
ambiguous genitalia.

genitalia respond exogenous testosterone. CAH manifestations also requir

treatment - steroid & mineralocorticoid replacement.
Genetic counseling is desirable because 17-alpha hydroxylase and 3-be
hydroxysteroid dehydrogenase deficiencies ~transmitted autosomal reces
traits.
Additional rare causes for deficiencies in testosterone production include L
cell agenesis, Leydig cell hypoplasia, abnormal Leydig cell gonadotropin
receptors, and delayed receptor maturation.

Androgen insensitivity (causing testicular feminization)

Syndromes of androgen insensitivity involve end organ failure
(external genitalia and prostate) in a 46, XY gonadal male fetus
to respond to appropriately produced levels of DHT.
basic pathophysiology of the lack of androgen effect on the
genitalia
Some are receptor (-); cytosol receptors cannot bind DHT.
Another variant is receptor(+) receptors apparently permit DHT
binding, but DHT does not lead to normal differentiation toward
the male phenotype.
Inheritance appears to be X-linked. Complete androgen
insensitivity presents in infancy only if the child has a shallow
blind-ending vagina, reflects lack of internal mllerian
development expected in an XY patient whose testes
manufacture MIS at reference range levels.
Inguinal hernias - common in testicular feminization, occasionally
detected.

 Despite a 46, XY karyotype and gonads with the

typical appearance of testes
a feminine gender assignment is unquestionable ~
completely feminine phenotype and because of
end-organ failure
diagnosis is crucial - syndrome is associated (+)
significant incidence of gonadal malignancies
(germinomas) ~ seminomas because tumors arise
in a testis.
gonadal malignancies ~ 6%, with incidence
rising > 30% by age 50 years
Sertoli cell and Leydig cell tumors,Tubular cell
adenomas, also fairly frequent, have a potential
for malignancy because neoplastic transformation
has been reported.

 Disagreement ~ best timing for gonadectomy

Scully~gonadectomy after puberty

The Children's Hospital of Philadelphia ~ remove testes
early because morbidity is minimal in a young child
hormone replacement requirement, vaginoplasty may be
required, vaginal dilation in some
An incomplete form of androgen insensitivity~spectrum
syndromes -very feminine (eg, Lubs syndrome) to
increasingly masculine (eg, Gilbert-Dreyfus syndrome) to
most masculine (eg, Reifenstein syndrome).
incomplete androgen insensitivity~ suggested by elevat
LH levels + reference range levels of plasma DHT and 5
alphareductase activity in genital skin fibroblasts.
Exogenous androgens do not cause adequate virilization

5-alpha-reductase deficiency

A 46, XY fetus w/ normal testes but lacks enzyme 5-alpha

reductase in cells of ext. genitalia & urogenital sinus cant
produce DHT
fetus born w/ minimally virilized ext. genitalia (eg,
pseudovaginal perineoscrotal hypospadias), has a degree
of phallic enlargement -action of testosterone
striking featureextreme virilization at puberty dramatic penile growth, masculine voice & muscle mass.
The only characteristics that do not develop are those
that depend on DHT (eg, prostatic enlargement, facial
hair, acne

5-alpha-reductase deficiency

Diagnosis of in a patient with a

46, XY karyotype ratio of serum testosterone to DHT N reference
range ratio is 8-16:1
5-alpha-reductase deficiency > 35:1.
Gender assignment ~ has been debated
because of the major virilization that occ
at puberty
1st 60 days of life, LH surge that obviates the
to carry out hCG stimulation, w/ may be usefu
exaggerate the testosterone-to-DHT ratio
characteristic of this syndrome.

TYPE IV
True hermaphrodite
Background: Ovotestis-both ovarian follicles
and testicular tubular elements
found exclusively in - true hermaphroditism
usually compartmentalized-connective tissue
separating the ovarian from testicular
components
rarely intermixture of elements occur
This diagnostic nomenclature is applied
regardless of the peripheral karyotype

TYPE IV
True hermaphrodite

Frequency: 1.Ovotestes 2. Ovaries 3.Testes

Ovaries & ovarian portions of ovotestes appear
N & demonstrate follicular growth w/ estradiol
production~ 50% of ovotestes show evidence of
ovulation
Estradiol in developing ovarian follicles inhibits
spermatogonia devt in adjacent or contralateral
seminiferous tubules
Degeneration & hyalinization of seminiferous
tubules w/ poor germ cell devt observed
frequently. Leydig cell hyperplasia also may
occur. Spermatogenesis in testis & ovotestis is
rare.

TYPE IV
True hermaphrodite

true hermaphroditism-ambiguous
genitalia at birth
s - as
majority affected have been reared
However, because of functioning N ovarian
tissue, most people w/ true hermaphroditism
experience breast devt at puberty, & 40% w/
a 46,XX peripheral karyotype menstruate

TYPE III

Mixed gonadal dysgenesis

MGD & dysgenetic PH are considered

together because of the similarities
found in these two causes of ambiguous
genitalia

TYPE III
Mixed gonadal dysgenesis
Term~ dysgenetic pseudohermaphroditism
(DMP) to describe - bilaterally dysgenetic testes &
incomplete virilization of the internal sex ducts
& external genitalia
Federman - similarities in karyotype, gonadal histology,
& phenotype that this group shares w/ pxs w/ MGD & w/ true
hermaphroditism
.
these 2 groups of patients - defect in sex chromosomes
that causes AbN testicular differentiation thus incomplete
virilization - ambiguous genitalia.
Precisely defined, DMP is an intersex state - bilaterally
dysgenetic testes w/ persistent internal MD structures,
cryptorchidism, & incomplete external virilization.
A dysgenetic testis histologically demonstrates
immature and hypoplastic testicular tubules in a
stroma characteristic of ovarian tissue but that lacks
oocytes.
This stroma similar to streak gonads - helps explain the
similarities of these syndromes

TYPE III
Mixed gonadal dysgenesis

Pxs w/ MGD have a streak gonad on 1 side w/ a

contralateral testis. Although degree of virilization varies,
pxs have a vagina and a uterus, & most have a
fallopian tube, at least on the side of the streak.
Most have mosaic karyotype, XO/XY
XO karyotype~short stature
DMP Pxs likely to have 46, XY karyotype
Internal mllerian remnants tend to be present in pxs w/
DMP who have an XO in the karyotype
Male PHs w/o internal mllerian remnants usually have
XO component; more virilization is observed both interna
& externally
Included in this group - Klinefelter syndrome w/ an XXY
karyotype or patients w/ the sex-reversal syndrome w/ an
XX karyotype.

TYPE III
Mixed Gonadal Dysgenesis
major feature shared by MGD and DMP is the risk of gonadal
malignancy when a Y chromosome is present in the karyotype.
~ 25% of gonads, including streak gonads malignant change, most
common gonadoblastoma, - gonadectomy before adulthood. Early
gonadectomy appears wise (1st decade)
seminomas and embryonal cell carcinomas
Gender assignment under debate
Glassberg, - no case reported of a tumor developing in fully descended
testis in MGD or DMP assign gender if sufficiently virilized

Rajfer and Walsh- elective feminine gender assignment for MGD

because a uterus & vagina always (+) & of patients markedly short w
have a high incidence of inadequate external virilization
MGD & DMP-consider gender assignment only for most
significantly virilized w/ completely descended testis.
Estrogen support is required if raised as . If the uterus remains in
place~ increase incidence of endometrial CA

TYPE III
Pure gonadal dysgenesis

class of intersex abnormality w/

bilateral streak gonads appearing as ovarian stroma
w/o oocytes
usually is not recognized - newborns phenotype
typically is completely female
undergo normal pubertal changes

Girls with Turner syndrome (45, XO) may be detected

earlier - short stature, webbed neck, and wide-space
nipples

Neither Turner syndrome nor the XX type of pure

gonadal dysgenesis appear to be assocd w/ increase
risk of gonadal malignancy

TYPE III
Pure gonadal dysgenesis

Therapy in these children (from an intersex

standpoint) primarily limited to appropriate estrogen
progesterone support.
The XY type of pure gonadal dysgenesis differ
problem because the bilateral streak gonads -significant potential for malignancy
1/3 develop a dysgerminoma or gonadoblastoma;
- gonadectomy important as soon as diagnosed
Pure gonadal dysgenesis syndromes represent
opportunities for genetic counseling. Turner
syndrome appears sporadically, suggesting a
postzygotic error;
however, the XX type of pure gonadal dysgenesis
an autosomal recessive transmission, XY type
apparently is an X-linked recessive

Workup &Treatment
Lab Studies:
Logical workup in infants with ambiguous
genitalia includes the following:

Chromosomal analysis
Endocrine screening
Serum chemistries/electrolyte tests
Androgen-receptor levels
5-alpha reductase type II levels
17-OHP levels

Summary definitions
True hermaphrodite: ovarian/testicular
tissue and ext. genitalia not normal
Male Pseudohermaphrodite: testes,ext.
genitalia female
Female Pseudohermaphrodite: ovaries,
ext. genitalia masculine characteristics

Male Pseudohermaphrodite
Androgen insensitivity syndrome
5 Alpha reductase deficiency
Testosterone biosynthesis defects

Female Pseudohermaphrodite
Congenital adrenal hyperplasia
Elevated androgens- circulation: drugs,
tumor

Clinical approach
Medical emergency
Congenital adrenal hyperplasia:
Electrolytes, 17OH progesterone
Team of experts
Assign sex
Phallus length
Psychological support

Imaging Studies:
Renal/bladder ultrasound
Genitography
CT scanning and MRI are usually not
indicated but may help identify internal
anatomy.

Procedures:
Exploratory laparotomy/gonadal biopsy
Diagnostic laparoscopy/gonadal biopsy
Histologic Findings: Histologic
analysis of gonadal biopsy specimens
may identify ovarian tissue, testicular
tissue, ovotestes, or streak gonads.

Treatment
Medical Care: depends on etiology & indicated for
conditions associated w/ ambiguous genitalia, including
CAH
Supplemental hormone therapy may be implemented if
gonadal function is compromised.
Surgical Care:
In virilized , surgical procedure - feminizing
genitoplasty & includes vaginoplasty and clitoroplasty

Undervirilized typically have hypospadias -surgical

reconstruction
Gender reassignment may be considered in patients
with male pseudohermaphrodism and genital inadequacy

Medications
Glucocorticoids -- anti-inflammatory
properties , cause profound and varied
metabolic effects
modify immune response
Children w/ CAH require
corticosteroid replacement for
survival Replacement also reduces
the production of corticotropin &,
therefore, the overproduction of
androgens.

Drug Name

Hydrocortisone (Hydrocortone, Cortef) -- Drug of choice

because of mineralocorticoid activity and glucocorticoid effect

Adult Dose

30-150 mg/d IV divided q8-12h

Pediatric Dose

10-20 mg/m2/d IV, divided into 2 equal doses

Contraindications

Interactions

Pregnancy
Precaution
s

Documented hypersensitivity; viral, fungal, or

tubercular skin infections

Corticosteroid clearance may decrease with estrogens; may increase

digitalis toxicity secondary to hypokalemia; effects decrease
with coadministration of barbiturates, phenytoin, and rifampin;
decreases effects of salicylates and vaccines used for immunization;
monitor for hypokalemia with coadministration of diuretics or
amphotericin B; antagonizes effects of anticholinergics;
may increase anticoagulant effects of warfarin;
decreases hypoglycemic effects of sulfonylureas and insulin;
increases toxicity of cyclosporine;
glucocorticoid therapy may inhibit growth-promoting effect of somatropin

C - Safety for use during pregnancy has not been established.

Caution in hyperthyroidism, osteoporosis, peptic ulcer disease,
cirrhosis, nonspecific ulcerative colitis, diabetes,
and myasthenia gravis

Treatment
Consultations:
Geneticist/genetic counselor
Endocrinologist
Surgeon
Obstetrician/urologist
Psychologist

 Medical/Legal Pitfalls:
Treatment for intersex states is
controversial.
Moratorium: on gender reassignment &
genital surgery until studies have been
completed on the long-term effects of
such surgery.

 best approach provide as much

information as possible so that they can
make informed decisions
Adequate counseling and support
ideal management team approach
including neonatologists, geneticists,
endocrinologists, surgeons, counselors,
and ethicists