1-The most common cause of female intersex

or ambiguous genitalia is congenital adrenal

hyperplasia.
* The commonest is 21-hydroxylase
deficiency (which account for 90 ٪ of cases of
CAH).
* CAH is autosomal recessive.
Phase II /reproductive block
2-Most of hermaphrodites are XX female 58 ٪
Normal and abnormal sexual
development(Disorders of Sex Development)

Dr.Nassrin Malik Aubead

 Management Should be immediate:
Objectives
1.Cortisol or corticosteron to suppress ACTH. ( Life long )
2.In salt loosing type ,correction of elect. defect.
3.Surgical correction of ext. genitalia in the form of:
A. Reduction
1.Will inunderstand
be able to the size of clitoris.
how the sex of each individual is
B. Division of the fused labial folds.
determined .

2. To know which abnormalities in sex determining factors that will

result in intersex.

3. Will be able to understand how these abnormalities are presented

clinically at birth, during childhood and adolescence

4. Will be able to reach to the diagnosis of different cases of intersex

and how to manage them

Sexual differentiation and normal subsequent development are
fundamental to continuation of human species .

Following fertilization, the human embryo will differentiate into a male

or female fetus, and subsequent development is genetically controlled.

The undifferentiated embryo contains both Wolffian and Mullerian

ducts.

The Wolffian ducts have the potential to develop into the internal organs
of the male , and the Mullerian ducts into the internal organs of the
female.
If the testis produces Mullerian inhibitor , the Mullerian ducts regress.
 Factors that determine sex are :-
A- Sex chromosomes:- (XX or XY) The embryo differentiation is controlled by sex
chromosome. Y chromosome contains SRY- gene (sex determining region on Y).
the gene of which present on the short arm of chr, if this gene is deficient, then there will be
no testicular formation .
this gene will induce the development of testes through TDF(testicular determining
factor),.TDF regulate H-Y Ag whose gene present on Y chr. or outosome. H-Y Ag is a plasma
membrane protein & is widely distributed in cells
The Chromosomes will determine the final functional morphology of the undifferentiated
Gonads by the following:
1.Presence of Y chr. in association with one or more X chr.; the gonads develop into testis.
2. If more than X chr. present with Y chr. ,the gonads differentiation to testis is
normal during intrauterine life but testicular development during puberty is impaired.
3.If two or more X chr. are present without Y chr. The undifferentiated Gonads will develop
into ovary.
4.If more than two X chr. Present, the subsequent ovarian development during
puberty is impaired
B- The effect of testicular function on sexual develop.

During IU life the presence of functioning testis will result in male phenotype

Absence or presence of non functioning testis will always lead to a female

phenotype whether ovaries are present or not.

So male development is the result of presence of testis & female development is

the result of absence of testis

This function of testis during IU life is through secretion of 2 substances which

are :

1. Testosterone from Leidg cells

2.MIF from Sertoli cells . It is aglycoprotein & it has aunilateral action &

Mullerian structures are sensitive to it only during the first 8 weeks of gestation
C- The response of end organs
Testosterone secreted from testis will initiate development of male ext. & int. genital
structures
The Wolfian structures are able of utilizing testosterone directly while ext. genitelia
utilize testosterone after conversion to dihydrotestosterone by 5α reductase enzyme

For effective utilization both hormones , it is necessary for testosterone to be bound to

receptors in the cytoplasm of cells .
So ineffective binding will lead to abnormal sexual develop

Failure of receptors or insensitivity of end organs may cause the phallus to be small,
and there will be failure of scrotal development .

As failure occurs ,we may see a phenotypeically female with XY chromosomes

(genetically male)
The absence of a Y chromosome and the presence of two X

chromosomes mean that Mullerian inhibitor is not

created, and the Mullerian ducts persist in the female.

The absence of testosterone means that the Wolffian ducts

regress,and failure of androgen to affect the cloaca leads to

an external female phenotype.

 Intersex
(Disorders of Sex Development)

An individual with ambiguous genitalia, neither

a male , nor a female).

Intersex disorders either

A- Early presented (child with ambiguous genitalia ).

B- Late onset presentation (at puberty).

Abnormal sexual developement
1.Abnormality in sex chr. which interfer with testicular develop. the only common one is
45 XO/46 XY mosaism leading to one form of gonadal dysgenesis.

2.Testis may be unable of producing testosterone either because of anatomical or

enzymatic testicular failure.

3.The end organ may be unable of utilizing testos. because of5α reductase deficiency or
failure of testosterone. binding(androgen insensitivity).

4.The production of MIF may be deficient leading to the growth of Mullerian system in a
male.

5.In a genetic female (46 X X) musculinization of ext. genitalia may result from excessive
androgen production as in congenital adrenal hyperplesia or from androgen from other
sources.

6.Rarely in agenetic female, the gene capable of production of H-Y Ag may be found on an
autosome leading to 46 XX male

7.True hermaphrodite i.e the presence of testicular & ovarian tissue in the same individual
 Pseudohermaphrodite:- Is an individual with the genetic constitution and
gonads of one sex and the genitalia of the other.

 Female pseudohermaphrodite :-
An individual with XX chromosomes, ovaries ,and has male external
genitalia.

 Male pseudohermaphrodite :- An individual with XY chromosomes, testes

,and has female external genitalia.

True hermaphrodite:-
The condition in which the individual has both ovaries and testes, is probably
due to XX/XY mosaicism and related mosaic patterns. and varying degrees of
virilization of the external genitalia.

Xo/XY mosaic = ambiguous external

genitalia
 Clinical presentation during infancy & childhood

The infant or childe with ambigouos genitalia may present in

anumber of ways:
1.Musclinized female Exclud in First step
2.Under musclinized male
3.True hertmaphrodite

At neonatal period: First is confirm diagnosis of CAH because it is a correctable

condition and the baby may die if it is of salt loosing type First step
So when a childe or neonate presented with ambiguous genitalia ,we should look for
the presence of testis up to the inguinal area and the first concern is to exclude a
musclinized female ( CAH or excessive androgen).
First step
If these causes had been excluded, then the diagnosis is either
an undermusclinized male or true hermaphrodite
 1-Genetically female (XX) with ambiguous genitalia

Masculinization due to high Female (46xx) True

androgen level hermaphrodite

Exogenous
CAH
androgen

Leutomy of Androgen secreating

drugs P.C.O.S
pregnancy tumours
 Posterior labial fusion
Genetically female (XX) with
ambiguous genitalia
 Clitoromegaly
Genetically female (XX) with
ambiguous genitalia
 \
In female , the external genitalia may be virilized , giving a musculine appearance.
This is the most commonly seen in a condition known as congenital adrenal
hyperplasia. It is the most common cause of female intersex, and
it is an autosomal recessive disorder which is due to enzymatic effect.

The commonest is 21-hydroxylase deficiency(which account for 90 ٪ of cases of

CAH)
This is result in a failure of conversion of 17α -hydroxyprogesterone to
desoxycortisol,
and also failure of conversion of progesterone to desoxycorticosterone.
 Two other enzyme deficiencies are recognized, although less
common :
 3 β- hydroxysteroid hydrogenase deficiency , and 11β - hydroxylase
deficiency.
CAH : failure of conversion of 17α -hydroxyprogesterone to desoxycortisol
 Failure of production of cortisol means that there is positive

feedback mechanism on the hypothalamus leads to an elevation of

adrenocorticotrophic hormone (ACTH).

 This in turn stimulate the adrenal gland to undergo a form of

hyperplasia, and the excessive production of steroid precursor

 (17α -hydroxyprogesterone) means that the adrenal gland

produces excessive amount of androgen.

 This androgen enters the fetal circulation and impacts on the

developing cloaca, thereby leading to virilization.

- 3 β Dehydrogenase

positive
feedback
mechanism on
hypothalamus
leads to an
elevation of
adrenocorticotro
phic hormone
(ACTH).
Clinical features
1. Clitoral hypertrophy.

2. Excessive fusion of labia minora which obscure the vagina & urethra forming an

artificial urogenital sinus which has an opening on the perineum near the base of

Clitoris, the lower part of the vagina may be obliterated by the development of a

male- type perineum and hence a vaginal orifice is not appearant.

3.Thickining of labia majora which may resemble scrotum of testis.

4.The uterus, fallopian tubes & vagina are present which open in the urogenital

sinus.

5.In some infant, a dangerous salt loosing syndrome may arise due to associated

aldosteron deficiency and the infant may die from wasting and vomiting within

few weeks of life if the diagnosis is delayed

Other causes of musclinized female
1. Androgen secreting tumor during pregnancy e.g androblastoma

2. The use of progestationl drugs that have androgenic effect

3.Idiopathic

The presentation of neonate or child is the same for CAH & no other metabolic defect The
management initially is to exclude CAH and if this is excluded, the treatment should be in
the form of surgical correction as in CAH

If musclinization of a genetic female from excessive androgen had been excluded, then
distinction must be made between an undermusclinized male & true hermaphrodite.

The distinction can be made only by laparotomy & gonadal biopsy . Laparoscopic biopsy is
not an adequate procedure for establishing the nature of a gonad in intersex.

Gonadal biopsy is not done to choose the sex of rearing, which is done according to the
suitability of the external genitalia for sexual life.

But still it is important to know the nature of the gonads in order to remove the
inappropriate tissue for the chosen sex
 Do laparotomy & gonadal biopss if :
2- Male (46 XY) with intersex disorders

A-Androgen insensitivity (Testicular feminization )

Karyotype is male (XY),but phenotypically female
( XY female)

Due to complete
androgen insensitivity
 B- Genetically male (XY) with ambiguous genitalia

Under masculinization
male (46 XY) True
(XY Female) testicular
hermaphrodite
feminization

Partial Androgen End organ

production defect insensitivity

partial
Testecular Partial5 alfa- reductase androgen
Anatomical
enzymatic deficiency insensitivity
defect
failure
Necessary for
utilization of
testosterone by
external genitalia

o
 Perineal hypospadias
Genetically male (XY) with ambiguous genitalia

5 Alfa reductase in genetic male

absent = female external genitalia
 Testes in phenotypic female
Genetically male (XY) with ambiguous genitalia

initial exam done to identify the presence or

absence of testis . If they are absent then the
diagnosis of CAH is raised
Anatomical testicular
defect
Causes:
1-True gonadal dysgenesis.
2-Atrophy of the testes due
to viral infection or
thrombosis (vanishing
testis). This result in:
3-Mutation at site of short 1- Absence of male
arm of chromosome Y
lead to TDF deficiency
(XY gonadal agenesis).
SO testicular absence lead to:
NO testosterone, MIS absent
This will result in :
Wolffian duct regretion, 3- MIS present so
female phenotype with
tube , uterus,vagina with
some masculization
usully not need surgical
correction.
Treatmeant:
Remove the gonads
streaks because
malignancy risk is 30 per
cent, estrogen and
progesterone
replacement at puberty
for sexual characteristic
development,and
menstruation
Testicular End organ insensitivity
enzymatic failure
The testes present 5 Alfa reductase deficiency
,but there is defect
in testosterone
There is failure of
production.
conversion of
testosterone to
Dihydrotestosteron
(which is biologically
internal organs
active), because of 5
(Wolffian duct
Alfa reductase
regression).
deficiency :
2-Under mascularised
Is familial condition
(ambiguous genitalia)
( inherited as autosomal
due to incomplete
recessive)
testosterone
Diagnosis confirmed by
deficiency.
giving HCG to
stimulate the gonads &
Mullerian duct
measuring
regress ( no tube,
testosterone level
uterus, or vagina)
before & after
treatment
Sex of rearing depend This will result in:
on the degree of Female phenotype.
mascularization, but But has male internal
usually female role organs.
the chosen one. At puberty excess
(surgery with androgen production
removal of gonads) may lead some
verillization ,and the
patient may wish to
change gender role
,but female role is
appropriate.
androgen insensitivity
Androgen insensitivity due to
absence of androgen receptors .
This will result in:
if complet insensitivity
1- Female phenotype.
2- No male internal organs(due to
receptors absence)
3- MIS present ,this will lead to
Mullerian duct regression ( no
tube, uterus, or vagina).
4- Patient at puberty has good
breast development, due to
conversion of excess androgen
to estrogen, there is absent or
scanty axillary and pubic hair,
and primary amenorrhoea.
If the defect is partial then the
presentation would be at
birth with ambiguous genitalia.
The management is as previous with
surgery
(reconstruction of ext. genitalia
with hormonal replacement at
puberty)
In child nothing done until the
time of puberty when
feminization occur at that time
,then remove the testes ,as the
risk of malignancy after
puberty is 5 per cent.
True hermaphrodite :
Is the presence of testicular and ovarian tissue in the
same individual .
Most of hermaphrodites are XX female 58 ٪

Some are XY mosaicim 46 XX\XY

46XX\47XXY
Other mosaics
 From most common to less one
Right + left

Testis + Ovary

Ovotestis + Ovary

Ovotestis + testis

Ovotestis + ovotestis

Most of hermaphrodites are XX female 58 ٪

The combination of gonads will determine the degree of virilization: the greater the

testicular component, the more virilized the resulting development and the more likely

the presence of Mullerian inhibitor.

Thus in the true hermaphrodites, it is possible to get co-existent Mullerian and Wolffian

structures in term of internal development, and varying degrees of masculinization of

the external genitalia, depending on the combination of gonads.

So the presentation at puberty would depend on the function of the gonads .e.g.

menstruation may occur at puberty in a hermaphrodite who had been thought to

be a male. So in such cases hysterectomy with removal of ovarian tissue should be done

with mastectomy if there is breast development

The patients my come at the age of 5-7 years, and then do full

investigations, and full chromosomal study by culturing lymphocytes.

We can do laproscopy to see the gonads and biopsy may need to be

taken ( we may find ovotestis in which there is both types of tissues

on biopsy).

Most commonly right testis with left ovary

 How to deal with intersex neonate
Has ambiguous genitalia
The baby will come into one of three categories:-
 In adequate virilized genetic male like partial or complete end
organ insensitivity to dihydrotestosterone or inadequate
testosterone production.

 Musculinized genetic female like in congenital adrenal

hyperplasia syndrome, or excess maternal androgen during
pregnancy.

 True hermaphrodite

The first problem is that the parents came for naming and sex of
newborn. one have to tell the parents that you are not sure about the
sex of the newborn, and that you need investigations to clarify it.
The initial evaluation of the infant with ambiguous genitalia
when a neonate or infant present with ambiguous genitalia , the initial exam.
done to identify the presence or absence of testis . If they are absent then the
diag. of CAH is raised & the following should be done:

History:

The history in a child with ambiguous genitalia should include the following

information: Prenatal exposure to androgens (eg, progesterones, danazol,

testosterone) or endocrine disrupters (phenytoin, aminoglutethimide

 Maternal virilization in pregnancy (placental aromatase deficiency) , Family

history of unexplained infant deaths (congenital adrenal hyperplasia) History

of consanguinity (or homogeneous population) (recessive disorders, eg, CAH,

5-alpha-reductase deficiency)

If no consanguinity = CAH and 5 alpha

reductase deficiency less likely
Physical examination : The physical examination should include careful inspection and
palpation of the genitalia. Palpation of the uterus may be possible through a combination of
gentle rectal examination with the examiner's fifth digit and suprapubic pressure with the
examiner's other hand. The presence or absence of a uterus must be confirmed
radiographically

Anogenital ratio

The anogenital ratio, which is independent of gestational age and body size, is the distance

between the anus and posterior fourchette divided by the distance between the anus and the

base of the clitoris. A ratio of >0.5 suggests virilization with some posterior labial fusion.
 Investigations
.
1. Karyotyping on a sample of cord blood: About 90 ٪are known within 48 hours , and

the true answer is at 6 weeks (by chromosomal study).

In the first 48 hours do Barr body from the buccal smear, if Barr body is + ve then the
Barr body = inactivated
baby is XX or XY mosaicim XX\XY 46XX\47XXY
chromosome X
but if it is –ve ,may be XY( male) or XO (turner`s syndrome in which there is a

complete female but ovarian failure which lead to the non –estrogenised female )

 The results of the peripheral blood karyotype permit classification of the infant
into one of three diagnostic categories, which determine

- XX virilization

- XY undervirilization

- Mixed sex chromosome pattern

2. Measurement of 17 α hydroxyprogesteron in blood increase. If this not

available then measurement of pregnantriol in urine is done.

3.Measurement of androgen level in urine by assaying urinary 17 oxosteroid.

4.Electrolyt level in serum , if salt loosing syndrome present then Na &Cl are low

and K is elevated. Activation of aldosterone receptors

5. Radiological studies:

Ultrasonography of the abdomen and pelvis can help to determine the presence

of gonads, uterus, and/or a vagina. Retrograde urethrogram may be necessary

to visualize the urethral and vaginal anatomy.

MRI
Management Should be immediate:
1.Cortisol or corticosteron to suppress ACTH. ( Life long )

2.In salt loosing type ,correction of elect. defect.

3.Surgical correction of ext. genitalia in the form of:

A. Reduction in the size of clitoris this is better done during neonatal period & is
either by amputation or by reduction clitoroplasty.

B. Division of the fused labial folds in order to expose the vagina and urethra. this
operation done at any age at the same time & it may need to be repeated later during
puberty.

Those patient can achieve normal menses & fertility but usually the menarche is
delayed 2 years specially in those with inappropriate hormonal control

Some patients may be presented with menstrual irregularity as oligomenorrhea ,

amenorrhea or even infertility specially in salt loosing type.
Notes:
•46 XX male dos not present as intersex but may have hypospadias.
Rarely in agenetic female, the gene capable of production of H-Y Ag
may be found on an autosome leading to 46 XX male

• 46 XY male with isolated MIF deficiency also dos not present as intersex but
Mullarian structures may be found in the abdomen of a male during laparotomy.

• OX (Tuner syndrome) is not cause an intersex however, it one cause of sex

development disorder
Turner syndrome —
Karyotype is 44 autosomes plus X0
The‘streak gonads’ do not function to produce oestrogen or oocytes. —

Diagnosis: is at birth or in early childhood from the clinical

appearance of the baby or due to short stature during childhood.
While 10% women, have delayed puberty where normal physical
changes of puberty cannot happen. —
Treatment: in childhood, is focused on growth, but in adolescence it
focuses on induction of puberty. Pregnancy is possible with ovum
donation. Psychological input and support is important
 After that we consult the parents and the patient properly

and do estimation to which pattern the patient is nearer (

male or female ) .

 If the patient has big phallus with lack of androgen ,we

may help by giving androgen If a genitalia is too small ,it

difficult to make phallus, so in this patient it is easier to
make a female than male ( correction not always go with
the chromosomal pattern), because it is easier to make a

THANK YOU
functioning vagina than making a functioning phallus.