Transcript Intersex

INTERSEX
Disorders of sexual development (DSD),
formerly termed intersex conditions, are
among the most fascinating conditions
encountered by the clinician. The ability
to diagnose these conditions has
advanced rapidly in recent years. In
most cases today, clinicians can
promptly make an accurate diagnosis
and counsel parents on therapeutic
options.
“Intersex” is a general term used for
a variety of conditions in which a
person is born with a reproductive
or sexual anatomy that doesn’t
seem to fit the typical definitions
of female or male.
INTERSEX
Intersex covers a diverse range of
conditions encompassing:
 individuals with standard male or
female genitalia, who may have a
variety of internal genital organs
and karyotypes, and
 also those with ambiguous
external genitalia.
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For example, a person might be born appearing
to be female on the outside, but having mostly
male-typical anatomy on the inside.
Or a person may be born with genitals that
seem to be in-between the usual male and
female types—for example, a girl may be born
with a noticeably large clitoris, or lacking a
vaginal opening, or a boy may be born with a
notably small penis, or with a scrotum that is
divided so that it has formed more like labia.
Or a person may be born with mosaic genetics,
so that some of her cells have XX chromosomes
and some of them have XY.
CLASSIFICATION OF INTERSEXUALITY
1.
Virilization of genetically female foetus
Female pseudohemaphroditism
2. Incomplete musculinization of
genetically male foetus
Male pseudohermaphroditism (XYFEMALE)
3. The presence of both ovarian and
testicular tissue in the same
individual
True hermaphroditism
4. Chromosomal abnormality
Mixed gonadal dysgenesis ( 45,X0 /
46,XY)
This terminology mainly reflects the
chromosomal sex or the gonadal
tissue associated with the disorder.
How many children are born with
intersex conditions?
 A conservative
estimate is that 1 in
2000 children born will be affected
by an intersex condition.
Aetiology
Most intersex conditions occur due to a
genetic or environmental disruption to
the pathway of fetal sexual development.
This disruption can be to:
 Gonadal differentiation or development,
 Sex steroid production,
 Sex steroid conversion,
 Tissue utilization of sex steroid.
•
Male pseudohermaphroditism
(XY- FEMALE)
Failure to produce
testosterone
 Anatomical testicular
failure (Pure XY
gonadal dysgenesis
(swyer’s syndrome),
testicular regression
syndrome)
 Leydig-cell agenesis
 Enzymatic testicular
failure
Failure to utilize
testosterone
 5-alpha-reductase
deficiency
 Androgen receptor
deficiency
* Complete androgen
insensitivity (TFS)
* Incomplete androgen
insensitivity
Anatomical testicular failure:
Failure of testicular differentiation and
development result from sex chromosomes
mosaicism or may be associated with normal
chromosomes in pure gonadal dysgenesis.
These patient have poor musculinization or
none,
uterus, tubes and vagina are present (in
contrast to other XY females).
Swyer’s syndrome
46, XY
No SRY OR its receptors
STREAK GONADS
- NO MIF (Uterus +)
- NO SEX STEROIDS
Female
external
Genitalia
Female
Internal
Genitalia
Treatment :
-removal of streak gonads during
childhood (risk of malignancy in 5%)
-puberty replacement therapy
(oestrogen and progesterone) to
produce secondary sexual development
and menstruation
46-XY/SRY
Leydig-cell agenesis
TESTIS  MIF
( partial/ complete absence
Of leydig-cells)
No or  testosterone
No or  DHT
Female or
ambiguous
external
Genitalia
± Male
Internal
Genitalia
Enzymatic testicular failure:
Many biosynthetic defect in the formation of
testosterone from cholesterol, usually the defect
is incomplete so there is external genital
ambiguity of various degree ,the uterus ,upper
vagina are absent because of production of
the MIF by the testes is normal .
The chosen sex is often female depend on
external organ suitability .surgery may be used
as previously described.
Testicular enzymatic
failure
46-XY/SRY
Testis  MIF
(defects in testosterone
Synthesis)
 testosterone precursors
DHT
Ambiguous
External
Genitalia
Male
Internal
Genitalia
Autosomal recessive enzyme
deficiency :
-20-22 desmolase
-3-ß-ol-dehydrogenase
-17-  -hydroxylase
-17,20-desmolase
-17-ß –hydroxysteroid
oxyreductase
5 alpha reductase deficiency
This enzyme deficiency is autosomal
recessive so family history of such cases
may be present. It affect the conversion of
testosterone to DHT required for
masculinization of the ext. genetalia in the
male (poor musculinization so placed in
female role) ,there is normal production of
MIF so always there is absence of the
uterus and vagina.
46-XY/SRY
Testis  MIF
5-alpha-reductase
deficiency
Testosterone
5--rductase
DHT
Female or
Ambiguous
external Genitalia
Male Internal
Genitalia
46-XY/SRY
TESTIS  MIF
Testosterone
Androgen insensitivity
syndrome
(Testicular feminization
syndrome)
5--reductase
DHT
Absent androgen
receptors
Female
External
Genitalia
Male
Internal
Genitalia
Incomplete form  Ambigious genitalia
Clinical features:
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Female phenotype.
primary amenorrhoea.
Normal breast development .
Scanty or absent pubic and axillary hair.
Absent uterus and tubes with short vagina.
Undescended or maldescended testes
(found in the abdomen ,groin or labia
majora).
Testosterone and oestrogen level are in
normal male range.
Diagnosis: female appearance +46XY.
 Emphasize that these are entirely
female despite their 46XY karyotype.
 5% risk of malignancy require
gonadectomy.
 Oestrogen (HRT) treatment may be
required.
 Surgery to elongate the vagina is
seldom required.
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Diagnosis of XY Female
Testosterone concentration
Low
Normal
Male level
Concentration of
Testosterone precurcers
High
Testicular
enzyme
Failure
Low
Absent testes or
Absent leydig-cell
Surgical exploration
DHT
Low
5 -reductase
Deficiency
Normal
Testicular
Feminization
Syndrome
True hermaphrodite:
The presence of both ovarian tissue containing
grafian follicle and testicular tissue containing
distinct tubules in one person.
 These patients presents with various degree of
sexual ambiguity (from maleness to femaleness)
 In the majority karyotype of 46XX(58%), other
less common as 46XX/XY, 46XY and 46XY/XXY.
 Regarding gonadal distribution ovotestis present
on one side and ovary on the other or ovary in
one side and testis on the other (two most
frequent).
 In the majority uterus and vagina are present.
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Diagnosis by biopsy. (Gonadal biopsy is not under
taken to determine the sex of rearing which should be
undertaken depending on the suitability of the external
genitalia for sexual life )
The sex chosen depend on functional
capability of external genitalia .
 inappropriate organ should be removed.
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FEMALE PSEUDOHERMAPHRODITISM
EXCESS FETAL
ANDROGENS
Congenital adrenal
hyperplasia
 21 -hydrxylase
deficiency
 11-hydroxylase
deficiency
 3ß-hydroxysteroid
dehydrogenase
deficiency
EXCESS MATERNAL
ANDROGENS
 Maternal androgen
secreting tumours
(ovary, adrenal)
 Maternal ingestion of
androgenic drugs
Congenital Adrenal Hyperplasia(CAH)
Is the most common cause of female intersex
(constituting approximately 60% of all
intersex cases) & is the most frequent cause of
ambiguous genitalia in the newborn.
Autosomal recessive disorder of enzyme
deficiency in the cortisol biosynthesis .
Commonest (90%): 21-hydroxylase deficiency
Less common : 3β-hydroxy steroid dehydrogenase
deficiency
11β-hydroxylase deficiency
Pathophysiology
The term congenital adrenal hyperplasia (CAH)
describes several autosomal recessive
disorders that result from complete or partial
deficiency of an enzyme involved in cortisol
and aldosterone synthesis, usually 21hydroxylase or less frequently 11-hydroxylase.
Symptoms of CAH and their severity are varied.
It may present in the neonate with ambiguous
genitalia and life threatening hypotension.
Alternatively, symptoms may be milder and
delayed until adolescence or adulthood. In this
late-onset form of CAH, symptoms reflect
accumulation of precursor C19 steroid
hormones. These precursors are converted to
dehydroepiandrosterone, androstenedione,
and testosterone, and signs of virilization
predominate.
 The
basic biochemical defect is
an enzymatic block that prevents
sufficient cortisol production.
Biofeedback via the pituitary
gland causes the precursor to
accumulate above the block.
Clinical manifestation of CAH
depends on which enzymatic
defect is present.
21-hydrxylase deficiency
congenital adrenal hyperplasia
Cholesterol
Pregnenolone
Progesterone
17-OH progesterone
Pituitary
ACTH
Adrenal cortex
21-hydroxylase
Cortisol
Androgens
Cortisol

Androgens
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Severe forms of congenital adrenal
hyperplasia are potentially fatal if
unrecognized and untreated because of
the severe cortisol and aldosterone
deficiencies that result in salt wasting,
hyponatremia, hyperkalemia,
dehydration, and hypotension.
Epidemiology
Typically due to a 21-hydroxylase deficiency,
classic congenital adrenal hyperplasia (CAH)
is one of the most common autosomal
recessive metabolic diseases, estimated to
occur in 1:10,000 to 1:15,000 births.
 Congenital adrenal hyperplasia caused by 11beta-hydroxylase deficiency accounts for 58% of all congenital adrenal hyperplasia
cases.
 Although CAH has been reported in a wide
range of ethnic groups, it is most common in
the Ashkenazi Jewish population.
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Clinical Presentation
Sex:
Because all forms of congenital adrenal
hyperplasia are autosomal recessive
disorders, both sexes are affected with equal
frequency. However, because accumulated
precursor hormones or associated impaired
testosterone synthesis impacts sexual
differentiation, the phenotypic consequences
of mutations or deletions of a particular gene
differ between the sexes.
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Age
Classic congenital adrenal hyperplasia is
generally recognized at birth or in early
childhood because of ambiguous
genitalia, salt wasting, or early
virilization.
Nonclassic adrenal hyperplasia is
generally recognized at or after puberty
because of oligomenorrhea or virilizing
signs in females.
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History:
The clinical phenotype of congenital adrenal
hyperplasia depends on the nature and
severity of the enzyme deficiency.
Although the information below is presented
according to chromosomal sex, the sex of a
neonate with congenital adrenal hyperplasia
is often initially unclear because of genital
ambiguity.
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Clinical presentation in females
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Females with severe forms of adrenal
hyperplasia due to deficiencies of 21hydroxylase, 11-beta-hydroxylase or 3-betahydroxysteroid dehydrogenase have
ambiguous genitalia at birth due to excess
adrenal androgen production in utero. This is
often called classic virilizing adrenal
hyperplasia.
affected females born with:
-Enlargement
of the clitoris
-Excessive fusion of the
genital fold obscure the
vagina and urethra
-Thickening , rugosity of the
labia majora
-Internal genital organ are
present.
-dangerous salt losing
syndrome may cause death
if not treated
In a nonclassic form of CAH, also known as
late-onset or adult-onset CAH,
hyperandrogenemia does not present until
puberty.
At puberty, activation of the adrenal axis
increases steroidogenesis, unmasking a mild
21-hydroxylase activity deficiency. Levels of
ACTH may increase due to the lack of
negative feedback by cortisol, further
exacerbating androgen production.
These patients often present with hirsutism,
acne, and anovulation. Thus, late-onset CAH
may mimic polycystic ovarian syndrome
(PCOS).
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Females with 17-hydroxylase deficiency
appear phenotypically female at birth but
do not develop breasts or menstruate in
adolescence because of inadequate
estradiol production. They may present
with hypertension.
Clinical presentation in males

21-hydroxylase deficiency in males is
generally not identified in the neonatal
period because the genitalia are normal.
If the defect is severe and results in salt
wasting, these male neonates present at
age 1-4 weeks with failure to thrive,
recurrent vomiting, dehydration,
hypotension, hyponatremia,
hyperkalemia, and shock (classic saltwasting adrenal hyperplasia).
Patients with less severe deficiencies of 21hydroxylase present later in childhood
because of the early development of pubic
hair, phallic enlargement, or both,
accompanied by accelerated linear growth
and advancement of skeletal maturation
(simple virilizing adrenal hyperplasia).
 In male infants, the disease may be
misdiagnosed as gastroenteritis or pyloric
stenosis, with potentially disastrous
consequences due to delayed treatment with
glucocorticoids.
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Investigation for suspected CAH:
-Karyotype
-17 alpha hydroxyprogesterone
measurement
-Electrolyte abnormality : Na, Cl , K.
-Pelvic ultrasound (internal genital organ)
Treatment (CAH):
Medical control of the underlying disorder:
Cortisol administration
Correction of electrolyte disorder
Surgical correction of the underlying anatomical
abnormality
with two type of surgery :
These patients are genetic females, potentially fertile
and must brought up in the female role regardless of
the degree of musculinization.
-reduction of the clitoris :amputation or reduction
clitoroplasty (best in the neonatal period)
-division of the fused labial fold (if thick better done well
after puberty)
Prognosis for CAH:
Delayed puberty up to 2 years
 menstrual abnormality .. oligomenorrhoea
to amenorrhoea.
 Reduced fertility.
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Congenital adrenal hyperplasia
The commonest cause of genital
ambiguity at birth
 21-Ohase deficiency is most
common form
 Autosomal reccessive
 Salt wasting form may be lethal
in neonates
 SERUM 17OH-progesterone
(21OHase)
  SERUM deoxycorticosterone,
11-deoxycotisol (11- OHase)
 Treatment : cortisol replacement
and ? Surgery
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AMBIGUOUS GENITALIA AT BIRTH
The external genital organs look unusual,
making it impossible to identify the sex of
the newborn from its outward appearance.
Ambiguous genitalia represent a social and
potential medical urgency that is best handled
by a team of specialists, which may include
urologists, neonatologists, endocrinologists,
and pediatric gynecologists.
Child with ambiguous genitalia may
be any of the following:
- Musculinized female due to congenital
adrenal hyperplasia (CAH), or androgen
stimulation from other source.
 - undermusculinized male.
 - True hermaphrodite.

MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
GENERAL GIUDELINES
 Medical and social emergency
 Avoid immediate declaration of sex
 Proper counselling of the parents
 Team management; obstetrician,
neonatologist, pediatric endocrinolgist,
genetist and paediatric surgeon.
MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
History : pregnancy; family
 Detailed examination : abdomen; pelvis;
external genitalia; urethral and anal openings.

Federman’s rule: a palpable gonad
below the inguinal ligament is testes
until proven otherwise
Investigations :
• Rule out cong. Adrenal hyperplasia: Serum electrolytes;
17-OHP level and urinary levels of 17-ketosteroids
• Karyotype ( buccal smear; blood)
• Pelvic US and sometimes MRI
• Skin biopsy; fibroblast culture to measure 5alphareductase activity or dihydrotestosterone binding
• Laparoscopy
• Gonadal biopsy (laparotomy)
A PROTOCOL FOR INVESTIGATION
OF A NEWBORN WITH AMBIGUOUS
GENITALIA
Karyotype all
Palpable gonad
NO
YES
CAH Sreen
. Biochemical profile
Positive
- US / MRI
-? Genitogram
Negative
. US / MRI /? genitogram
. ? Gonadal biopsy
SURGICAL CONSIDERATIONS
Phallic / clitoral reduction if the assigned
sex is female, before 3 years of age
 Removal of intra-abdominal gonads /
streaks in newborns carrying Y
chromosome
 Vaginal construction / repair is better
performed around puberty

INTERSEXUALITY PRESENTING AT
ADOLESCENCE
Primary amenorrhea
- Complete androgen
insesitivity (TFS)
- Congenital anorchia
( early testicular
regression syndrome)
- Complete leydig-cell
agenesis
- Some forms of enzymatic
testicular failure
Ambiguous genitalia
- Neglected congenital
adrenal hyperplasia
- Mixed gonadal dysgenesis
- Partial androgen resistance
- Congenital anorchia ( Late )
- Testicular enzymatic failure
- Leydig cell agenesis
( incomplete)
- True hermaphrotidism
Transsexualism
Brain sex: cerebral differentiation to a male or
female orientation.
 Transsexualism occurs when a person strongly
believes that he or she belong to the opposite
sex.
 This is typically a lifelong feeling and results in
varied degrees of physical/external changes
 These patients should be referred to the
psychiatrist
Other chromosomal abnormalities of
sexual developement
Klinefelter syndrome XXY +ve Bar body
male+medical problem
Turner syndrome
Xo -ve Bar body
female + medical problem
super female
XXX
two+ve
Bar body
Turner syndrome:
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45XO karyotype.
Present as delayed puberty with short stature.
Absent secondary sexual characteristics.
Wide carrying angle of the arm.
Webbed neck.
broad chest with widely spaced nipples.
Associated medical problems as colour blindness,
coarctation of the aorta.
Streak ovaries (non functioning).
Normal internal genital organs.
Markedly elevated gonadotrophin (LH,FSH)
Treatment :
Induction of puberty by long treatment of
oestrogen.
 Induction of menstruation by adding
progesterone to oestrogen after 2 years of
oestrogen treatment.
 If karyotype reveal 46XX(gonadal dysgenesis)
the gonads have 30% risk of malignant
change
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KLINEFILTER SYNDROME:
Appearance essentially is male.
 Scrotal testis ,small azoospermic (infertile).
 Small penis with normal potency.
 Karyotype of 47XXY(chromatin positive) rare
as 48 XXXY ,mosaics of XX and XY.
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Super female:
Karyotype is XXX
 mental subnormality
 hypoplastic genitalia
 Scanty menstruation or amenorrhoea
