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INTERSEX
Ambigous external genitalia; gonads of one or both sexes.
The word ‘Hermaphrodite’ is derived from:
 Hermaphroditus, son of Hermes, Greek god and messenger of the gods, and,
 Aphrodite, goddess of love.
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Immense problem for the parents and child
Evaluation is a social if not strictly a medical emergency
Early sex assignment and its ensuing surgical reinforcement is of the utmost
importance
Gender identification established by 2 years
EMBRYOLOGY AND AETIOLOGY
Disorders in embryogenesis and gender differentiation may be:
1. genetic
2. gonadal, or
3. hormonal.
GENETIC SEX
Genetic sex is established at the time of fertilisation.
Ovum (22 autosomes + X-chromosome) + spermatozoa (22 autosomes and either an X or
a Y chromosome) come together to form the embryo.
Until the 6th week of gestation, the gonad is indifferent. After that, it differentiates.
The presence of a Y chromosome results in testicular development.
In the absence of a Y chromosome, the gonad differentiates into an ovary (passive).
A hormone-like substance in the Y chromosome (the HY antigen) is thought to be
responsible for the differentiation of the indifferent gonad into a testis.
But everything is not that simple. Differentiation into an ovary may not be an entirely
passive process and it is thought that other, as yet unknown factors, may play an
important role in gonadal differentiation.
GONADAL SEX
At about 6 weeks, the embryonal gonads differentiate into one or other sex.
In the XY (male) embryo:
 the Mullerian ducts regress
 the Wolffian ducts differentiate into the epididymis, vas deferens, seminal vesicles and
prostate
the external genitalia masculinize.
In the presence of ovaries:
 the Wolffian duct involutes
 the Mullerian ducts differentiate into fallopian tubes, uterus and proximal vagina.
the external genitalia feminize.
Castration in utero before differentiation  F genital differentiation.
Hypophysectomy in the F  No effect.
Hypophysectomy in the M  Internal genitalia unaffected, but impaired virilisation of
external genitalia.
Jost: ‘Maleness has to be actively imposed. If it escapes control, it becomes female.’
HORMONAL FACTORS
Undifferentiated extermal genitalia
genital tubercle
genital folds
genital swellings
uro-genital sinus
Male
head of the penis
shaft of the penis
scrotum
prostate
Female
clitoris
labia minora
labia majora
lower vagina
 Testosterone is produced by the Leydig cells of the testis. It stimulates
development of the Wolffian ducts and causes differentiation of the external
genitalia into male.
 Placental HCG, during organogenesis, controls testosterone secretion.
 Later, foetal pituitary LH becomes important and stimulates penile lengthening.
 For testosterone to be effective, it must be delivered to the target tissue and
converted by 5-reductase to dihydroxytestosterone. Dihydroxytestosterone then
combines with a protein binding receptor which starts off the process of
differentiation into the male.
 Mullerian regression factor is produced by the Sertoli cells of the foetal testis and
causes regression of the Mullerian ductal system.
 In the absence of testosterone, differentiation occurs towards female structures.
Wolffian
ducts
Mullerian
ducts
Wolffian
ducts
Mullerian
ducts
Vas deferens
Seminal vesicles
Epidiymis
Fallopian tubes
Uterus
Upper third of
vagina
 In summary sexual development of the fetus depends on normal systemic,
chromosomal, gonodal, and endocrinologic processes
 Any disruption results in a number of embryological defects
SYNDROMES
Classification- based on the differentiation of the gonad
1. Female pseudohermaphrodite - Two ovaries
a. XX congenital adrenal hyperplasia
2. Male pseudohermaphrodite - Two testes
a. XY 5 alpha reductase deficiency
b. XY androgen insensitivity syndrome
3. True hermaphrodite - Ovary and/or testis and/or ovotestis
4. Mixed gonadal dysgenesis - Testis plus streak gonad
5. Pure gonadal dysgenesis - Bilateral streak gonads
Congenital adrenal hyperplasia
 males present with normal genitalia but demonstrate sexual and somatic precocity
within 1st 6 months of life becoming more evident by 4-5 years of age. There may be
enlargement of penis, scrotum and prostrate with appearance of pubic hair and
advanced bone age.
 Females present with virilisation (ambiguous genitalia – female pseudohermaphrodite
 autosomal recessive disorder of adrenal corticosteroid biosynthesis due to
deficiency of a particular enzyme
 worldwide incidence of 1 in 13,000 children
 syndrome shows 3 enzymatic deficiencies
1. 21-hydroxylase – most common
2. 11-hydroxylase
3. 3-betahydroxysteroid dehydrogenase
 causes masculinization of the external genitalia because of overproduction of
androgenic intermediary metabolites
 clinically range from a mildly enlarged clitoris to a complete male penis
 Among the many causes of intersex, only CAH represents a real medical emergency in
the newborn period.
 salt losing form (hyponatremia, hyperkalemia and increased urinary sodium losses.)
require lifelong replacement of glucocorticoids and mineralocortocoids
 Females should be raised as female.
 They are fertile
Surgical management
 traditional approach to the female with ambiguous genitalia due to adrenal hyperplasia
is clitoral recession early in life (3-6 months), followed by vaginoplasty after puberty.
 This approach has recently been challenged by vocal groups of intersex patients
Androgen insensitivity syndrome: testicular feminization
 X-linked recessive condition resulting in a failure of normal masculinization of the
external genitalia in chromosomally male individuals.
 Due to loss-of-function mutation in the androgen receptor (AR) gene
 failure of virilization can be either complete androgen insensitivity syndrome (CAIS)
or partial androgen insensitivity syndrome (PAIS), depending on the amount of
residual receptor function.
 Individuals with CAIS have female external genitalia with normal labia, clitoris, and
vaginal introitus but have normal testes with normal production of testosterone and
normal conversion to dihydrotestosterone (DHT), which differentiates this condition
from 5-alpha reductase deficiency
 usually a short vagina with no cervix. Occasionally the vagina is nearly absent. AIS
individuals are clearly women. At puberty, the testes are stimulated by the pituitary
gland, and produce testosterone. Because testosterone is chemically very similar to
estrogen, some of the testosterone converts back to estrogen (aromatizes) in the
bloodstream. This estrogen produces breast growth, though it may be late.
 Women with AIS do not menstruate, and are not fertile. Because the development of
pubic and underarm hair, in women as well as in men, depends upon testosterone,
most AIS women have no pubic or underarm hair, but some have sparse hair.
 In contrast to medical morbidity, psychological morbidity is common. Phenotypic
females who are discovered to be genetic males may have psychosocial problems.
 Management:
o orchidectomy
 theoretical risk of malignant degeneration
 timing of such surgery has been debated. Historically, early surgery was
assumed preferable to avoid raising uncomfortable psychosexual issues
during adolescence or young adulthood. More recently, surgery during the
late teenage years or early 20s has been preferred to allow patient to decide
o vaginal lengthening procedures
 timing again debated – now best to wait until the patient is sufficiently
mature to participate actively in treatment decisions
Male pseudohermaphrodotism: 5-Alpha-Reductase Deficiency
 Autosomal recessive and sex limited (affecting only males)
 presents in genetic males with 46XY
 deficiency of the type 2 isozyme 5-alpha-reductase, which transforms testosterone to
DHT
 the external genitalia is inadequately masculinised
 spectrum of findings exist ranging from minimal undervirilization presenting with
normal male anatomy, except for isolated micropenis or hypospadias, to severe
undervirilization presenting as normal female external genitalia with mild clitoral
enlargement as the only physical finding
 hallmark of 5-ARD is an elevated ratio in serum of the testosterone-to-DHT ratio
 major issue for individuals with 5-ARD is gender assignment. Almost all children
with 5-ARD are assigned a female gender at birth.
 Traditional approach is to raise as females although this has been called into question:
1. No markers to predict which infant will want to transition to become male
during adolescent
2. Surgically feminizing the infant with 5-ARD makes male reconstruction even
more difficult if needed later.
3. issue of diminished sexual sensation and function in the clitoris of surgically
altered children is being raised by a vocal group of former patients. They claim
that their surgery left them with diminished-to-painful sexual response.
 Female identity:
o bilateral orchiectomy and restructuring of the labioscrotal folds into clear labia
before puberty to prevent masculinization
o typically have shallow vaginal vaults that are amenable to dilatation
o occasionally have clitoral hypertrophy and reduction is required
 Male identity
o evidence suggests that DHT therapy administered prior to puberty may increase
penile size. DHT therapy is ineffective once puberty starts
Ovotestes: True hermaphroditism
 rarest form, <10% of intersex cases
 gonadal tissue contains both ovaries and testes
 46XX in 80%
 Gonadal findings may be any combination of ovary, testis, or ovotestis. An ovotestis is
most common and is found in approximately two thirds of patients. When an ovotestis
is present, one third of the patients exhibit bilateral ovotestes. A testicle, when present,
is more likely to exist on the right (57.4%), and an ovary, when present, is more
common on the left (62%).
 Testicular tissue in ovotestes involves an increased risk of gonadal cancer.
 Appearance of the genitalia varies widely in this condition, and while ambiguity is the
rule, the tendency is towards masculinization.
 in the majority there is inadequate phallic development and should be raised as
females
 Management
o Surgical removal of the testis and the testicular portion of the ovotestis
o Reconstruction of the external genitalia as for CAH
o
Mixed gonadal dysgenesis
 characterised by unilateral testis, contralateral streak gonad, persistent mullerian duct
structures
 streak gonad on one side with a contralateral testis. Although degree of virilization
varies, all patients have a vagina and a uterus, and most have a fallopian tube, at least
on the side of the streak.
 Most patients with MGD have a mosaic karyotype, XO/XY
 external anatomy similar to CAH
 incidence of malignant degeneration in the dysgenic gonad is 50%
 Management
o raised as females
o bilateral gonadectomy
o surgical correction of external genitial as for adrenogenital syndrome
Pure gonadal dysgenesis
 bilateral streak gonads appearing as ovarian stroma without oocytes
 phenotype typically is completely female.
 present at puberty, at which point, they do not undergo normal pubertal changes. Girls
with Turner syndrome (45,XO) may be detected earlier by noting the characteristic
associated anomalies of short stature, webbing of the neck, and wide-spaced nipples.
 Neither Turner syndrome nor the XX type of pure gonadal dysgenesis appear to be
associated with increased risk of gonadal malignancy.
 Therapy in these children (from an intersex standpoint) primarily is limited to
appropriate estrogen and progesterone support.
DIAGNOSIS
 A child’s sex is assigned only after a full genetic, endocrinologic, and
genitourinary evaluation
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detailed history
careful physical examination
nuclear chromatin study
cytogenetic characterization
cystoscopy and IVP
laparoscopy for internal morphology of the genitourinary system
gonadal biopsy
hormonal assays
 regardless of genetics, the child’s anatomy is more important in determining the
childs sex
MANAGEMENT
 Simpler to reduce the clitoris and create a neovagina than create an inadequate penis,
thus most are raised as females
 Multidisciplinary approach is vital
o paediatric surgeon
o urologist
o plastic surgeon
o paediatrician
o geneticists
o child psychiatrist or pediatric psychologist
 Recommendation by patient advocate group Intersex Society of North America
o Following diagnostic work-up, newborns with intersex should be given a gender
assignment as boy or girl, depending on which of those genders the child is more
likely to feel as she or he grows up.
o Gender assignment does not involve surgery; it involves assigning a label as boy
or girl to a child.
o Surgeries done to make the genitals look “more normal” should not be performed
until a child is mature enough to make an informed decision for herself or
himself.
Surgery
 Usually a triad of
o clitoral hypertrophy
o vaginal opening at the base of the clitoris
o fusion of the labia minora
 surgical options
o one stage procedure for clitorovaginoplasty
o creation of labia minora from flaps of phallic skin and foreskin
o labioscrotal V-Y plasty
o use of perineal flaps
o various faciocutaneous flaps
o myocutaneous flaps (eg gracilis)
 post op importance of dilatation to reduce strictures
o commenced 2 weeks after surgery and continued for 6 months minimum with
gradual tapering