Download Ambiguous Genitalia An Approach

INTERSEX
Dr. Ahmed Al Sayyad
CHEO / University of Ottawa
Sexual Differentiation
 Gonadal
differentiation at 6-8 wk gestation
 TDF gene (Y-chromosome):
• stimulates gonads towards testicular
differentiation
 Absence
of TDF:
• gonads differentiate into ovaries
Phenotypic Differentiation
around 8th week of gestation
 Wolffian duct from mesonephros
 Müllerian duct from coelomic epithelium
 Endocrine effect during this phase is crucial:
 Begins
• paracrine action of hormones produced by
ipsilateral gonad
• testis (MIS, T)  male internal genitalia
• ovary (nil)  female internal genitalia
Endocrine Effects on Phenotypic
Development
 Müllerian-inhibiting
substance:
• produced by fetal testes
• found on chromosome 19
 Causes
almost complete regression of
Müllerian duct derivatives:
• utriculus masculinus, appendix testis
 Important
in testicular differentiation
Endocrine Effects on Phenotypic
Development
 Testosterone:
• produced by fetal Leydig cells
 Regulates male phenotypic development
 Multiple steps in effect of testosterone:
• production, 5-alpha reductase, AR
• T  Wolffian duct (male internal genitalia)
• DHT  male external genitalia (includes
prostate)
Endocrine Effects on Phenotypic
Development
 Wolffian
duct:
• requires testosterone for development
• epididymis, vas deferens, seminal vesicle
 Müllerian
duct:
• does not require hormonal stimulation
• does require MIS be absent
• oviduct, uterus, cervix, upper vagina
External Genitalia Differentiation
(8-16 wk gestation)
 Male
(requires DHT):
• labioscrotal fold = scrotum
• urethral fold / groove = urethra
• genital tubercle = glans penis
 Female
(requires nil):
• labioscrotal fold = labia majora
• urethral fold = labia minora
• genital tubercle = glans clitoris
External Genitalia Development
Clinical Assessment - History
 Maternal
androgen exposure:
• endogenous (hormone producing tumors)
• exogenous (medication)
 Family
history:
• AGS / infant death
• abnormal sexual development
• infertility / amenorrhea
• parental consanguinity
Clinical Assessment - Physical
Examination
 Abdominal
exam
• rectal exam to feel for uterus
 Inguinal
/ scrotal exam for gonads
• if palpable = testis
 Phallic
size
 Urethral orifice location
 Hyperpigmentation of labioscrotal folds
• excess ACTH (AGS)
Clinical Assessment - Further
Testing
 Lab:
• karyotype (72 hour)
• serum 17 OH-progesterone
 Radiography:
• genitogram
• abdominal / pelvic ultrasound
 Operative:
• endoscopy of urogenital sinus
• laparoscopy/laparotomy and gonadal biopsy
Intersex Classification
 Classification
based on gonadal status:
• Over-androgenized female (ovary + ovary)*
• Under-androgenized male (testis + testis)*
• True hermaphrodite (ovary + testis)
• Mixed gonadal dysgenesis (testis + streak)
• Pure gonadal dysgenesis (streak + streak))
* “pseudo-hermaphrodite” is being phased out
Over-androgenized Female
 Most
common form of intersex
 Karyotype = 46 XX
 TDF gene not present
 Ovarian tissue only
 Normal female internal genitalia
 External genitalia virilized:
• potency of androgen
• time of exposure
• duration of exposure
Over-androgenized Female
 Congenital
adrenal hyperplasia (CAH)
comprises majority of cases
 Exposure to maternal androgens is rare but
can occur
Over-androgenized Female (CAH)
 Most
common inheritance pattern in CAH
is autosomal recessive
 Enzymatic deficiency results in reduced
production of glucocorticoids
 Lack of feedback inhibition on
hypothalamus and pituitary:
•  ACTH production
•  adrenal androgen release
Over-androgenized Female (CAH)
 21-hydroxylase
deficiency most common
• 50% of patients “salt losers”
• death at 7-10 days post-natally (adrenal crisis)
• serum 17- hydroxyprogesterone assay
 Medical
management of CAH crucial:
• corticosteroid ± mineralocorticoid
• prevent death and metabolic complications
• allow normal development of 2° sexual
characteristics, fertility
Over-androgenized Female (CAH)
 Female
gender assignment usual:
• controversy with Prader V
 Müllerian
structures always present
 Surgical intervention (?):
• feminizing genitoplasty ± vaginoplasty
 Antenatal
treatment may minimize degree of
virilization
Under-androgenized Male
 Very
diverse group
 Karyotype = 46 XY
 Testicular tissue only
 Lack of fetal virilization from wide variety of
defects or deficiencies
 Phenotypic range broad
• may even resemble normal female
Under-androgenized Male
Androgen Insensitivity
 Most
common form of UAM
 Assay serum testosterone, DHT:
• usually after HCG stimulation
 Fibroblast
cultures of genital skin:
• absence of DHT binding
 PCR
can be done to detect receptor
abnormalities
Under-androgenized Male
Androgen Insensitivity
 Testicular
feminization (complete AI):
• phenotypically normal female with a short
vagina
 Presentation:
• primary amenorrhea
• testes found in inguinal hernias in female
 Maintenance
of female gender appropriate
with estrogen supplementation
 Testicles should be removed (cancer risk)
Under-androgenized Male
Androgen Insensitivity
Under-androgenized Male
Androgen Insensitivity
 Incomplete
insensitivity:
• phenotype can run the gamut
• clitoromegaly, partial fusion of labio-scrotal
folds, short blind ending vagina
 Female
gender assignment  gonadectomy:
• prevent virilization in puberty
• obviate cancer risk
 In
males  early genital reconstruction
Under-androgenized Male
Enzymatic defects
 Wide
variety of potential defects:
• abnormal testosterone synthesis
• inadequate conversion to DHT
 Phenotype:
• no Müllerian structures (MIS present)
• under-virilized external genitalia
Under-androgenized Male
Enzymatic defects
 5-
reductase deficiency prevents conversion
of T to DHT
 Autosomal recessive inheritance
 Phenotypically severe perineoscrotal
hypospadias with undescended testes
 T/DHT ratio may aid in diagnosis
Under-androgenized Male
 Primary
Hypogonadism
• baseline high levels of gonadotropins
• do not respond to HCG stimulation
 Hypogonadotropic Hypogonadism
• baseline low levels of gonadotropins
• respond to HCG stimulation
True Hermaphroditism
 Uncommon:
10% of intersex
 Karyotype:
• 60-70% 46XX
• remainder 46XY or a mosaic
 Characterized
by presence of ovarian and
testicular tissue
 Gender assignment based on anatomical
findings (75% male)
True Hermaphroditism
 Internal
genitalia conform to ipsilateral
gonad:
• vas with testicle
• fallopian tube with ovary
• either (both) with ovotestis
 Contradictory
gonadal / ductal tissue should
be removed once gender assigned
 External genitalia reconstructed according to
gender assignment
True Hermaphroditism
 Gonadal
configuration can vary:
• testis one side, ovary other side
• ovotestis with contralateral normal testis or
ovary
• bilateral ovotestes
Mixed Gonadal Dysgenesis
 Second
most common cause of intersex
 Karyotype:
• 46XY/45XO mosaic
 Unilateral
testis with dysgenetic (streak)
gonad contralaterally
 Testis has Sertoli and Leydig cells but no
germinal elements
 Risk of gonadoblastoma
Mixed Gonadal Dysgenesis
 Internal
genitalia variable (±MIS)
 External genitalia:
• hypospadias
• partial labioscrotal fusion
• undescended testes
 Gender
assignment:
• female most common (bilateral gonadectomy)
• male if markedly virilized and orchiopexy
feasible
Pure Gonadal Dysgenesis
 Bilateral
dysgenetic (streak) gonads
 Present as females with sexual infantilism:
• external genitalia are not ambiguous
 Immature
Müllerian structures are present:
• low levels of fetal MIS
Pure Gonadal Dysgenesis
 Turner’s
syndrome:
• 45 XO
• characteristic phenotype
 Swyer’s
syndrome:
• 46 XY
• at risk for gonadoblastoma (30%)
 46
XX:
• low tumor risk
Other Genetic Abnormalities
 Klinefelter’s
syndrome:
• male phenotype
• impaired sexual maturation
• gynecomastia
• azoospermia
 Typical
karyotype 47 XXY
Other Genetic Abnormalities
 XX
Sex reversal
• rare phenotypic males with 46XX karyotype
• often have hypospadias and gynecomastia
• usually fragments of Y chromosome short arm
found in distal short arm of X chromosome
Summary
 Intersex
is a challenging and complicated
situation, but when understood can often be
dealt with effectively
 Many potential medical, social, and
psychological ramifications
 Multidisciplinary approach involving
urology, endocrinology, genetics and social
work is essential