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
 Begins around 8th week of gestation
 Wolffian duct from mesonephros
 Müllerian duct from coelomic epithelium
 Endocrine effect during this phase is crucial:
• 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