INTERSEX

1
INTERSEX

• Dr. Ahmed Al Sayyad
• CHEO / University of Ottawa

2
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

3
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

4
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

5
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)

6
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

7
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

8
External Genitalia Development
9
Clinical Assessment - History

• Maternal androgen exposure
• endogenous (hormone producing tumors)
• exogenous (medication)
• Family history
• AGS / infant death
• abnormal sexual development
• infertility / amenorrhea
• parental consanguinity

10
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)

11
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

12
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

13
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

14
Over-androgenized Female

• Congenital adrenal hyperplasia (CAH) comprises
  majority of cases
• Exposure to maternal androgens is rare but can
  occur

15
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

16
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

17
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

18
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

19
Under-androgenized MaleAndrogen 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

20
Under-androgenized MaleAndrogen 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)

21
Under-androgenized MaleAndrogen Insensitivity
22
Under-androgenized MaleAndrogen 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

23
Under-androgenized MaleEnzymatic defects

• Wide variety of potential defects
• abnormal testosterone synthesis
• inadequate conversion to DHT
• Phenotype
• no Müllerian structures (MIS present)
• under-virilized external genitalia

24
Under-androgenized MaleEnzymatic 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

25
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

26
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)

27
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

28
True Hermaphroditism

• Gonadal configuration can vary
• testis one side, ovary other side
• ovotestis with contralateral normal testis or
  ovary
• bilateral ovotestes

29
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

30
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

31
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

32
Pure Gonadal Dysgenesis

• Turners syndrome
• 45 XO
• characteristic phenotype
• Swyers syndrome
• 46 XY
• at risk for gonadoblastoma (30)
• 46 XX
• low tumor risk

33
Other Genetic Abnormalities

• Klinefelters syndrome
• male phenotype
• impaired sexual maturation
• gynecomastia
• azoospermia
• Typical karyotype 47 XXY

34
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

35
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