INTERSEX
Paul F Austin, MD, FAAP
Associate Professor of Surgery
Division of Pediatric Urology
St. Louis Children’s Hospital
Washington University School of Medicine
CURRENT CONCEPTS OF
DISORDERS OF SEXUAL
DEVELOPMENT
Paul F Austin, MD, FAAP
Associate Professor of Surgery
Division of Pediatric Urology
St. Louis Children’s Hospital
Washington University School of Medicine
DSD
THIS IS THE COOL STUFF!
SEXUAL DEVELOPMENT
• Genetic composition
• Gonadal differentiation
• Genital expression
CHROMOSOMAL COMPOSITION
• TDF
– Testes determining factor
– Male phenotype determination
– Short arm of Y chromosome
• SRY gene
– HMG-box
– Mutations = gonadal dysgenesis &
sterility
• Only 15 - 20% with XY gonadal dysgenesis
GENE EXPRESSION
GONADAL DIFFERENTIATION
• SOX genes
– S = SRY Related
– OX = HMG-box
– Autosomal genes
• Other genes
– WT1
• Denys-Drash syndrome
– Wilm’s tumor & genital abnormalities
– SF-1
GENETIC INFLUENCE
GONADAL DIFFERENTIATION
GENETIC INFLUENCE
BRAIN SEXUAL DIFFERENTIATION
• Sexually dimorphic gene expression in
mouse brain precedes gonadal differentiation
– > 50 candidate genes for differential sex expression
– > 7 murine genes
• Differential expression between the developing brains of
male and female mice at stage 10.5 days post coitum
before any gonadal hormone influence.
Dewing et al, Molecular Brain Research 118 (2003) 82–90.
INTERNAL DUCTAL
DIFFERENTIATION
• Testosterone
– Leydig cells
• MIS
– Sertoli cells
GONADAL DEVELOPMENT
INTERNAL GENITALIA
7-8
weeks
EXTERNAL DUCTAL
DIFFERENTIATION
• Testosterone
– Masculinizes external genitalia but…….
• Dihydrotestosterone
– Necessary for “complete” ♂ phenotypic
expression
T
5 -reductase
DHT
INTERSEX
OLD CLASSIFICATION
•
•
•
•
Female pseudohermaphrodite
Male pseudohermaphrodite
True hermaphrodite
Gonadal dysgenesis
INTERSEX CLASSIFICATION
GONADAL TISSUE
DISORDER
GONADS PRESENT
Female pseudohermaphrodite
Male pseudohermaphrodite
True hermaphrodite
Mixed gonadal dysgenesis
Pure gonadal dysgenesis
Ovaries only
Testes only
Ovary & testis
Testis & streak
Streak gonad only
DSD CLASSIFICATION
• Sex chromosome DSD
–
–
–
–
Kleinfelter
Turner
Mixed gonadal dysgenesis
Ovotesticular DSD
• 46 XX DSD
– Disorders of gonadal development
– Androgen excess (CAH, ect.)
• 46 XY DSD
– Disorders of :
• Gonadal development
• Androgen synthesis
• Androgen action
SEXUAL DEVELOPMENT
• Genetic composition
• Gonadal differentiation
• Genital expression
SEXUAL AMBIGUITY
ANDROGEN-MEDIATED
• Inappropriate over-exposure to androgens
• Deficiency of androgens
• Inability to recognize androgens
46 XX DSD
(FEMALE PSEUDOHERMAPHRODITE)
• Androgen exposure
– Exogenous
– Endogenous
46 XX DSD
ETIOLOGY
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•
•
•
Congenital adrenal hyperplasia (CAH)
Maternal progesterone ingestion
Maternal virilizing tumors
Idiopathic
CAH
• Most common cause of intersex
– 60% of intersex cases
– 1/15,000
– Enzymatic defect
CHOLESTEROL METABOLISM
CHOLESTEROL METABOLISM
21-OH DEFICIENCY
• 90% of cases
• 75% salt wasting
– “Crisis” = 7-14 days
CHOLESTEROL METABOLISM
21-OH DEFICIENCY
MEASURE
17-OH PROGESTERONE
CHOLESTEROL METABOLISM
11-OH DEFICIENCY
• 2nd most common CAH
• Hypertensive
46 XY DSD
(MALE PSEUDOHERMAPHRODITE)
• Deficiency of androgens
• Inability to recognize androgens
• Persistent Müllerian duct syndrome
46 XY DSD
INADEQUATE
TESTOSTERONE SYNTHESIS
• Leydig cell agenesis or hypoplasia = rare
• Enzymatic defects
– Cholesterol Testosterone
– 3 involve adrenal gland or testes
• 20,22-desmolase defect
• 3- hydroxysteroid dehydrogenase deficiency
• 17- hydroxylase defect
– 2 involve testes only
• 17,20 desmolase deficiency
• 17- hydroxysteroid dehydrogenase deficiency
INADEQUATE
TESTOSTERONE SYNTHESIS
TESTOSTERONE SYNTHESIS
17- hydroxysteroid dehydrogenase deficiency
•
•
•
•
Most common
Autosomal recessive or X-linked
No interference to adrenal steroids
Initially female with complete virilization
at puberty
– Gender role reversal: ♀ ♂
INADEQUATE SYNTHESIS OF
DIHYDROTESTOSTERONE
• 5 -reductase type 2 deficiency
– Serum T is normal
– Normal internal male genitalia
– Variable phenotypic expression
5 -reductase deficiency
• Pseudovaginal perineoscrotal hypospadias
– Autosomal recessive
• Dominican Republic
• Gender role reversal at puberty: ♀ ♂
– DX = HCG stim test
• T:DHT > 14:1
ANDROGEN INSENSITIVITY
• Androgen receptor defect
• Partial
– Reifenstein’s Syndrome
– Gilbert-Dreyfus Syndrome
– Lubs Syndrome
• Complete
– Testicular feminization
TESTICULAR FEMINIZATION
COMPLETE ANDROGEN INSENSITIVITY
•
•
•
•
Normal testes
No Wolffian duct development
No Müllerian duct development
Typically discovered:
– Inguinal exploration for bilateral hernias
– Testicle found during primary amenorrhea
workup
MIS DEFICIENCY
PERSISTENT MÜLLERIAN DUCT SYNDROME
•
•
•
•
Hernia uteri inguinalis
Found during hernia repair in a boy
Autosomal recessive or X-linked
No need to remove uterus and fallopian
tubes
– Closely adherent
– Risk devascularization
– No malignancy risk
SEX CHROMOSOME DSD
GONADAL DYSGENESIS
• Mixed gonadal dysgenesis
• Pure gonadal dysgenesis
MIXED GONADAL DYSGENESIS
• 2nd most common DSD disorder
• 45XO/46XY
• Testes + Streak
– Asymmetry of internal and external genitalia
• Rule of 3’s
– Penis & 2 gonads
MIXED GONADAL DYSGENESIS
• Testes are dysgenetic
– Absent germinal elements from seminiferous
tubules
• Malignant degeneration
– Both testes and streak gonad
– Gonadoblastoma, seminoma, dysgerminoma
– Necessitate gonadectomy
SYNDROMES WITH
GONADAL DYSGENESIS
• Denys-Drash syndrome
– Triad
• Wilm’s tumor
• DSD
• progressive nephropathy
• Frasier syndrome
– 46XY DSD & nephrotic syndrome
PURE GONADAL DYSGENESIS
•
•
•
•
•
Bilateral streak gonads
Present as failure to reach menarche
Turner syndrome – 45XO
46XX
Swyer’s syndrome – 46XY
SEX CHROMOSOME DSD
TRUE HERMAPHRODITE
• Rare
• Testicular + Ovarian tissue
– Ovotestes + Ovotestes
– Testes & Ovary
– Ovotestes + Ovary/Testicle
• 46XX - majority
WORKUP
DSD
• History
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–
–
–
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Maternal exposures
Familial
Infant deaths
Infertility & amenorrhea
Fetal development
WORKUP
DSD
• Physical exam
– Phallus size
• Penis < 2 cm stretched
• Clitoris > 7 mm
– Labia/scrotum
• Fusion abnormalities
• Rugation
• Color
– Gonads
• Palpable in scrotum
– Invariably testes
WORKUP
DSD
• Gonads
– Palpable in scrotum
• Invariably testes
WORKUP
DSD
• Karyotype
• Hormonal/Endocrine
• Imaging
– U/S
– Genitogram
DSD TEAM
• Multidisciplinary
– Endocrine
– Genetics
– Urology
– Psychology/Psychiatry
– Gynecology
– Ethicist
GENDER / SEX ASSIGNMENT
• Helps pts define the way they “see
themselves” and interact with
others
• Gender Identity
• Sexual orientation
• Sex typical behavior (gender role)
• Ability to reproduce
GENDER / SEX ASSIGNMENT
• Shared decision making
– Family
– DSD Team
