sex ambigus dr bambang tridjaja
DESCRIPTION
teksTRANSCRIPT
Bambang TridjajaBambang Tridjaja
Dept Child HealthDept Child Health
Faculty of Medicine UIFaculty of Medicine UI
Bambang TridjajaBambang Tridjaja
Dept Child HealthDept Child Health
Faculty of Medicine UIFaculty of Medicine UI
IntroductionIntroduction Intersex is not
always ambiguous Ambiguous
genitalia Confused family
social emergency sensitive approach
Growth and development effect
IntroductionIntroduction
Diagnosis ?
Physical factors in sexual Physical factors in sexual developmentdevelopmentPhysical factors in sexual Physical factors in sexual developmentdevelopmentCHROMOSOMECHROMOSOMECHROMOSOMECHROMOSOME
GONADGONADGONADGONAD
HORMONEHORMONEHORMONEHORMONE
INTERNAL INTERNAL GENITALIA GENITALIA INTERNAL INTERNAL
GENITALIA GENITALIA
EXTERNAL EXTERNAL GENITALIA GENITALIA EXTERNAL EXTERNAL GENITALIA GENITALIA
Sex DeterminationSex Determination
Sex DifferentiationSex Differentiation
46, XY; 46, XX46, XY; 46, XX
Testes; OvariumTestes; Ovarium
Testosterone, AMH, DHTTestosterone, AMH, DHT
Sex DeterminationSex DeterminationSex DeterminationSex Determination
ChromosomeChromosome
GonadGonad
Sex DeterminationSex Determination
Chromosome (Genetic)Chromosome (Genetic)GonadGonad
Chromosome Chromosome
MALEMALE
XYXY
XXYXXY
XXXYXXXY
XXYYXXYY
XYYXYY
(OY)(OY)
FEMALEFEMALE
XXXX
XXXXXX
XXXXXXXX
XXXXXXXXXX
XO (Turner Syndrome)XO (Turner Syndrome)
Conclusion: Chromosome Y (+) = Male Conclusion: Chromosome Y (+) = Male Conclusion: Chromosome Y (+) = Male Conclusion: Chromosome Y (+) = Male
Sex DeterminationSex DeterminationSex DeterminationSex Determination
ChromosomeChromosome
GonadGonad
Mother
Male fetus
(XY)
Testes
Primordial Gonad
Wolffian Duct
Vas deferensEpididymis
No uterus, No Fallopian Tube.
??
1950’s: Jost
Mother
Male Fetus
(XY)
Testes
Primordial Gonad
Wolffian Duct
No vas deferens &epididymis
Uterus (+), Fallopian (+).
?
XX
XX
Mother
Male Fetus
(XY)
Testes
Primordial Gonad
Wolffian Duct
Vas deferens& epididymis formed
Uterus (+), Fallopian tube (+)
XXTestosteroneTestosterone
Mother
Male Fetus
(XY)
Testes
Primordial Gonad
Wolffian Duct
vas deferens& epididymis (+)
No uterus, No Fallopian tube
XXTestosteroneTestosteroneTestosteroneTestosterone
Anti-Müllerian hormoneAnti-Müllerian hormoneAnti-Müllerian hormoneAnti-Müllerian hormone
Mother
Male Fetus
Male Fetus
(XY)
Primordial Gonad
Testes
Wolffian DuctWolffian Duct
Vas deferens& epididymis formed
No uterus, No Fallopian
TestosteroneTestosteroneTestosteroneTestosteroneAnti-Müllerian hormoneAnti-Müllerian hormoneAnti-Müllerian hormoneAnti-Müllerian hormone
ConclusionConclusionConclusionConclusion
Chromosomal Sex and Chromosomal Sex and Development of Embryonic Development of Embryonic GonadsGonads
Chromosomal Sex and Chromosomal Sex and Development of Embryonic Development of Embryonic GonadsGonads
ROAD TO TDF (=SRY)ROAD TO TDF (=SRY)ROAD TO TDF (=SRY)ROAD TO TDF (=SRY)
Genetic SexGenetic SexGenetic SexGenetic Sex
Sex Sex DifferentiationDifferentiation
Sex Sex DifferentiationDifferentiation
HormoneInternal genitalia differentiation External genitalia differentiation
Sex Sex DifferentiationDifferentiation
Sex Sex DifferentiationDifferentiation
HormoneInternal genitalia differentiation (testosterone and AMH) External genitalia differentiationExternal genitalia differentiation
Testosterone
AMH (+)
(-)
Internal Genitalia Internal Genitalia DifferentiationDifferentiationInternal Genitalia Internal Genitalia DifferentiationDifferentiation
Testosterone & AMH
(+)
(-)
Sex Sex DifferentiationDifferentiation
Sex Sex DifferentiationDifferentiation
HormoneInternal genitalia differentiation Internal genitalia differentiation (testosterone and AMH)(testosterone and AMH) External genitalia differentiation (Dihydrotestosterone)
External Genitalia External Genitalia DifferentiationDifferentiationExternal Genitalia External Genitalia DifferentiationDifferentiation
Testis
Leydig cells Sertoli cells
Testosterone Anti Mullerian hormone(AMH)
5-alpha-reductase
Direct actions Dihydrotestosterone Supression of Mullerian ducts(persist upper 1/3 vagina, uterus, Fallopian tubes)
StimulatesWolffianducts
Testicular descent (assisted by AMH)
External genitalia
Epididymis
Vas deferens
Seminal vesicles
Obliteration of lower 2/3 vagina
Genital tubercle glans penis
Urethral fold Fusion of shaft of penis
Labioscrotal swellings scrotum
Sexual differentiation in male. (Brook CGD. A guide to the practice of paediatric endocrinology, 1-st ed. Cambridge University Press; 1993. P. 1-17)
External Genitalia External Genitalia DifferentiationDifferentiationExternal Genitalia External Genitalia DifferentiationDifferentiation
46,X46,XYY (SRY gene +) (SRY gene +)TestisTestis
Bipotential gonad
Anti-Müllerian Hormone
(AMH)
Anti-Müllerian Hormone
(AMH)
Müllerian Duct Müllerian Duct Müllerian Duct Müllerian Duct
TestosteroneTestosterone
Wolffian ductWolffian ductWolffian ductWolffian duct
Male External Male External Genitalia Genitalia Male External Male External Genitalia Genitalia
Dihydrotestosterone
(DHT)
Dihydrotestosterone
(DHT)
MALEMALE
Leydig Leydig CellsCells
Sertoli Sertoli CellsCells
XX(Epididymis, vas (Epididymis, vas
deferens, deferens, Seminal vesicle)Seminal vesicle)
5-reductase
46,XX (SRY gene -)46,XX (SRY gene -)OvariumOvarium
Bipotential gonad
No Anti-Müllerian Hormone
(AMH)
No Anti-Müllerian Hormone
(AMH)
Müllerian ductMüllerian ductMüllerian ductMüllerian duct
Testosterone (-)Testosterone (-)
Wolffian ductWolffian ductWolffian ductWolffian duct
Female external genitalia Female external genitalia Female external genitalia Female external genitalia
No Dihydrotestostero
ne (DHT)
No Dihydrotestostero
ne (DHT)
FEMALEFEMALE
XXUterus, tuba, vaginaUterus, tuba, vagina
WHAT CAN GO WHAT CAN GO WRONG?WRONG?WHAT CAN GO WHAT CAN GO WRONG?WRONG?
Exercise
46,XY 46,XY TestisTestis
Bipotential gonad
Anti-Müllerian Hormone
(AMH)
Anti-Müllerian Hormone
(AMH)
Müllerian Duct Müllerian Duct Müllerian Duct Müllerian Duct
TestosteroneTestosterone
Wolffian ductWolffian ductWolffian ductWolffian duct
Male External Male External Genitalia Genitalia Male External Male External Genitalia Genitalia
Dihydrotestosterone
(DHT)
Dihydrotestosterone
(DHT)
MALEMALE
Leydig Leydig CellsCells
Sertoli Sertoli CellsCells
XX(Epididymis, vas (Epididymis, vas
deferens, deferens, Seminal vesicle)Seminal vesicle)
5-reductase
Female External Female External Genitalia???? Genitalia???? Female External Female External Genitalia???? Genitalia????
46,XY 46,XY TestisTestis
Bipotential gonad
Anti-Müllerian Hormone
(AMH)
Anti-Müllerian Hormone
(AMH)
Müllerian Duct Müllerian Duct Müllerian Duct Müllerian Duct
TestosteroneTestosterone
Wolffian ductWolffian ductWolffian ductWolffian duct
Female External Female External Genitalia???? Genitalia???? Female External Female External Genitalia???? Genitalia????
Dihydrotestosterone
(DHT)
Dihydrotestosterone
(DHT)
MALEMALE
Leydig Leydig CellsCells
Sertoli Sertoli CellsCells
XX
5-reductase
XX
46,XY46,XYTestisTestis
Bipotential gonad
Anti-Müllerian Hormone
(AMH)
Anti-Müllerian Hormone
(AMH)
Müllerian Duct Müllerian Duct Müllerian Duct Müllerian Duct
TestosteroneTestosterone
Wolffian ductWolffian ductWolffian ductWolffian duct
Female External Female External Genitalia Genitalia Female External Female External Genitalia Genitalia
Dihydrotestosterone
(DHT)
Dihydrotestosterone
(DHT)
MALEMALE
Leydig Leydig CellsCells
Sertoli Sertoli CellsCells
XX
5-reductase
XXLACK OF ANDROGEN RECEPTORS
External Genitalia External Genitalia DifferentiationDifferentiationExternal Genitalia External Genitalia DifferentiationDifferentiation
Androgen Insensitivity Androgen Insensitivity SyndromeSyndromeAndrogen Insensitivity Androgen Insensitivity SyndromeSyndrome
Undervirilization Phenotype: female
ambiguous
Batch et al. Rep. Med. Rev 1992;1:131-50
The female end of the partial androgeninsensitivity syndrome: 46 XY infant with labial testes, partial labial fusion and clitoromegaly.
Newborn infant with complete androgen insensitivity syndrome. Although the genitalia are female, the testes are palpable in the inguinal region.
Ambiguous
Non ambiguous
AIS – X linked inheritance
AIS – X linked inheritance
46,XX (SRY gene -)46,XX (SRY gene -)OvariumOvarium
Bipotential gonad
““Male” external Male” external genitalia ???genitalia ???““Male” external Male” external genitalia ???genitalia ???
FEMALEFEMALE
adrenal
46,XX (SRY gene -)46,XX (SRY gene -)OvariumOvarium
Bipotential gonad
No Anti-Müllerian Hormone
(AMH)
No Anti-Müllerian Hormone
(AMH)
Müllerian ductMüllerian ductMüllerian ductMüllerian duct Wolffian ductWolffian ductWolffian ductWolffian duct
Male external Male external genitalia ???genitalia ???Male external Male external genitalia ???genitalia ???
FEMALEFEMALE
XXUterus, tuba, vaginaUterus, tuba, vagina
adrenal
46,XX (SRY gene -)46,XX (SRY gene -)OvariumOvarium
Bipotential gonad
No Anti-Müllerian Hormone
(AMH)
No Anti-Müllerian Hormone
(AMH)
Müllerian ductMüllerian ductMüllerian ductMüllerian duct Wolffian ductWolffian ductWolffian ductWolffian duct
Male external Male external genitalia ???genitalia ???Male external Male external genitalia ???genitalia ???
FEMALEFEMALE
XXUterus, tuba, vaginaUterus, tuba, vagina
adrenal
Androgen
Adrenal Steroid Adrenal Steroid BiosynthesisBiosynthesis
Adrenal Steroid Adrenal Steroid BiosynthesisBiosynthesis cholesterol
Pregnenolone 17-OH Pregenolone DHEA Progesterone 17-OH Progesterone Androstenedione 11-DOC 11-deoxycortisol TESTOSTERONETESTOSTERONE Corticosterone CORTISOLCORTISOL 18-hydroxycorticosterone ALDOSTERONALDOSTERON
Congenital Adrenal Congenital Adrenal HyperplasiaHyperplasia
Congenital Adrenal Congenital Adrenal HyperplasiaHyperplasia
Virilization of female Hypoadrenalism (hypocortisolism):
Addison crisis: shock, hypoglycemia, electrolyte imbalance, metabolic acidosis
Increased ACTH: Hyperplasia adrenal, hyperpigmentation
Potential fertile female: no sex reassignment
Autosomal recessive inheritance Long life treatment
Intersex ClassificationIntersex ClassificationIntersex ClassificationIntersex Classification
FPHFPH MPHMPH GDGD THTHChromosoChromosomeme
46,XX 46,XY ⇌ ⇌
GonadGonad Ova Testes Streak Ovo-testes
HormoneHormone Virilization
Virilization ⇌ ⇌
Internal Internal GenitaliaGenitalia
Female Male ⇌ ⇌
External External GenitaliaGenitalia
Normal Ambiguous
Normal Ambiguous
Normal Ambiguous
Normal Ambiguous
Diagnostic Steps in Diagnostic Steps in Ambiguous GenitaliaAmbiguous GenitaliaDiagnostic Steps in Diagnostic Steps in Ambiguous GenitaliaAmbiguous Genitalia History
Family and Obstetric history Symptoms of virilisation
Physical examination Signs of virilisation Addison’s crisis, Failure to thrive,
Hypertension Genital: hypospadia, gonads, clitoromegaly,
labioscrotal fusion, urogenital sinus
Diagnostic Steps in Diagnostic Steps in Ambiguous Genitalia Ambiguous Genitalia Diagnostic Steps in Diagnostic Steps in Ambiguous Genitalia Ambiguous Genitalia
CHROMOSOMECHROMOSOMECHROMOSOMECHROMOSOME
GONADGONADGONADGONAD
HORMONEHORMONEHORMONEHORMONE
INTERNAL INTERNAL GENITALIA GENITALIA INTERNAL INTERNAL
GENITALIA GENITALIA
AMBIGUOUS AMBIGUOUS GENITALIA GENITALIA
AMBIGUOUS AMBIGUOUS GENITALIA GENITALIA
Sex DeterminationSex Determination
Sex DifferentiationSex Differentiation
•Karyotype (chromosome, Karyotype (chromosome, FISH etc)FISH etc)•Molecular AnalysisMolecular Analysis
•Karyotype (chromosome, Karyotype (chromosome, FISH etc)FISH etc)•Molecular AnalysisMolecular Analysis
•PalpationPalpation•Imaging (USG)Imaging (USG)•Hormonal (HCG)Hormonal (HCG)
•PalpationPalpation•Imaging (USG)Imaging (USG)•Hormonal (HCG)Hormonal (HCG)
•Gonad: androgen, AMH, Gonad: androgen, AMH, •AdrenalAdrenal
•Gonad: androgen, AMH, Gonad: androgen, AMH, •AdrenalAdrenal
•Palpation (RT)Palpation (RT)•Imaging (USG, Imaging (USG, genitogram, etc)genitogram, etc)
•Palpation (RT)Palpation (RT)•Imaging (USG, Imaging (USG, genitogram, etc)genitogram, etc)
Important Important messagemessage
Important Important messagemessage1. Ambiguous genitalia represent a social
emergency and medical emergency2. Chromosome analysis is the first step
in every ambiguous genitalia patients3. Gonad in a “labioscrotal” fold is almost
sure a testis 4. Basic mechanism for ambiguous
genitalia is due to over – under virilization
Important Important messagemessage
Important Important messagemessage5. Most phenotype appearance are not
pathognomonic for a certain condition6. Remember the sequence of sex
differentiation to do laboratorium workup
7. Refer the patient to the pediatric endocrinologist for diagnostic conformation and further patient management