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