Bambang Tridjaja Dept Child Health Faculty of Medicine UI

Introduction

Intersex is not always ambiguous Ambiguous genitalia

Confused family social emergency sensitive approach Growth and development effect

Introduction

Diagnosis ?

Physical factors in sexual development

CHROMOSOME

46, XY; 46, XX

Sex Determination

GONAD

Testes; Ovarium
Sex Differentiation

HORMONE

Testosterone, AMH, DHT

INTERNAL GENITALIA

EXTERNAL GENITALIA

Sex Determination
Chromosome Gonad

Sex Determination
Chromosome Gonad

(Genetic)

Chromosome

MALE
XY

FEMALE
XX

XXY
XXXY

XXX
XXXX XXXXX XO (Turner Syndrome)

XXYY
XYY (OY)

Conclusion: Chromosome Y (+) = Male

Sex Determination
Chromosome Gonad

Mother
(XY) Male fetus

Primordial Gonad

1950s: Jost

Testes

?
No uterus, No Fallopian Tube.

?
Wolffian Duct
Vas deferens Epididymis

Mother
(XY) Male Fetus

Primordial Gonad

X
Uterus (+), Fallopian (+).

Testes

?
Wolffian Duct
No vas deferens & epididymis

Mother
(XY) Male Fetus

Primordial Gonad

X
Uterus (+), Fallopian tube (+)

Testes Testosterone

Wolffian Duct
Vas deferens & epididymis formed

Mother
(XY) Male Fetus

Primordial Gonad

X
Anti-Mllerian hormone
No uterus, No Fallopian tube

Testes Testosterone

Wolffian Duct
vas deferens & epididymis (+)

Conclusion
Mother
(XY) Male Fetus Primordial Gonad

Testes

Anti-Mllerian hormone

Testosterone

Wolffian Duct No uterus, No Fallopian Vas deferens & epididymis formed

Chromosomal Sex and Development of Embryonic Gonads

ROAD TO TDF (=SRY)

Genetic Sex

Sex Differentiation
Hormone

Internal genitalia differentiation External genitalia differentiation

Sex Differentiation
Hormone

Internal genitalia differentiation (testosterone and AMH) External genitalia differentiation

Internal Genitalia Differentiation

Testosterone Testosterone & AMH

AMH
(+)
(+)

(-) (-)

Sex Differentiation
Hormone

Internal genitalia differentiation (testosterone and AMH) External genitalia differentiation (Dihydrotestosterone)

External Genitalia Differentiation

External Genitalia Differentiation

MALE Testis
Sertoli Cells

Bipotential gonad
46,XY (SRY gene +)
Leydig Cells

Anti-Mllerian Hormone (AMH)

5a-reductase

Testosterone

Mllerian Duct

Dihydrotestosterone (DHT)

Wolffian duct
(Epididymis, vas deferens, Seminal vesicle)

Male External Genitalia

FEMALE Ovarium

Bipotential gonad
46,XX (SRY gene -)

No Anti-Mllerian Hormone (AMH)

Testosterone (-)

Mllerian duct
Uterus, tuba, vagina

No Dihydrotestosterone (DHT)

Wolffian duct

Female external genitalia

WHAT CAN GO WRONG?

Exercise

MALE Testis
Sertoli Cells

Bipotential gonad
46,XY
Leydig Cells

Anti-Mllerian Hormone (AMH)

5a-reductase

Testosterone

Mllerian Duct

Dihydrotestosterone (DHT)

Wolffian duct

Female External Genitalia???? (Epididymis, vas deferens, Male External Genitalia

Seminal vesicle)

MALE Testis
Sertoli Cells

Bipotential gonad
46,XY
Leydig Cells 5a-reductase

Anti-Mllerian Hormone (AMH)

Testosterone

Mllerian Duct

Dihydrotestosterone (DHT)

Wolffian duct

Female External Genitalia????

MALE Testis
Sertoli Cells

Bipotential gonad
46,XY
Leydig Cells 5a-reductase

Anti-Mllerian Hormone (AMH)

Testosterone
Dihydrotestosterone (DHT)

Mllerian Duct

LACK OF ANDROGEN RECEPTORS

Wolffian duct
Female External Genitalia

External Genitalia Differentiation

Androgen Insensitivity Syndrome

Undervirilization Phenotype: female ambiguous

Non ambiguous

Newborn infant with complete androgen insensitivity syndrome. Although the genitalia are female, the testes are palpable in the inguinal region.

Ambiguous
The female end of the partial androgen insensitivity syndrome: 46 XY infant with labial testes, partial labial fusion and clitoromegaly.

Batch et al. Rep. Med. Rev 1992;1:131-50

AIS X linked inheritance

FEMALE Ovarium

Bipotential gonad
46,XX (SRY gene -)

adrenal

Male external genitalia ???

FEMALE Ovarium

Bipotential gonad
46,XX (SRY gene -)

adrenal

No Anti-Mllerian Hormone (AMH)

Mllerian duct
Uterus, tuba, vagina

Wolffian duct

Male external genitalia ???

FEMALE Ovarium

Bipotential gonad
46,XX (SRY gene -)

adrenal

No Anti-Mllerian Hormone (AMH)

Androgen

Mllerian duct
Uterus, tuba, vagina

Wolffian duct

Male external genitalia ???

Adrenal Steroid Biosynthesis

cholesterol

Pregnenolone 17-OH Pregenolone Progesterone 17-OH Progesterone

11-DOC

Corticosterone

11-deoxycortisol

Androstenedione

DHEA

TESTOSTERONE

CORTISOL

18-hydroxycorticosterone

ALDOSTERON

Congenital Adrenal Hyperplasia

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 Classification
FPH
Chromosome Gonad Hormone Internal Genitalia External Genitalia
46,XX Ova Virilization Female
Normal Ambiguous

MPH
46,XY Testes Virilization Male Normal Ambiguous

GD
Streak

TH
Ovo-testes

Normal Ambiguous

Normal Ambiguous

Diagnostic Steps in Ambiguous Genitalia

History

Family and Obstetric history Symptoms of virilisation

Signs of virilisation Addisons crisis, Failure to thrive, Hypertension Genital: hypospadia, gonads, clitoromegaly, labioscrotal fusion, urogenital sinus

Physical examination

Diagnostic Steps in Ambiguous Genitalia

CHROMOSOME Sex Determination GONAD Karyotype (chromosome, FISH etc) Molecular Analysis Palpation Imaging (USG) Hormonal (HCG) Gonad: androgen, AMH, Adrenal INTERNAL GENITALIA Palpation (RT) Imaging (USG, genitogram, etc)

HORMONE Sex Differentiation

AMBIGUOUS GENITALIA

Important message
1. 2.

3.

4.

Ambiguous genitalia represent a social emergency and medical emergency Chromosome analysis is the first step in every ambiguous genitalia patients Gonad in a labioscrotal fold is almost sure a testis Basic mechanism for ambiguous genitalia is due to over under virilization

Important message
5. 6.

7.

Most phenotype appearance are not pathognomonic for a certain condition Remember the sequence of sex differentiation to do laboratorium workup Refer the patient to the pediatric endocrinologist for diagnostic conformation and further patient management