Abnormalities of Sexual Determination and Differentiation

8/2/2019 Abnormalities of Sexual Determination and Differentiation

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Abnormalities of sexualdetermination and differentiation

by :Bikin Suryawan,dr.Sp.A(K)


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Levels of Sexual Differentiation

Gonads

Internal Genitalia

External Genitalia


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Bipotential Gonads

WT-1

SF-1

Intermediatemesoderm Genital ridge BipotentialGonad

Germ cellsYolk sac

endoderm C-Kit/ Steel

WT-1

SF-1


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Gonadal Determination

SRY

WnT4

SOX-9

BipotentialGonad

OvaryDAX-1

Testis


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Development of Male Internal Genitalia

SF-1 AMH

receptorSertoli Cell

Leydig Cell

AMH

Testis

Testosterone

Mullerian Duct

Regression

SF-1

Steroid genes

AMH gene

Androgen

receptor

Wolffian DuctStabilisation


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Development of External Genitalia

DehydroTestosterone(DHT)

Testosterone

UndifferentiatedExternal Genitalia

SF-1Steroid genes

Androgenreceptor

Leydig Cells

5a reductase

No Androgen

Placental HCG(First trimester)

Pituitary LH2nd & 3rd trimester

Female ExternalGenitalia

Male ExternalGenitalia


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Steroid BiosynthesisCholesterol

Progesterone

DOC

18Hydroxycorticosterone

Aldosterone

Pregnenolone

Corticosterone

17a-OHpregnenolone

17a-OHprogesterone

11-deoxycortisol

Cortisol

DHEA

Androstenedione

StAR

Testosterone

TestisAdrenal

Dehydrotestosterone

Leydig Cells


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Gender Identity

Genital differentiation develops a gender identity feelshimself or herself to be a male or female.

Gender identity is based partly on the physical appearance

of the external genitalia but also on the poorly understoodeffects of antenatal hormone exposure on the brain, otherunknown factors.

The genital appearance largely determines the initialbehavior of the parents and, to an extent, that of youngchildren themselves.

Gender specific behavior may be observed during earlychildhood


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Classification of intersex

1.Undifferentiated or absent gonads

2.True hermaphroditism

3.Male pseudo-hermaproditism

4.Female pseudo-hermaphroditism


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1.Undifferentiated or absent gonads

XY pure gonadal dysgenesis

Congenital anorchia (vanishing testes)

2. True hermaphroditism

Presence of both ovarium and testiculartissue


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3. Male pseudo-hermaphroditism

Absent testis

Absent biosyntesis

Target organ resistance

Other


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Leydig cell hypoplasia (1 in 106

).Testosterone synthesis defects

StAR deficiency

3b hydroxysteroid dehydrogenase deficiency

17a hydroxylase deficiency

17 b hydroxysteroid dehydrogenase deficiency

Testosterone action defects

5 a reductase deficiency

Androgen insensitivity syndrome


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4. Female pseudo-hermaphroditism

CAH: 21-hydroxylase, 11-hydroxylase

Excess of maternal androgens

Non-specific, associated with other

congenital anomali

Idiopathic


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Virilisation and MaternalSteroids.

Progestagens cross the placenta and areandrogenic.

Virilisation in 3% of female infants of motherstaking progestagens during pregnancy.

Virilisation dependent on androgenic activity, time

and dose.Labial fusion does not occur if progestagen takenafter 12 wks.

Glucocorticoids do not lead to virilisation.


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CAH (21 HydroxylaseDeficiency)

Fetal androgen and 17 OH progesteronelevels.

Therefore androgen levels from birth.Non-classical CAH does not present withvirilisation at birth.

Electrolyte ( K, Na, pH) disturbancesdo not occur until 8-10 days due toprotective effect of maternal aldosterone.Cutfield WS. J Pediatr 1995;126:118-21


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CAH (Early defects)

StAR deficiency

P450scc deficiency (not in humans)

3b hydroxysteroid dehydrogenasedeficiency

17a hydroxylase deficiency

Lead to undervirilisation in males asandrogen synthesis as well as cortisol andaldosterone blocked.

Do not virilise female infants except 3bOHD


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Diagnostic work-up of intersex conditions

History and clinical examination Symptoms of virilization in the mother

Drugs during pregnancy

Unexplained infant deaths

Genital ambiguity, short stature or pronounced hirsutism in the family.

Parental consanguinity

Investigations

Karyotype: XX Karyotype

XY kariatip

True hermaphrodites


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XX Karyotype

Na, K in suspect CAH salt loss

Kidney USG

Anatomi internal genitalia by USG

Cytoscopy. Laparoscopy

Plasma 17 hydroxyprogesteron in 21 OH def

Plasma deoxycorticosterone in 11 hydroxylase def

Plasma pregnenolone in 3 hydroxysteroid dehydrogenase

def

Occasionally a urinary steroid profil,plasma steroidlevels,USG and radiography for infant virilized


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XY Karyotype

Testosteron, DHT, prekursor androstenedion and DHEA before and

after hCG injection of 1500 units i.m

Sex hormone binding globulin (SHBG) for degree of androgen

insensitivity

It is possible LHR genes in case early failure of testicular development

Genital skin fibroblasts can be obtained for assay of androgen receptor

leves

Hematuria and proteinuria for drash syndrome

7-Dehydrocholesterol levels for Smith-Lemli-Opitz syndrome Anti-Mullerian hormone (MIF) for functioning testicular tissue


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True Hermaphrodites

Laparoscopy for internal genitalia (gonads

and uterus)

Biopsy or remove gonadal tissueincompatible with the assigned sex

Tissue karyotyping should again be

performed


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Therapy

Female sex of rearing Dependent on the precise diagnosis

Femile with clitoris is enlargedcliteroplasty CAHhydrocortison to suppress ACTH levels and to

normal growth rate and skeletal maturation

In Neonates CAH hydrocortison dose 30mg/m2 daily,15-25mg/m2 daily, and 12-15mg/m2 daily from 2 years

onwards

In complete forms of androgen insensitivity syndrometestis are removed either in early life or after puberty


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Male sex of rearing

Normalized external genitalia hypospadias repair,vaginal remnats and any internal female structures can alsobe removed

GnRH analogs or hCG can be testicular decent Orchidopexy

Testosterone inj. 25 mg testosterone esters im every 3weeks on three occasions for increase penile size, topical

testosterone cream 2,5% for 3 months At puberty absence of functioning testes testosterone

replacement treatment is required, 50 to 250 mg every 3-4weeks


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Micropenis

Def: a stretched penile length


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Testicular Descent

Determined by:Insulin-like factor 3 Transabdominal phase

AMH

GubernaculumIntra-abdominal pressure

DHT Inguino-scrotal phase

Testosterone

LH, FSH

T. Klonisch et al. Developmental Biology 270 (2004) 1 18


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Bilateral Cryptorchidism

Ultrasound:

Only sensitive at detection of inguinal testeswhich can be detected by palpation.

Soap test useful in detecting inguinal testes.

Detected 13% of impabable testes.

Very insensitive in detection of intra-abdominal

testes.

Weiss RM. J Urol 1986;135:936-8


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Cryptorchidism and Fertility

Unilateral cryptorchidism:31% oligospermia, 14% azoospemia.

Paternity rate 65-80% (cf 85% in normals)

Bilateral cryptorchidism:31% oligospermia, 42% azoospemia.

Paternity rate 50-60%

Cryptorchidism >2 yrs of age, progressiveloss of spermatagonia.

Elder JS. Pediatr Clin North Am 1987;34:1033-53.


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Cryptorchidism and Anti-Sperm Antibodies (ASA)

Presumed disruption of blood: testes barrier.

10-30% have ASA.

titres of ASA with puberty.Infertile men with cryptorchidism 66% ASA.

Infertile men without cryptorchidism 2.8%

ASA.ASA may be associated with infertility incryptorchidism.

Sinisi. J Urol 1998;16:1834-7.


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Abnormalities of Sexual Determination and Differentiation