Abnormalities of sexual determination and differentiation

by :

Bikin Suryawan,dr.Sp.A(K)

Levels of Sexual Differentiation

Gonads Internal Genitalia External Genitalia

Bipotential Gonads
WT-1

Intermediate mesoderm

WT-1

Genital ridge
SF-1 SF-1

Bipotential Gonad

Germ cells
Yolk sac endoderm C-Kit/ Steel

Gonadal Determination
Bipotential Gonad
SRY

Ovary
DAX-1 WnT4

SOX-9

Testis

Development of Male Internal Genitalia

Testis
Sertoli Cell
SF-1 AMH AMH gene SF-1 AMH receptor Mullerian Duct Regression

Leydig Cell

Testosterone

Steroid genes

Androgen receptor Wolffian Duct Stabilisation

Development of External Genitalia

Undifferentiated External Genitalia No Androgen Male External Genitalia Androgen receptor

Female External Genitalia Placental HCG (First trimester)

Pituitary LH 2nd & 3rd trimester

DehydroTestosterone (DHT)
5a reductase

Testosterone
SF-1 Steroid genes Leydig Cells

Cholesterol

Steroid Biosynthesis
17a-OHpregnenolone 17a-OHprogesterone 11-deoxycortisol Testosterone Cortisol Dehydrotestosterone DHEA Androstenedione

StAR
Pregnenolone Progesterone DOC Corticosterone 18Hydroxycorticosterone

Adrenal
Aldosterone

Leydig Cells Testis

Gender Identity
Genital differentiation develops a gender identity feels himself 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 understood effects of antenatal hormone exposure on the brain, other unknown factors. The genital appearance largely determines the initial behavior of the parents and, to an extent, that of young children themselves. Gender specific behavior may be observed during early childhood

Classification of intersex
1.Undifferentiated or absent gonads 2.True hermaphroditism 3.Male pseudo-hermaproditism 4.Female pseudo-hermaphroditism

1.Undifferentiated or absent gonads

XY pure gonadal dysgenesis Congenital anorchia (vanishing testes)

2. True hermaphroditism
Presence of both ovarium and testicular tissue

3. Male pseudo-hermaphroditism
Absent testis Absent biosyntesis Target organ resistance Other

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

4. Female pseudo-hermaphroditism
CAH: 21-hydroxylase, 11-hydroxylase Excess of maternal androgens Non-specific, associated with other congenital anomali Idiopathic

Virilisation and Maternal Steroids.

Progestagens cross the placenta and are androgenic. Virilisation in 3% of female infants of mothers taking progestagens during pregnancy. Virilisation dependent on androgenic activity, time and dose. Labial fusion does not occur if progestagen taken after 12 wks. Glucocorticoids do not lead to virilisation.

CAH (21 Hydroxylase Deficiency)

Fetal androgen and 17 OH progesterone levels. Therefore androgen levels from birth. Non-classical CAH does not present with virilisation at birth. Electrolyte ( K, Na, pH) disturbances do not occur until 8-10 days due to protective effect of maternal aldosterone.
Cutfield WS. J Pediatr 1995;126:118-21

CAH (Early defects)

StAR deficiency P450scc deficiency (not in humans) 3b hydroxysteroid dehydrogenase deficiency 17a hydroxylase deficiency Lead to undervirilisation in males as androgen synthesis as well as cortisol and aldosterone blocked. Do not virilise female infants except 3bOHD

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

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 steroid levels,USG and radiography for infant virilized

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

True Hermaphrodites
Laparoscopy for internal genitalia (gonads and uterus) Biopsy or remove gonadal tissue incompatible with the assigned sex Tissue karyotyping should again be performed

Therapy
Female sex of rearing
Dependent on the precise diagnosis Femile with clitoris is enlarged cliteroplasty 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 syndrome testis are removed either in early life or after puberty

Male sex of rearing

Normalized external genitalia hypospadias repair, vaginal remnats and any internal female structures can also be removed GnRH analogs or hCG can be testicular decent Orchidopexy Testosterone inj. 25 mg testosterone esters im every 3 weeks 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 3-4 weeks

Micropenis
Def: a stretched penile length <- 2 SD average for age, or < 2 cm at birth and < 4 cm before normal puberty Etiology: hypogonadotropic hypogonadism, pituitary def, GH def, primary hypogonadism and incomplete androgen insensitivity syndrome Management:depend of etiology, testosteron ester or topical testosteron or hCG or gonadotropins, respond poorly surgery or gender reassignment

Testicular Descent
Determined by: Insulin-like factor 3 Transabdominal phase AMH Gubernaculum Intra-abdominal pressure DHT Inguino-scrotal phase Testosterone LH, FSH
T. Klonisch et al. Developmental Biology 270 (2004) 1 18

Bilateral Cryptorchidism
Ultrasound: Only sensitive at detection of inguinal testes which 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

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, progressive loss of spermatagonia.
Elder JS. Pediatr Clin North Am 1987;34:1033-53.

Cryptorchidism and AntiSperm 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 in cryptorchidism.
Sinisi. J Urol 1998;16:1834-7.