Table 14: Factors involved in normal sexual differentiation

Y = Testis determining gene

Chromosomal factors

X = 5cc-reductase gene, androgen receptor gene

 

Gonadal factors

19 = АМН - receptor gene Testis = TST, АМН

 

Biochemical (endocrine) factors

TST -DHTST

Wolffian duct External genitalia

Andrenal androgens-----------

TST = testosterone; АМН = anti-Mullerian hormone; DHTST = dihydrotestosterone

With very few exceptions, a normal 46XX or 46XY karyotype leads to normal sex determination and gonadal differentiation. The presence of the so-called SRY gene (sex-determining region Y) on the short arm of the Y chromosome leads to differentiation of the foetal gonad into testis, while the absence of one X chromosome (i.e. 45X0) will lead to early loss of gonadal germ cells and ovarian fibrous degeneration.

The normally functioning foetal testis induces further somatic male differentiation by means of: a) anti-Mullerian hormone (АМН), secreted by the Sertoli cells, which is responsible for Mullerian duct regression; and b) testosterone (TST) secreted by the Leydig cells, which is responsible for the maintenance and male differentiation of the Wolffian ducts and virilization of the urogenital sinus and external genitalia (genital tubercle), after its intracellular conversion to dihydrotestosterone (DHTST) by 5a reductase.

Table 15: Somatic male differentiation via testicular hormones

Testis

Leydig cells

TST

5a

DHTST

Genital tubercle

Male external genitalia

Both АМН and DHTST need the presence of their respective cellular receptors in order to exercise their function. Disorders of АМН or TST (DHTST) biosynthesis or action may lead to intersex states. The fact that the androgen-receptor gene lies on the X chromosome explains the virilization of the female foetus in the AGS.

Table 16: Effects of inadequate biosynthesis or action of АМН, TST or DHTST

 

AMH^	Retention of Mullerian structures
TSU	Inadequate differentiation of Wolffian duct structures (i.e. epididymis, vas deferens, seminal vesicles)
DHTSTl	Inadequate differentiation of genital tubercle -> inadequate masculinization of external genitalia (severe hypospadias, microphallus)

АМН = anti-Mullerian hormone, TST = testosterone, DHTST = dihydrotestosterone

CLASSIFICATION

The classification proposed by Allen in 1976 (based on gonadal histology with subclassifications made primarily by aetiology), has the advantage that gonadal histology is less uncertain to interpret than is dependence on karyotype or morphology of the external genitalia.