A Practical Approach to Intersex

M. David Bomalaski

Disclosures

Urol Nurs. 2005;25(1):11-18, 23-24. 

In This Article

Genitalia Differentiation

In both males and females, two sets of genital ducts form: the wolffian (mesonephric) duct, which goes on to form the male genital ducts (vas deferens, seminal vesicles, and epididymis), and the müllerian duct, which forms the female genital ducts (fallopian tubes, uterus, and proximal vagina). The wolffian duct forms initially as the drainage system of the primitive mesonephros, with the müllerian duct forming concurrently along the genital ridge during the 6th week of life. The presence of Sertoli cells in the male-differentiated gonad produces müllerian inhibiting substance (MIS). This is a paracrine substance leading to ipsilateral regression of the müllerian duct. In the absence of MIS, the müllerian duct will autonomously develop along female gender lines. In the absence of testosterone, the external genitalia remain phenotypically female.

At approximately the same time as MIS secretion, the Leydig cells of the testis start to secrete testosterone. This also acts as a paracrine (locally acting) hormone-stimulating ipsilateral wolffian duct development. Between the 9th and 12th week of gestation, if testosterone is present, the ambiguous external genitalia undergo male differentiation. The external genitalia require the conversion of testosterone to the metabolically active dihydrotestosterone (DHT) by the microsomal enzyme 5-reductase. DHT leads to the midline fusion of the labioscrotal folds creating the scrotum, urethra, and male phallus. If labioscrotal fusion has not occurred by the 12th week, further androgen exposure will lead to phallic growth but will not result in further midline fusion. In the final trimester, under the influence of MIS, testosterone, mechanical pressures, and neurologic mediation, the testicles descend into the scrotum (Pajkrt & Chitty, 2004). Figure 1 shows where problems with gonadal and genital differentiation can arise. Starting in the upper left-hand, if the testis determining factor (TDF) is present, a testis will form; if absent and two X chromosomes are present, an ovary will form. If TDF is absent from a Y chromosomal fetus, if there is a solitary X or Y chromosome, or if mixtures of XX and XY cells co-exist in the same individual (chromosomal mosaicism), then a problem in gonadal differentiation is possible. In this way, chromosomal sex determines gonadal sex.

Assuming no problems in gonadal differentiation, hormonal factors at both the local paracrine and global endocrine level come into play for male internal and external genital development. This is what is meant by gonadal sex determining phenotypic sex. Female genital development is passive. If an ovary is present but there is androgen stimulation, either in the form of exogenous androgens from the mother or endogenous androgens from an adrenal source, then the female genitalia will undergo virilization. If a testis is present, MIS leads to apoptosis of the müllerian ducts, testosterone leads to development of the wolffian ducts, and conversion of testosterone to DHT leads to external genitalia differentiation. If the Sertoli cells fail to secrete MIS, müllerian ductal structure will remain, even in the presence of normal testosterone production by the Leydig cells. If the Leydig cells fail to produce testosterone, if there is a testosterone receptor deficiency, or if there is a deficiency of 5-reductase, there may be varying levels of undervirilization.

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