Section: USMLE

2) A genotypic male (XY) is born with feminized external genitalia. The testes are retained within the abdominal cavity, and the internal reproductive tracts exhibit the normal male phenotype. Which of the following could account for this abnormal development?

1. Complete androgen resistance
2. 5α-reductase deficiency
3. 17α-hydroxylase deficiency
4. Sertoli-only syndrome
5. Testicular dysgenesis

In utero differentiation of the Wolffian ducts into the normal male phenotypic internal reproductive tract requires testosterone, but not dihydrotestosterone. On the other hand, differentiation of the indifferent external genital slit into the penis, prostate, and scrotum does require dihydrotestosterone. A congenital absence of 5α-reductase in these tissues will result in feminization. If left untreated, the affected individuals are generally phenotypic females until puberty, at which time increased amounts of testosterone result in virilization ("penis-at-twelve" syndrome). If discovered early, a male gender assignment can be supported with administration of dihydrotestosterone to increase penis size. If discovered after infancy, a female gender assignment can be supported with estrogen substitution therapy and prophylactic orchiectomy.

With complete androgen resistance, the external genitalia are feminized, but neither the male-type nor the female-type internal tracts develop. In the absence of the androgen receptor, the Wolffian ducts will degenerate. The Müllerian ducts will also degenerate because of the normal effect of testicular Müllerian regression factor.

With 17a-hydroxylase deficiency, the testes cannot synthesize testosterone, resulting in feminization of the external genitalia and degeneration of the Wolffian ducts. Normal secretion of Müllerian regression factor should also cause the degeneration of the Müllerian ducts. Because of the excessive secretion of deoxycorticosterone by the adrenal cortex, these individuals are usually hypertensive.

The Sertoli-only syndrome refers to the situation in which only the Sertoli cells of the seminiferous tubules are present (germinal cell aplasia). Spermatogenesis is absent in these individuals, who also show increased plasma levels of FSH because of decreased Sertoli cell secretion of inhibin. They may exhibit both male-type and female-type internal tracts because of the absence of Müllerian regression factor. The Leydig cells, however, have normal function and result in normal secretion of testosterone, so that both male-type internal tracts and external genitalia develop.

Testicular dysgenesis results in poor in utero development of the testes with concomitantly decreased secretion of testosterone and Müllerian regression factor. The Wolffian duct structures may degenerate, and the external genitalia may be feminized. Female-type internal tracts may develop because of the decreased secretion of Müllerian regression factor.