Sexually dimorphic expression of estrogen receptors, but not of androgen receptors in human fetal external genitalia.

Using immunohistochemistry, we investigated the distribution of androgen receptors (AR) and estrogen receptors (ER) in the external genitalia of human male and female fetuses at 18-22 weeks gestation. In the male, the corpus cavernosum, and the stroma of the inner prepuce, scrotum, and periphery of the glans were AR rich. The corpus spongiosum, a well defined structure that surrounds the penile urethra in the neonate, was not yet developed at this fetal age, but the periurethral mesenchyme (presumably the primordium of the corpus spongiosum) was intensely AR positive. In contrast, the epithelium of the preputial skin, penile shaft skin, and scrotal skin were AR negative. The urethral plate in the distal glans was nonpatent and was filled with a meshwork of AR-negative epithelial cells. Canalization of the AR-negative urethral plate was observed to begin where it joined the patent distal penile urethra, which was AR positive. Male external genitalia lacked ER, ruling out a direct influence of maternal estrogen on male genital development. Interestingly, female external genital structures contained AR, and the distribution of AR and staining intensity were strikingly similar to that in the male. The distribution of AR in the female provides a mechanism to explain how female external genitalia become masculinized if exposed to elevated androgen levels in the first trimester. Moreover, it implies that in the male, these AR indeed mediate androgen-dependent male external genital development. Female fetal external genitalia were also intensely ER positive in the stroma of the labia minora and in the periphery of the glans and inner prepuce. The presence of ER suggests that maternal estrogen may play a direct role in female external genital development, challenging the widely held view that female external genital development is passive because it can occur in the absence of fetal gonadal hormones.