Development of the human prepuce and its innervation.

Development of the human prepuce was studied over the course of 9-17 weeks of gestation in 30 specimens. Scanning electron microscopy revealed subtle surface features that were associated with preputial development, namely the appearance of epidermal aggregates that appeared to be associated with formation of the preputial fold. Transverse and sagittal sections revealed that the epidermis of the glans is considerably thicker than that of the penile shaft. We described a novel morphogenetic mechanism of formation of the preputial lamina, namely the splitting of the thick epidermis of the glans into the preputial lamina and the epidermis via the intrusion of mesenchyme containing red blood cells and CD31-positive blood vessels. This process begins at 10-11 weeks of gestation in the proximal aspect of the glans and extends distally. The process is likely to be androgen-dependent and mediated via androgen receptors strategically localized to the morphogenetic process, but signaling through estrogen receptor may play a role. Estrogen receptor alpha (ESR1) has a very limited expression in the developing human glans and prepuce, while estrogen receptor beta (ESR2) is expressed more broadly in the developing preputial lamina, epidermis and urethra. Examination of the ontogeny of innervation of the glans penis and prepuce reveals the presence of the dorsal nerve of the penis as early as 9 weeks of gestation. Nerve fibers enter the glans penis proximally and extend distally over several weeks to eventually reach the distal aspect of the glans and prepuce by 14-16 weeks of gestation.