Development of the human prepuce and its innervation

Abstract

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.

A closer look at iatrogenic hypospadias

“…Standard anatomical texts and most studies describe the "glans penis" as the "anterior (expanded) end of the corpus spongiosum" with diagrams showing the urethra that runs through the glans and is therefore surrounded by spongiosal tissue Cunha, Sinclair, Cao, & Baskin, 2020). Dr Friedrich Gustav Jacob Henle, however, first described the gradual termination of the corpus spongiosum on the fossa navicularis (glanular urethra), the ligamentous structure within the glans and its fine fibrous extensions (septum glandis) around the fossa navicularis (Henle, 1877;Özbey, 2019a).…”

Reproductive tract biology: Of mice and men

“…The mouse prepuce develops as a result of midline fusion of the preputial swellings, for which there is no human counterpart. Moreover, malformations of the mouse external prepuce elicited by developmental exposure to exogenous estrogens differ substantially from spontaneous preputial malformations in humans (Cunha et al, 2019c;Cunha et al, 2015;Mahawong et al, 2014a, b). Development of the mouse internal prepuce has only been described superficially (Schlomer et al, 2013;Sinclair et al, 2016a), but the data clearly establish that the mouse internal prepuce and the human prepuce differ greatly in anatomy and development even though both are integral to the glans penis (Cunha et al, 2019c;Liu et al, 2018aLiu et al, , 2018b.…”

“…Morphogenesis of the external prepuce of the mouse occurs via a developmental mechanism entirely different from that of human preputial development (Cunha et al, 2019c;Liu et al, 2018aLiu et al, , 2018b. See companion paper, "Development of the human prepuce" Cunha et al, (2019c).…”

“…Likewise, estrogen-induced malformation of the mouse penile urethral meatus (Mahawong et al, 2014a, b;Sinclair et al, 2016a;Sinclair et al, 2016b) is completely different from human hypospadias, which is illustrated in an accompanying paper (Cunha et al, 2019c). These differences led us to question the use of estrogen-induced mouse penile malformations as a model for human hypospadias (Cunha et al, 2015(Cunha et al, , 2019cSinclair et al, 2016b). Flutamide-induced rat and mouse hypospadias appears to be a better model for hypospadias (Sinclair et al, 2017;Zheng et al, 2015).…”

Development of the external genitalia

“…Since then several theories of human preputial development have emerged. In the course of examining development of the human glans penis, novel data emerged suggesting an entirely different developmental mechanism (Cunha et al, 2019c). For this purpose 30 human fetal specimens were studied from 9 to 17 weeks of gestation.…”