Possible testosterone redundancy for 5α-dihydrotestosterone in the masculinization of mouse external genitalia

Abstract

The development of embryonic external genitalia (eExG) into characteristic male structures, such as urethra and penile erectile tissues, depends on 5α-dihydrotestosterone (DHT).Although the corpus cavernosum (CC) is well known as essential for erectile function in adults, its developmental process and its dependency on DHT have been unknown. To reveal the dimorphic formation of the murine CC from the embryonic stage, we first analyzed the production of the protein vascular endothelial growth factor receptor-2 (FLK1) via its expression (hereinafter referred as "expression of FLK1") and the expression of alphasmooth muscle actin (ACTA2) and collagen type 1 (COL1A1) in developing external genitalia. The 5-α reductase type 2 encoded by the SRD5A2 gene has been suggested to be a crucial enzyme for male sexual differentiation, as it converts testosterone (T) into DHT in the local urogenital organs. In fact, SRD5A2 mutation results in decreased synthesis of DHT, which leads to various degrees of masculinized human external genitalia (ExG). We further investigated the expression profile of SRD5A2 during the formation of the murine CC. We observed that SRD5A2 was expressed in smooth muscle of the CC. To determine the role of SRD5A2 in CC formation, we analyzed the formation of erectile tissue in the male Srd5a2 KO mice and measured the levels of androgens in the ExG by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Intriguingly, there were no obvious defects in the CCs of male Srd5a2 KO mice, possibly due to increased T levels. The current study suggests possible redundant functions of androgens in CC development.

Exploring rat corpus cavernosum alterations induced by finasteride treatment and withdrawal

“…In this context, it is interesting to note that levels of T in the corpus cavernosum, which we reported to be increased after subchronic drug treatment, are negatively correlated with NOS activity (p = 0.01; r = −0.69), while tissue levels of DHT, which we demonstrated to be decreased, are positively correlated with OTC activity (p = 0.01; r = + 0.71). This is particularly interesting because, even if previous observations already indicated the presence of the enzyme 5α-R type II in the corpus cavernosum, 50,51 to our knowledge this is the first observation suggesting that a local change in T metabolism is linked to mechanisms associated with ED.…”

Emerging structural and pathological analyses on the erectile organ, corpus cavernous containing sinusoids

“…Because it needs to function as an insertional organ for ejaculation, its unique development and pathogenesis are known. [38][39][40][41] The copulatory organ has been described for significant structural and functional diversification among species. [42][43][44] Mouse erectile system contains the penile bone (baculum) which develops gradually around puberty.…”

“…Erectile tissue containing CC shows unique tissue character as a copulatory organ. Because it needs to function as an insertional organ for ejaculation, its unique development and pathogenesis are known 38–41 . The copulatory organ has been described for significant structural and functional diversification among species 42–44 .…”

“…Along with such condensation, proper input of canonical Wnt signaling has been shown 76 . In addition, local conversion of testosterone to dihydrotestosterone (DHT) by SRD5A enzyme has been also suggested in the region 38 . Possible actions of local androgen (DHT) and other signals regulating CC and mesenchymal development still require analyses.…”

“…76 In addition, local conversion of testosterone to dihydrotestosterone (DHT) by SRD5A enzyme has been also suggested in the region. 38 Possible actions of local androgen (DHT) and other signals regulating CC and mesenchymal development still require analyses. Related with the cell migration for CC, the role of androgen induced migration of pericytes has been described.…”