Mammalian genital enhancement is a complex process that may include the generation of epithelial, muscle, and dermal structures and their interactions (Cowan, [@B9]). The development of the epithelium, connective tissue, smooth muscle, and peritoneum is controlled by different stages of genital remodeling. A variety of cells including nerve cells, cells of the mesenchymal origin, and immune cells play important roles in this process. The interaction between different cells and their surrounding structures has led to formation of the male genitalia (Cowan, [@B9]). According to genetic analyses and gene expression studies, many genetic mutations have been found to lead to various forms of cryptorchidism in animals and men. Human patients with testicular dysgenesis exhibit defects in many transcription factors and genes such as *WT1* and *GATA4* (Smith et al., [@B46]). In general, these mutations may alter the development of the genitalia including testis. For instance, mice with a *Foxl2* mutation (*Foxl2*^−/−^ mice) are infertile because of defects in the development of the Müllerian and Wolffian ducts (Wan et al., [@B50]). Testicular dysgenesis is characterized by abnormal testis cord formation, defects in follicle formation, and the aberrant differentiation of spermatozoa in mice (Koubova et al., [@B19]; Woo et al., [@B51]). Moreover, germ cells are not derived from the same lineage as somatic cells in the adult mouse gonads (Woo et al., [@B51]). During sexual development in mammals, mesenchymal *Wt1* (*Wt1*^+^ mesenchymal cells) secrete steroidogenic factor-1 and vascular endothelial growth factor to induce the development of the primordial sex organs (Chen et al., [@B8]). *Wt1*^+^ cells are involved in the differentiation of Sertoli cells and other Sertoli cell-related cells, such as steroidogenic factor-1 (SF-1)-positive peritubular myoid cells (Chen et al., [@B8]). Moreover, *Wt1*^+^ mesenchymal cells contribute to the proliferation of germ cells in the fetal ovary (Chen et al., [@B8]). In addition, testicular defects are also characterized by the deficiency of gonadotropin in mice (Chen et al., [@B8]). Therefore, an understanding of the molecular mechanism of genital development in animals and men should help researchers to design and develop new methods for human male infertility. Effects of Testicular Hormones on Male Genitalia {#s4} ================================================ It has been reported that testicular hormones including T and inhibin B have various important roles in regulating gonadal development and physiology (Krege, [@B20]). T plays an important role in the development of male external genitalia (Santillan and Shaffer, [@B43]). In mouse fetal gonads, the development of the male external genitalia is blocked when T levels are low. In adult mouse gonads, the development of male external genitalia is maintained by binding of T to androgen receptor (AR). In addition to AR, androgen-binding protein (ABP) is another critical receptor of T in testis. *Ar* is encoded by *Wt1* and *Ar* is expressed at an early stage of gonad development in the mouse gonad, which suggests that ABP may also have important roles in male genital development (Sakai et al., [@B42]). It has been reported that T may play different roles in the development of male genitalia in chicken, rat, and mice. *In vitro* studies have shown that testosterone stimulates androgen receptor expression, which suggests that T may be an essential hormone for the development of male external genitalia in chickens (Sawada et al., [@B44]). For rat, prenatal exposure to T leads to increases in *Ar* and *Wt1* mRNA levels, suggesting that T may affect gonadal development at a later developmental stage. The results of *in vivo* studies show that T regulates the development of gonadal cords, induces *Wt1* expression in neonatal rat testis, and suppresses the differentiation of Sertoli cells (de Vries and Kremer, [@B10]). Moreover, in *Xenopus laevis*, the androgen receptor also plays an important role in early male external genitalia formation, and it has been found to stimulate testis cord formation in the gonads (Wibowo et al., [@B52]). However, the expression of androgen receptor is at a very low level during testis cord formation in embryonic chicken testes (Liu et al., [@B28]). It has been reported that the administration of both T and dihydrotestosterone reduces the size of the vas deferens in postnatal day 10 rats (Miyazaki et al., [@B34]). In addition, testis cords are not present in the postnatal testes of rats after dihydrotestosterone administration (Miyazaki et al., [@B34]). When the gonads from postnatal mice are treated with T, the width of the seminiferous tubules is reduced, but the height of the seminiferous epithelium is increased. It has also been found that the development of germ cells in postnatal testis cords is suppressed (Koo et al., [@B18]). Moreover, the prenatal treatment with an antagonist of AR results in defects in Leydig cell function, testicular atrophy, and an absence of seminiferous tubule development, which suggests that androgen plays an important role in the development of Leydig cells and seminiferous tubules in testes of postnatal rats (Ogawa et al., [@B39]). It has been demonstrated that Leydig cells and Sertoli cells are generated by a common precursor cell that expresses glial cell-derived neurotrophic factor, which is consistent with the findings of a previous study (Bouma et al., [@B5]). Moreover, when dihydrotestosterone binds to AR in a neonatal mouse testis, Leydig cell precursors are differentiated into Leydig cells through the expression of steroidogenic factor-1 and the activation of β-catenin (Ogawa et al., [@B39]). In addition to androgen, other hormones including insulin-like growth factor-1, glial cell-derived neurotrophic factor, and fibroblast growth factor 2 play important roles in the development of the male genitalia. In addition, the interaction between these hormones may have an impact on the differentiation of germ cells (Li et al., [@B25]). In conclusion, these studies have shown that T plays different roles in the development of male genitalia in different animals. It has been reported that androgen plays an important role in Leydig cell differentiation in rats (Ogawa et al., [@B39]). It has also been shown that T may induce the differentiation of Leydig cells through insulin-like growth factor-1 and fibroblast growth factor 2 in mice (Bhattacharya et al., [@B3]). The Leydig cells in rats and mice have different developmental mechanisms. Thus, *in vitro* and *in vivo* studies on Leydig cell differentiation require further study. In addition, it has been reported that the prenatal treatment with dihydrotestosterone results in defects in Leydig cell function, testicular atrophy, and an absence of seminiferous tubule development in mice (Ogawa et al., [@B39]). It may be helpful to screen more hormones that regulate Leydig cell differentiation during the development of male genitalia. The Effects of Androgens on Male External Genitalia Development {#s5} =============================================================== In a previous study, it has been reported that *in vivo* androgen depletion leads to defects in external genitalia formation in male chickens, which suggests that androgens play an important role in the development of external genitalia in chickens (Sawada et al., [@B44]). Therefore, the role of androgens in male genitalia development is an important topic for reproductive medicine. It has been reported that the serum testosterone level is low in patients with Klinefelter syndrome (XX males) (Kim et al., [@B17]). It has also been shown that androgen administration or a hypogonadal condition can affect the development of male external genitalia in Klinefelter syndrome (XX males) and 46,XY individuals (Kim et al., [@B17]). It has been found that 46,XY Klinefelter patients exhibit malformations of the external genitalia compared to 46,XY individuals, which indicates that the high androgen level in Klinefelter syndrome (XX males) may affect the development of male external genitalia. It has also been reported that there are differences in the levels of estrogens, androgens, and their metabolites in 46,XY men, 46,XX males, 46,XX females, and 46,XY females during the development of male external genitalia (Vardi et al., [@B49]). This suggests that endogenous hormones might affect the development of male external genitalia. However, further studies should be conducted to determine the levels of hormones in the development of male external genitalia. A more complete picture of the roles of androgens in the development of male external genitalia in humans remains to be elucidated. However, a considerable number of studies have been conducted on the development of testicular Leydig cells and Sertoli cells and their interactions during the development of the male external genitalia in animals and men. Androgens Receptors and the Effects of Androgens on Male External Genitalia Development {#s6} ======================================================================================= As an important transcription factor of Sertoli cells,