Spatiotemporal dynamics of androgen signaling underlie sexual differentiation and congenital malformations of the urethra and vagina

Abstract

Disorders of sex development (DSDs) are congenital anomalies that affect sexual differentiation of genitourinary organs and secondary sex characters. A common cause of female genital virilization is congenital adrenal hyperplasia (CAH), in which excess androgen production during development of 46XX females can result in vaginal atresia, masculinization of the urethra, a single urogenital sinus, and clitoral hypertrophy or ambiguous external genitalia. Development of the vagina depends on sexual differentiation of the urogenital sinus ridge, an epithelial thickening that forms where the sex ducts attach to the anterior urethra. In females, the sinus ridge descends posteriorly to allow the vaginal opening to form in the vulva, whereas in males and in females with CAH, androgens inhibit descent of the sinus ridge. The mechanisms that regulate development of the female urethra and vagina are largely unknown. Here we show that the timing and duration of, and the cell population targeted by, androgen signaling determine the position of vaginal attachment to the urethra. Manipulations of androgen signaling in utero reveal a temporal window of development when sinus ridge fate is determined. Cell type-specific genetic deletions of androgen receptor (Ar) identify a subpopulation of mesenchymal cells that regulate sinus ridge morphogenesis. These results reveal a common mechanism that coordinates development of the vagina and feminization of the urethra, which may account for development of a single urogenital sinus in females exposed to excessive androgen during a critical period of prenatal development.vagina | urethra | androgen | mouse | development

Molecular mechanisms of development of the human fetal female reproductive tract

“…In contrast, in females the Müllerian epithelium of the uterovaginal canal contacts the endodermal epithelium of the urethra in a caudal position near the vaginal introitus. In mice the cranial positioning of the Müllerian duct-UGS junction in males is due to signaling through androgen receptors in the mesenchyme (Larkins et al, 2016). Patients with congenital adrenal hyperplasia (and thus elevated androgen levels) are masculinized to variable degrees (Speiser et al, 2010), and in many cases the vagina does not terminate caudally in the vaginal vestibule, but instead is attached to the urethra in a more cranial position (Larkins et al, 2016).…”

“…In mice the cranial positioning of the Müllerian duct-UGS junction in males is due to signaling through androgen receptors in the mesenchyme (Larkins et al, 2016). Patients with congenital adrenal hyperplasia (and thus elevated androgen levels) are masculinized to variable degrees (Speiser et al, 2010), and in many cases the vagina does not terminate caudally in the vaginal vestibule, but instead is attached to the urethra in a more cranial position (Larkins et al, 2016). The localization of AR observed in mesenchyme associated with the human vaginal plate/urethral junction is in the appropriate position to alter the Müllerian duct-UGS junction should androgen levels be elevated.…”

Genetic Architecture Underlying Nascent Speciation—The Evolution of Eurasian Pigs under Domestication

“…The incompatibility in angiogenesis may have resulted from growth rate mismatch between an outstanding performance in the Large White and ordinary performance in the Min pig ( Zhang 1986 ). The androgen receptor signaling pathway is important for sexual development in both males and females ( Chang et al 2013 ; Larkins et al 2016 ), and the incompatibility in it may have affected hybrid inviability or hybrid male inviability during the embryo development.…”

Reproductive tract biology: Of mice and men

“…In mice, the Müllerian duct/UGS junction becomes situated cranially in males and more caudally in females, even though the initial point of contact of the Müllerian ducts with the UGS is high (near the bladder) in both sexes. The subsequent male/female positional difference in mice is attributed to the timing and the duration of androgen action during fetal stages (Larkins et al, 2016). The absence of androgen action in females accounts for a more caudal positioning of the Müllerian duct/UGS junction in mice, while androgen action in males accounts for the more cranial positioning of the Müllerian duct/UGS junction.…”

“…The mechanism of this sexually dimorphic positioning of the Müllerian duct/UGS junction in humans has not been explored adequately. However, the proposed role of androgens (based upon mouse studies) in positioning the Müllerian duct/UGS junction in males and females (Larkins et al, 2016) is doubtful in humans for several reasons: (a) The initial cranial position of the human Müllerian duct/UGS junction described previously (Cunha et al, 2018c;Koff, 1933) in males is established at about 8 weeks of gestation when androgen levels are low or non-existent. (b) The fetal testes begin testosterone production at about 8-10 weeks of gestation (Siiteri and Wilson, 1974).…”