Uroplakin and androgen receptor expression in the human fetal genital tract: Insights into the development of the vagina

Purpose: Although a dual origin of the vagina has been popularized, other t heories support a mullerian or wolffian duct origin or various combinations of these structures and the urogenital sinus. Uroplakins are specialized m embrane proteins of the urothelial plaque, constituting the asymmetrical un it membrane of the bladder, and represent specific molecular markers of uro thelial differentiation. We hypothesize that the epithelium of the dorsal w all of the urogenital sinus is involved in the formation of the sinovaginal bulbs and will express uroplakins. In addition, localization of the androg en receptor and its temporal expression during development may in part expl ain the varied effects of androgens on the lower female genital tract in co ngenital adrenal hyperplasia. Materials and Methods: Lower genitourinary tracts from 4 human female fetus es (9 to 18 weeks) were serially sagittally sectioned. Representative secti ons were stained with hematoxylin and eosin, rabbit antibodies against panu roplakin and antibodies to the androgen receptor. Results: At 9 weeks of gestation the urogenital sinus showed evidence of ev agination and the formation of the sinovaginal bulbs. The urothelium of the entire urogenital sinus expressed uroplakins including the region of the d orsal wall involved in evagination and formation of the sinovaginal bulbs. The mullerian ducts were in direct contact with the area of urogenital sinu s evagination but were not in continuity with the sinus. Androgen receptors were expressed in the epithelium and the stroma of the urogenital sinus, s inovaginal bulbs, and mullerian and wolffian ducts. By 14 weeks androgen re ceptor expression was almost absent in the urothelium of the urogenital sin us, and the epithelium and surrounding stroma of the lower vagina and mulle rian ducts. Conclusions: The area of evagination of the urogenital sinus expresses urop lakins, is involved in the formation of the sinovaginal bulbs and further s ubstantiates the urogenital sinus origin of the lower vagina. Since testost erone inhibits formation of the lower vagina, the timing of exposure to sys temic testosterone in congenital adrenal hyperplasia will determine the phe notypic appearance of the external genitalia and effect of testosterone on the development of the lower genital tract. If exposure to testosterone occ urs after 12 weeks only clitoromegaly occurs. Androgen receptor is absent i n the urogenital sinus urothelium, vaginal epithelium and mullerian duets b y 14 weeks, suggesting that these tissues become androgen insensitive and v aginal development will proceed normally after that critical time.