New Insights into the Role of Androgens in Wolffian Duct Stabilization in Male and Female Rodents

Androgen-mediated wolffian duct (WD) development is programmed between embryonic d 15.5 (e15.5) and 17.5 in male rats, and WD differentiation has been shown to be more susceptible to reduced androgen action than is its initial stabilization. We investigated regulation of these events by comparing fetal WD development at e15.5-postnatal d0 in male and female androgen receptor knockout mice, and in rats treated from e14.5 with flutamide (100 mg/kg/d) plus di-n(butyl) phthalate (500 mg/kg/d) to block both androgen action and production, testosterone propionate (20 mg/kg/d) to masculinize females, or vehicle control. In normal females, WD regression occurred by e15.5 in mice and e18.5 in rats, associated with a lack of epithelial cell proliferation and increased apoptosis, disintegration of the basement membrane, and reduced epithelial cell height. Exposure to testosterone masculinized female rats including stabilization and partial differentiation of WDs. Genetic or chemical ablation of androgen action in males prevented masculinization and induced WD regression via similar processes to those in normal females, except this occurred 2-3 d later than in females. These findings provide the first evidence that androgens may not be the only factor involved in determining WD fate. Other factors may promote survival of the WD in males or actively promote WD regression in females, suggesting sexually dimorphic differences in the preprogrammed setup of the WD. (Endocrinology 150: 2472-2480, 2009)