The Development of a Male Pseudohermaphroditic Rat Using an Inhibitor of the Enzyme 5α-Reductase*

Abstract

Incomplete masculinization of the external genitalia occurred in male Sprague-Dawley rats treated with a potent inhibitor of enzyme 5 alpha-reductase at the critical period of sexual differentiation in utero. The studies were performed using the 5 alpha-reductase inhibitor, 4-methyl-4-aza-5-pregnan-3-one-20[s] carboxylate, one of a series of aza steroids known to competitively inhibit the enzyme 5 alpha-reductase. The degree of inhibition of male external genital development was dependent upon the dose of the inhibitor, and at a dose of 36 mg/kg X day, there was complete feminization of the external genitalia of the male animal with a urogenital sinus and a pseudovagina. These studies provide conclusive evidence for the hypothesis that 5 alpha-reductase activity and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) formation are essential for normal differentiation of male external genitalia. Epididymidis, vasa deferentia, and seminal vesicles were present at all doses of the inhibitor, suggesting testosterone dependency. However, confirmation of the testosterone dependency of Wolffian ductal differentiation awaits further studies, particularly comparison studies with the rabbit and dog, since Wolffian ductal differentiation in the rat, unlike the rabbit and dog, is not abolished with the antiandrogen, cyproterone acetate. The presence of prostatic buds, despite complete external genital feminization, was unexpected and suggests that these structures may have different thresholds of response for dihydrotestosterone. Prostatic differentiation may have a much lower threshold, requiring less dihydrotestosterone for differentiation.

Identification of genes expressed in the rat prostate that are modulated differently by castration and Finasteride treatment

“…prostate growth), under specific conditions each hormone displays properties that suggest roles in the modulation of specific functions. It is clear that DHT is crucial for the normal development of the male external genitalia and of the prostate (Imperato-McGinley et al 1985, George & Peterson 1988. In contrast, testosterone appears to play essential roles in promoting spermatogenesis and Wolffian duct development, as well as gonadotropin regulation.…”

“…The current study was designed to begin to address these questions in a more general fashion using a tissue (the rat prostate) in which the importance of DHT formation is well established (Imperato-McGinley et al 1985, George & Peterson 1988. Three features have been incorporated into this study to simplify the analysis of results.…”

“…Patients deficient in this enzyme show a phenotype characterized by female external genitalia and the absence of prostatic development, but with normal virilization of the male Wolffian duct-derived internal organs. Equally important, pharmacological studies have demonstrated that the administration of specific inhibitors of the 5 -reductase enzyme(s) in animals during development causes defects of phenotypic male development that mirror the defects of virilization observed in patients with 5 -reductase type II deficiency (Imperato-McGinley et al 1985, George & Peterson 1988.…”

Molecular genetic cascades for external genitalia formation: An emerging organogenesis program

“…Evidence supporting the crucial role of androgen is based on pharmacological and genetic data. Androgen antagonists (Silversides et al, 1995;Suzuki et al, 2002) or inhibitors of its synthesis (Imperato-McGinley et al, 1985;Clark et al, 1990) interfere with testicular function and external genitalia development. Mutations in androgen receptor gene (Murakami, 1987;Yeh et al, 2002;Sato et al, 2003) or for androgen synthetic enzymes (Andersson et al, 1991;Wilson, 1992) result in abnormalities in male sexual differentiation and development.…”

Steroid 5.ALPHA. Reductase mRNA Type I is Differentially Regulated by Androgens and Glucocorticoids in the Rat Liver

“…Although each hormone displays potent effects in biological assays of androgen action, under specific conditions, each hormone displays properties that suggest roles in the modulation of specific functions. It is clear that DHT is crucial for the normal development of the male genitalia and of the prostate [1,2]. In contrast, testosterone appears to play essential roles in promoting spermatogenesis and Wollfian duct development, as well as gonadotropin regulation.…”