PROC. V. INT. CONGR. ENDOCRINOLOGY, VOL. I

On the basis of detailed endocrine studies in the developing embryo and studies of testosterone metabolism in tissues and cultured fibroblasts from patients with pseudovaginal perineoscrotal hypospadias, it is now clear that the molecular mechanisms involved in virilization of the Wolffian duct are fundamentally different from those in the urogenital sinus and the anlage of the external genitalia. However, several aspects of this phenomenon are still puzzling. First, it is not clear why testosterone can virilize one tissue but not the other; this is particularly intriguing since the administration of dihydrotestosterone in pharmacological amounts can virilize both types of tissues. Elucidation of the molecular basis for this phenomenon might provide fundamental insight into the physiological role and significance of dihydrotestosterone in androgen physiology. Second, the further elucidation of the nature of mutations in the 5α-reductase enzyme will not only provide insight into the regulation of dihydrotestosterone formation in target tissues but may yield insight into the mechanisms of enzymatic differentiation among tissues as well. Finally, several unexplained aspects of the Type 2 mutation required explanation. In particular, it is not clear why virilization at puberty appears to be more effective than during embryogenesis, and it is critical that all the regulatory factors that influence dihydrotestosterone formation and action can be identified. Nevertheless, it is clear that the combined genetic and endocrine approach provides valuable insight into the pathology as well as the normal physiology of male phenotypic development.