Abstract
Mammalian sex determination (male versus female) is largely controlled by genes, whereas sex differentiation (development of reproductive structures) is largely controlled by hormones. Work in the 20th century indicated that female external anatomy was a “default” pathway of development not requiring steroids, whereas male genital development required testicular testosterone plus dihydrotestosterone (DHT) made in genital skin according to a “classic” pathway. Recent work added the description of an alternative “backdoor” pathway of androgen synthesis discovered in marsupials. Unique “backdoor steroids” are found in human hyperandrogenic disorders, and genetic disruption of the pathway causes disordered male sexual development, suggesting it plays an essential role. O’Shaughnessy and colleagues now show that the principal human backdoor androgen is androsterone and provide strong evidence that it derives from placental progesterone that is metabolized to androsterone in nontesticular tissues. These studies are essential to understanding human sexual development and its disorders.
Highlights
Wilson discovered that testosterone secreted by the testis could be 5α-reduced to a more potent androgen, dihydrotestosterone (DHT), in genital skin [7], leading to the “two-androgen” model of male sexual differentiation, in which testosterone virilizes the Wolffian ducts and DHT virilizes the male external genitalia and urethra [8]
This model was not strictly proven and required examination of the hormones produced in the testis and genital skin during early fetal development, and for this purpose, conventional laboratory animals proved cumbersome at best
The wallaby provided the means for testing the “conventional wisdom” that testosterone is the androgen in the circulation while DHT is made and acts locally in the genital skin
Summary
Wilson discovered that testosterone secreted by the testis could be 5α-reduced to a more potent androgen, dihydrotestosterone (DHT), in genital skin [7], leading to the “two-androgen” model of male sexual differentiation, in which testosterone virilizes the Wolffian ducts (to form the seminal vesicle and ejaculatory ducts) and DHT virilizes the male external genitalia and urethra [8]. The pioneering studies of Marilyn Renfree provided an animal model in which the accuracy of this pathway in the developing male could be tested: the Tammar wallaby [10,11,12].
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