Clinical implications of androgen synthesis via 5alpha-reduced precursors

During embryogenesis, the male external genitalia are formed by the action of the potent androgen, dihydrotestosterone (DHT). DHT is produced in human genital skin and prostate from testosterone via the action of 5alpha-reductase type 2. The biological relevance of this pathway to DHT is evidenced by patients with mutations in the gene encoding 5alpha-reductase type 2, which causes severely undermasculinized external genitalia in genetic males. In contrast, this paradigm of androgen physiology does not explain some clinical observations, such as the differences noted in the virilization of females with various congenital adrenal hyperplasias. An alternate pathway to DHT was elucidated in the tammar wallaby pouch young, and studies in knockout mice showed that this pathway uses 5alpha-reductase type 1 to convert 17-hydroxyprogesterone to 5alpha-reduced androgen precursors. Flux via the alternate or 'backdoor' pathway has been implicated in human diseases such as P450 oxidoreductase deficiency, polycystic ovarian disease, and congenital adrenal hyperplasia. A better understanding of the 5alpha-reduced or 'backdoor'pathway to DHT in human disorders of androgen excess will provide pharmacotherapy opportunities to effectively treat androgen excess in females.