Figure 1. Androgen synthesis pathways in prostate cancer. In testicular androgen synthesis­, luteinizing hormone-releasing hormone (LHRH) stimulates release of luteinizing hormone (LH) from the pituitary gland, which signals the testes to secrete testosterone [a(1)]. Testosterone enters the prostate cancer cell and is converted to the potent androgen dihydrotestosterone (DHT) by 5-a reductase (5aR) [d]. DHT binds and activates the androgen receptor (AR) [e], which in turn initiates transcription of oncogenic genes increasing cell growth,
proliferation and survival [f].

In castration-resistant androgen synthesis, the pituitary gland also signals the adrenal gland to initiate an adrenocorticotropic hormone (ACTH)-mediated androgen synthesis pathway [a(2)]. The switch from dependence on the testicular to the adrenal androgen synthesis pathway can occur following surgical or chemical castration, leading to tumor regrowth. Through a series of reactions catalyzed by cytochrome P450 17 a-hydroxylase/17, 20 lyase (CYP17), cholesterol is converted into dehydroepiandrosterone (DHEA) [b(2)].The CYP17 inhibitor abiraterone blocks the production of DHEA and downstream androgen synthesis in the adrenal androgen synthesis pathway. However, it may incompletely inhibit this step and lead to resistance. Hydroxysteroid 3b dehydrogenase 1 (HSD3B1), the gene that encodes 3bHSD1, catalyzes the rate-limiting step in the pathway that converts DHEA to testosterone, which is then converted to DHT to activate AR [c(2)]. DHEA may also be converted to DHT independently of testosterone through a 3bHSD1-dependent pathway [c(3)]. A gain-of-stabilization mutation in HSD3B1 can increase the flux from DHEA to DHT, possibly allowing sufficient production of DHT from the residual androgen precursors remaining during abiraterone treatment leading to therapeutic resistance. Inhibitors of 3bHDS1 may prevent this resistance pathway.