Through the Looking-Glass: Reevaluating DHEA Metabolism Through HSD3B1 Genetics

Dehydroepiandrosterone (DHEA) and DHEA sulfate together are abundant adre-nal steroids whose physiological effects are mediated through their conversion to potent downstream androgens. 3 beta-Hydroxysteroid dehydrogenase isotype 1 (3 beta HSD1) facilitates the rate-limiting step of DHEA metabolism and gates the flux of substrate into the distal portion of the androgen synthesis pathway. Nota-bly, a germline, missense-encoding change, HSD3B1(1245C), results in expres-sion of 3 beta HSD1 protein that is resistant to degradation, yielding greater potent androgen production in the periphery. In contrast, HSD3B1(1245A) encodes 3 beta HSD1 protein that is easily degraded, limiting peripheral androgen synthesis. These adrenal-permissive (AP) and adrenal-restrictive (AR) alleles have recently been associated with divergent outcomes in androgen-sensitive disease states, underscoring the need to reevaluate DHEA metabolism using HSD3B1 genetics.