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

• Published in: Trends in endocrinology and metabolism 2020-09, Vol.31 (9), p.680-690
• Main Authors: Naelitz, Bryan D., Sharifi, Nima
• Format: Article
• Language: English
• Subjects: 3β-hydroxysteroid dehydrogenase isotype 1; adrenal steroids; androgens; dehydroepiandrosterone; genetics; HSD3B1
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2020.05.006

Dehydroepiandrosterone (DHEA) and DHEA sulfate together are abundant adrenal steroids whose physiological effects are mediated through their conversion to potent downstream androgens. 3β-Hydroxysteroid dehydrogenase isotype 1 (3βHSD1) facilitates the rate-limiting step of DHEA metabolism and gates the flux of substrate into the distal portion of the androgen synthesis pathway. Notably, a germline, missense-encoding change, HSD3B1(1245C), results in expression of 3βHSD1 protein that is resistant to degradation, yielding greater potent androgen production in the periphery. In contrast, HSD3B1(1245A) encodes 3βHSD1 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. In vitro studies using prostatic cell lines demonstrated that the adrenal-permissive HSD3B1 allele encodes 3βHSD1 protein resistant to degradation, resulting in enhanced DHEA metabolism and increased androgen biosynthesis.Multiple clinical cohort studies have demonstrated that inheritance of the adrenal-permissive allele increases hazard for progression, metastasis, and death in patients with castration-sensitive prostate cancer treated with ADT.Respiratory function worsens in a dose-dependent fashion with inheritance of the adrenal-restrictive allele in patients with severe asthma on glucocorticoid therapy, suggesting that suppressed DHEA metabolism in peripheral tissue dysregulates the immune response.HSD3B1 genotype may explain phenotypic variation in autoimmune disease, menopausal changes, and clinical responses to DHEA supplementation.