The role of 5-reduction in physiology and metabolic disease: evidence from cellular, pre-clinical and human studies

• 5-reductases are steroid hormone-metabolising enzymes that hold crucial roles in human physiology. • Alterations in 5-reductase activity have been associated with metabolic disease, PCOS, inflammation and bone health. • Understanding their role may open opportunities to enhance their potential as disease biomarkers or therapeutic targets. The 5-reductases (5α-reductase types 1, 2 and 3 [5αR1−3], 5β-reductase [5βR]) are steroid hormone metabolising enzymes that hold fundamental roles in human physiology and pathology. They possess broad substrate specificity converting many steroid hormones to their 5α- and 5β-reduced metabolites, as well as catalysing crucial steps in bile acid synthesis. 5αRs are fundamentally important in urogenital development by converting testosterone to the more potent androgen 5α-dihydrotestosterone (5αDHT); inactivating mutations in 5αR2 lead to disorders of sexual development. Due to the ability of the 5αRs to generate 5αDHT, they are an established drug target, and 5αR inhibitors are widely used for the treatment of androgen-dependent benign or malignant prostatic diseases. There is an emerging body of evidence to suggest that the 5-reductases can impact upon aspects of health and disease (other than urogenital development); alterations in their expression and activity have been associated with metabolic disease, polycystic ovarian syndrome, inflammation and bone metabolism. This review will outline the evidence base for the extra-urogenital role of 5-reductases from in vitro cell systems, pre-clinical models and human studies, and highlight the potential adverse effects of 5αR inhibition in human health and disease.