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J Day, Endocrinology & Metabolic Medicine, Imperial College London, London, United Kingdom
H Tutill, Endocrinology & Metabolic Medicine, Imperial College London, London, United Kingdom
A Purohit, Endocrinology & Metabolic Medicine, Imperial College London, London, United Kingdom
M Reed, Endocrinology & Metabolic Medicine, Imperial College London, London, United Kingdom

Correspondence: Michael Reed, Email: m.reed{at}imperial.ac.uk

Abstract

17β-Hydroxysteroid dehydrogenases (17β-HSDs) are enzymes which are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form which is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17β-HSDs have been identified to date, and with one exception, 17β-HSD Type 5 (17β-HSD5), an aldo-keto reductase (AKR), they are all short chain dehydrogenases / reductases (SDRs), although overall homology between the enzymes is low. Although named as 17β-HSDs, reflecting the major redox activity at the 17β-position of the steroid backbone, the activities of these fourteen enzymes vary, with several of the 17β-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism.

Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17β-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17β-HSD1, 3, and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.