The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology

Abstract 17β-Hydroxysteroid dehydrogenase (17β-HSD) controls the last step in the formation of all androgens and all estrogens. This crucial role of 17β-HSD is performed by at least five 17β-HSD isoenzymes having individual cell-specific expression, substrate specificity, regulation mechanisms, and reductive or oxidative catalytic activity. Both estrogenic and androgenic 17β-HSD activities were found in all 25 rhesus monkey and 15 human peripheral intracrine tissues examined. Type 1 17β-HSD is a protein of 327 amino acids catalyzing the formation of 17β-estradiol from estrone. Its x-ray structure was the first to be determined among mammalian steroidogenic enzymes. Initially crystallized with NAD, the crystal structure of type 1 17β-HSD has just been determined as a complex with 17β-estradiol, thereby illustrating the conformation of the substrate-binding site. Type 2 17β-HSD degrades 17β-estradiol into estrone and testosterone into androstenedione, and type 4 17β-HSD mainly degrades 17β-estradiol into estrone and androst-5-ene-3β, 17β-diol into dehydroepiandrosterone. Types 3 and 5 17β-HSD, on the other hand, catalyze the formation of testosterone from androstenedione in the testis and peripheral tissues, respectively. The various types of human 17β-HSD, because of their tissue-specific expression and substrate specificity, provide each peripheral cell with the necessary mechanisms to control the level of intracellular androgens and/or estrogens, a new area of hormonal control that we call intracrinology.