Minireview: Aromatase and the Regulation of Estrogen Biosynthesis—Some New Perspectives

There is a growing awareness that androgens and estrogens have general metabolic roles that are not directly involved in reproductive processes. These include actions on vascular function, lipid and carbohydrate metabolism, as well as bone mineralization and epiphyseal closure, in both sexes. In postmenopausal women, as in men, estrogen is no longer solely an endocrine factor, but instead is produced in a number of extragonadal sites and acts locally at these sites in a paracrine and intracrine fashion. These sites include breast, bone, vasculature, and brain. Within these sites, aromatase action can generate high levels of E2 locally without significantly affecting circulating levels. Circulating C(19) steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possibly from the mid to late reproductive years. This may be a fundamental reason why women are at increased risk for bone mineral loss and fracture and possibly decline of cognitive function, compared with men. Aromatase expression in these various sites is under the control of tissue-specific promoters regulated by different cohorts of transcription factors. Thus, in principle, it should be possible to develop selective aromatase modulators that block aromatase expression, for example, in breast, but allow unimpaired estrogen synthesis in other tissues such as bone.