There is 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 estradiol locally without significantly affecting circulating levels. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possible 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 promotors regulated by different cohorts of transcription factors. Thus in principle, it should be possible to develop selective aromatase modulators (SAMs) that block aromatase expression, for example, in breast, but allow unimpaired estrogen synthesis in other tissues such as bone.

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It is now apparent that in men and in postmenopausal women, estrogens have important physiological and pathophysiological roles. However, importantly, these actions are at a ocal level, namely paracrine, autocrine, and even 'intracrine' rather than endocrine in the classical sense. Thus for example local estrogen biosynthesis in the bones of men plays a hitherto unsuspected role in the maintenance of bone mineralization and in epiphyseal fusion; and in the testes, estrogen is essential for male germ cell development. On the other hand, in postmenopausal women, the mesenchymal cells of the breast are the major source of estrogen responsible for breast cancer development. This realization points to the importance of circulating C 19 precursors in the maintenance of adequate estrogen biosynthesis in extragonadal sites and suggests the possiblility of new therapies to block Endocrine-Related Cancer (1999) 6 131-137 estrogen synthesis in a tissue-specific fashion.