Estrogen--the good, the bad, and the unexpected.

1 Introduction In the last decade or so, our knowledge of the roles of the steroids referred to as 'sex hormones' namely testosterone and estradiol, has undergone a quiet revolution. In the first place, models of androgen and estrogen insufficiency, whether they be natural or engineered, have revealed new and unexpected roles for sex steroids, some of which have nothing to do with reproduction. Furthermore both categories of steroid have roles in both sexes which blunts the definition of the terms 'androgen' and 'estrogen'. Secondly, the gradual acceptance of the role of local steroid hormone action, particularly as it applies in postmenopausal women and in men, provides new insights into the significance of paracrine and intracrine actions, and requires a re-evaluation of the importance of circulating steroid hormone levels. This article will attempt to review both of these developments, particularly in the context of the work of this laboratory on the aromatase knockout (ArKO) mouse and the role of local aromatase expression within the breast and breast cancer. The concept of local estrogen biosynthesis Models of estrogen insufficiency have revealed new and unexpected roles for estrogens in both males and females. These models include natural mutations in the aromatase gene, as well as mouse knockouts of aromatase and the estrogen receptors (1-6). In addition there is one man described with a natural mutation in the ERα (7). Some of the roles of estrogens apply equally to males and females and do not relate to reproduction, for example the bone, vascular and Metabolic Syndrome phenotypes. In postmenopausal women and in men, estradiol does not appear to function as a circulating hormone, instead it is synthesised in a number of extragonadal sites such as breast, brain and bone where its actions are mainly at the local 2 level as a paracrine or intracrine factor. Thus in postmenopausal women and in men, circulating estrogens are not the drivers of estrogen action, rather they reflect the metabolism of estrogens formed in these extragonadal sites, they are reactive rather than proactive (8). Importantly, estrogen biosynthesis in these sites depends on a circulating source of androgenic precursors such as testosterone. Table 1 shows the plasma steroid levels in postmenopausal women and in men. As can be seen, the levels of estrone and estradiol in the plasma of postmenopausal women are extremely low, lower in fact than those in the circulation of men; and moreover the levels …