Aromatase, nuclear receptors, adipose tissue and breast cancer: Women’s Health and Menopause

Models of estrogen insufficiency have revealed new and often unexpected roles for estradiol in both females and males [1]. These models include natural mutations in humans of the aromatase gene, of which there are some ten cases known, of whom two are men, as well as one man with a mutation in the estrogen receptor (ER) α. They also include mice with targeted disruptions of the ERα and ERβ, the double ERα and β knockout [2 – 4], as well as the aromatase knockout (ArKO) mouse [5]. Some of these roles challenge the definition of the terms estrogen and androgen. For example the lipid and carbohydrate phenotype of estrogen insufficiency is nonsexually dimorphic and appears to apply equally to males and females [6,7], as does the bone phenotype of undermineralization and failure of epiphyseal closure. Even more dramatically, the role of estradiol in male germ cell development would indicate that at least in this local context estradiol would be more appropriately defined as an androgen [8]. The second important point is that in men and in postmenopausal women when the ovaries cease to produce estrogens, estradiol does not function as a circulating hormone. It is no longer an endocrine factor, instead estradiol is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor [9,10]. These sites include the mesenchymal cells of adipose tissue, osteoblasts and chondrocytes of bone, numerous sites in the brain, and also the Leydig cells and germ cells of the testes. Thus circulating levels of estrogens in postmenopausal women and in men do not drive estrogen action.