Role of aromatase in sex steroid action.

Our understanding of the role of oestrogens in both males and females has expanded greatly in recent years. Hitherto unanticipated roles have emerged that question the very definitions of the terms ‘oestrogen’ and ‘androgen’ as they are currently used. Considerable emphasis has been placed on the regulation of extragonadal oestrogen biosynthesis, in particular that which occurs in adipose tissue, bone and brain, and its importance in the well-being of the elderly (Simpson et al. 1997). Although the ovaries are the principal source of systemic oestrogen in the premenopausal nonpregnant woman, other sites of oestrogen biosynthesis are present throughout the body and these become the major sources of oestrogen beyond menopause. These sites include the mesenchymal cells of the adipose tissue and skin (reviewed in Simpson et al. 1997), osteoblasts (Bruch et al. 1992) and perhaps chondrocytes in bone, vascular endothelial (Bayard et al. 1995) and aortic smoothmuscle cells (Sasano et al. 1999) as well as a number of sites in the brain, including the medial preoptic/anterior hypothalamus, the medial basal hypothalamus and the amygdala (Naftolin et al. 1975). These extragonadal sites of oestrogen biosynthesis possess several fundamental features which differ from those of the ovaries. Principally, the oestrogen synthesised within these compartments is probably biologically active only at local tissue level in a paracrine or ‘intracrine’ fashion (Labrie et al. 1997a). Thus the total amount of oestrogen synthesised by these extragonadal sites may be small, but the local tissue concentrations achieved are probably quite high and exert significant biological influence locally. Thus these sources of oestrogen play an important, but hitherto largely unrecognised, physiological and pathophysiological role. After menopause, adipose tissue becomes the main source of oestrogen (Siiteri & MacDonald 1973, Simpson et al. 1997). Therefore, in the post-reproductive years, the degree of a woman’s oestrogenisation is mainly determined by the extent of her adiposity. This is of clinical importance since corpulent women are relatively protected against osteoporosis (Melton 1997), and the incidence of Alzheimer’s disease is lower in more corpulent postmenopausal women than in their slimmer counterparts (V W Henderson, personal communication). Conversely, obesity is positively correlated with breast cancer risk (Huang et al. 1997). In the case of males, it has been estimated that the testes can account for (at best) 15% of circulating oestrogens (Hemsell et al. 1974), and local production of oestrogens, both intratesticular and extragonadal, is of physiological significance throughout adult life. For example, the Leydig cells (Tsai-Morris et al. 1985) and other cells of the testes, including germ cells in various stages of differentiation (Nitta et al. 1993), produce oestradiol, which has an important role in spermatogenesis. Oestrogen production in bone appears to be as vital for the maintenance of bone mineralisation and the prevention of osteoporosis in men as it is in women. This is supported by studies of men with either a mutation of the gene encoding the aromatase enzyme (Morishima et al. 1995, Carani et al. 1997) or a mutation of the oestrogen receptor (Smith et al. 1994). These individuals exhibit failure of epiphysial fusion, osteopenia and delayed bone age. Recently, we have observed that male mice with a null mutation in the aromtase gene (ArKO mice), also exhibit alterations in bone histomorphometry characteristic of under-mineralisation (Oz et al. 2000). This commentary was presented at the Symposium on Enzymes and Steroid Hormone Action at the 19th Joint Meeting of the British Endocrine Societies with EFES, March 2000, Birmingham, UK 149