Role of aromatase in sex steroid action.
Role of aromatase in sex steroid action.
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DOI：
10.1677/jme.0.0250149
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发表时间：
2000-10
影响因子：
3.5
通讯作者：
Evan R. Simpson
中科院分区：
文献类型：
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作者：
Evan R. Simpson
近年来，我们对雌激素在男性和女性中的作用的理解大大扩展。最近出现了一些意想不到的作用，这些作用对目前使用的术语“雌激素”和“雄激素”的定义提出了质疑。相当多的重点放在性腺外雌激素生物合成的调节上，特别是发生在脂肪组织、骨骼和大脑中的雌激素生物合成，及其在老年人健康中的重要性（Simpson等人，1997）。虽然卵巢是绝经前非妊娠妇女全身雌激素的主要来源，但全身其他部位也存在雌激素生物合成，这些部位成为绝经后雌激素的主要来源。这些部位包括脂肪组织和皮肤的间充质细胞（Simpson等1997年综述），成骨细胞（Bruch et al. 1992），可能还有骨中的软骨细胞、血管内皮细胞（Bayard等，1995）和主动脉平滑肌细胞（Sasano等，1999）以及大脑中的许多部位，包括内侧视前区/下丘脑前部，内侧基底下丘脑和杏仁核（Naftolin等，1975）。这些雌激素生物合成的性腺外部位具有几个与卵巢不同的基本特征。主要地，在这些隔室中合成的雌激素可能仅在局部组织水平以旁分泌或“内分泌”方式具有生物活性（Labrie等人，1997 a）。因此，这些性腺外部位合成的雌激素总量可能很小，但局部组织浓度可能很高，并在局部产生显著的生物学影响。因此，这些雌激素来源发挥着重要的，但迄今为止在很大程度上未被认识到的生理和病理生理作用。绝经后，脂肪组织成为雌激素的主要来源（Siiteri & MacDonald 1973，Simpson et al. 1997）。因此，在生育后的岁月里，女性雌激素化的程度主要取决于她的肥胖程度。这一点具有临床意义，因为肥胖的女性相对更容易预防骨质疏松症（Melton 1997），肥胖的绝经后女性阿尔茨海默病的发病率低于苗条的绝经后女性（V W亨德森，个人交流）。相反，肥胖与乳腺癌风险呈正相关（Huang et al. 1997）。在雄性动物中，据估计睾丸（最多）可占循环雌激素的15%（Hemsell等人，1974），睾丸内和性腺外雌激素的局部产生在整个成年期具有生理意义。例如，Leydig细胞（Tsai-Morris等，1985）和睾丸的其他细胞，包括处于不同分化阶段的生殖细胞（Nitta等，1993），产生雌二醇，雌二醇在精子发生中具有重要作用。骨中雌激素的产生对于维持骨矿化和预防男性骨质疏松症与女性一样重要。这得到了芳香酶编码基因突变（Morishima et al.1995，Carani et al.1997）或雌激素受体突变（Smith et al.1994）男性研究的支持。这些个体表现出骨骺融合失败、骨质减少和骨龄延迟。最近，我们观察到芳香酶基因无效突变的雄性小鼠（ArKO小鼠）也表现出矿化不足的骨组织形态计量学特征改变（Oz等人，2000）。这篇评论发表于2000年3月在英国伯明翰举行的第19届英国内分泌学会与EFES联合会议上的酶和类固醇激素作用研讨会149
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