Abstract：
Estrogens are involved in a number of physiological functions, including in the development of the brain, growth, reproduction and metabolism. The biological actions of estrogens are achieved by binding to estrogen receptors (ERs) in numerous types of tissues. ERα and ERβ belong to the nuclear receptor superfamily and the G‑protein coupled ER1 (GPER1) is a membrane receptor. The primary biologically active estrogen, 17β‑estradiol demonstrates a high affinity for ERs. Mechanistically, estrogens bind to the ERs in the nucleus, and the complex then dimerize and bind to estrogen response elements (EREs) located in the promoter regions of the target genes. This is referred to as the genomic mechanism of ERs\' function. Furthermore, ERs can also act through kinases and other molecular interactions leading to specific gene expression and functions, referred to as the non‑genomic mechanism. While ERα and ERβ exert their functions via both genomic and non‑genomic pathways, GPER1 exerts its function primarily via the non‑genomic pathways. Any aberrations in ER signaling can lead to one of a number of diseases such as disorders of growth and puberty, fertility and reproduction abnormalities, cancer, metabolic diseases or osteoporosis. In the present review, a focus is placed on three target tissues of estrogens, namely the bones, the breasts and the brain, as paradigms of the multiple facets of the ERs. The increasing prevalence of breast cancer, particularly hormone receptor‑positive breast cancer, is a challenge for the development of novel antihormonal therapies other than tamoxifen and aromatase inhibitors, to minimize toxicity from the long treatment regimens in patients with breast cancer. A complete understanding of the mechanism of action of ERs in bones may highlight options for novel targeted treatments for osteoporosis. Likewise, the aging of the brain and related diseases, such as dementia and depression, are associated with a lack of estrogen, particularly in women following menopause. Furthermore, gender dysphoria, a discordance between experienced gender and biological sex, is commonly hypothesized to emerge due to discrepancies in cerebral and genital sexual differentiation. The exact role of ERs in gender dysphoria requires further research.
摘要：
雌激素参与许多生理功能，包括大脑的发育，增长,繁殖和新陈代谢。雌激素的生物学作用是通过与多种类型的组织中的雌激素受体（ER）结合而实现的。ERα和ERβ属于核受体超家族，G蛋白偶联ER1（GPER1）是膜受体。主要的生物活性雌激素，17β-雌二醇对ER具有高亲和力。机械上,雌激素与细胞核中的ER结合，然后该复合物二聚化并与位于靶基因启动子区域的雌激素反应元件(ERE)结合。这被称为ERs功能的基因组机制。此外，ER还可以通过激酶和其他分子相互作用发挥作用，导致特定的基因表达和功能，称为非基因组机制。虽然ERα和ERβ通过基因组和非基因组途径发挥其功能，GPER1主要通过非基因组途径发挥其功能。ER信号的任何异常都可能导致许多疾病之一，例如生长和青春期障碍，生育和生殖异常，癌症,代谢疾病或骨质疏松症。在本次审查中，重点放在雌激素的三个目标组织上，即骨头，乳房和大脑,作为ER的多个方面的范例。乳腺癌的患病率越来越高，尤其是激素受体阳性乳腺癌，除了他莫昔芬和芳香化酶抑制剂以外的新型抗激素疗法的开发是一个挑战，将长期治疗方案对乳腺癌患者的毒性降至最低。对ERs在骨骼中的作用机制的完整理解可能会突出用于骨质疏松症的新型靶向治疗的选择。同样，大脑的老化和相关疾病，比如痴呆症和抑郁症，与缺乏雌激素有关，尤其是绝经后的女性。此外，性别烦躁不安，有经验的性别和生物性别之间的不一致，通常被假设是由于大脑和生殖器性分化的差异而出现的。ERs在性别焦虑中的确切作用需要进一步研究。
