Shelly Wendy, Draper Michael W, Krishnan Venkatesh, Wong Mayme, Jaffe Robert B
Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California, USA.
Obstet Gynecol Surv. 2008 Mar;63(3):163-81. doi: 10.1097/OGX.0b013e31816400d7.
Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials.
近期关于选择性雌激素受体调节剂（SERM）的临床数据为重新评估SERM概念提供了依据。SERM活性的分子基础涉及配体SERM与雌激素受体（ER）的结合，导致构象变化，从而促进与共激活因子或共抑制因子蛋白的相互作用，并随后启动或抑制靶基因的转录。SERM活性是每个ER配体所固有的，其通过在靶细胞中的特异性相互作用实现其独特的作用模式，从而导致组织选择性作用。我们讨论了早期SERM的雌激素和抗雌激素作用，例如用于诱导排卵治疗的枸橼酸氯米芬，以及三苯乙烯类的他莫昔芬，其在乳腺中具有ER拮抗剂活性，用于预防和治疗ER阳性乳腺癌。自他莫昔芬研发以来，已对其他三苯乙烯类SERM进行了乳腺癌预防研究，包括屈洛昔芬、艾多昔芬、托瑞米芬和奥司米芬。其他SERM最近已进入临床开发阶段，包括苯并噻吩类（雷洛昔芬和阿佐昔芬）、苯并吡喃类（奥米普明、左美洛昔芬和EM - 800）、拉索昔芬、哌仑多昔芬、巴多昔芬、HMR - 3339以及已被批准用于乳腺癌治疗的抗雌激素药物氟维司群。SERM对含有ER的组织有影响，如乳腺、骨骼、子宫和泌尿生殖组织以及大脑，并且对心血管风险标志物也有影响。目前的证据表明每种SERM都有独特的一系列临床活性。SERM作用模式的差异表明每个临床终点都必须单独评估，并且关于任何特定SERM的结论只能通过适当的临床试验来确定。
