Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
Pfizer Canada Inc, Kirkland, QC, Canada.
Menopause. 2018 Sep;25(9):1033-1045. doi: 10.1097/GME.0000000000001095.
This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development.
This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors.
SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety.
Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms.
本综述描述了选择性雌激素受体调节剂（SERMs）及其与雌激素联合应用，即组织选择性雌激素复合物（TSEC）的历史发展，并探讨了未来 TSEC 发展的潜力。
本综述基于文献检索（PubMed）和作者对 TSEC 研发的经验，以叙述性综述的形式呈现。
SERMs 在各种组织中具有雌激素和抗雌激素作用；然而，没有一种单一的药物能够在治疗绝经症状方面达到最佳的激动剂和拮抗剂平衡。临床上，一些 SERMs 可预防骨质疏松症和乳腺癌，但会加重血管舒缩症状。雌激素可缓解绝经热潮红和泌尿生殖系统症状，并减少骨质流失，但在绝经激素治疗中添加孕激素以预防子宫内膜癌会增加阴道出血风险、乳房触痛，并可能增加乳腺癌风险。为了寻找一种更耐受的有效绝经治疗方法，人们开始研究 TSEC。由结合雌激素/巴多昔芬组成的 TSEC 的临床开发增加了对仔细考虑组合成分及其各自剂量以平衡安全性和疗效的重要性的认识。巴多昔芬在骨骼中是雌激素受体激动剂，但在子宫内膜中是拮抗剂/降解剂，这使其成为 TSEC 成分的成功因素。迄今为止研究的其他口服 TSEC 组合并未显示出类似的子宫内膜安全性。
选择 SERM、选择剂量以及评估安全性和疗效的临床试验数据是确保 TSEC 治疗绝经症状的安全性和充分疗效的关键。
