Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss
Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss
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DOI：
10.1016/j.steroids.2014.06.004
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发表时间：
2014-11-15
期刊：
影响因子：
2.7
通讯作者：
Jenkins, Simon N.
中科院分区：
文献类型：
--
作者：
Komm, Barry S.;Mirkin, Sebastian;Jenkins, Simon N.
结合雌激素（CE）联合选择性雌激素受体调节剂（SERM）苯多昔芬（BZA）是缓解绝经期症状和预防绝经后骨质丢失的新选择。开发组织选择性雌激素复合物（TSEC）CE/BZA的基本原理是将CE的益处与SERM的组织特异性特性相结合，以抵消子宫内膜和乳腺组织的雌激素刺激。TSEC为有子宫的女性提供了传统雌激素-孕激素治疗（EPT）的无孕激素替代方案。临床前研究支持巴多昔芬作为SERM的选择，并证明CE/BZA与其他潜在的TSEC配对相比，提供了雌激素受体激动剂/拮抗剂活性的最佳平衡。CE/BZA的初始临床开发侧重于确定适当的剂量比，该剂量比将在对乳腺或子宫内膜刺激极小或无刺激的情况下证明有效性。临床研究证实了所选剂量在维持骨量、缓解血管扩张症状、外阴阴道萎缩和性交困难以及改善绝经后妇女性功能方面的疗效。潮热的减少也转化为改善更年期特定的生活质量和睡眠。与EPT不同，与安慰剂相比，FDA批准的CE 0.45 mg/BZA 20 mg剂量不会引起乳腺密度或子宫内膜的变化，也不会增加乳房疼痛。在长达2年的临床试验中，CE 0.45 mg/BZA 20 mg具有良好的耐受性特征，冠心病、静脉血栓栓塞和闭经的发生率与安慰剂相似。因此，CE 0.45 mg/BZA 20 mg是EPT的一种有效、耐受性良好的替代药物，可缓解绝经后有子宫女性的绝经期症状并预防骨质疏松症。(C)2014爱思唯尔公司All rights reserved.
Conjugated estrogens (CE) combined with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA) is a new option for alleviating menopausal symptoms and preventing postmenopausal bone loss. The rationale for developing the tissue selective estrogen complex (TSEC) CE/BZA was to combine CE's benefits with the SERM's tissue-specific properties to offset estrogenic stimulation of endometrial and breast tissue. TSECs provide a progestin-free alternative to traditional estrogen-progestin therapy (EPT) in women with a uterus. Preclinical studies supported bazedoxifene as the SERM of choice and demonstrated that CE/BZA provided an optimal balance of estrogen receptor agonist/antagonist activity compared with other potential TSEC pairings. Initial clinical development of CE/BZA focused on determining the appropriate dose ratio that would demonstrate efficacy with minimal to no stimulation of the breast or endometrium. Clinical studies confirmed the efficacy of the selected doses for maintaining bone mass; relieving vasomotor symptoms, vulvar-vaginal atrophy, and dyspareunia; and improving sexual function in postmenopausal women. Reduction of hot flashes also translated into improved menopause-specific quality of life and sleep. Unlike EPT, the FDA-approved dose of CE 0.45 mg/BZA 20 mg does not cause a change in breast density or the endometrium, or increase breast pain compared with placebo. In clinical trials up to 2 years, CE 0.45 mg/BZA 20 mg has a favorable tolerability profile and rates of coronary heart disease, venous thromboembolism, and amenorrhea similar to placebo. Therefore, CE 0.45 mg/BZA 20 mg is an effective, well-tolerated alternative to EPT for menopausal symptom relief and osteoporosis prevention for postmenopausal women with a uterus. (C) 2014 Elsevier Inc. All rights reserved.