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Tissue selective estrogen complex combinations with bazedoxifene/conjugated estrogens as a model

Abstract The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator (SERM) with one or more estrogens. Different TSECs are associated with distinct gene expression profiles in mammary gland and endometrial tissue according to the individual SERM and estrogen components. Few TSECs have been evaluated outside the laboratory. In preclinical trials, bazedoxifene (BZA) was distinct from other SERMs, with a neutral effect on mammary gland and endometrial tissue, and an antagonist effect on these tissues when combined with conjugated estrogens (CE). The only TSEC in an advanced stage of clinical development pairs BZA with CE. In large, randomized clinical trials, two doses, BZA 20 mg/CE 0.45 and 0.625 mg, reduced menopausal symptoms and prevented bone loss in postmenopausal women with a favorable safety profile on the breast, endometrium, and ovary, and with cardiovascular and venous thrombosis events similar to placebo. Improvements were seen in sleep, health-related quality of life, and treatment satisfaction. Compared with traditional, progestogen-containing hormone therapy, BZA/CE had higher rates of amenorrhea and reduced breast pain, with changes in breast density from baseline similar to placebo. Future TSECs identified in preclinical studies need to be tested in rigorous phase-3 clinical trials for effectiveness, safety and tolerability.