The antagonist properties of Bazedoxifene after acute treatment are shifted to stimulatory action after chronic exposure in the liver but not in the uterus

Abstract

A promising alternative to conventional hormone therapy for postmenopausal symptoms is treatment combining Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), and conjugated equine estrogen (CE). This combination is also known as a tissue-selective estrogen complex (TSEC). Understanding the tissue-specific actions of SERMs and the TSEC remains a major challenge to try to predict their clinical effects. The aim of this study was to compare acute versus chronic treatment with BZA, CE or CE + BZA in two major targets of estrogens, the uterus and the liver. In these two tissues, acute treatment with CE, but not with BZA, induced similar gene expression change than the most important endogenous estrogen, 17-β estradiol (E2). Acute induction of gene expression by E2 or by CE was antagonized by the addition of BZA. Concomitantly, BZA alone or in combination with E2 or CE induced a partial degradation of ERα protein after acute exposure. In uterus, chronic treatment of BZA alone had no impact on tissue weight gain or on epithelial cell proliferation, and also antagonized CE-effect in uterus, thereby mimicking the acute effect. By contrast, in the liver, chronic BZA and CE + BZA elicited agonistic transcriptional effects similar to those of CE alone. In addition, at variance to BZA acute effect, no change in ERα protein abundance was observed after chronic treatment in this tissue. These experimental in vivo data highlight a new aspect of the time-dependent tissue-specific action of BZA or TSEC, i.e. they can act acutely as antagonists but become agonists after chronic treatment. This shift was observed in liver tissue, but not in proliferative sex target such as the uterus.

Keywords: Bazedoxifene; Estrogen receptor (ER); Hormone therapy; Liver; Menopause; Tissue-selective estrogen complex (TSEC).