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.

Effects of conjugated estrogen and bazedoxifene on hemostasis and thrombosis in mice

“…Thus, ERα protein levels were evaluated by immunohistochemistry, which is essentially qualitative rather than quantitative. As previously observed for the uteri (27), BZA treatment alone or in combination with CE did not affect the level of vaginal tissue ERα when evaluated by immunohistochemistry (Fig. 1D).…”

“…1D). A previous publication (27) and the present report demonstrate that BZA antagonizes the action of CE in two sex target tissues: the uterus and the vagina.

Figure 1Effect of chronic treatment of CE, BZA and CE + BZA on the vagina in mice. (A) Uterus and vagina weights (mg) after chronic treatment with bazedoxifene (BZA, 10 mg/kg/day), conjugated equine estrogen (CE, 3 mg/kg/day) alone or in combination (BZA + CE).

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“…After a chronic treatment, BZA did not impact the level of ERα in vaginal tissue (Fig. 1D) as on the uterus tissue (27). BZA has been described to modify the conformation of ERα, inducing proteosomal degradation (37).…”

“…The powders were solubilized in a solution of hydroxypropyl-β-cyclodextrin in HEPES buffer. The treatment doses of CE and BZA were chosen according to results from previous in vivo studies (27). Blood was collected from the inferior vena cava of these mice to explore coagulation factor defects (Diagnostica Stago).…”

Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol

“…SERMs such as BZA capitalize on the unique complexity of this system to produce agonist or antagonist responses in each tissue. In addition, BZA induces the degradation of estrogen receptor alpha (ERα) via the ubiquitin proteasome system to further oppose proliferation of uterine and breast tissue (4).…”