Actions of SERMs

Fig. 3.2. Potential genomic and nongenomic activation routes thatmaybe induced by natural or synthetic ER ligands. The hypotheses that explain the tissue-selective action of SERMs include (a) selective activation of ER subtypes, (b) different changes in the 3D configuration of the ligand-ER complex, (c) recruitment of coactivator and corepressor proteins, and (d) activation of alternative response elements in certain inducible genes...

Figure 3.2 provides a summary of the different mechanisms that have been hypothesized to explain the selective tissue action of SERMs. 

Cellular and Molecular Basis for Acute Nongenomically Mediated Actions of SERMs... 

The most extensively used animal model to evaluate the action of SERMs on bone has been the ovariectomized (OVX) rat. In rats, tamoxifen antagonizes bone resorption and uterine growth (Turner et al. 1987,1988) and reduces the number and size of osteoclasts. The inhibitory effect on bone resorption of tamoxifen has also been reported in dogs and immobilized male rats (Wakley et al. 1988 Waters et al. 1991). As an antiresorptive agent, however, tamoxifen is less effective than 17/3-estradiol (17/9E2) (Williams et al. 1991) and has no effect when the endogenous production of estrogens is normal (Evans et al. 1994). 

This chapter will analyze some specific traits of CVD that will be used to review the principal variables that have exhibited sensitivity to estrogen agonism. Then, current information on the particular actions of SERMs will be presented. 

Table 11.1. Actions of SERMs on uterus. Predinical data (Gottardis et al. 1990)...

The complex, tissue-specific actions of SERMs have been described B. L. Riggs and L. C. Hartmann, N Engl J Med 348 618-629 (2003). 

It is of interest that studies with estrogens have shown that the inhibition of bone turnover found in short-term studies translates into increased BMD and decreased fracture rate in long-term studies (Ettinger et al, 1985 Field et al., 1993 Lufkin et al., 1992 Weiss et al., 1980). The estrogen-like action of SERMs in the bone should thus lead to a decrease in bone fractures as confirmed recently in the MORE trial (Cummings et al, 1999). 

The antiestrogenic and some of the estrogen-iike actions of SERMs can be expiained by the different conformations of the ER-a compiexes attracting novei coactivators or corepressors (CoR) (Fig. 46.5) to moduiate estrogen action at different sites, in this modei, the receptor wouid be the same at each site, yet the coactivators and corepressors wouid be distributed differentiy at different targets (130). 

Molecnlar Mechanisms of SERM Action as a Means of Understanding their Tissue-Selective Activities... 

Recently, leaders in the pharmaceutical industry have developed a list of desired properties for a fourth generation of SERMs (Table 2). In general, future SERMs must oppose endogenous hormone action in the breast and reproductive system while displaying full estrogenic effects in the cardiovasculature, bone and central nervous systems. Additional criteria are that fourth generation compounds possess superior bioavailability compared with existing SERMs and have... 

Only in-depth knowledge of the mechanisms of the action of estrogens and of other ligands for their receptors will permit a deeper understanding of the foundations on which the specificity of action on tissue for each SERM are based. This is perhaps among those challenging frontiers of knowledge that carry with it the potential to impact society in a profound way. 

Finally, a major question in SERM development is whether the new compounds will behave like estrogens with respect to cardiovascular events, which would be a worthless property given the results of the WHI trial (Writing Group for the Women s Health Initiative Investigators 2002 Women s Health Initiative Steering Committee 2004). This is a complex issue that will depend on the unique profile of action of the new SERM on the different components of the atherosclerosis process and the patient population and study design and conduct that is implemented. 

Action of Selective Estrogen Receptor Modulators (SERMs) Through the Classical Mechanism of Estrogen Action... 

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