Effects of SERMs on important indicators of cardiovascular health: lipoproteins, hemostatic factors, and endothelial function
Introduction
Selective estrogen receptor modulators (SERMs) are a class of compounds that bind to estrogen receptors, producing varying degrees of estrogen agonist effects in some domains (bone and lipids) and estrogen antagonist effects in others (breast and uterus).1 Tamoxifen was the first clinically used compound recognized to have a partial estrogen agonist/antagonist profile. Some2, 3 but not all4 clinical trials of tamoxifen as adjuvant therapy for breast cancer have also found significant reductions in cardiovascular events among women assigned to tamoxifen treatment. This observation has led to speculation that tamoxifen or another SERM might be a reasonable alternative to conventional estrogen replacement for postmenopausal women.
Raloxifene, a benzothiophene derivative of tamoxifen, was the first compound other than tamoxifen to be identified as a SERM because it prevented bone loss due to estrogen deprivation but did not cause endometrial hyperplasia in rats.5 It is currently approved only to treat osteoporosis, but there is great interest in determining whether it may benefit the cardiovascular system as well. Droloxifene, a compound structurally similar to tamoxifen, appears to share some of its beneficial effects6, 7 but remains an investigational agent and has not been as thoroughly studied as the other two compounds. The cardiovascular effects of other SERMs, such as idoxifene and toremifene, have not been studied in detail. A discussion of other compounds that may have partial estrogen agonist/antagonist effects, such as soy phytoestrogens or tibolone, is beyond the scope of this brief review. We will focus on three areas known to be important indicators of cardiovascular health: lipids and lipoproteins, hemostatic factors, and markers of endothelial function.
Section snippets
Lipid effects of SERMs
A summary of the reported effects of SERMs on lipids appears in Table 1. A specific discussion of what is known for each agent follows.
Effects of SERMs on hemostasis
There are fewer data in the literature concerning the effects of SERMs on hemostatic and fibrinolytic factors. The available information is summarized in Table 2 and discussed in detail for each agent below.
Effects of SERMs on endothelial function
Few data are available regarding SERMs and endothelium-dependent vasodilator responses. Experiments using vessel rings from rabbits have shown that raloxifene has vasorelaxant effects comparable to 17β-estradiol in similar doses.33, 34 However, in nonhuman primates with diet-induced atherosclerosis, tamoxifen had no effects on coronary vasomotor responses to acetylcholine (an endothelium-dependent response), whereas conjugated equine estrogen produced significant increases in epicardial
Conclusions
Based on the currently available data, a few patterns emerge regarding the effects of SERMs on cardiovascular risk factors. In general, this class of agents appears to lower LDL, albeit to a lesser extent than estrogen, while having no effects on HDL or triglyceride levels. On the other hand, they consistently lower fibrinogen and Lp(a), perhaps even to a greater degree than estrogen, and there is some encouraging evidence that they may have favorable effects on endothelial function as well.
Acknowledgements
The authors thank John Kenyon for his assistance in the research for this article.
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