Selective Estrogen-Receptor Modulators — Mechanisms of Action and Application to Clinical Practice

Abstract

he selective estrogen-receptor modulators (serm s ) represent a major therapeutic advance for clinical practice. Unlike estrogens, which are uniformly agonists, and antiestrogens, which are uniformly antagonists, the SERMs exert selective agonist or antagonist effects on various estrogen target tissues. The SERMs are chemically diverse compounds that lack the steroid structure of estrogens ( Fig. 1) but possess a tertiary structure that allows them to bind to the estrogen receptor. Although some members of this class of drugs have been available for decades, their tissue-specificity in humans has only recently been recognized. Certain phytoestrogens, such as genistein, also appear to have SERM-like properties.In this article we review the emerging understanding of the molecular basis of action of SERMs, summarize their tissue-selective agonist-antagonist effects, and place in perspective their therapeutic uses as compared with estrogen or nonestrogen alternatives.In the classic model of estrogen action, the unoccupied nuclear estrogen receptor resides in the nuclei of target cells in an inactive form. Binding to an agonist, such as estradiol, alters the physicochemical properties of the estrogen receptor, allowing the receptor dimer to interact with specific DNA sequences (estrogen response elements) within the promoters of responsive genes. 1 The DNA-bound estrogen receptor then regulates target-gene transcription, either positively or negatively (Fig. 2). However, the recognition that tamoxifen and other SERMs have tissue-specific agonist-antagonist activity led to the realization that the classic model was incomplete and that estrogen action was more complex than had been thought. 2,3 The mechanisms of the tissueselective, mixed agonist-antagonist action of SERMs, although still only partly understood, are gradually becoming clearer.Most of the unique pharmacology of SERMs can be explained by three interactive mechanisms: differential estrogen-receptor expression in a given target tissue, differential estrogen-receptor conformation on ligand binding, and differential expression and binding to the estrogen receptor of coregulator proteins (Fig. 2).First, target cells for estrogen action contain varying concentrations of homodimers of one or both of two species of estrogen receptors -estrogen receptor a and estrogen receptor b -as well as estrogen receptor a -estrogen receptor b heterodimers. Mice with genetic disruptions of estrogen receptor a and estrogen receptor b display different phenotypes, demonstrating that each receptor has a distinct action. 4,5 Estrogen receptor a is almost always an activator, whereas estrogen receptor b can inhibit the action of estrogen receptor a by forming a heterodimer with it. Moreover, microarray analysis in mice with deletions of estrogen receptor a or estrogen receptor b showed t mechanisms of action A correction has been published: N Engl J Med 348(12):1192. See last page of this PDF.

Postmenopausal Hormone Use and Symptoms of Gastroesophageal Reflux

“…The SERMs are a diverse group of compounds that exert selective estrogen agonist or antagonist effects, depending upon the target tissue and are routinely recommended for the treatment or prevention of breast cancer. 15 As SERM use continues, clinicians should be aware that patients may experience an increase in GERD symptoms. In fact, it is worth noting that raloxifene use was associated with a significantly increased risk of dyspepsia in a large, randomized, placebo-controlled trial assessing the effects of raloxifene on cardiovascular events and breast cancer.…”

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

“…These substances have estrogenic effects in selected target tissues, but no effects or antiestrogenic effects in others (Nilsson and Gustafsson, 2002;Meegan and Lloyd, 2003;Riggs and Hartmann, 2003;Cos et al, 2003). This definition was originally based on the preferential binding affinity of selected isoflavones to ERβ over ERα ?…”

Sex steroids and the GH axis: Implications for the management of hypopituitarism

“…Examples of SERMs in therapeutic use are clomiphene, tamoxifen and raloxifene. Tamoxifen exerts central estrogen receptor antagonistic but peripheral agonistic effect on the liver [45,46]. As discussed above, estrogen drives GH secretion, a paracrine action that is unmasked by tamoxifen which blocks estrogen action and reduces GH secretion.…”