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Review
. 2014 Aug 28:9:1437-52.
doi: 10.2147/CIA.S66690. eCollection 2014.

Selective estrogen receptor modulators: tissue specificity and clinical utility

Stephen Martinkovich  1 , Darshan Shah  1 , Sonia Lobo Planey  1 , John A Arnott  1
Affiliations
Review

Selective estrogen receptor modulators: tissue specificity and clinical utility

Stephen Martinkovich et al. Clin Interv Aging. .

Abstract

Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs.

Keywords: SERMs; estrogen receptors; selective estrogen receptor modulators.

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Figures

Figure 1
Figure 1
Model for SERM tissue specificity. Notes: SERM tissue specificity depends on numerous factors: 1) SERMs have differential and specific affinity for ER subtypes; 2) ER subtypes are differentially expressed in target tissues and can be heterogeneously expressed in a particular tissue; 3) SERM binding induces specific conformational changes in ER that influence dimerization and binding to various co-factors that can determine resultant target gene (X) activation or repression; 4) Co-factors (ie, activators and repressors) are differentially expressed in target tissues; and 5) ER-SERM complexes can bind directly to an ERE or be directed to bind other transcriptional motifs as a result of binding to various co-factors. Abbreviations: ER, estrogen receptor; ERE, estrogen response element; SERM, selective estrogen receptor modulators.
Figure 2
Figure 2
SERM tissue activity and clinical action in breast, uterus, and bone. Abbreviations: ER, estrogen receptor; SERM, selective estrogen receptor modulators.
See this image and copyright information in PMC

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