Selective Estrogen Receptor Modulators for BPH

New Factors on the Ground

M Garg; D Dalela; D Dalela; A Goel; M Kumar; G Gupta; S N Sankhwar


Prostate Cancer Prostatic Dis. 2013;16(3):226-232. 

In This Article

ERβ-modulation in BPH: Potential Beneficial Effects

SERMs are generally nonsteroidal compounds that affect ER signaling in the tissue-specific way. The SERMs exert selective effects on various tissues that are estrogen sensitive, including the prostate. These SERMs may act as either agonists or antagonists depending upon the site of action, unlike the estrogens, which are uniformly agonists, and the pure anti-estrogens, which are uniformly antagonists.[24] There is sufficient evidence which suggests that the beneficial effects of estradiol are mediated by ERβ,[25–27] while ERα might be responsible for aberrant proliferation. Therefore, it would be highly desirable to have agents that are capable of neutralizing the ill-effects of increased estradiol signaling in the aged prostate by upregulating the ERβ expression and downregulating ERα receptors.

Different natural and synthetic ERβ-selective ligands have been identified,[28,29] which provide the beneficial effects of estrogens while avoiding their unwanted side effects. The β-selective SERMs significantly increased the transcript and protein levels of ERβ and markedly reduced those of ERα in BPH stromal cells.[3] Hence, SERMs have the potential of effectively controlling prostate hyperplasia through favorable modifications in intraprostatic stromal–epithelial cross-talk by increasing signaling through ERβ and simultaneously decreasing signaling through ERα.[3]

Various studies have suggested that this targeted approach for treating BPH through the use of SERMs, and more specifically ERβ agonist, would be of benefit.[26,30]

Many epidemiological and experimental researches have shown that dietary estrogens are beneficial to men's health.[29,31,32] This may be evident from the fact that men living in Western nations have higher incidence of prostate cancer and BPH, plausibly because of their lower dietary phytoestrogen intake, as compared with their counterparts in Asian countries.[33–35] Many of these phytoestrogens are found to display ERβ receptor selectivity, especially compounds whose core structures have isoflavone or flavones group. Genistein, a naturally occurring SERM which shows 22-fold selectivity for ERβ, is an isoflavone usually found in soy.[36] Liquiritigenin (component of an herbal extract) is another natural ERβ-selective (20-fold) phytoestrogen, and the new ERβ-selective ligands may be synthesized using its pharmacophore.[37]

Different types of ERβ-selective agonists have been classified as

  1. Agents which have higher binding affinity to ERβ receptors as compared with a-receptors,[38] for example, ERB-041 (WAY-202041)

  2. Agents that bind to both ERs with equal affinity, but only activate transcription with ERβ, for example, MF101, nyasol and liquiritigenin

  3. Agents which have both characteristics of greater binding and transcriptional activity with ERβ, for example, diarylpropionitrile.