Selective Estrogen Receptor Modulators for BPH
The activation of ERβ leads to an anti-proliferative response that is not influenced by alterations in systemic androgen levels or activation of ERα, as demonstrated by using tissue recombination technology. Using intact aromatase knockout mice, a study demonstrated that the administration of an ERβ-specific agonist abrogates existing hyperplastic prostatic pathology.
In our study, we found that the viability and proliferation of human BPH-derived stromal cells was reduced dose dependently by SERMs at concentration ranging from 0.625 to 10μM. 4-Hydroxytamoxifen most effectively and significantly reduced stromal cell viability followed by DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2H-1-benzopyran (BP) and tamoxifen, which were almost equipotent. On the other hand, all these SERMs were nearly equipotent in reducing the proliferation of BPH stromal cells.
In a study by Yang et al., raloxifene antagonized the estrogen-stimulated proliferation in cultured prostate stromal cells. Estradiol (E2), when used alone, induced the proliferation of the WPMY-1 (stromal cell line) by 31% (P<0.05). However, tamoxifen, raloxifene and finasteride antagonized the proliferation of these cells when used along with E2 by 16, 17 and 25% respectively (P<0.05), showing that SERMs can have additive effects over and above the one exerted by finasteride.
Various growth factors such as transforming growth factor-β1, fibroblast growth factor and insulin-like growth factor-1 (IGF-1) are the key regulators of cell proliferation and extracellular matrix turnover. These agents are all subject to alteration with age and are potential triggers for the initiation of stromal hyperplasia.
Prostatic IGF-1 gene expression has been correlated positively with both BPH and prostate cancer, while epidermal growth factor receptor (EGFR) protein has been localized predominantly in BPH tissues. We found that ormeloxifene (a SERM) significantly downregulated IGF-1 expression, whereas hydroxytamoxifen and tamoxifen also reduced EGFR level in BPH stromal cells. However, BP not only decreased IGF-1 and EGFR transcript levels, but also concurrently increased the transcripts of growth regulatory peptide TGF-β1, whose impaired function has been directly correlated with pathogenesis of BPH. Thus, SERMS may have potential to directly affect the levels of growth factors.
Prostatic inflammation may be one of the important factors in the pathogenesis of human BPH. BPH nodules are thought to be associated with chronic inflammatory infiltrates, mainly composed of activated T-cells and macrophages. These inflammatory cells produces cytokines (IL-2 and IFNγ) that may support fibromuscular growth in BPH. While ERα have been shown to induce inflammation, ERβ has been suggested to have anti-inflammatory effects. Fispemifene, a novel SERM, showed anti-inflammatory action in the dorsolateral prostate by decreasing the number and density of inflamed acini. As reported by Sharma et al., Sprague-Dawley rats on soy diet were found to have reduced risk of chronic prostatitis and this mechanism may be responsible for the lower incidence of BPH in Asian men consuming soy. Though there are sufficient data that the regular consumption of soy prevents the obstructive voiding of BPH, confirmatory clinical evidence is still lacking.
ERβ also induces apoptosis in the prostate in addition to having anti-proliferative effect, and mechanism of ERβ action is mediated by tumor necrosis factorα (TNFα) and is androgen independent. In our study we found that BP sensitizes BPH stromal cells to caspase-8-mediated apoptosis though extrinsic pathway by significantly upregulating the mRNA levels of TNF family death receptors and its ligands (Fas/FasL). Human BPH explants exposed to SERMs at 5.0 μM concentration for 7 days were studied, which revealed the apoptosis of mainly the stromal cells in BPH tissue, which was maximum in case of hydroxytamoxifen and minimum in case of ormeloxifene. Ki-67 labeling was notably reduced in SERM-treated BPH explants as compared with control.
Ex vivo data by Glienke et al. clearly demonstrate that the administration of hydroxytamoxifen at concentrations from 10 to 20 μM induces apoptosis in human prostate stromal cells. The induction of apoptosis was more effective with hydroxytamoxifen than with tamoxifen though clinical studies could not confirm the effects of tamoxifen treatment on BPH.
ERβ agonists induce apoptosis in different cells of estrogen-deficient aromatase knockout mice, that is, luminal, prostatic stromal and basal epithelial cells. ERβ agonists fail to respond in the TNFα knockout mice, demonstrating TNFα-induced apoptosis in the stromal cells. In addition to the direct effect of ERβ agonists on the stromal nodules of BPH, they also disrupt stromal–epithelial interactions, which are important for proliferation and differentiation of prostatic epithelial cell. By targeting the stromal component, the aberrant cycle of paracrine signaling breaks, and thus ERβ agonists may affect both stroma and epithelial cells, explaining their potential therapeutic use. The pathway of apoptosis induced by ERβ agonist is different from that of castration. While ERβ agonists induce apoptosis via activation of caspase-8, castration does so by using caspase-9 and as opposed to apoptosis induced by castration, ERβ agonists cause apoptosis in both the androgen-dependent or -independent cells (Figure 1 and Table 1).
(Enlarge Image)
Figure 1.
Proposed mechanisms involved in beneficial effect of selective estrogen receptor modulator (SERMs) in BPH. EGFR, epidermal growth factor receptor; IGF-1, insulin-like growth factor-1; TNF-α, tumor necrosis factor α; TGFβ, tumor growth factor.
ERβ-modulation in BPH: How Does It Work?
Anti-proliferative Response
The activation of ERβ leads to an anti-proliferative response that is not influenced by alterations in systemic androgen levels or activation of ERα, as demonstrated by using tissue recombination technology. Using intact aromatase knockout mice, a study demonstrated that the administration of an ERβ-specific agonist abrogates existing hyperplastic prostatic pathology.
In our study, we found that the viability and proliferation of human BPH-derived stromal cells was reduced dose dependently by SERMs at concentration ranging from 0.625 to 10μM. 4-Hydroxytamoxifen most effectively and significantly reduced stromal cell viability followed by DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2H-1-benzopyran (BP) and tamoxifen, which were almost equipotent. On the other hand, all these SERMs were nearly equipotent in reducing the proliferation of BPH stromal cells.
In a study by Yang et al., raloxifene antagonized the estrogen-stimulated proliferation in cultured prostate stromal cells. Estradiol (E2), when used alone, induced the proliferation of the WPMY-1 (stromal cell line) by 31% (P<0.05). However, tamoxifen, raloxifene and finasteride antagonized the proliferation of these cells when used along with E2 by 16, 17 and 25% respectively (P<0.05), showing that SERMs can have additive effects over and above the one exerted by finasteride.
Inhibition of Growth Factors
Various growth factors such as transforming growth factor-β1, fibroblast growth factor and insulin-like growth factor-1 (IGF-1) are the key regulators of cell proliferation and extracellular matrix turnover. These agents are all subject to alteration with age and are potential triggers for the initiation of stromal hyperplasia.
Prostatic IGF-1 gene expression has been correlated positively with both BPH and prostate cancer, while epidermal growth factor receptor (EGFR) protein has been localized predominantly in BPH tissues. We found that ormeloxifene (a SERM) significantly downregulated IGF-1 expression, whereas hydroxytamoxifen and tamoxifen also reduced EGFR level in BPH stromal cells. However, BP not only decreased IGF-1 and EGFR transcript levels, but also concurrently increased the transcripts of growth regulatory peptide TGF-β1, whose impaired function has been directly correlated with pathogenesis of BPH. Thus, SERMS may have potential to directly affect the levels of growth factors.
Anti-inflammatory Effects
Prostatic inflammation may be one of the important factors in the pathogenesis of human BPH. BPH nodules are thought to be associated with chronic inflammatory infiltrates, mainly composed of activated T-cells and macrophages. These inflammatory cells produces cytokines (IL-2 and IFNγ) that may support fibromuscular growth in BPH. While ERα have been shown to induce inflammation, ERβ has been suggested to have anti-inflammatory effects. Fispemifene, a novel SERM, showed anti-inflammatory action in the dorsolateral prostate by decreasing the number and density of inflamed acini. As reported by Sharma et al., Sprague-Dawley rats on soy diet were found to have reduced risk of chronic prostatitis and this mechanism may be responsible for the lower incidence of BPH in Asian men consuming soy. Though there are sufficient data that the regular consumption of soy prevents the obstructive voiding of BPH, confirmatory clinical evidence is still lacking.
Pro-apoptotic Effects
ERβ also induces apoptosis in the prostate in addition to having anti-proliferative effect, and mechanism of ERβ action is mediated by tumor necrosis factorα (TNFα) and is androgen independent. In our study we found that BP sensitizes BPH stromal cells to caspase-8-mediated apoptosis though extrinsic pathway by significantly upregulating the mRNA levels of TNF family death receptors and its ligands (Fas/FasL). Human BPH explants exposed to SERMs at 5.0 μM concentration for 7 days were studied, which revealed the apoptosis of mainly the stromal cells in BPH tissue, which was maximum in case of hydroxytamoxifen and minimum in case of ormeloxifene. Ki-67 labeling was notably reduced in SERM-treated BPH explants as compared with control.
Ex vivo data by Glienke et al. clearly demonstrate that the administration of hydroxytamoxifen at concentrations from 10 to 20 μM induces apoptosis in human prostate stromal cells. The induction of apoptosis was more effective with hydroxytamoxifen than with tamoxifen though clinical studies could not confirm the effects of tamoxifen treatment on BPH.
ERβ agonists induce apoptosis in different cells of estrogen-deficient aromatase knockout mice, that is, luminal, prostatic stromal and basal epithelial cells. ERβ agonists fail to respond in the TNFα knockout mice, demonstrating TNFα-induced apoptosis in the stromal cells. In addition to the direct effect of ERβ agonists on the stromal nodules of BPH, they also disrupt stromal–epithelial interactions, which are important for proliferation and differentiation of prostatic epithelial cell. By targeting the stromal component, the aberrant cycle of paracrine signaling breaks, and thus ERβ agonists may affect both stroma and epithelial cells, explaining their potential therapeutic use. The pathway of apoptosis induced by ERβ agonist is different from that of castration. While ERβ agonists induce apoptosis via activation of caspase-8, castration does so by using caspase-9 and as opposed to apoptosis induced by castration, ERβ agonists cause apoptosis in both the androgen-dependent or -independent cells (Figure 1 and Table 1).
(Enlarge Image)
Figure 1.
Proposed mechanisms involved in beneficial effect of selective estrogen receptor modulator (SERMs) in BPH. EGFR, epidermal growth factor receptor; IGF-1, insulin-like growth factor-1; TNF-α, tumor necrosis factor α; TGFβ, tumor growth factor.
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