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: Validation in Animal BPH Model and Human Cell Lines

Recently, responses of ERβ-selective ligands have been demonstrated in various animal studies. Norman[58] proved in rodent prostate models that involution of the ventral prostate occurs with the use of ERβ-selective ligands. Also with the administration of an ERβ-specific agonist, prostatic epithelial hyperplasia ablates whereas an ERα-specific agonist did not produce any such effect as demonstrated in studies with knockout mice models.[36] These findings suggest that ERβ-specific agonists have sufficient potential to be used as new agents for the pharmacological intervention and management of prostatic hyperplasia.

Our in vivo studies in rat[3] indicated that irrespective of the molecular structure and mechanism of action, the SERMs universally and significantly reduce prostate weight. This response was better in combination with a 5α-reductase inhibitor, finasteride. We found that the ventral prostate of adult mature rats receiving tamoxifen, BP and ormeloxifene each at 1.0 mg kg−1 dose for 21 days regressed significantly by 37%, 32%, 36% respectively.

Histological investigations on human BPH tissue[3] revealed that finasteride, when used alone, effectively reduced acinar diameter but cause marginal decrease in epithelial cell height, while SERMs caused extreme thinning of epithelium along with dilation of acini. This was accompanied with complete disappearance of epithelial invaginations, a feature most prominently seen in BPH tissue. However, when both finasteride and SERM were used in combination, a substantial reduction in both epithelial cell height and acinar diameter was evident. Thus, SERMs can potentiate the action of 5-α reductase inhibitors for a better response.

Yang et al.[39] studied the effect of raloxifene on prostatic stromal hyperplasia in rats. Quantitative analysis of rat prostate indicated that in the tamoxifen and raloxifene groups, the number of acini was decreased, and the appearance of epithelial cells changed from columnar to flat or low columnar type. In addition, the smooth muscle cell layer that surrounds the acini became thinner. Further improvement had not been seen with combination of finasteride and raloxifene compared with that of raloxifene alone. Yang showed that both the proliferation of prostatic stromal and epithelial cells could be inhibited by SERMs. The immunohistochemistry staining results showed that raloxifene was found to be a more potent agent that caused reversal of smooth muscle cell thickness. Herein, authors provide the strong evidence that raloxifene may have a beneficial role in the rat prostate hyperplasia.

Gene expression profiling along with studies in βERKO mice further enhanced our knowledge about molecular basis of ERβ-mediated effects within cells and their importance in pathophysiology of BPH (Table 2).

Different theories emphasizing the causative mechanism of BPH pathogenesis have been described in literature. In dihydrotestosterone hypothesis, it is postulated that castration in men before puberty lead to failure of BPH to develop.[59] Embryonic reawakening theory[60] enumerates reawakening of the embryonic induction potential of prostatic stroma through involvement of various mechanisms including growth factors such as transforming growth factor.[61] Last, in stem cell theory, BPH develops through stem cells number increase or in clonal expansion of transit or amplifying cells.[62]

As discussed, SERMs have beneficial effects on BPH by modifying the growth factors. More recently Hu et al.[63] in their experimental work cultured stem/progenitor cells from normal human prostate using a prostasphere assay and showed that these cells express high levels of ER including ERα, ERβ and GPR30 but not androgen receptors. These stem cells had a proliferative response on exposure to 1 nM estradiol-17β and are specific targets for estrogen action in the prostate. On stimulatory response of these receptors, augmented signals alter the normal cell proliferative and apoptotic pathways in a number of estrogen-target tissues including prostate. This molecular aspect highlights the potential for SERMs in targeting diseased stem cells by modifying these signals for the treatment of prostate diseases.

Ho and Habib[64] in their recent study discussed that the estrogens effect the prostate through various mechanisms, such as aromatase expression and apoptosis, and via prostaglandin E2 and SERMs can influence these intraprostatic estrogen levels and are potential therapeutic targets for the treatment of BPH.

With these studies, there is ample evidence that SERMs may be of benefit for the treatment or prevention of BPH, and it is high time to explore these agents through clinical prospective trials to ascertain their efficacy in treatment of prostatic hyperplasia, subject to satisfactory pharmacokinetic and toxicity testing.[65,66]