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

Limitations and Approaches for Identifying ERβ-selective Ligands

The ERβ through regulating different physiological functions has a potential of becoming therapeutic target for various pathological states. However, the clinical application of SERMs for the treatment of BPH may not be as simple as it appears to be, as there are several other aspects that can complicate this issue, including the variability of ERα and ERβ expression in prostate diseases. Because of the structural characteristics and similar ligand-binding cavity of ERα and ERβ, it has been difficult to identify ERβ ligands with high affinity, potency and selectivity.[67] Thus, it is challenging to develop ERβ-selective ligands for therapeutic use and this is one of the reason for the hinderance of use of these agents, although their beneficial effects are known for long time. Furthermore, the effect of expression or function of ER splice variants and mutations on prostate growth has not been fully understood.[68,69] ERs may exert both ligand-dependant and -independent activities through genomic and non-genomic pathways.[70,71]Although these factors may be more crucial in prostate cancer as compared with BPH, these are the certain aspects in estrogen signaling and transcription that require further investigation and research.

Nevertheless, since the discovery of ERβ in 1996, development of newer more selective ERβ ligands has been a field of active research, and great efforts are going on in this field.[58,72,73] With the advancement in techniques, several different mechanisms have been used to identify and create the ERβ-selective ligands; for example, Neubauer et al.[74] developed a ERβ agonist, which is a inhibitor of prostate growth but has no action on the immune system, while a ERβ agonist, which has immune suppressant property without effecting the prostate, was described by Elloso et al.[75] Structural core of known ERβ-selective ligands are modified to new compounds with greater selectivity and/or potency, such as isoflavone core structure of genistein.[76] By modifications of the phenolic hydroxyl groups or nitrile groups of ER[77] or by using cells with stably integrated estrogen-responsive element genes, new better molecules may be developed. Also it is now known that ligand binding does not always correlate directly with transcriptional activity, and ER ligands may be receptor subtype selective in either concentration-dependent manner or at the transcriptional level. With these aspects in mind, future development of SERMs or β-selective ligands may be designed with dimer selectivity as well as tissue and subtype selectivity.[78]

Additional obstacle in BPH study is the lack of ideal experimental model for BPH. Some animals such as dogs, mouse and rodents have prostate that is hormone responsive and thus suitable in BPH research, although their prostate anatomy varies significantly from that of humans.[79] As such, bladder outlet obstruction resulting from BPH has been insufficiently described in these models. But with the genetic manipulations and advancements in molecular altered pathways, some of these problems have been tackled and transgenic animal models have been developed and utilized.[80] Nicholson et al.[81] recently described a model of BPH and bladder outlet obstruction induced in mice with testosterone (T) and 17β-estradiol (E(2)) combination, and found that this model is suitable for better understanding molecular mechanisms of BPH. Nevertheless, there is definite need of novel and genetically suitable models that help in better understanding of basic mechanisms and development of more effective therapies for BPH.