Treatment options for benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a disease of the prostate in which benign enlargement leads to partial constriction of the urethra and reduced urinary flow rates during micturition are observed. BPH is prevalent in men over 60 with about 50% of all males in this age group developing symptomatic BPH. Symptomatic BPH is characterised by symptoms that include increased frequency of urination, especially at night (nocturia), difficulty or delay in initiating urination (hesitancy), reduced force of the urinary stream and post-void dribbling. Current therapy options fall into two categories: surgery and pharmacotherapy. Significant morbidity is associated with surgery but this currently remains the gold-standard treatment option for many sufferers of the disease. Current pharmacotherapy is not curative and treatment with pharmaceuticals has mainly targeted the alleviation of the symptomatic manifestation of the disease. The most effective treatment option is the use of non-selective alpha-adrenergic antagonists. These block the smooth muscle contraction of the prostate that is associated with the obstructive symptoms described above. Other existing treatments have been targeted at the irritative, static or proliferative component of the disease. These agents, 5a-reductase (5aR) inhibitors, despite wide prescription initially, have yielded disappointing results in the clinic with limited symptomatic relief and reduction in prostate size mainly confined to those individuals with an exceptionally enlarged prostate. The proliferative (or static) component is observed in discrete regions of the prostate, predominantly in the stromal cell layer. Future drug therapies are being developed to treat both the dynamic and static components of BPH. Firstly, through pharmacological characterisation of the prostate, it is now possible to target a1-adrenoceptor antagonists that are selective for the prostate rather than acting in both the prostate and the cardiovascular system. It has been hypothesised that these agents will have fewer cardiovascular side-effects, and several of these are currently in early to late phase clinical trials. Secondly, companies are continuing to developing new generations of 5aR inhibitors that target both isoforms of this enzyme (5aR1 and 5aR2), despite poor clinical symptomatic relief observed with the first generation 5aR inhibitor, finasteride (Proscar, Merck), which is selective for the 5aR2 over the 5aR1 isoform. Through extensive research it has become evident that the proliferative component of BPH involves a complex relationship between androgens and growth factors. 5aR inhibitors lower dihydrotestosterone (DHT) levels, the main mediator of androgen action in theprostate, which in turn leads to modest inhibition of prostate growth and some symptom relief. It is now becoming evident that growth factors are important in the development of BPH and a new generation of BPH drug therapies now include diverse categories of drugs such as androgen receptor antagonists, luteinising hormone releasing hormone (LHRH) antagonists, aromatase inhibitors, proteinase inhibitors, tyrosine kinase inhibitors and cell control agents. The success of these compounds remains to be proved and initial clinical data demonstrate poor side-effect profiles and varying efficacy. However, innovation in drug development for the treatment of BPH continues to be high and novel mechanisms are being suggested in the current literature. This exciting and developing drug therapy area is growing rapidly and, as our understanding of the cell-cell interactions in the prostate increases, novel approaches for the treatment of BPH will be developed.