Treatment of Benign Prostatic Hyperplasia (BPH)

MEDICAL THERAPY FOR BPH – MONOTHERAPY AGENTS

Medical therapy is now first-line treatment for most men with symptomatic BPH. They are non-invasive, reversible, cause minimal side effects, and significantly improve symptoms (75, 130). With these recommendations, the rates of prescriptions for the medical management for BPH have increased drastically over the past decade (131-132). This increased interest has further lead to the development of safer, more efficacious agents.

Alpha-Blockers

There are 3 main components to clinically significant BPH: static, dynamic and detrusor muscle components as outlined above. The dynamic component is associated with an increase in smooth muscle tone of the prostate. These smooth muscle cells contract under the influence of noradrenergic sympathetic nerves, thereby constricting the urethra. Prostatic tissue contains high levels of both alpha₁ and alpha₂ adrenoceptors – 98% of the alpha₁ adrenoceptors are associated with stromal elements of the prostate. Thus alpha₁-receptor blockers relax smooth muscle, resulting in relief of bladder outlet obstruction that enhances urine flow. Different subtypes of alpha₁ receptors have been identified, with alpha_1A predominating. Two alpha_1A-adrenoceptors generated by genetic polymorphism have been identified with different ethnic distributions but similar pharmacologic properties.

Prazosin

Prazosin (titrated up to 5mg day) has been shown to significantly increase flow rates by 36-59% compared to placebo 6-28% but 17% of men discontinued the drug due to side effects such as dizziness (21%), headache (14%), syncope (3.4%) and retrograde ejaculation (13%).

Alfuzosin

Alfuzosin (5 mg bid or10 mg daily) has shown symptom score reduction of 31-65% (compared to placebo 18-39%) and flow rate increases of 22-54% (compared to placebo 10-30%). Hence the results were similar to those of prazosin but with only 3-7% discontinuations due to dizziness (3-7%), headache (1-6%) and syncope (<1 %).

Terazosin

Terazosin (2-10mg) had a symptom score reduction of 40-70% (compared to placebo 16-58%) and improved flow rates 19-40% (placebo 5-46%). Between 9-15 % of men discontinued the drug, related to dizziness (10-20%), headache (1-7%), asthenia (7-10%), syncope (0.5-1.0%) and postural hypotension (3-9%). Thus terazosin was effective and superior to placebo in reducing symptoms and increasing the peak urinary flow rate. The effect of terazosin on the peak urinary flow rate was apparent in studies as soon as 8 weeks of therapy. Most importantly, the effect of terazosin on symptoms and peak urinary flow rate was independent of the baseline prostate size for the range of prostate volumes reported.

Doxazosin

Doxazosin (4-12mg/day) is a selective alpha₁-adrenoceptor antagonist and produced a significant increase in maximum urinary flow rate (2.3 to 3.6 ml. per sec) at doses of 4 mg, 8 mg, and 12 mg, and an average flow rate compared with placebo. The increase in maximum flow rate was significantly greater than a placebo within 1 week of initiating therapy and the drug significantly decreased patient-assessed total, obstructive, and irritative BPH symptoms. Blood pressure was significantly lower with all doxazosin doses compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 48% of patients on doxazosin compared to 35% on placebo, with only 11% discontinuing treatment (a similar number to placebo). The main side effects were dizziness (15-24%), headache (12%) and hypotension (5-8%) and abnormal ejaculation (0.4%).

Tamsulosin

Tamsulosin (0.4 mg once daily dose) is a selective alpha-blocker for the alpha_1A subtype which predominates in the human prostate, having 12 times more affinity for the receptors in the prostate than in the aorta thereby reducing side effects mediated through blood vessels receptors. Symptom scores were reduced by 20-50% (placebo 18-30%), flow rates improved 20-45% (placebo 5-15%) but only 3-7% of men discontinued drug because of dizziness (3-20%), headache (3-20%), syncope (0.3%) and retrograde ejaculation (5-10%). The rate of retrograde ejaculation was much higher than alfuzosin but the blood pressure-lowering side effects are less with tamsulosin. There are different formulations including extended-release with lower pharmacological peaks and troughs which may offer fewer side effects.

Silodosin

Silodosin (8mg daily) is similar to tamsulosin being a selective blocker for the alpha_1A receptor subtype. Symptoms scores were reduced by 40-50% (placebo 20-30%), flow rates improved by 17-30% (placebo 5-14%). Despite these favorable urinary outcomes, a significant proportion of patients experienced ejaculatory dysfunction (13-23%). These rates are higher compared to tamsulosin, however, discontinuation rates secondary to ejaculatory dysfunction remain at 1-2%. Typical side effects include thirst (10%), loose stools (9%) and dizziness (5%).

5-alpha reductase inhibitors

The enzyme 5-alpha reductase is crucial in the amplification of androgen action in the prostate by modulating the conversion of testosterone to DHT. Within the prostate, 90% of testosterone is converted to DHT (72, 150). There are 2 isoforms of the enzyme 5-alpha reductase which are encoded by separate genes (151). Type 1 isoenzyme is expressed highly in the skin, liver, hair follicles and sebaceous glands, and prostate whereas type 2 is responsible for male virilization of the male fetus, and in adulthood resides in the prostate, genital skin, facial and scalp follicles (152-153). Inhibitors of these enzymes potentially decrease serum and intra-prostatic DHT levels, thus reducing prostatic tissue growth.

Finasteride

Finasteride was the first of these to be trialed in humans and shown to decrease DHT levels. It acts predominantly on the type 2 isoenzyme of 5-alpha reductase and has until recently been the only available 5-alpha reductase inhibitor. There is some evidence that patients on finasteride experience fewer serious complications associated with the progression of BPH compared with those prescribed an alpha-blocker, such as acute urinary retention or undergoing BPH-related surgery, but more prospective data are needed. Dutasteride is also available and blocks both isoenzymes of 5-alpha reductase. Dutasteride shows a 60-fold greater inhibition of the type 1 isoenzyme than finasteride and is also active against the type 2 isoform. Finasteride reduces serum DHT levels by 65-70% and prostatic levels by 85-90%, although the intraprostatic levels of testosterone are reciprocally elevated as the testosterone is not being converted to DHT.

Dutasteride

Dutasteride unlike finasteride blocks both the type I and Type II 5-alpha reductase isomers. In terms of monotherapy, a one year randomized, double-blinded comparison of finasteride and dutasteride in men with BPH (EPICS: Enlarged Prostate International Comparator Study) found a trend for dutasteride improvement over finasteride in IPSS (International Prostate Symptom Score) that did not reach statistical significance (abstract). Another non-randomized comparative trial with 240 patients, published only in abstract form, showed a small improvement in AUASI and Q_max for dutasteride. However, dutasteride and finasteride have never been compared in long-term therapy, either as monotherapy or in combination with an alpha-blocker. These medications appear to exert continued effects beyond 1 year so comparison after only 1 year is likely to be premature.

The tolerability of 5-alpha reductase inhibitors in most studies has been excellent with the most relevant adverse effects being related to sexual function. They include reduced libido, erectile dysfunction, and, less frequently, abnormal ejaculation. Specifically for dutasteride in the Combat study, in the monotherapy arm of 1623 patients the side effect were: erectile dysfunction (6.0%) ; retrograde ejaculation (0.6%); altered (decreased) libido (2.8%); ejaculation failure (0.5%); semen volume decreased (0.3%); loss of libido (1.3%); breast enlargement (1.8%); nipple pain (0.6%); breast tenderness (1.0%) and dizziness (0.7%).

Phosphodiesterase 5 Inhibitors

Phosphodiesterase 5 (PDE5) inhibitors (e.g. sildenafil, tadalafil and vardenafil) have been used predominantly to treat erectile dysfunction in men. However, recent data suggests they also have efficacy in treating LUTS secondary to BPH. Specifically, the cyclic nucleotide monophosphate cyclic GMP represents an important mediator in the control of the lower urinary tract outflow region (bladder, urethra). PDE5 inhibitors exert effects by several mechanisms including: calcium-dependent relaxation of endothelial smooth muscle, alteration of the spinal micturition reflex pathways and increased blood flow to the lower urinary tract. PDE inhibitors are regarded as efficacious, have a rapid onset of action and favourable effect-to-side-effect ratio (171).

Anticholinergic Medications

High-level evidence suggests that for selected patients with bladder outlet obstruction due to BPH and concomitant detrusor overactivity, combination therapy with an alpha-receptor antagonist and anticholinergic can be helpful (176). Such agents help particularly with the irritative urinary symptoms of frequency and urgency. Caution is recommended, however, when considering these agents in men with an elevated residual urine volume or a history of spontaneous urinary retention (164).

Botulinum Toxin A Injection

Injection of botulinum toxin A into the prostate is a novel treatment for LUTS secondary to BPH. First reported in 2003 (177), trans-perineal injection of 100 units of botulinum toxin into each lobe of the prostate under trans-rectal guidance is required. In this randomized controlled trial, thirty patients demonstrated significant improvement in IPSS (65% decrease) and serum PSA (51% decrease) compared to controls, who had injections of saline without botulinum toxin A, at a median follow-up of 20 months. Subsequent long term follow-up of 77 patients up to 30 months has shown similar results – significant reduction in IPSS (approximately 50% lower), significant improvement in maximum flow rate (approximately 70% higher), and significant reduction in serum PSA values (approximately 50% lower). Importantly, no adverse events were noted (178).