Benign Prostatic Hyperplasia: Current Treatment Strategies

Benign prostatic hyperplasia (BPH)— histologically defined as stromal and epithelial hyperplasia beginning in the periurethral transitional zone of the prostate—affects up to 80% of 80-year-old men.^1,2 With progressive prostatic enlargement, bladder outlet obstruction can result. Although the exact mechanism is unknown, lower urinary tract symptoms (LUTS) can signal progressive BPH.

Here we review current therapeutic options for BPH, including active surveillance; medical therapy (α-blockers, 5α-reductase inhibitors, anticholinergics, phosphodiesterase 5 [PDE-5] inhibitors, and phytotherapy); minimally invasive therapies (MITs), such as transurethral microwave therapy (TUMT) and transurethral needle ablation (TUNA); laser therapies; and botulinum toxin injection.

ACTIVE SURVEILLANCE

This approach is appropriate for patients with minimal LUTS (American Urological Association Symptom Score [AUA SS] of 7 or lower) or those with only mild to moderate symptoms (AUA SS of 8). Active surveillance is distinguished from watchful waiting in that patients are monitored annually for disease progression with a history, physical examination, AUA SS, and a bother score.² If symptoms or bother scores worsen, or if clinical sequelae such as retention or infection develop, treatment is warranted.

MEDICAL THERAPY

Before the late 1970s, the only treatment for patients with BPH was surgical resection, such as open prostatectomy or transurethral resection of the prostate (TURP). In 1978, Caine and colleagues³ reported that phenoxybenzamine(Drug information on phenoxybenzamine), a nonselective α-blocker, was an effective treatment for patients with BPH. This seminal observation formed the basis for substantial research, with the result that α-blockers are currently the initial treatment for most men with symptomatic BPH.

α-Blockers. α-Blockers work by antagonizing the α-adrenergic receptors on the smooth muscle in the prostate.⁴ The α_1a is the predominant receptor in the human prostate.⁵

Currently available α-blockers include doxazosin(Drug information on doxazosin), terazosin, alfuzosin(Drug information on alfuzosin), and tamsulosin(Drug information on tamsulosin). They are long acting (once-daily dosing) and α_1a- selective. A meta-analysis by Djavan and Marberger⁶ demonstrated a comparable magnitude of improvement in both AUA SS and urinary flow. Tamsulosin and alfuzosin had adverseeffect profiles comparable to those of placebo. Patients treated with terazosin(Drug information on terazosin) and doxazosin, however, had a 4% to 10% greater dropout rate because of adverse effects than did patients receiving placebo. The adverse effects were typically dizziness, asthenia, somnolence, and headache.^7,8

Ejaculatory dysfunction occurs more frequently with tamsulosin, but the increased frequency is not large enough to be consistently detected in comparative studies.⁹ Both doxazosin and terazosin require dose titration when treatment is initiated because of the potential for hypotension. Tamsulosin and alfuzosin do not.

The Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized patients with hypertension and other cardiac risk factors to receive either doxazosin or chlorthalidone, a diuretic. The doxazosin arm was terminated early because of a statistically significant (25%) higher incidence of major cardiovascular disease events, particularly congestive heart failure.¹⁰ Based on that study, the AUA 2003 Consensus Panel recommended that α-blockade should not be used as monotherapy for patients who have both BPH and hypertension and that a second agent should be used to manage the hypertension.²

The Medical Therapy of Prostatic Symptoms (MTOPS) study and the Alfuzosin Long-Term Efficacy and Safety Study (ALTESS) showed that α-blockers improve BPH symptoms and increase time to disease progression but do not prevent overall progression (defined as acute urinary retention and the need for invasive therapy).^11,12 These studies also showed that α-blockers are less effective in men with large prostates and that dropout rates are relatively high after 3 to 4 years of therapy.

5α-Reductase inhibitors. 5α- Reductase inhibitors manage BPH by decreasing prostate volume. Dihydrotestosterone (DHT) is the primary androgen involved in prostatic growth. 5α-Reductase inhibitors (finasteride and dutasteride(Drug information on dutasteride)) prevent the conversion of testosterone to DHT by competitively inhibiting the enzyme 5α-reductase. There are 2 isoforms of 5α-reductase enzyme, types 1 and 2. Finasteride(Drug information on finasteride) is a selective inhibitor of only the type 2 enzyme, whereas dutasteride inhibits types 1 and 2.

The 4-year Proscar Long-term Efficacy and Safety Study (PLESS) showed that finasteride increased flow rate, decreased AUA SS, reduced prostate volume by 32%, lowered the risk of acute urinary retention by 57%, and reduced the need for BPH-related surgery by 55%.¹³ The MTOPS study demonstrated that finasteride significantly reduced the risk of clinical progression of BPH by 34% compared with placebo and reduced the risk of acute urinary retention and the need for invasive therapy.¹¹ The latter events (acute urinary retention and the need for invasive therapy) were not reduced in men receiving doxazosin monotherapy. The Prostate Cancer Prevention Trial (PCPT) showed that after 7 years, finasteride has an added benefit of decreasing the risk of prostate cancer by 24.8%.¹⁴

Dutasteride therapy had effects similar to those of finasteride. Roehrborn¹⁵ compared dutasteride with placebo and noted a decreased risk of acute urinary retention and BPHrelated surgery, a continuing improvement in flow rate and urinary symptoms, and a reduction in prostate volume. There was also a 50% reduction in the incidence of prostate cancer.¹⁶ The ongoing Reduction by Dutasteride in Prostate Cancer Events (REDUCE) trial is studying the effects of that drug on the incidence and progression of prostate cancer.¹⁶

Finasteride and dutasteride are well tolerated. Adverse effects (occurring in fewer than 1% of patients) include impotence, decreased libido, ejaculatory disorders, and gynecomastia. In most trials, men who experience adverse effects do so during the first year, with few additional subsequent adverse effects. 5α- Reductase inhibitors tend to have a greater effect in improving total symptom severity, frequency scores, and peak flow rates on prostates of larger volume.¹⁷

Combination therapy (an α- blocker plus a 5α-reductase inhibitor). The MTOPS study showed that management with a combination of finasteride and doxazosin reduced the clinical progression of BPH by 66% compared with treatment with finasteride or doxazosin alone (34% and 39%, respectively).¹¹ While patients in all 3 active treatment arms (finasteride alone, doxazosin alone, and combination) showed a significant improvement in symptom scores compared with placebo, the combination arm was superior.

The Combination Therapy of Dutasteride and Tamsulosin Trial (CombAT) is a 4-year, multicenter, randomized, double-blind, parallel group study comparing the benefits of tamsulosin monotherapy, dutasteride monotherapy, and combination therapy in men older than 50 with an International Prostate Symptom Score (IPSS) greater than 12 and a prostate volume greater than 30 cc.¹⁸ Preliminary 2-year data show a statistically significant reduction in IPSS with combination therapy (6.2 point decrease) versus either dutasteride or tamsulosin monotherapy (4.9 and 4.3 point decrease, respectively). A statistically significant improvement in maximum urinary flow rate (Q_max) from baseline was also noted in the combination therapy arm (2.4 mL/s) compared with the dutasteride and tamsulosin monotherapy arms (1.9 and 0.90 mL/s improvement, respectively).

The MTOPS trial suggests that α-blockers manage symptoms with a relatively rapid onset of action but do not prevent disease progression. This observation gave rise to a strategy of initially combining an α-blocker and a 5α-reductase inhibitor for a short duration (3 to 6 months) followed by withdrawal of the α-blocker and continuation of 5α-reductase inhibitor monotherapy

The Symptom Management After Reducing Therapy (SMART-1) study examined such an approach using dutasteride and tamsulosin. Men were randomized to tamsulosin and dutasteride(Drug information on tamsulosin + dutasteride) for 24 weeks, after which 50% discontinued tamsulosin.¹⁹ Most patients (84%), with an initial IPSS of less than 20, who were switched to monotherapy had sustained improvement in BPH symptoms. Therefore, most patients with mild to moderate BPH symptoms may benefit from an initial short duration of combination therapy followed by 5α-reductase monotherapy.

Combined α-blocker therapy and anticholinergic therapy. Patients with BPH often have concomitant irritative voiding symptoms because of an overactive bladder (OAB). Kaplan and colleagues20 performed a randomized, double-blind, placebo-controlled trial comparing tolterodine(Drug information on tolterodine) extended-release (ER), tamsulosin, tolterodine ER plus tamsulosin, and placebo in patients who had mild to moderate BPH and OAB. They found a statistically significant reduction in incontinence, frequency, and nocturia in the tolterodine ER plus tamsulosin group. These patients also had a statistically significant improvement in IPSS and quality of life.

The incidence of acute urinary retention requiring catheterization was low in all arms (less than 0.5%); patients treated with tolterodine ER and those treated with tolterodine ER plus tamsulosin had only a statistically insignificant increase in postvoid residual volume (PVR) from baseline (5- to 6-mL). Blake-James and associates, 21 in a meta-analysis, observed similar results. Anticholinergic use did not significantly alter flow rates, and PVR was increased by only 11.6 mL (statistically insignificant). The rate of acute urinary retention was low (0.3%) and similar in all arms. Based on these data, anticholinergics appear to be safe to use in patients with both BPH and OAB.

PDE-5 inhibitors. Recent studies have shown that PDE-5 is present in human prostate and bladder tissue. This coupled with the observation that erectile function declines in men with increasing severity of LUTS prompted an initial evaluation of PDE-5 inhibitors as a treatment for LUTS. McVary and colleagues²² showed that both the IPSS and the BPH Impact Index were improved in men receiving tadalafil(Drug information on tadalafil). Larger trials are needed to confirm these initial observations.

Phytotherapy. In 2002, more than 2.5 million adults reported using Serenoa repens (saw palmetto).²³ In 1999, an estimated $1 billion was spent on phytotherapy for BPH, and spending has probably increased since that time.²⁴ Despite the widespread use of plant extracts, recent studies do not support their effectiveness in the management of BPH. Bent and coworkers²⁵ conducted a randomized, controlled, double-blind trial in 225 men comparing saw palmetto with placebo. They found no difference in change in AUA SS, Q_max, prostate size, quality of life, and adverse effects between the 2 groups. Until more data are produced, phytotherapy use remains controversial and cannot be currently recommended as a management option for BPH.