Medical Management of Benign Prostatic Hypertrophy in Older Men

Introduction

Benign prostatic hypertrophy (BPH) is the most common cause of lower urinary tract symptoms (LUTS) in aging men and can occur in up to 70% of men over age 60.¹ Symptoms can be progressive and often impact quality of life and even activities of daily living. Complications of BPH include obstructive nephropathy, recurrent urinary tract infections, and acute urinary retention. There are several management options for BPH currently available. This article reviews the evidence for the major medical treatment modalities for BPH available today. The aging population is heterogeneous, however, and management strategies for a community-dwelling older man may be different than those for older men living in long-term care (LTC) settings. Several treatment strategies, ranging from nonpharmacologic and surveillance to medical therapy to minimally invasive and surgical techniques, are appropriate based on severity of clinical symptoms. Quality-of-life issues must always be taken into consideration as well.

History

The exact cause for BPH is not well understood. It is known that the prostate enlarges as men age, that symptoms typically start by the fourth decade, and that by age 60 more than half of all men have some symptoms related to BPH. LUTS collectively includes common clinical manifestations of BPH such as increased frequency of urination, nocturia, hesitancy, urgency, and weak urinary stream. There is modest correlation among LUTS, peak urinary flow rates, and prostate volume, but the symptoms do not always match histologic findings. Specifically, benign prostatic hypertrophy refers to a histologically defined condition of stromal and epithelial hyperplasia of the prostate, particularly in the periurethral transitional zone.² Histologic evidence of BPH does not always confer symptoms. Likewise, LUTS are not specific to BPH and may be due to other pathologies of the urinary system that warrant further investigation. If it is not known whether symptoms are due to BPH, a diagnostic workup for other causes such as urethral stricture, bladder neck contracture, prostate carcinoma, bladder stones, urinary tract infection, prostatitis, and neurogenic bladder should be performed. Medical comorbidities common in the geriatric male population (eg, type 2 diabetes, neurologic disease), as well as treatment with drugs that can impair bladder function (such as anticholinergics), can also cause LUTS and need to be further clarified.

Once it is established that the male patient has LUTS from BPH, there are four main treatment strategies: nonpharmacologic/surveillance, medical therapy, minimally invasive techniques, or invasive approach. Particular emphasis will be placed on medical therapy in this article.

Surveillance

In men who convey symptoms that are either not very bothersome or stable, nonpharmacologic interventions such as double voiding and scheduled voiding may be of help, and surveillance is often appropriate. Many older patients are already taking several medications and may be hesitant to add more medical therapy. Alternatively, men may mistakenly feel that such symptoms are a part of normal aging and may not offer complaints, thus the physician should inquire about LUTS. If symptoms are elicited, standardized validated scales such as the American Urological Association (AUA) symptom score, which addresses seven factors—frequency, hesitancy, nocturia, weak stream, intermittent stream, incomplete emptying, and urgency—can be used to assess severity; it must be noted that it is not intended to be used for differential diagnosis purposes.³ In general, in men who have mild symptoms (defined as AUA scale of 0-7), periodic monitoring and surveillance is appropriate. If symptoms worsen, treatment may be initiated based on a discussion of goals of care with the patient. If clinical issues such as infection or urinary retention are present, pharmacologic treatment is indicated.

Medical Management

Before 1970, the only treatment available for men with symptomatic BPH was surgical. Today, there are several medical therapies available that draw from several classes of medications. Four options are available in terms of medical therapy: alpha blockers, 5-alpha-reductase inhibitors (5ARIs), a combination of alpha blockers and 5ARIs, and anticholinergic therapy (Table).

Alpha Blocker Monotherapy
Alpha blockers are currently the initial preferred treatment in men with symptomatic BPH, and have a rapid onset of action. Their use is based on the study by Caine and colleagues,⁴ which demonstrated that phenoxybenzamine, a nonselective alpha blocker, relieved symptoms in men with BPH by inhibiting alpha adrenergic–mediated contractions of the smooth muscle of the prostate and bladder neck.⁵ Unlike phenoxybenzamine, currently used alpha blockers—terazosin, doxazosin, tamsulosin, and alfuzosin—are selective for the alpha-1 receptors in the urinary system.

A meta-analysis showed statistically significant improvements in symptom scores with all four alpha-blocker agents as compared to placebo.⁶ Side-effect profiles differ, however. Alpha-1 receptors have several different subtypes, and the predominant subtype in the prostate and bladder neck is the alpha-1a receptor.⁷ Newer agents tamsulosin and alfuzosin are specific to the alpha-1a adrenergic receptor and do not require titration; moreover, the incidence of systemic side effects is lower as compared to terazosin and doxazosin, as demonstrated in another meta-analysis by Djavan et al.⁸ In this study, treatment of BPH with older agents doxazosin and terazosin had higher drop-out rates due to side effects as compared to the newer agents tamsulosin and alfuzosin. These new agents, more specific for the prostate alpha-1a subtype receptor in the lower urinary tracts, had side-effect profiles similar to placebo.⁸

In a Cochrane review, 17 studies involving over 5000 patients were reviewed to evaluate the effectiveness and adverse effects of the alpha blocker terazosin for symptomatic treatment of urinary symptoms associated with BPH. Mean age was 65 years, and study subjects were 82% white. At baseline, men had moderate benign prostatic obstruction as measured by urologic scales and flow rates. The data demonstrated that terazosin improved symptom scores and flow rates over placebo or the 5ARI finasteride, but was similar to other alpha blockers. It also found that adverse effects for terazosin were greater than placebo, and included dizziness, asthenia, headache, and postural hypotension.⁹

In addition, the Medical Therapy Of Prostatic Symptoms (MTOPS) study,¹⁰ the first double-blind, placebo-controlled study to assess impact of medical therapy on risk of BPH progression, randomized 3047 men age 50 years and older with moderate-to-severe LUTS to one of four arms: placebo, doxazosin alone, finasteride alone, or combination of doxazosin and finasteride. While each arm of the study showed a statistically significant effect in reducing overall clinical progression versus placebo, doxazosin alone had a slight superiority in reducing symptoms as compared to finasteride alone; however, as will be discussed later, combination therapy proved to be the most effective over either agent alone.¹⁰

In situ analysis of tissue taken from patients with BPH and treated with terazosin and doxazosin suggested that these agents might induce apoptosis in glandular epithelium; however, large-scale studies did not show any effect of alpha blockers on reducing prostate volume.¹¹ Although the treatment of BPH with alpha blockers has demonstrated a significant reduction in the risk of clinical progression relative to placebo, they are less effective in men with larger prostate volumes, and have not been shown to reduce prostate volume or the overall long-term risk of acute urinary retention or BPH-related surgery.¹⁰

Alpha blocker monotherapy in men with hypertension. Intuitively, it may make sense to use one drug to treat both hypertension and LUTS associated with BPH. However, the AUA Practice Guidelines Committee recommends that alpha blockade should not be used as monotherapy for patients with both BPH and hypertension, and that a second agent should be used.¹² The rationale for this recommendation is based on evidence from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT),¹³ which randomized patients with hypertension and other cardiovascular risk factors to receive either doxazosin or the diuretic chlorthalidone for treatment of hypertension. The doxazosin arm was terminated early due to a statistically significant increase of cardiovascular events, particularly congestive heart failure.¹³ Therefore, alpha-1 receptor antagonists, particularly doxazosin, should be avoided in patients with heart failure.

5-Alpha-Reductase Inhibitor Monotherapy
This class of drugs includes dutasteride and finasteride and, according to several studies, appears to be among the most effective agents for men with larger prostate volumes.^14,15 These agents work by preventing the conversion of testosterone to the androgen dihydrotestosterone (DHT), which has an important role as the primary androgen involved in prostatic growth.¹⁶ There are two isoenzymes of 5ARI. Dutasteride inhibits types 1 and 2, while finasteride only selectively inhibits type 2. These agents have a considerably slower onset to maximum effect, typically 6-12 months, as compared to alpha blockers and seem to work best in patients with large prostate volumes, described, according to one study, as prostate volume typically greater than 40 mL.¹⁷

The MTOPS study, discussed above, demonstrated that over a mean follow-up of 4.5 years, finasteride significantly reduced the risk of clinical progression of BPH by 34% as compared to placebo, as well as reduced the risk for acute urinary retention and the need for invasive therapy.¹⁰ Both finasteride and dutasteride, though generally well tolerated, have adverse effects that must be discussed with patients, which include impotence, decreased libido, ejaculatory disorders, and gynecomastia.

Combination Therapy of Alpha Blockers and 5-Alpha-Reductase Inhibitors
Two previous 12-month clinical trials, one from the Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study¹⁸ (which compared terazosin, finasteride, and combination therapy with placebo), as well as the Prospective European Doxazosin and Combination Therapy Trial¹⁹ (which compared doxazosin, finasteride, and combination therapy with placebo), found no benefit of combination therapy over monotherapy. These trials focused on longitudinal changes in the AUA symptom score and maximal urine flow rate.

The MTOPS study, however, which had a much longer mean follow up of 4.5 years, concentrated on the impact of medical therapy upon clinical progression of BPH and long-term reduction in risk of associated complications. This trial demonstrated that long-term therapy with the alpha blocker doxazosin and the 5ARI finasteride reduced the risk of overall clinical progression of BPH significantly more than with either agent alone. In addition, in men with larger prostate volumes and rising prostate-specific antigen levels, univariate analysis revealed that risk of both acute urinary retention and need for invasive therapy were significantly reduced with combination therapy or finasteride alone, but not with doxazosin alone.¹⁰ Thus, the MTOPS study clearly demonstrated that combination therapy was the most effective overall treatment, especially in those patients who had increased prostate volumes and were also at highest risk of disease progression.

While the results of the MTOPS trial are indeed promising, applying this treatment to all elderly men is not always appropriate either. First of all, each intervention arm of the MTOPS study (doxazosin alone, finasteride alone, and combination) demonstrated statistically significant improvements in symptom scores versus placebo. Also, because many physicians work in LTC settings with the oldest and frailest subset of the elderly population, it is important to note that the mean ages in each of the groups ranged from 62.6 to 62.7 with +/- SD of 7 years. Thus, it is not clear how applicable these results are to the frailest segment of the population. Therefore, use of combination therapy should be considered in conjunction with other factors including disease burden and quality of life.

Anticholinergic and Alpha Blocker Therapy
When men present with symptoms indicative of overactive bladder, such as strong urge to void or frequency, anticholinergic therapy is often initiated. Despite the fact that newer agents are more specific to bladder receptors, side effects can still be problematic, particularly in the frail elderly. Additionally, there is legitimate concern as to whether decreasing detrusor contractility increases the risk for acute urinary retention in cases of men who have concomitant BPH and overactive bladder. Only one randomized, double-blind controlled trial, by Kaplan and colleagues,²⁰ was found at the time of this review that addressed this issue of using alpha blockers in combination with anticholinergic agents. Men with BPH were randomized to four groups: tolterodine ER (anticholinergic), tamsulosin (alpha blocker), both tolterodine ER plus tamsulosin, or placebo. The authors found that the group using tolterodine ER in combination with tamsulosin experienced significant reductions in LUTS as compared to placebo, that this combination was well tolerated, and that the most common adverse effect was dry mouth. Postvoid residual volumes changed minimally and were not statistically significant. The incidence of acute urinary retention requiring catheterization was low, suggesting that it may be safe to use anticholinergic medication in patients with both BPH and overactive bladder. Again, however, the average age of the population in both groups tended to be younger, and patients age 80 years and older represented 6% or less of each intervention group. Thus, the benefits of this approach-de-novo in younger, healthier patients may be quite appropriate, whereas its application in patients age 80 years and above and those in LTC settings may need to be weighed against risks, adverse reactions, and patient factors such as cognitive status, functional status, and potential impact on quality of life. While results are promising, further studies should be done to determine safety and efficacy, particularly in the oldest old.

Minimally Invasive Techniques and Other Surgeries

These techniques are mentioned as an alternative to surgery and include transurethral needle ablation (TUNA) and transurethral microwave therapy (TUMT). They have been gaining widespread use owing to the ability to be performed as an office procedure and a good safety profile. Once considered equivalent to transurethral resection of the prostate (TURP), recent studies have not confirmed their long-term effectiveness. A meta-analysis on TUNA therapy demonstrated that as compared to TURP, it increased quality-of-life scores and symptoms by 50-60% from baseline. Re-treatment rate, however, was 7.4 times higher in the TUNA group versus TURP; however, TUNA has a significantly lower complication rate than TURP.²¹ Similarly, a meta-analysis comparing TUMT to TURP demonstrated higher re-treatment after TUMT versus TURP. In addition, higher peak flows and improvement in urinary symptom scores improved in both but were higher in TURP versus TUMT.²² In conclusion, despite 20% morbidity rate, TURP remains the gold standard of treatment of BPH, but minimally invasive techniques are an alternative in patients who continue to experience bothersome LUTS who either do not respond or adhere to medical therapy and are not good surgical candidates. Laser therapies are being widely employed for treatment of symptomatic BPH and include photoselective laser vaporization of the prostate, Holmium laser enucleation of the prostate, and Holmium laser ablation.

Summary

A number of medical therapies have become available to aging men as the baby boomers enter their 60s. Surveillance is appropriate for men who are experiencing minimal symptoms or who wish to defer pharmacotherapy. Initiating medical therapy should always be made with patient input whenever possible to discuss treatment goals. Medical therapy is appropriate if there are worsening clinical manifestations of disease, such as increasing or bothersome LUTS. Initial treatment should consist of newer, selective alpha-1a subtype blockers—tamsulosin and alfuzosin—which act on receptors found predominantly in prostate tissue and are better tolerated with respect to systemic side effects. Combination therapy with an alpha-blocking agent and a 5ARI may be appropriate, especially in patients who have enlarged prostates and are therefore likely to have higher risk for disease progression. 5ARI agents have a much slower onset of action as compared to alpha blockers and can take up to 6-12 months for maximal effect; thus, many patient factors should be considered prior to initiating this approach in frail elderly persons. In men who have heart failure, doxazosin should not be utilized due to increased risk for cardiovascular events, especially congestive heart failure. If medical therapy is not effective, minimally invasive techniques, laser therapy, and TURP are all viable options and should be considered after discussion with patients and their families after a careful consideration of comorbid illness, risks assessment, severity of symptoms, and quality-of-life indicators.

The author reports no relevant financial relationships.

Dr. Srulevich is a faculty member, Division of Geriatric Medicine, Crozer-Keystone Center for Geriatric Medicine, Crozer-Chester Medical Center, Upland, PA, and Clinical Assistant Professor of Medicine, Temple University School of Medicine, Philadelphia, PA.