While the mainstay of medical treatment for BPH continues to be alpha-adrenergic blockers and 5alpha-reductase inhibitors, combination therapy provides expanded options and can result in a delay in the time to clinical progression.

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Benign prostatic hyperplasia (BPH) is one of the most common diseases afflicting older men. Data from a number of autopsy studies conducted in the 1980s indicate that the prevalence of the disease increases with age. These studies found pathologic evidence of BPH in 8% of men between 31 and 40 years of age, with a marked increase thereafter to more than 70% in men aged 61 to 70. Similarly, analysis of the United Kingdom General Practice Research Database (UK GPRD) demonstrated that the occurrence of lower urinary tract symptoms (LUTS) suggestive of BPH increased linearly between the ages of 45 and 85 years. The prevalence of LUTS increased from 3.5% in men in their late 40s to 35% in men in their late 80s.¹

 

Drugs mentioned in this article

Alfuzosin (UroXatral) Doxazosin (Cardura) Dutasteride (Avodart) Finasteride (Proscar) Indoramin (Baratol, Doralese)* Phenoxybenzamine (Dibenzyline) Prazosin (Minipress) Tamsulosin (Flomax) Terazosin (Hytrin) Vardenafil (Levitra) Verapamil *Only available in the United Kingdom.

The condition is usually first diagnosed when the patient presents to his physician complaining of urinary difficulties. Patients generally seek treatment only when their symptoms become sufficiently bothersome, or quality of life (QOL) becomes impaired, or both.² The symptoms of BPH result primarily from the secondary effects of the disease on the urethra and bladder and can be classified as obstructive or irritative (see Table 1).^2,3 Although obstructive symptoms, such as urinary hesitancy, straining to void, decreased force of the urinary stream, and urinary retention, are often associated with reduced urinary flow rates, these symptoms do not always correlate well with objective measures of disease severity.

 

TABLE 1 Clinical symptoms of benign prostatic hypertrophy

Obstructive Decreased force of stream Hesitancy Incomplete emptying Intermittency Straining Terminal dribbling Irritative Dysuria Nocturia Urge incontinence Urgency Urinary frequency

Sexual dysfunction in men with BPH may be secondary to BPH symptoms, such as sleep disturbance or psychological anxiety caused by severe urinary difficulties.⁴ The recent Multi-National Survey of the Aging Male reported a high prevalence of LUTS and sexual problems in older men.⁵ The trial enrolled 14,254 men in 7 countries between 50 and 80 years of age. Of the 12,815 men who completed a questionnaire, 90% had LUTS, 49% reported erection difficulties, 46% experienced ejaculatory disturbance, and 7% felt pain during sexual intercourse. Nevertheless, 83% of the sample reported being sexually active. While symptoms were severe in 6% of men, moderate in 25%, and mild in 59%, only 11% were medically treated.⁵ Problems in each domain of sexual function (erection, intercourse satisfaction, orgasmic/ejaculatory function, sexual desire, and overall satisfaction) were strongly related to the severity of LUTS, but were independent of age and other comorbidities.

Medical versus surgical treatment of BPH

The last decade has seen a paradigm shift away from surgery toward pharmacotherapy for the first-line management of BPH. This shift has occurred despite surgical approaches displaying superior efficacy in terms of symptom score reduction and improvements in urinary flow. Whereas clinicians often seek to improve objective measures of disease, patients are often more interested in symptom relief and in reducing the impairment of their QOL.⁶ They also wish, if possible, to avoid invasive surgery and hospitalization.

On this basis, medical therapy is now considered the treatment of choice for most patients, with surgical intervention generally reserved for patients who fail to respond to pharmacologic therapy. Further indications for surgical intervention include acute urinary retention, recurrent urinary tract infections (UTIs), bladder calculi, obstructive uropathy, hydronephrosis, renal insufficiency, overflow incontinence, and severe recurrent hematuria related to dilated veins on the prostate gland.³

When surgery is indicated, transurethral resection of the prostate (TURP) remains the gold standard by which newer procedures, such as transurethral needle ablation, transurethral microwave thermotherapy, and interstitial laser coagulation are measured.^2,3 Although these minimally invasive treatments offer shorter hospital stays or outpatient management and fewer risks of postoperative complications than TURP, no large-scale direct comparisons have been performed, and their long-term efficacy, safety, and cost-effectiveness have yet to be clearly determined.² For certain patients who have a large prostate (with BPH the normally walnut-sized gland may expand to the size of a golf ball, or larger) and who are on anticoagulation therapy, newer technologies have special appeal.

In a study of 457,664 US Medicare beneficiaries, age-adjusted rates of TURP for BPH declined by approximately 40% in black men and by approximately 50% in white men from 1984 to 1990 and from 1991 to 1997.⁷ The UK GPRD study revealed an incremental increase in the use of medical therapy for LUTS/BPH between 1992 and 1998, reflecting the growing availability and acceptance of new pharmacologic treatments.¹ In concert with this change, the interval between the initial diagnosis of LUTS/BPH and prostatic surgery progressively increased, and patients who did not receive medical therapy required prostatic surgery significantly earlier than treated patients. Newer medications, such as alfuzosin, were associated with a significantly lower failure rate (defined as a change in therapy, catheterization, or prostatic surgery) than older drugs such as prazosin and indoramin.¹

Alpha-adrenergic blocker therapy

The first alpha-blocker studied for the treatment of BPH was the nonselective alpha₁-/alpha₂-adrenergic antagonist phenoxybenzamine. While a considerable body of evidence demonstrated that phenoxybenzamine improves the symptoms of BPH, concerns regarding cardiovascular adverse events and possible carcinogenicity have diminished its use.⁸ In addition, although both alpha₁- and alpha₂-receptors are present in prostate tissue, the contraction of prostatic smooth muscle is largely a function of alpha₁-receptor activation. This fact, coupled with the finding that the adverse events associated with nonselective alpha-receptor blockade are primarily a function of alpha₂-receptor antagonism, has led to the development of a number of alpha₁-selective agents.

These drugs, such as terazosin, doxazosin, tamsulosin, and alfuzosin, have similar efficacy in relieving the symptoms of BPH.⁹ The main difference between them is the safety profile. For example, terazosin is associated with a number of adverse events related to the effects of alpha blockade on nonprostatic tissue, including dizziness, asthenia, somnolence, and rare instances of syncope.² Alpha-blockers, such as doxazosin, should be used with caution in combination with other antihypertensive agents such as verapamil because of the risk of hypotension. There is also a similar but rather smaller risk of the same effect with phosphodiesterase inhibitors such as vardenafil.

Three subclasses of the alpha₁ receptor have been identified in the lower urinary tract: alpha₁A, alpha₁B, and alpha₁D. All 3 subtypes have been shown to be present in prostate tissue from individuals with and without BPH. In tissue from patients with BPH, subtype alpha₁A predominates (85%), with smaller amounts of alpha₁D (14%) and negligible amounts of alpha₁B receptors detected. Subtypes alpha₁D and, to a lesser extent, alpha₁A are present in detrusor muscle. The spinal cord contains primarily alpha₁D-receptors.¹⁰ Bladder outlet resistance appears to be mediated via alpha₁A-receptors; however, animal data indicate that alpha₁D-receptor antagonism inhibits detrusor instability.

On this basis, it has been suggested that selective alpha₁A- and alpha₁D-blockade may be the best therapeutic option for men with BPH, especially given that increased vascular expression of alpha₁B has been observed in elderly patients, predisposing them to greater risk of cardiovascular side effects from alpha₁B-receptor blockade. However, clinical results with an investigational alpha₁A-selective receptor blocker showed no improvement in symptoms or flow rate over placebo.^11,12 Additionally, the agent induced hypotensive side effects similar to those caused by available non-subtype-selective agents. This finding supports the concept that there is no clear relationship between receptor subtype selectivity and clinical uroselectivity (improvement in symptoms with minimal systemic cardiovascular effects). Only clinical uroselectivity is important for the treatment of BPH. Tamsulosin, according to radioligand binding studies, has a greater affinity for alpha₁A and alpha₁D receptors than alpha₁B receptors.¹³ It is uroselective, demonstrating functional selectivity for urinary tissue over cardiovascular tissue.^9,14 Alfuzosin has demonstrated uroselectivity in animal studies.¹⁵

Tamsulosin The efficacy and tolerability of tamsulosin have been established in a number of short-term (12- to 13-week) randomized, double-blind, placebo-controlled clinical trials in both Europe and the United States. In all of these trials, tamsulosin was associated with significant improvement in symptoms (as measured by the American Urological Association [AUA] Symptom Score in the United States and the Boyarski Score in Europe) and urinary peak flow rate relative to placebo.¹⁶

Tamsulosin was well-tolerated in these trials, with an overall incidence of adverse events similar to placebo. In all studies, however, abnormal ejaculation (including ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease) was more frequent in tamsulosin recipients than in placebo recipients. The rate of abnormal ejaculation in a 64-week open extension of 2 previous 13-week clinical trials rose to 30% (289 of 949 patients), and was a common reason for study dropout (2%).¹⁷ Abnormal ejaculation, however, is reversible on cessation of the drug and other studies have shown a lower incidence of this side effect.¹⁸ Ejaculation disturbances in men treated with tamsulosin may be caused by bladder neck closure impairment, seminal vesicle contraction, or both.¹⁹

Cardiovascular effects are also seen with tamsulosin. In the pivotal trials, although orthostatic hypotension was relatively low, dizziness was reported in 14.9% and 17.1% of patients taking 0.4 and 0.8 mg, respectively, compared with 10.1% for those receiving placebo. In addition, in these same studies, rhinitis, possibly due to some nasal vasodilatory effects, was also dose related and was noted in 13.1% of patients on 0.4 mg, 17.9% of those on 0.8 mg, and 8.3% on placebo.

Alfuzosin This agent is used extensively in Europe for the treatment of BPH and has recently been approved by the FDA for use in the United States. The efficacy of immediate-release alfuzosin as treatment for BPH has been established in a number of European trials of up to 6 months' duration. In each of these studies, alfuzosin significantly improved symptom scores and peak urinary flow rate compared with placebo. The overall incidence of adverse events was generally similar in alfuzosin versus placebo recipients. In addition to the original immediate-release formulation of the drug, which is taken as 2.5 mg tid, 2 newer formulations have been developed (a sustained-release formulation given as 5 mg bid and a recently developed extended-release formulation administered as 10 mg once daily). Both the sustained- and extended-release formulations of alfuzosin were also significantly more effective than placebo in short-term studies.

The results of 2 randomized double-blind trials using the once-daily formulation, plus a pooled analysis including a third US trial, demonstrated that alfuzosin was significantly more effective than placebo.^9,20-22 In addition the European study demonstrated that the extended-release formulation was as effective as the immediate-release formulation. Both studies were of 3 months' duration and demonstrated the efficacy of once-daily alfuzosin in improving symptoms and increasing peak urinary flow (see Figure 1).^9,23

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The overall incidence of treatment-related adverse events, including those related to cardiovascular side effects and sexual function, was similar in alfuzosin and placebo recipients in both studies. Orthostatic events and BP changes were similar to those following placebo administration even in elderly patients and in those on other antihypertensive treatments, while dizziness was reported in 5.7% of patients receiving 10 mg daily of alfuzosin compared with 2.8% of the placebo patients.⁹ The incidence of abnormal ejaculation in alfuzosin recipients was comparable to that observed in placebo patients.^9,23 Central effects may be responsible for some of the differences observed between tamsulosin and alfuzosin.

5Alpha-reductase inhibitor therapy

Although BPH is a multifactorial process, ample evidence exists that the condition is androgen-dependent. Men castrated before reaching puberty do not develop BPH; similarly, individuals with genetic abnormalities that inhibit androgen production or action have diminished or no prostatic growth.²⁴

The primary prostatic androgen, dihydrotestosterone (DHT), is derived from testosterone via the action of the enzyme 5alpha-reductase.²⁴ Two isoforms of this enzyme have been identified: type 1 and type 2. Type 1 5alpha-reductase is present in most 5alpha-reductase producing tissues, whereas type 2 5alpha-reductase is predominant in genital tissues, including the prostate. The key role of DHT in prostatic growth is perhaps best illustrated by the finding of abnormal prostate development in males with familial incomplete male pseudohermaphroditism type 2, in which an autosomal recessive mutation leads to a deficiency in 5alpha-reductase enzyme.²⁵

DHT is more potent than testosterone and has a higher affinity for the androgen receptor than the parent compound. This enables DHT to accumulate in the prostate even when circulating testosterone levels are low and may explain the paradox of high prostatic DHT levels in the presence of diminishing plasma testosterone levels in aging men.²⁴ Two 5alpha-reductase inhibitors—finasteride and dutasteride—are available in the Unites States.

Finasteride The key role of DHT in prostate development led to studies of 5alpha-reductase inhibitors as a potential treatment for BPH. In early human studies, finasteride was found to suppress plasma DHT levels without affecting testosterone levels.

In subsequent randomized placebo-controlled studies, administration of finasteride to men with BPH for 1 to 2 years was accompanied by reductions in prostate size of 15% to 21%.^26,27 The decreases in prostate mass were accompanied by significant improvements in urinary flow rate and symptom scores compared with placebo. A meta-analysis of randomized clinical trials evaluating the use of finasteride as treatment for BPH concluded that the efficacy of the drug is related to the size of the prostate; thus, the drug may not be suitable for men with smaller prostates. Moreover, since in the absence of cancer prostate-specific antigen (PSA) acts as a surrogate for prostate volume, finasteride may not be effective in men with PSA values of less than 1.4 mg/mL.²⁸

Another important caveat is that finasteride therapy decreases serum levels of PSA by as much as 50%.²⁹ This may have implications for the management of prostate cancer, for which PSA levels are a well-established marker. It appears, however, that the ability of PSA to distinguish between men with and without prostate cancer is not adversely affected by finasteride treatment.²⁹

The overall incidence of adverse events was similar in finasteride- and placebo-treated patients in these studies. However, the subset of adverse events related to sexual function (erectile dysfunction [ED], impaired libido, and ejaculation disorders) was markedly more frequent with finasteride than placebo. Indeed, adverse events related to sexual function were the most frequently reported drug-related adverse event in the 2-year Proscar Safety Plus Efficacy Canadian Trial (PROSPECT) and the Proscar Worldwide Efficacy and Safety Study (PROWESS).^26,27 In both of these studies, the incidence of ED and ejaculation disorders was significantly higher for finasteride recipients than placebo recipients (see Table 2).^26,27 The higher rate of newly reported sexual dysfunction in PROWESS could be attributed to a greater willingness of the patient to discuss sexually-related events or to an increased awareness of sexual dysfunction with finasteride.²⁶ No reason was given for the difference in incidence in PROSPECT, although total symptom and obstruction symptom scores were higher at baseline with finasteride than with placebo.²⁷

 

TABLE 2 Finasteride and adverse events related to sexual function
	Ejaculation disorder (%)		Erectile dysfunction (%)		Decreased libido (%)
Study name	Finasteride	Placebo	Finasteride	Placebo	Finasteride	Placebo
PROSPECT/ PROWESS26,27	7.7	1.7	15.8	6.3	10.0	6.3
3-year study30	3.5	1.1	5.0	2.0	4.8	2.5
Primary Care Investigators31	3.3	0.9	7.4	3.3	4.9	2.9
Key: PROSPECT, Proscar Safety Plus Efficacy Canadian Trial; PROWESS, Proscar Worldwide Efficacy and Safety Study.

Similarly, an analysis of safety data from 2 large trials that compared finasteride with placebo in the treatment of BPH found that adverse events relating to sexual function were significantly more frequent with active treatment.³⁰ The incidence of reduced libido and ejaculation disorders, but not ED, decreased during open-label extensions of these trials. An additional US primary care study involving men with BPH treated with finasteride or placebo also found that the incidence of sexual adverse events was significantly higher in finasteride versus placebo recipients.³¹

More recent data on the effects of finasteride on sexual function come from the Proscar Long-term Efficacy and Safety Study.³² Results from this 4-year study demonstrated that finasteride produced significantly more drug-related sexual adverse experiences (15%) than placebo (7%) during the first year of therapy. There was no difference in the incidence of new sexual adverse experiences between treatments (7% in each group) during the remainder of the study. It is, however, not only the occurrence of sexual adverse events that is important to the patient, but the symptomatic response to therapy as well. Results from PROWESS demonstrated that compared with placebo, finasteride provided symptomatic improvement that was sustained over the 2-year study period.²⁶

Dutasteride The FDA has recently approved the dual 5alpha-reductase inhibitor dutasteride. Its development was based on the rationale that suppression of both isoforms of 5alpha-reductase would result in better and more consistent suppression of serum DHT than is seen with the selective inhibition of type 2 5alpha-reductase that occurs with finasteride. In a phase II study in men with BPH, dutasteride (0.5, 2.5, or 5 mg/d) for 24 weeks was associated with a significantly greater percent reduction in DHT than finasteride (5 mg/d) or placebo.²⁴ Dutasteride, like finasteride, is indicated to reduce the risk of surgery and acute urinary retention.

As with finasteride, the side effects of dutasteride are primarily sexual (decreased libido, ED, ejaculatory disorders, and gynecomastia). Results from 3 placebo-controlled studies in 4325 patients demonstrated that significantly more patients reported ED, decreased libido, or ejaculation disorders with dutasteride during the first 6 months of treatment than with placebo.³³ Similarly, dutasteride can lower the concentrations of PSA, and this fact should be taken into account when patients who are being treated with dutasteride for BPH are monitored for prostate cancer.³⁴

Combination therapy

The recently completed Medical Therapy of Prostatic Symptoms study was conducted to determine whether combined treatment with an alpha-blocker (doxazosin) and a 5alpha-reductase inhibitor (finasteride) would be more effective than either drug alone. Men with BPH were randomized to treatment with doxazosin, finasteride, combination therapy, or placebo and were followed for an average of 4.5 years.

The results of this study indicated that a greater delay in the time to clinical progression of BPH was observed with a combination therapy than with either drug alone. A delay in the time to clinical progression was defined as the occurrence of 1 of these end points: greater than 4-point increase in AUA Symptom Score, acute urinary retention, incontinence, renal insufficiency, and recurrent UTI. The risk reduction relative to placebo was doxazosin 39%, finasteride 34%, and combination therapy 67%.³⁵ Frequently occurring adverse events were similar to those seen in previously reported trials.

In the final analysis, which patient receives which therapy will depend upon the individual circumstances and on an informed discussion between the doctor and the patient. An economic analysis of combination therapy should be conducted to determine the benefits of this treatment.

PRODUCED BY KRISTEN GEORGI

Dr Kirby discloses that he has no financial involvement with any companies doing business in this field.

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Men's Health: Selecting long-term medical therapy for BPH. Patient Care August 2004;38:38-45.