A Primary Care Physician’s Perspective on Benign Prostatic Hyperplasia

Abstract

Primary care clinicians are generally the first point of contact for men who suffer troublesome symptoms of benign prostatic hyperplasia. Although a subset of these patients will ultimately require referral to a urologist for an invasive procedure to provide symptom control, the majority can be appropriately managed in the ambulatory setting. Most symptomatic men respond favorably to α-blockers, which provide prompt improvement in symptoms such as nocturia. Although α-blockers may control troublesome lower urinary tract symptoms, there is no suggestion that they forestall the need for surgery or reduce the likelihood of development of acute urinary retention. Therefore, clinicians need to become familiar with use of 5-α-reductase inhibitors, as this is the only class of pharmacotherapy that has been shown to have a diseasemodifying effect.

Most middle-aged and older men have histologic benign prostatic hyperplasia (BPH) on serial section of the prostate. Indeed, should men survive to beyond age 85 years, essentially all (>85%) will manifest BPH (Table 1).¹

Table 1.

Histologic Benign Prostatic Hyperplasia: Disease Burden

	Biopsy
Age, y	Prevalence, %
30	10
60	60
85	85

Data from Beduschi R et al. Geriatrics. 1998;53(3):24–28, 33–34, 37–40.¹

It is necessary to define the 3 primary classifications of BPH before describing its epidemiologic pattern, because clinicians may be easily confused by the blurred boundaries of current terminology for prostaterelated disorders. The term BPH has been commonly used to define 1 of 3 scenarios (Table 2). The first, microscopic BPH, is a histologic finding seen in as many as 90% of senior men by age 85 years.² Microscopic BPH may or may not be associated with lower urinary tract symptoms (LUTS). In the second scenario, macroscopic BPH, the prostate gland may be palpably enlarged on rectal examination. Gland size, however, does not predict the presence or absence of LUTS. The third scenario, clinical BPH, is marked by the presence of LUTS and an enlarged prostate gland—defined by either clinical description, transrectal ultrasound of the prostate, or digital rectal examination—in the absence of any other etiologic explanation for these symptoms.

Table 2.

Benign Prostatic Hyperplasia (BPH): Terminology

Microscopic BPH: histologic hyperplasia with stromal and epithelial proliferation Macroscopic BPH: gross prostatic enlargement Clinical BPH: symptoms referable to macroscopic and/or microscopic BPH

From Beduschi R et al. Geriatrics. 1998;53(3):24–28, 33–34, 37–40.¹

Most clinicians have been initially educated that BPH is properly termed benign prostatic hypertrophy. Only in the past decade has the accuracy of this terminology been challenged by the recognition that prostate tissue undergoes hyperplasia. In any case, the foundation of knowledge about the prostate has been conceptually reduced to the overly simplistic reasoning that the enlarged gland produces a mechanical obstruction to flow through the urethra. Although it is true that gland enlargement contributes to the symptoms, LUTS appear to be as much related to deranged histopathology as to simple gland enlargement. Indeed, the correlation between gland size, LUTS severity, and degree of outlet obstruction is not strong.²

The normal prostate gland is histologically divided into the stroma and the epithelium. The stroma contains the smooth muscle component of the prostate gland; the epithelium contains the glands. In the normal prostate gland, the stroma-to-epithelium ratio is approximately 2:1; in BPH, this ratio changes to approximately 5:1.³ The transitional zone of the prostate (also called the preprostatic zone) is the site of development of histologic BPH. The capsule investing the prostate gland is dense and inflexible, so enlargement of any zone may transmit inward pressure onto the urethra. Yet, this simple obstructive phenomenology is insufficient to explain all of the symptoms of BPH and does not elucidate why some men with very large prostate glands have no symptoms whatsoever.

The key to understanding the evolution of LUTS appears to reside in the imbalance of smooth muscle that develops as BPH progresses. Because the stroma contains the smooth muscle and the stroma-to-epithelium ratio more than doubles in BPH, there is a concomitant and proportionate imbalance in prostatic smooth muscle growth. The smooth muscle of the prostate is under α-adrenergic control; stimulation of α-adrenergic receptors results in contraction of this smooth muscle and further encroachment on the urethral lumen. Indeed, the prostatic muscle tone may be visualized as hypertonic, or hyperresponsive, smooth muscle that is also excessive in mass. When this hyperresponsive, overgrown mass of smooth muscle is stimulated by sympathetic stimuli, LUTS occur. Indeed, α-adrenergic stimuli in seemingly innocuous cough-cold preparations, such as phenylephrine (Neo-Synephrine; Bayer Consumer Care, Morristown, NJ), by augmenting sympathetic tone, may be responsible for induction of urinary retention. Conversely, α-adrenergic blockade reduces prostatic smooth muscle tone. This, combined with the relaxation of smooth muscle in the bladder neck seen with α-adrenergic receptor blockade, reduces urethral obstructive and irritative symptoms (Table 3).

Table 3.

Lower Urinary Tract Symptoms

Irritative:

Pollakisuria* Nocturia Urgency Dysuria Incontinence

Obstructive:

Weak or intermittent stream Hesitancy Terminal dribbling Double voiding Straining Sensation of incomplete emptying

^*Clinicians sometimes mistakenly label urinary frequency as polyuria; the latter indicates increased volume and number of episodes of micturition (as in diabetes) Though rarely used, pollakisuria (or pollakiuria) is the correct term for increased frequency of urination.

Clinical Presentation

Most men with BPH have had symptoms for years before they seek consultation with a health care provider. There are numerous reasons for this. In a recent survey detailing the 10 clinical entities patients find most embarrassing to discuss with their family physician, prostate-related issues ranked fourth (Table 4).⁴

Table 4.

Top 10 Clinical Entities Patients Find Most Embarrassing to Discuss With Their Family Physician

Impotence Sexually transmitted diseases Physical and sexual abuse Prostate problems Incontinence of bladder or bowels Emotional problems (eg, depression) Eating disorders Alcohol or drug abuse Birth control and sex (especially teenagers) Menopause

Data from Preboth MA et al. Am Fam Physician. 1999.59:18.⁴

Some men believe that changes in urinary function with age are “just part of getting older.” Others may have had an acquaintance who suffered a surgical misadventure (eg, incontinence, impotence) subsequent to transurethral resection of the prostate and, hence, are loath to broach the topic lest the same fate befall them. Additional reasons for not seeking treatment include the gradual, insidious nature of the symptoms; an unawareness of the medical therapies available; and previous adverse events associated with a firstgeneration α-blocker.

When men address their health care providers about BPH, it is usually because the condition is encroaching upon their quality of life.⁵ The most widely accepted and commonly used tool to quantify symptom burden from LUTS is the American Urological Association (AUA) Symptom Index for BPH (see McVary, Table 2, p. S6).⁶ This index allows men and their clinicians to stratify symptom burden, follow this over time, and assess the impact of interventions. In general, a change in symptom score of at least 3 points is required before the change is considered significant. Once an AUA symptom score has been obtained, patients are categorized as having mild (0–7 points), moderate (8–19 points), or severe (>19 points) symptoms. Although intuitively it would seem that persons with severe symptom scores merit aggressive intervention, observational studies indicate that as many as 33% of such men fare well with no medical treatment over the long term (Table 5).⁷ Thus, in addition to an AUA symptom score, patients are usually asked to complete a “bother index,” indicating whether the symptoms they have are of little or of great burden.

Table 5.

Natural History of Benign Prostatic Hyperplasia^*

Baseline	Therapy Method at Year 4, %
Symptoms (n)	TURP	Drug Therapy	No Therapy
Mild (84)	10	26.7	63.3
Moderate (326)	24.1	31.0	44.9
Severe (89)	39.4	27.3	33.3

^*500 men with a clinical diagnosis of benign prostatic hyperplasia who were candidates for elective transurethral resection of the prostate (TURP).

Data from Barry MJ et al. J Urol. 1997;157:10–15.⁷

The AUA symptom score is most useful for quantifying the frequency of adverse symptoms. However, even when symptoms are frequent, if the patient is not bothered by them, there is no need for intervention. Some men with troublesome urinary symptoms present to a clinician either at the prompting of their spouse or because of concerns that such symptoms might reflect serious underlying disease, especially cancer. Under such circumstances, reassurance alone may be sufficient to satisfy the patient.

Prediction of which patients with BPH will ultimately have progression of symptoms or require invasive intervention is only modestly successful. Therefore, patients should be reassured that, if and when symptoms impair their quality of life to the point at which they want symptom modulation, there are pharmacologic and invasive treatments available.

Pharmacotherapy

α-Blockers

The α-adrenergic receptors in the genitourinary tract are predominantly located in the bladder neck, prostate smooth muscle, urinary sphincteric smooth muscle, and vascular wall of the corpora cavernosa. α-Adrenergic receptors are diffusely located in the vascular wall of the entire arterial tree, which explains the origin of hypotension and first-dose syncope sometimes experienced when anti-hypertensive α-blockers (doxazosin, prazosin, terazosin) are employed. The first α-blocker used for the treatment of hypertension was phenoxybenzamine, a nonspecific α₁- and α₂-receptor blocker. Because of adverse effects, this agent was generally restricted to use in situations such as hypertensive urgency and pheochromocytoma. Nonetheless, data indicating relief of acute urinary retention with parenteral phenoxybenzamine were heartening harbingers of the future role of more specific, better-tolerated α-blocking agents (Table 6).

Table 6.

Selected α-Blockers and Their Indications

Drug	Blockade Type	Indication
Phenoxybenzamine	α1 and α2	PHEO
Prazosin	α1	HTN
Terazosin	α1	HTN, BPH
Doxazosin	α1	HTN, BPH
Tamsulosin	α1	BPH

PHEO, pheochromocytoma; HTN, hypertension; BPH, benign prostatic hyperplasia.

The advent of prazosin heralded a new period of α-blockade as an antihypertensive therapeutic choice. For a while, the concept of “two for one” prompted many clinicians to prescribe α-blockers for hypertension in men with BPH. However, in 2000, the doxazosin arm of the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was prematurely discontinued because of the futility of finding a significant difference in primary outcome, as well as the drug’s adverse impact on cardiovascular outcomes, particularly heart failure (statistically significant 25% higher rate of major secondary end point—combined cardiovascular disease outcomes).⁸ As a result, α-blockers are no longer considered appropriate primary therapy for hypertension. Rather, diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers offer sufficient advantage to relegate α-blockers to a last-line therapeutic position. Therefore, it would be unwise for clinicians to choose a long-acting α-blocker (doxazosin, terazosin) to treat both hypertension and BPH, unless the patient had failed (or been intolerant to) the other classes of antihypertensive agents.

The clinical trial that provided greatest substantiation of the role of α-blockers in BPH was an “intermediate-term” trial comparing finasteride, a 5-α-reductase inhibitor, with terazosin.⁹ At first, the results of this trial seemed to indicate that terazosin was effective, finasteride was not, and the combination was no better than terazosin alone (Table 7). On reconsideration of these data, however, it became clear that the trial was of too short duration to capitalize on the long-term effects of 5-α-reductase inhibitors. Moreover, the population was selected in such a way that the subjects were more likely to respond favorably to α-blockade than to 5-α-reductase inhibition; that is, they had relatively small prostate glands and, hence, were the group least likely to have an early positive impact from α-reductase inhibition. If anything, this study confirmed the durability of the beneficial effects of α-blockers over a 1-year period.

Table 7.

The Efficacy of Terazosin, Finasteride, or Both for Benign Prostatic Hyperplasia^*

	Change in	Change in
Agent	AUA Symptom Score	Qmax (mL/s)
Placebo	−2.6	+1.4
Finasteride	−3.2	+1.6
Terazosin	−6.1	+2.7
Finasteride + terazosin	−6.2	+3.2

^*1-year trial (N = 1229) comparing terazosin, 10 mg/d; finasteride, 5 mg/d; finasteride plus terazosin; and placebo.

AUA, American Urological Association; Q_max, peak urinary flow rate.

Data from Lepor H et al. N Eng J Med. 1996;335:533–539.⁹

Since the valuable effects of α-blockers on the bladder neck and prostatic smooth muscle were recognized, tamsulosin, an α₁-adrenergic receptor antagonist, has been developed. This agent has the advantage of once-daily dosing and, because of its lack of affinity for cardiovascular smooth muscle receptors, does not have to be titrated and is not associated with first-dose syncope. The α1-adrenergic receptors appear to be preferentially segregated in the bladder neck and prostatic urethral smooth muscle. This attribute lends itself particularly well to relaxing these hypertonic muscles in BPH. Unfortunately, relaxation of the bladder sphincter can also cause retrograde ejaculation, which, although it does not change the experience of orgasm, is problematic for some men.

Alfuzosin (not available in the United States; marketed in Europe under the trade name Xatral by Sanofi-Synthelabo, Paris, France) is unusual among the α-blockers available for treatment of BPH in that it appears to be uroselective. That is, although not a selective α₁-adrenergic receptor antagonist like tamsulosin, alfuzosin does not appear to be associated with the same cardiovascular adverse effects as prazosin, doxazosin, and terazosin. In addition, recent data indicate that men with BPH shoulder a disproportionate burden of sexual dysfunction,¹⁰ and it appears that alfuzosin may have a favorable effect on sexual dysfunction associated with BPH. No head-to-head comparisons of alfuzosin with other α-blockers in a single population have been made.

Recently, a precaution was added to the package insert of sildenafil warning that administration of an α-blocker within 4 hours of sildenafil may lead to an exaggerated hypotensive response. This information is believed to refer to prazosin, doxazosin, and terazosin. Because tamsulosin has no cardiovascular affinity, it should be safe to use this agent concomitantly with sildenafil.

α-Blockers can successfully control symptoms in men with BPH. Nonetheless, many patients will have symptom progression that necessitates surgical intervention unless a disease-modifying agent is employed to alter the course of the condition. In this regard, 5-α-reductase inhibitors show great promise.

5-α-Reductase Inhibitors

The primary trophic hormone for prostatic growth, proliferation, and hyperplastic pathology appears to be dihydrotestosterone (DHT), which is produced through conversion of testosterone by the enzyme 5-α-reductase. A 5-α-reductase inhibitor will predictably reduce levels of DHT. After treatment with a 5-α-reductase inhibitor, testosterone levels are normal or slightly increased, consistent with feedback limbs that drive testosterone levels higher as pituitary feedback from lower DHT levels prompts luteinizing/follicle-stimulating hormone production.

Two isoforms of 5-α-reductase are known to exist. Finasteride, the first drug in this class, exclusively impacts 5-α-reductase type 2, which is believed to be the primary source of prostatic DHT. Patients taking finasteride typically experience a sustained 50% to 70% reduction in DHT levels. Recently, dutasteride, an inhibitor that blocks both isoforms of 5-α-reductase, has been approved by the FDA for the treatment of BPH. This agent reduces DHT levels by 60% to 80% or more as a result of the dual enzyme inhibition. Whether the additional reduction of DHT will be more beneficial than that seen with finasteride remains to be determined.

5-α-Reductase inhibitors are particularly effective in patients with large prostate glands (≥45 g). α-Blockers, despite their efficacy for symptom control, do not ultimately alter the disease course. Therefore, the combination of α-blockers and 5-α-reductase inhibitors has been suggested as a rational treatment approach. Indeed, several recent trials indicate that only 5-α-reductase inhibitors are effective in reducing gland size progression, the need for invasive procedures, and hospitalizations for acute urinary retention.^11,12

When patients present with LUTS due to BPH, the clinician must strategize whether symptom control, disease modification, or both are needed. For patients with small prostate glands, the efficacy of 5-α-reductase inhibitors is uncertain. For patients with large prostates, combination therapy should be considered. The favorable effects of 5-α-reductase inhibitors are usually not discernible for at least 6 months and may require a year to fully manifest. Therefore, initiating therapy with an α-blocker for symptom control, followed by a 5-α-reductase inhibitor for disease modification, is a reasonable strategy. There is some suggestion that the α-blocker may be safely discontinued 8 to 12 months after successful 5-α-reductase inhibitor therapy; however, because there is no long-term toxicity associated with α-blocker therapy, patients who find symptom control insufficient with 5-α-reductase inhibitors alone may continue combination therapy.

Although the US Preventive Services Task Force still considers prostate-specific antigen (PSA) screening to be “indeterminate” in value,¹³ the majority of clinicians offer PSA screening to most of their patients aged 50 years or older. That being the case, clinicians need to be aware that treatment with a 5-α-reductase inhibitor, in addition to shrinking prostate size, produces a predictable halving of PSA levels. Therefore, after 1 year of treatment, PSA levels should be interpreted as double their measured values. It is possible that 5-α-reductase inhibitors may favorably affect the development of other prostatic neoplasia, and this issue is currently under investigation.

Phytotherapy

Use of phytotherapy is commonplace among middle-aged men with BPH. Initial data on agents such as saw palmetto and African plum are encouraging, but no studies to date provide sufficiently stringent data that clinicians can rely on to guide therapeutic decision making. In addition, treatment with such agents is not innocuous, as demonstrated in the following case report¹⁴:

• A 65-year-old man takes Prostata (catalog purchase) for 2 weeks. He experiences jaundice and discontinues the product.

• On physical examination, the abdomen is nontender; liver and spleen are nonpalpable.

• Laboratory studies show total serum bilirubin = 8.2 mg/dL; aspartate aminotransferase > 1000 IU/L; alanine aminotransferase > 1000 IU/L.

• Biopsy is done; jaundice resolves over approximately 3 months.

Even if sufficiently rigorous data are provided for the therapeutic effects of nonproprietary substances, clinicians would face the dilemmas that product consistency is not assured to the same degree as substances monitored by the FDA and that the capture data for adverse effect profiles are not nearly as wellstructured as those for traditional pharmaceutical agents. Nevertheless, many patients will use these agents despite warnings about their limitations; therefore, it behooves the clinician to have a basic knowledge of these products.

When to Refer

Any time the clinician is uncertain about the progress of a patient with BPH, it is appropriate to consider urologic referral for specialized testing. There are a number of generally recognized indications for surgical intervention, usually reflecting significant tissue damage distinct from the prostate gland: refractory urinary retention with failed catheter removal, recurrent urinary tract infection, recurrent gross hematuria, BPH-induced bladder stones, and BPH-induced renal insufficiency.

Although the variety of approaches for extirpation of prostate tissue continues to expand, the choice of therapeutic modality is typically out of the hands of the primary care clinician. There are vocal enthusiasts for each of many different techniques for prostate surgery. The individual experience of the surgeon is crucial in this regard and often fosters the choice of which modality to employ.

Conclusion

BPH is generally remediable with traditional pharmacotherapy. Recent insights suggest that clinicians should provide an opportunity for the patient to choose symptomatic therapy, disease-modifying therapy, or both, based on expense, adverse effect profile, and long-term planning with counsel from the health care provider. Combination therapy is increasingly recognized as appropriate initial treatment for patients with bothersome symptoms and a large prostate gland.

Main Points.

• α-Adrenergic blockade reduces prostatic smooth muscle tone. This, combined with the relaxation of smooth muscle in the bladder neck seen with α-adrenergic receptor blockade, reduces urethral obstructive and irritative symptoms.

• When men address their health care providers about benign prostatic hyperplasia, it is usually because the condition is encroaching upon their quality of life.

• The doxazosin arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial was prematurely discontinued because of the futility of finding a significant difference in primary outcome, as well as the drug’s adverse impact on cardiovascular outcomes, particularly heart failure. As a result, α-blockers are no longer considered an appropriate primary therapy for hypertension.

• 5-α-Reductase inhibitors (ie, dutasteride, finasteride) provide substantial sustained reductions in dihydrotestosterone levels, ultimately leading to favorable disease-modifying effects.

• 5-α-Reductase inhibitors are particularly effective in patients with large prostate glands (≥45 g). α-Blockers, despite their efficacy for symptom control, do not ultimately change the disease course.