Preventing Progression in Men with Mild Symptoms of Benign Prostatic Hyperplasia: A Potential Role for Phytotherapy

Abstract

Prevalence of benign prostate hyperplasia (BPH) is increasing with the aging population worldwide. Throughout the 20th century, men with minimally symptomatic BPH were generally advised to defer treatment. Treatment deferral or watchful waiting has always appeared reasonable because mild lower urinary tract symptoms suggestive of bladder outlet obstruction are not bothersome and are often regarded as part of the aging process, progression is usually slow, and symptoms often regress spontaneously. This review examines the evidence of the natural history of BPH, highlighting the group of patients with mild symptoms, the risk factors for progression, and the potential role of phytotherapy in this group of men.

Benign prostatic hyperplasia (BPH) is the most prevalent of all conditions in aging men, with the population prevalence in the 40- to 79-year age group estimated at 25%.^1–4 It is the most common benign adenoma in the male and represents a clinically significant cause of bladder outflow obstruction in up to 40% of men during their lifetime. As men in this age group account for 20% of the 727 million population of Europe, there are approximately 36 million European men with BPH.⁵ It is thus evidence that BPH constitutes a significant burden both on individuals and society at large as well as providing an important component of the workload both of family practitioners and urologists. Men with BPH commonly present with lower urinary tract symptoms (LUTS) that affect their quality of life (QOL) and interfere with activities of daily living.^6,7 BPH is being diagnosed more and more commonly because of increasing life expectancy and a general trend to seek medical advice at an earlier stage of the disease.

The last decade has seen considerable advances in our understanding of the demographics and natural history of BPH. It is increasingly clear that identifying men with progressive disease could have clinical utility in directing therapy to those most likely to benefit from a preventive approach. The following paragraphs review the data on the natural history of BPH and examine strategies for stratifying men with BPH by baseline risk factors to identify those at highest risk of progressive disease. Finally, the role of phytotherapy in prevention of BPH progression is discussed.

BPH—A Progressive Disease?

There is an emerging body of knowledge revealing that BPH is a progressive condition in many men. A number of studies have sought to determine the natural history of BPH; these can be broadly classified into longitudinal studies and the placebo arms of clinical trials. The definition of progression varies in different studies. Some have examined single endpoints such as increases in prostate volume (PV), deterioration in urinary flow or symptoms, and episodes of acute urinary retention (AUR) or surgery. Others have used composite endpoints in which men experiencing changes in any of a number of parameters have been regarded as having progressive disease. One of the largest and longest-running longitudinal studies, the Olmsted County study, has provided strong evidence for the progressive nature of BPH. Ninety-two-month data demonstrated a worsening of symptom severity over the time course of the study, with a mean annual increase in International Prostate Symptom Score (IPSS) of 0.34 points.⁸ Indeed, 31% of men reported at least a 3-point increase in American Urological Association Symptom Index (AUA-SI) over this 92-month period. The largest European study on men with mild symptoms of bladder outlet obstruction (BOO) (IPSS < 8) showed that 31% of these men eventually progressed from the mild symptom group to the moderate symptom (IPSS 8–18) or severe symptom (IPSS 19–35) group after 48- month follow-up⁹ (Figure 1). Even for the rest of the men who did not qualify for clinical progression to a more severe symptom group, most of them had worsening of IPSS of at least 1 point. Similar worsening of symptom severity from baseline was found in the longitudinal Forth Valley study from Scotland, which had a 5-year follow-up period.¹⁰ Among 1042 men with mild symptoms of BPH, 17.5% progressed symptomatically. A potential criticism of data examining deteriorations in LUTS, bother, and QOL and decisions in therapeutic intervention is that these endpoints are subjective. More objective measures of BPH progression can be obtained from measurement of PV and urinary flow as well as from the incidence of AUR. Changes in PV—more specifically, transitional zone volume (TZV), the primary area of prostatic growth—are important parameters because they represent an assessment of the degree of fixed BOO. Data from large-scale clinical studies with the dual 5α-reductase inhibitor dutasteride have shown an increase in TZV over the 24-month duration of the study among men treated with placebo.¹¹ In a recent study, Djavan and colleagues⁹ demonstrated a 25% increment in TZV in men who had clinical progression. Similarly, the Medical Therapy of Prostatic Symptoms (MTOPS) study group was able to demonstrate an 18% increase in total PV in placebo-treated men from baseline to the end of the study.¹²

Figure 1.

Outcome of 446 patients with mild symptoms of bladder outlet obstruction (International Prostate Symptom Score [IPSS] < 8) over 4 years. Data from Djavan B et al.⁹

Occurrence of AUR is a serious morbid event usually accompanied by discomfort, hospitalization, and surgery. The Olmsted County study showed an increase in the risk of AUR associated with increasing age,¹³ a finding that was confirmed by a longitudinal study of health workers.¹⁴ The overall risk of AUR for men is very real—it has been estimated that an average 60-year-old man has a 23% chance of developing AUR if he survives another 20 years.¹³ Even among men with mild symptoms of BOO, 4.9% eventually developed an episode of acute retention in a 48- month follow-up period.⁹ Among the adverse events contributing to clinical progression in the MTOPS study, AUR events were much more prevalent than renal insufficiency due to BPH, recurrent urinary tract infections or urosepsis, and urinary incontinence.¹² Peak urinary flow rate (Q_max) also provides objective evidence for progression of the disease. However, great controversy surrounds the usefulness of this surrogate endpoint. Considerable individual and instrumental variability in measurement of Q_max limits its accuracy. Despite this drawback, Roberts and associates¹⁵ reported a consistent decline in peak flow rates across all age groups in the longitudinal Olmsted County study. The overall annualized percentage decline in the peak flow rate was 2% per year. Taken together, these data provide strong evidence for the progressive nature of BPH with regard to symptoms, bother, flow, risk of AUR, and underlying increases in postvoid residual (PVR).

Can Men Likely to Progress Be Identified?

The 2 most extensively investigated risk factors for progression of BPH are serum prostate-specific antigen (PSA) level and PV. Serum PSA levels have been shown to have predictive value for increases in PV,^16,17 deterioration in Q_max, increases in LUTS, and decreases in QOL, as well as for the risk of AUR and the need for BPH-related surgery.^18,19 Patients with PSA levels ≥ 1.4 ng/mL were associated with an increased risk of AUR, annual prostate growth as much as 3.3 mL, greater symptom severity, and decreases in Q_max and QOL.^16,19,20 Similarly, PV is an important risk factor for progression; greater PVs are predictive of AUR and surgery.^13,18,21 The Proscar Long-term Efficacy and Safety Study group demonstrated an increase in risk of AUR from 8.9% in the lowest PV tertile to 22.0% in the highest PV tertile in the placebo group of this 4-year trial. The same trend was observed for the highest PSA value tertile as compared with that of the lowest PSA value.¹⁶ In the longitudinal Olmsted County study, it was shown that men with PVs > 30 mL on transrectal ultrasound (TRUS) had almost 4 times the odds of experiencing AUR compared with those with PVs < 30 mL.¹³ Other identified risk factors for AUR included age,^13,14,22 peak flow rate,¹³ PVR,²² and symptom severity^13,22 (Table 1).

Table 1.

Baseline Prognostic Factors Associated With Symptom Progression and Acute Urinary Retention (AUR)

	Age	Qmax	PSA	PVR	IPSS	Volume
Symptom progression22	↑	↓	↑	↑	↓	↑
AUR13	↑	↓	↑		↑	↑

^↑The higher the baseline value, the higher the risk.

^↓The lower the baseline value, the higher the risk.

Symptom progression: increase in AUA symptom score of at least 4 points.

AUA, American Urological Association; IPSS, International Prostate Symptom Score; PSA; prostate-specific antigen; PVR, postvoid residual; Q_max, peak urinary flow rate.

Using a global definition of clinical progression incorporating worsening symptoms and/or the occurrence of AUR or BPH-related surgery, Djavan and coworkers⁹ demonstrated that an artificial neural network (ANN) incorporating age, PSA, IPSS, obstructive symptom score (OSS), irritative symptom score, QOL score, flow rate, total PV, and TZV provided 82% accuracy in predicting disease progression in men with mild symptoms of BOO (IPSS < 8). The variables of importance for disease progression in the ANN analysis were, in order of significance, PSA, OSS, and TZV. With regard to symptomatic progression as defined by an increase over baseline of at least 4 points in the AUA symptom score, the MTOPS study group identified large baseline PV, high serum PSA value, increased age, high PVR, and low Q_max as risk factors for progression.²²

An interesting analysis was performed to determine whether unimodal or multimodal approaches to predicting progression are more advantageous. Roehrborn and colleagues²³ compared use of a single risk factor (serum PSA level), combined risk factors (serum PSA level, symptom problem index, Q_max, frequency of urination ≤ 2 hours, and hesitancy) and an algorithm for predicting clinical progression, and demonstrated that PSA level alone was comparable with multimodal and algorithmic approaches for predicting the occurrence of AUR.²³

TRUS and magnetic resonance imaging (MRI) remained the most accurate methods for estimating PV. Digital rectal examination is known to underestimate prostate size up to 55% as compared with TRUS.^24,25 Serum PSA level as a proxy for PV,^26,27 after exclusion of prostate cancer, is a more practical tool because it avoids the interoperator variability of PV estimation and the cost of ultrasound or MRI. A PSA level cutoff of 1.5 ng/mL is a useful single test for identifying men with mild symptoms of BOO who are at risk for clinical progression.⁹

Potential Role of Phytotherapy in Men With Mild Symptoms of BOO

The use of nontraditional therapies in men with LUTS has increased greatly in recent years owing to a variety of factors,²⁸ including patient dissatisfaction with standard pharmacologic and surgical treatments, increased marketing of nonprescription products through the media and Internet, and a philosophic congruence between alternative therapies and patient values and beliefs.^29,30 The most popular phytotherapy is saw palmetto (Serenoa repens; Permixon; Pierre Fabre Medicament, Castres, France), which is derived from the berry of the American dwarf palm tree found in many areas of the southeastern United States. Its major mechanism of action is still uncertain, although a number of possible mechanisms have been suggested, including inhibition of 5α-reductase types 1 and 2,^31–35 decrease of epidermal growth factor concentration,³⁶ inhibition of in vitro basic fibroblast growth factor, and epidermal growth factor-induced prostate epithelial cell proliferation.³⁴

This unique phytotherapeutic agent has been tested in multiple trials for symptomatic BPH.^37–41 The largest meta-analysis concerning Serenoa repens published to date concluded that the use of this agent significantly improved voiding symptoms and increased urinary flow rates by 1.93 mL/s compared with placebo.⁴² Compared with 5α-reductase, Carraro and associates³⁹ found that both an extract of Serenoa repens and finasteride decreased IPSS, improved QOL, and increased Q_max with equal efficacy, but patients taking Serenoa repens fared better in terms of libido and potency.³⁹ Similarly, Debruyne and coworkers⁴⁰ demonstrated that Serenoa repens and tamsulosin (α-blocker) were equivalent in terms of improvements in IPSS and Q_max in the medical treatment of LUTS in men with BPH, during and up to 12 months of the therapy. Both compounds were well tolerated; however, ejaculation disorders occurred frequently in the tamsulosin group. However, not all investigators reported promising results. In a recent placebo- controlled trial, patients on Serenoa repens did not achieve significant improvements in IPSS and Q_max as compared with the placebo group.⁴³

Because phytotherapy is generally associated with minimal side effects, its role for prevention of BPH progression is being examined. In a recent prospective trial on men with mild symptoms of BOO (IPSS < 8), Serenoa repens yielded some promising results over a 24-month period. Compared with the control group, the rate of clinical progression (defined as symptom progression and/or occurrence of AUR) was significantly lower at the end of the study (16% vs 22%; P = .03). Significant improvements in the IPSS, QOL, and Q_max parameters were also demonstrated in the group receiving Serenoa repens.⁴⁴ Of course, practical considerations exist regarding the chronic use of medication in men with mild symptoms of BOO. Compliance with medication is, at best, tenuous. Even when medication is provided without cost and patients are followed up on a regular basis, the drop-off rate with medication approaches 10% to 20% annually. Thus, identification of “at-risk” men with mild symptoms of BOO may provide the basis for initiation of pharmacotherapy such as Serenoa repens. In a recent longitudinal study by Djavan and colleagues,⁹ PSA level cutoff of 1.5 ng/mL and TZV of more than 25 mL accurately predicted 82% of the men whose symptoms eventually progressed. These patients would potentially benefit from phytotherapy.

Conclusion

BPH is a progressive disease, and a substantial number of men with mild symptoms of BOO (IPSS < 8) will have symptomatic progression and/or develop AUR. PSA level and PV are common predictors of clinical progression in many trials. Phytotherapy may help to reduce the progression rates and improve urinary flow in men with risk factors. Further studies to compare phytotherapy with α-blockers and 5α-reductase inhibitors in delaying clinical progression in men with mild symptoms of BOO will be useful.

Main Points.

• The last decade has seen considerable advances in our understanding of the demographics and natural history of benign prostatic hyperplasia (BPH). It is increasingly clear that identifying men with progressive disease could have clinical utility in directing therapy to those most likely to benefit from a preventive approach.

• There is an emerging body of knowledge revealing that BPH is a progressive condition in many men. Longitudinal studies and the placebo arms of clinical trials used endpoints such as increases in PV, deterioration of urinary flow, and acute urinary retention (AUR) to demonstrate the progressive nature of BPH.

• Patients with BPH who are likely to have progression of symptoms can be identified by analyzing PV and prostate-specific antigen (PSA) level. Serum PSA levels have been shown to have predictive value for increases in PV, deterioration in peak urinary flow rate, increases in lower urinary tract symptoms, and decreases in quality of life, as well as for the risk of AUR and the need for BPH-related surgery. Transrectal ultrasound and magnetic resonance imaging are the most accurate methods for estimating PV.

• The use of nontraditional therapies, especially Serenoa repens (saw palmetto), has increased greatly in recent years because of patient dissatisfaction with standard pharmacologic and surgical treatments, increased marketing of nonprescription products through the media and Internet, and a philosophic congruence between alternative therapies and patient values and beliefs. Because phytotherapy is generally associated with few side effects, its role in stemming the progression of BPH is being examined. Further studies comparing phytotherapy with α-blockers and 5α-reductase inhibitors will be helpful.