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

Treatment Review

TREATMENT REVIEW Preventing Progression in Men With Mild Symptoms of Benign Prostatic Hyperplasia: A Potential Role for Phytotherapy Yan Kit Fong, MD, Sibylle Marihart, MD, Mike Harik, MD, Bob Djavan, MD, PhD Department of Urology, University of Vienna, Vienna, Austria 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. [Rev Urol. 2004;6(4):187-192] © 2004 MedReviews, LLC Key words: Benign prostatic hyperplasia • Watchful waiting • Progression • Phytotherapy • Serenoa repens enign 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 B VOL. 6 NO. 4 2004 REVIEWS IN UROLOGY 187 Treating Mildly Symptomatic BPH continued 70 60 Patients (%) 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. 50 Clinical progression* 40 Worse IPSS 30 Same IPSS 20 Better IPSS 10 0 12 mo 24 mo 36 mo 48 mo *Clinical progression: 1. IPSS increase by 3 pts or more. 2. Migration to worse IPSS group. 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 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-twomonth 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 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 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 188 VOL. 6 NO. 4 2004 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. 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 48month 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 REVIEWS IN UROLOGY 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 5
-reductase inhibitor dutasteride have shown an increase in TZV over the 24-month duration of the study among men Treating Mildly Symptomatic BPH 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 placebotreated men from baseline to the end of the study.12 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 48month 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 infec- Table 1 Baseline Prognostic Factors Associated With Symptom Progression and Acute Urinary Retention (AUR) Symptom progression AUR13 22 Age Qmax PSA PVR IPSS Volume ↑ ↓ ↑ ↑ ↓ ↑ ↑ ↓ ↑ ↑ ↑ ↑: 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; Qmax, peak urinary flow rate. 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 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. tions or urosepsis, and urinary incontinence.12 Peak urinary flow rate (Qmax) 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 Qmax limits its accuracy. Despite this drawback, Roberts and associates15 reported a consistent decline in peak flow rates across all been shown to have predictive value for increases in PV,16,17 deterioration in Qmax, increases in LUTS, and decreases in QOL, as well as for the risk of AUR and the need for BPHrelated 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 Qmax 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 severity13,22 (Table 1). 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 VOL. 6 NO. 4 2004 REVIEWS IN UROLOGY 189 Treating Mildly Symptomatic BPH continued 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 Qmax as risk factors for progression.22 An interesting analysis was performed to determine whether unimodal or multimodal approaches to 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 The most popular phytotherapy is saw palmetto (Serenoa repens), which is derived from the berry of the American dwarf palm tree found in many areas of the southeastern United States. 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, Qmax, 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 190 VOL. 6 NO. 4 2004 (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 5
-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 an extract of Serenoa repens and finasteride decreased IPSS, improved QOL, and increased Qmax 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 (
-blocker) were equivalent in terms of improvements in IPSS and Qmax 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 Qmax 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 sig- 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. 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 5
-reductase, Carraro and associates39 found that both REVIEWS IN UROLOGY nificantly lower at the end of the study (16% vs 22%; P = .03). Significant improvements in the IPSS, QOL, and Qmax 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. Treating Mildly Symptomatic BPH therapy may help to reduce the progression rates and improve urinary flow in men with risk factors. Further studies to compare phytotherapy 7. The identification of “at-risk” men with mild symptoms of BOO may provide the basis for initiation of pharmacotherapy such as Serenoa repens. 9. Even when medication is provided without cost and patients are followed up on a regular basis, the drop-off rate with medication approaches 8. 10. 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. Phyto- with
-blockers and 5
-reductase inhibitors in delaying clinical progression in men with mild symptoms of BOO will be useful. 11. References 12. 1. 2. 3. 4. 5. 6. Chute CG, Panser LA, Girman CJ. The prevalence of prostatism: a population-based survey of urinary symptoms. J Urol. 1993;150:85-89. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet. 1991;338:469-471. Garraway WM, Russell EB, Lee RJ. Impact of previously unrecognized benign prostatic hyperplasia on the daily activities of middleaged and elderly men. Br J Gen Pract. 1993; 43:318-321. Simpson RJ, Lee RJ, Garraway WM, et al. Consultation patterns in a community of men with benign prostatic hyperplasia. Br J Gen Pract. 1994;44:499-502. World Health Organization. World Health Annual of Statistics; 1991. Welsch G, Weinger K, Barry MJ. Quality-of-life impact of lower urinary tract symptom severity: results from the Health Professionals Follow-up Study. Urology. 2000;59:245-250. 13. 14. 15. 16. Girman CJ, Jacobsen SJ, Tsukamoto T, et al. Health-related quality of life associated with lower urinary tract symptoms in four countries. Urology. 1998;51:428-436. Jacobsen SJ, Girman CJ, Guess HA, et al. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol. 1996;155:595-600. Djavan B, Wammack R, Dobrovits M, et al. Predictors of progression in men with mild symptoms of bladder outlet obstruction. J Urol. 2002;167(suppl):A1054, 268. Lee AJ, Garraway WM, Simpson RJ, et al. The natural history of untreated LUTS in middle aged and elderly men over a period of 5 years. Eur Urol. 1998;34:325-332. Roehrborn CG, Boyle P, Nickel JC, et al. Efficacy and safety of a dual inhibitor of 5alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434-441. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387-2398. Jacobsen SJ, Jacobson DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997;158:481487. Meigs JB, Barry MJ, Giovannucci E, et al. Incidence rates and risk factors for acute urinary retention: the health professionals follow up study. J Urol. 1999;162:376-382. Roberts RO, Jacobsen SJ, Jacobson DJ, et al. Longitudinal changes in peak urinary flow rates in a community based cohort. J Urol. 2000;163:107-113. Roehrborn CG, McConnell JD, Leber M, et al. Serum prostate specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology. 1999; 53:473-481. 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
-blockers and 5
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Effects of long term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate. 1998;37:77-83. Descotes JL, Rambeaud JJ, Deschaseaux P. Placebo controlled evaluation of the efficacy and tolerability of Permixon in benign prostatic hyperplasia after exclusion of placebo responders. Clin Drug Invest. 1995;9:291-297. Cukier J, Ducasso J, Le Guillou M. Permixon versus placebo. Results from multicenter trial. CR Ther Pharmacol Clin. 1999;4:15-21. Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostatic hyperplasia: a randomized international study of 1098 patients. Prostate. 1996;29:231-240. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Prog Urol. 2002: 12:384-394. Gerber GS, Kuznetsov D, Johnson BC, et al. Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology. 2001;58:960-965. Boyle P, Robertson C, Lowe F, et al. Metaanalysis of clinical trials of permixon in the treatment of symptomatic benign prostatic hyperplasia. Urology. 2000;55:533-539. Willetts KE, Clements MS, Champion S, et al. Serenoa repens extract for benign prostate hyperplasia: a randomised controlled trial. BJU Int. 2003;92:267-270. Hruby S, Djavan B, Reissigl A, et al. Progression delay in men with mild symptoms of bladder outlet obstruction: a prospective comparative study of phytotherapy, watchful waiting and placebo. J Urol. 2003;169(suppl):A1288, 332.