Medical therapy for benign prostatic hyperplasia: new terminology, new concepts, better choices

This article discusses 3 areas of medical therapy for benign prostatic hyperplasia (BPH) that are undergoing extensive research and evaluation: 1) the use of muscarinic receptor antagonists to treat lower urinary tract symptoms (LUTS) in men with BPH; 2) the definition of an "enlarged prostate"; and 3) sexual function and LUTS. Fears of worsening obstructive symptoms or causing acute urinary retention often keep practitioners from prescribing muscarinic receptor antagonists to men who might have concomitant bladder outlet obstruction; a multicenter, multinational, double-blind study showed that tolterodine is safe for men with low postvoid residual volumes. Most urologists accept that a prostate volume of more than 40 mL is consistent with an enlarged prostate; there is more debate regarding prostate volumes of 30 to 40 mL. Recently presented data suggest that combination medical therapy might be effective for men having prostates with volumes of more than 25 mL. The association between voiding and sexual function has been increasingly recognized and investigated, and there seem to be common pathophysiologic mechanisms governing both conditions. Targeted treatment algorithms addressing both conditions seem warranted.     

Quality of life and sexual function in patients with benign prostatic hyperplasia

Incidence of benign prostatic hyperplasia (BPH), one of the most common conditions affecting adult men, increases dramatically after the age of 50. The various symptoms of BPH, which include lower urinary tract symptoms (LUTS), can adversely affect quality of life (QOL). Many men with BPH and LUTS wait until symptoms become significantly bothersome before seeking medical attention. Evaluating the exact severity and significance of symptoms has been difficult with previous methodology. Over the last decade, assessment tools have become available to quantify the symptoms of BPH and LUTS. This article addresses the impact of BPH, its management, and the overall effects it has on QOL.     

Lower urinary tract symptoms, benign prostatic hyperplasia, erectile dysfunction, and phosphodiesterase-5 inhibitors

Many patients who present to their healthcare provider with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) will also have erectile dysfunction (ED), and vice versa. Although alpha-adrenergic receptor blockers and 5-alpha-reductase inhibitors are highly effective in treating BPH-associated LUTS, these agents have sexual adverse effects that cause many men to discontinue therapy. The discovery of nitric oxide as a major factor in the mechanism of erection has led to the development of new drugs for ED, including the phosphodiesterase (PDE) inhibitors. Preliminary data support the theory that inhibition of PDE isoenzymes in the prostate may improve LUTS due to BPH through relaxation of prostatic smooth muscle. Further studies of PDE inhibitors in men with ED and BPH-associated LUTS are indicated.     

Landmark studies impacting the medical management of benign prostatic hyperplasia

The treatment of benign prostatic hyperplasia (BPH) has changed dramatically over the past 10 years. Phase 3 studies of the safety and effectiveness of alpha-blockers (eg, terazosin and doxazosin) and 5-alpha-reductase inhibitors (eg, finasteride) for the treatment of BPH began to appear in the literature in 1992. This article reviews the results of landmark studies of these agents, either separately as monotherapy or as combined therapy, for the treatment of BPH. The relationship between prostate size and lower urinary tract symptoms (LUTS) is discussed. Although prostate volume is not as strongly correlated with these symptoms as was once believed, it has been shown to be an important predictor of risk for developing acute urinary retention. alpha-Blockers represent an effective treatment for LUTS independent of prostate volume; the clinical benefit of finasteride for LUTS is limited primarily to men with large prostates. Finasteride decreases the risk of progression to acute urinary retention and the requirement for surgical intervention; this benefit is greatest in men with enlarged prostates.     

Relationship between Lifestyle and Health Factors and Severe Lower Urinary Tract Symptoms (LUTS) in 106,435 Middle-Aged and Older Australian Men: Population-Based Study

Background

Despite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large-scale population-based evidence is limited.

Objective

To describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study.

Design, Setting, and Participants

A cross-sectional analysis of questionnaire data from 106,435 men aged ≥45 years, living in New South Wales, Australia.

Outcome Measures and Statistical Analysis

LUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors.

Results

Overall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45–49 to ≥80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68–0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76–0.91)). Odds were elevated among current smokers versus never-smokers (OR = 1.64 (1.43–1.88)), obese versus healthy-weight men (OR = 1.27 (1.14–1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24–1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51–5.93)).

Conclusions

LUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention.     

Lower Urinary Tract Symptoms,Depression, Anxiety and Systemic Inflammatory Factors in Men: A Population-Based Cohort Study

Background

The relationship between lower urinary tract symptoms (LUTS) and common mental health disorders such as depression and anxiety in men remains unclear. Inflammation has recently been identified as an independent risk factor for LUTS and depression. This study aimed to assess the association between depression, anxiety and LUTS, and the moderating influence of systemic inflammation, in the presence of other biopsychosocial confounders.

Methods

Participants were randomly-selected from urban, community-dwelling males aged 35–80 years at recruitment (n = 1195; sample response rate:67.8%). Of these, 730 men who attended baseline (2002–5) and follow-up clinic visits (2007–10), with complete outcome measures, and without prostate or bladder cancer and/or surgery, neurodegenerative conditions, or antipsychotic medications use, were selected for the present study. Unadjusted and multi-adjusted regression models of incident storage and voiding LUTS and incident depression and anxiety were combined with serum inflammatory markers (high-sensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), interleukin–6 (IL–6), myeloperoxidase (MPO), soluble e-selectin (e-Sel)) and socio-demographic, lifestyle, and health-related factors. Hierarchical multiple regression was used to assessed the moderating effect of inflammatory markers.

Results

The incidence of storage, voiding LUTS, depression and anxiety was 16.3% (n = 108), 12.1% (n = 88), 14.5% (n = 108), and 12.2% (n = 107). Regression models demonstrated that men with depression and anxiety at baseline were more likely to have incident storage, but not voiding LUTS (OR: 1.26, 99%CI: 1.01–4.02; and OR:1.74; 99%CI:1.05–2.21, respectively). Men with anxiety and storage LUTS at baseline were more likely to have incident depression (OR: 2.77, 99%CI: 1.65–7.89; and OR:1.45; 99%CI:1.05–2.36, respectively), while men with depression and voiding LUTS were more likely to have anxiety at follow-up (OR: 5.06, 99%CI: 2.81–9.11; and OR:2.40; 99%CI:1.16–4.98, respectively). CRP, TNF-α, and e-Sel were found to have significant moderating effects on the development of storage LUTS (1.06, 0.91–1.96, R² change: 12.7%), depression (1.17, 1.01–1.54, R² change: 9.8%), and anxiety (1.35, 1.03–1.76, R² change: 10.6%), respectively.

Conclusions

There is a bidirectional relationship between storage, but not voiding, LUTS and both depression and anxiety. We observed variable moderation effects for selected inflammatory markers on the development of depression, anxiety and storage LUTS.     

Cardiovascular Risk Factors and Ethnicity Are Independent Factors Associated with Lower Urinary Tract Symptoms

Objectives

To determine the lower urinary tract symptoms (LUTS) profile and factors affecting its degree of severity including cardiovascular risk profile, age, ethnicity, education level and prostate volume in a multiethnic Asian setting.

Materials and Methods

We conducted a cross-sectional study of 1021 men aged 40–79 years with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The severity of LUTS was assessed using the International Prostate Symptom Score (IPSS). Potential factors associated with LUTS including age, ethnicity, education, history of hypertension, diabetes and hypercholesterolemia, height, weight, and prostate volume were evaluated using univariable and multivariable analyses.

Results

There were 506 (50%) men found to have moderate-to-severe LUTS attaining an IPSS above 7. Overall, nocturia (45.5%) was the most frequently reported symptom. Multivariable analysis showed that age, ethnicity, prostate volume and history of hypertension and hypercholesterolemia were independent factors associated with severity of LUTS (p < 0.05). Considering individual lower urinary tract symptoms, we found a strong association of storage symptom with history of hypertension and hypercholesterolemia. Malay men were significantly bothered by post micturition symptom compared to their Chinese and Indian counterparts. Stratified analyses of LUTS demonstrated a mutually exclusive cardiovascular risk factors profile defined by ethnicity.

Conclusion

Severity of LUTS varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity and cardiovascular risk factors including hypertension and hypercholesterolemia may also need to be taken into account in managing men with LUTS.     

Comparative Effectiveness of Oral Drug Therapies for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia: A Systematic Review and Network Meta-Analysis

Introduction

Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) are common in elder men and a number of drugs alone or combined are clinically used for this disorder. But available studies investigating the comparative effects of different drug therapies are limited. This study was aimed to compare the efficacy of different drug therapies for LUTS/BPH with network meta-analysis.

Materials and Methods

An electronic search of PubMed, Cochrane Library and Embase was performed to identify randomized controlled trials (RCTs) comparing different drug therapies for LUTS/BPH within 24 weeks. Comparative effects were calculated using Aggregate Data Drug Information System. Consistency models of network meta-analysis were created and cumulative probability was used to rank different therapies.

Results

A total 66 RCTs covering seven different therapies with 29384 participants were included. We found that α-blockers (ABs) plus phosphodiesterase 5 inhibitors (PDE5-Is) ranked highest in the test of IPSS total score, storage subscore and voiding subscore. The combination therapy of ABs plus 5α-reductase inhibitors was the best for increasing maximum urinary flow rate (Qmax) with a mean difference (MD) of 1.98 (95% CI, 1.12 to 2.86) as compared to placebo. ABs plus muscarinic receptor antagonists (MRAs) ranked secondly on the reduction of IPSS storage subscore, although monotherapies including MRAs showed no effect on this aspect. Additionally, PDE5-Is alone showed great effectiveness for LUTS/BPH except Qmax.

Conclusions

Based on our novel findings, combination therapy, especially ABs plus PDE5-Is, is recommended for short-term treatment for LUTS/BPH. There was also evidence that PDE5-Is used alone was efficacious except on Qmax. Additionally, it should be cautious when using MRAs. However, further clinical studies are required for longer duration which considers more treatment outcomes such as disease progression, as well as basic research investigating mechanisms involving PDE5-Is and other pharmacologic agents alleviate the symptoms of LUTS/BPH.     

Pathophysiology of benign prostatic hyperplasia in the aging male population

Nearly all men will develop histological benign prostatic hyperplasia by the age of 80, but the degree of prostatic enlargement resulting from the hyperplasia is highly variable. Historically, it has often been assumed that the pathophysiology of lower urinary tract symptoms (LUTS) in men is the result of bladder outlet obstruction associated with prostatic enlargement. The observation that prostatic enlargement, bladder outlet obstruction, and LUTS are all age-dependent has been interpreted to indicate that these phenomena were causally related, but there is insufficient evidence for this. Undoubtedly, some men' prostatic enlargement causes obstruction and symptoms. Based upon the available data, however, this subset appears to be extremely small. Because of the many urological and nonurological conditions that cause LUTS and age-dependent changes in bladder and neurological function, it is unlikely that there exists a single dominant etiology for the aging male population. If this is the case, then the optimal management of LUTS will require different and possibly combination therapies.     

Is There a Role for alpha-Blockers for the Treatment of Voiding Dysfunction Unrelated to Benign Prostatic Hyperplasia?

alpha-Adrenoreceptor antagonists have become the primary medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). It was presumed that the primary mechanism by which alpha-blockers reduced lower urinary tract symptoms (LUTS) was by relaxation of smooth muscle in the prostate through a sympathetic response. Reduction of outlet resistance leads to changes in bladder function, thus improving both storage and voiding symptoms. However, it was observed that many patients with BPH-associated LUTS had significant improvement in storage symptoms without subjective or objective improvement in voiding. Storage symptoms associated with detrusor overactivity (frequency, urgency, and urge incontinence) are typically thought of as being parasympathetically mediated, and therefore anticholinergic medications have been the mainstay of pharmacological treatment, but recent work has suggested that several nonparasympathetic-mediated mechanisms may cause detrusor overactivity. Because alpha receptors appear to play a role in lower urinary tract function at multiple sites and levels, alpha-blockers could be used to treat voiding dysfunction not related to BPH. In addition, these nonprostate effects should be gender-independent, making the use of alpha-blockers plausible in women with specific types of voiding dysfunction.     

Urinating Standing versus Sitting: Position Is of Influence in Men with Prostate Enlargement. A Systematic Review and Meta-Analysis

Background

It is suggested that the body posture during urination can influence urodynamic parameters in patients with Lower Urinary Tract Symptoms (LUTS) to an extent approaching pharmacological interventions. In this article, the influence of body position during micturition on maximum urinary flow rate (Qmax), voiding time (TQ) and post-void residual volume (PVR) in healthy males and patients with LUTS is analyzed by means of a systematic review and meta-analysis.

Evidence Acquisition

A systematic search was conducted in 14 medical databases. Studies comparing urodynamic parameters in standing versus sitting position were eligible for inclusion. Studies were stratified according to health status of included male participants: healthy individuals and patients with LUTS. Standardized mean differences for Qmax, TQ and PVR were pooled in a random effects model.

Results

Eleven articles were included. In men with LUTS, a significantly lower PVR (−24.96 ml; 95%CI −48.70 to −1.23) was shown in sitting position compared to standing. In accordance, Qmax was increased (1.23 ml/s; 95%CI −1.02 to 3.48), and TQ was decreased (−0.62 s; 95%CI −1.66 to 0.42) in sitting position, although these differences did not reach statistical significance. In healthy men, Qmax (0.18 ml/s; 95% CI −1.67 to 2.02), TQ (0.49 s; 95%CI −3.30 to 4.27) and PVR (0.43 ml; 95%CI −0.79 to 1,65) were similar in sitting and standing position.

Conclusion

For healthy men, no difference is found in any of the urodynamic parameters. In patients with LUTS, the sitting position is linked with an improved urodynamic profile.     

PPARγ: a molecular link between systemic metabolic disease and benign prostate hyperplasia

The emergent epidemic of metabolic syndrome and its complex list of sequelae mandate a more thorough understanding of benign prostatic hyperplasia and lower urinary tract symptoms (BPH/LUTS) in the context of systemic metabolic disease. Here we discuss the nature and origins of BPH, examine its role as a component of LUTS and review retrospective clinical studies that have drawn associations between BPH/LUTS and type II diabetes, inflammation and dyslipidemia. PPARγ signaling, which sits at the nexus of systemic metabolic disease and BPH/LUTS through its regulation of inflammation and insulin resistance, is proposed as a candidate for molecular manipulation in regard to BPH/LUTS. Finally, we introduce new cell and animal models that are being used to study the consequences of obesity, diabetes and inflammation on benign prostatic growth.     

Developments in the scientific and clinical understanding of fibromyalgia

Our understanding of fibromyalgia (FM) has made significant advances over the past decade. The current concept views FM as the result of central nervous system malfunction resulting in amplification of pain transmission and interpretation. Research done over the past years has demonstrated a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the etiopathogenesis of FM. Various external stimuli such as infection, trauma and stress may contribute to the development of the syndrome. The management of FM requires an integrated approach combining pharmacological and nonpharmacological modalities. The recent Food and Drugs Administration approval of pregabalin, duloxetine and milnacipran as medications for FM may herald a new era for the development of medications with higher specificity and efficacy for the condition. As our understanding of the biological basis and the genetic underpinning of FM increases, we hope to gain a better understanding of the true nature of the disorder, to better classify patients and to attain more rational therapeutic modalities.     

Evaluating men with benign prostatic hyperplasia

The clinical manifestations of benign prostatic hyperplasia (BPH) include lower urinary tract symptoms (LUTS), poor bladder emptying, urinary retention, detrusor instability, urinary tract infection, hematuria, and renal insufficiency. However, the majority of men with BPH present with LUTS only. Because LUTS can indicate a variety of conditions, evaluation of symptomatic men must first aim to identify or exclude BPH and, if present, assess its severity. It is important to assess symptom severity at baseline and during follow-up, using the American Urological Association Symptom Index or the International Prostate Symptom Score. Further testing can then be tailored to narrow the diagnosis and guide treatment decisions. Factors such as patient age and concomitant malignancy will also affect management, but the main goal of treatment remains the improvement of quality of life for the patient.     

Medical Attendance for Lower Urinary Tract Symptoms Is Associated with Subsequent Increased Risk of Outpatient Visits and Hospitalizations Based on a Nationwide Population-Based Database

Introduction

Lower urinary tract symptoms (LUTS), which encompass storage, voiding, and postmicturition symptoms, are highly prevalent and recognized globally. Based on a nationwide population-based database, this study tests the hypothesis that medical attendance for LUTS is associated with a subsequent increase in the number of outpatient visits and hospitalizations, with differences among medical specialties and age groups.

Methods

Participants were selected from a random population sample of approximately one million people as a representative cohort of National Health Insurance (NHI) enrollees in Taiwan. Participants had at least three outpatient service claims with a coding of LUTS during the recruitment period 2001–2004. Both the LUTS group and non-LUTS control group were monitored for subsequent outpatient visits and hospitalizations, excluding LUTS-related healthcare services, for 2 years following the index date. The results were categorized based on medical specialty and age group.

Results

The outpatient visit rates (no. per person-year) and adjusted incidence rate ratios (IRRs) (95% confidence interval (CI) were significantly higher in urology (4.51, 95%CI 4.15–4.91) and gynecology (1.82, 95%CI 1.76–1.89) for the LUTS group. They were also significantly high in other departments, including internal medicine (1.25), general practice (1.13), Chinese medicine (1.77), family medicine (1.19), surgery (1.38), and psychiatry (1.98). Similarly, the hospitalization rate (no. per 1000 person-year) and adjusted IRRs (95% CI) were significantly higher in urology (5.50, 95% CI = 4.60–6.50) and gynecology (1.60, 95% CI = 1.35–1.90), as well as in internal medicine (1.55) and surgery (1.56), but not in psychiatry (1.12). Furthermore, the IRRs differed among 3 age groups.

Conclusions

A significantly higher number of outpatient visits and hospitalizations were observed for individuals with LUTS, compared to the control group, and the effects differed with the advancement of age. This study broadens understanding of LUTS by viewing their impact on healthcare services with multiple and overlapping systems, rather than considering them exclusively as symptoms of traditional diseases of the bladder and urethra.     

Risk of Hospitalization for Acute Cardiovascular Events among Subjects with Lower Urinary Tract Symptoms: A Nationwide Population-Based Study

Background and Purpose

Lower urinary tract symptoms (LUTS) have been reported to be associated with metabolic syndrome and may predispose subjects to cardiovascular disease. The magnitude of the impact on the medical care remains to be elucidated. Based on a population-based claims dataset in Taiwan, we explored the association between LUTS and the risk of subsequent hospitalization for acute cardiovascular events.

Materials and Methods

Among a representative sample of one million subjects from nationwide health insurance enrollees, subjects with codes of LUTS in service claims and without previous cardiovascular diseases including stroke were compared with age- and sex-matched non-LUTS subjects in subsequent hospitalization for acute coronary syndrome or stroke from the recruited date (between 2001–2004) to 2009. The risk of outcomes was assessed with Kaplan-Meier curves and the impact of LUTS was estimated with Poison regression analysis and Cox proportional hazards models.

Results

We included 4,553 LUTS subjects and 22,765 matched non-LUTS subjects, with a mean age of 47 years and 43% of men. Hypertension, diabetes, and hyperlipidemia were more prevalent in the LUTS group. The incidence rate of the composite endpoint was significantly higher in the LUTS group than in the non-LUTS group (5.4/1000 vs. 4.0/1000 person-years). The difference mainly derived from stroke rather than acute coronary syndrome. After adjusting for age, sex, diabetes, hypertension, and hyperlipidemia in multivariable analysis, LUTS remained a significant predictor (hazard ratio, 1.29; 95% confidence incidence, 1.06–1.50).

Conclusion

Subjects free of cardiovascular disease and presenting with LUTS are at risk of subsequent hospitalization for acute cardiovascular events, mainly stroke. The information might prompt practitioners encountering such patients to undergo appropriate diagnostic and preventive measures.     

(Phenylpiperidinyl)cyclohexylsulfonamides: development of alpha1a/1d-selective adrenergic receptor antagonists for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS)

Although alpha(1) adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by CV-related side-effects that are caused by the subtype non-selective nature of the current drugs. To overcome this problem, it was hypothesized that a alpha(1a/1d) subtype selective antagonist would bring more benefit for the therapy of BPH/LUTS. In developing such selective alpha(1a/1d) ligands, a series of (phenylpiperidinyl)cyclohexylsulfonamides has been synthesized and evaluated for binding to three cloned human alpha(1)-adrenergic receptor subtypes. Many compounds showed equal affinity for both alpha(1a) and alpha(1d) subtypes with good selectivity versus the alpha(1b) subtype.     

Androgens and estrogens in benign prostatic hyperplasia: past, present and future

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs.     

Improved mood and remission of symptoms in long-term major depression using vagus nerve stimulation

This is a case study of a 68-year-old woman with previously unremitting depression. The patient came to our care in 1994 following a series of treatment interventions that did not alter the course of chronic depression. We report our treatment approach and results seen with this patient, including her tepid response to traditional antidepressants and the positive results seen in the past year using vagus nerve stimulation (VNS) therapy. The patient experienced broad gains in measures of depression severity and well-being under her current treatment regimen. She has had no serious adverse events associated with the regimen, which includes VNS therapy and decreased doses of common antidepressant medications.