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.     

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.     

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.     

Current medical therapies for men with lower urinary tract symptoms and benign prostatic hyperplasia: achievements and limitations

Over the last 20 years, our understanding of the pathophysiology and symptomatology of men with lower urinary tract symptoms (LUTS) has become increasingly more sophisticated. With this increase in sophistication, our utilization of various medical therapies, either alone or in combination, has also increased the understanding of the roles of individual medications, combinations of medications, and the benefits of different types of intervention. The rapid decline of the use of transurethral resection of the prostate (TURP) and other surgical procedures for benign prostatic hyperplasia (BPH) in the 1990s is due in part to the introduction of medical therapy. This article reviews the current state of medical therapy for men with LUTS and highlights its promises and its current limitations.     

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.     

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.     

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.     

Alpha blockers for the treatment of benign prostatic hyperplasia

The evolution of alpha blocker therapy for benign prostatic hyperplasia (BPH) has focused on improving convenience and tolerability. Indications for treating BPH include reversing signs and symptoms or preventing progression of the disease. The indication that most commonly drives the need for intervention is relief of lower urinary tract symptoms (LUTS) with the intent of improving quality of life. Alpha blockers are the most effective, least costly, and best tolerated of the drugs for relieving LUTS. Four long-acting alpha 1 blockers are approved by the Food and Drug Administration for treatment of symptomatic LUTS/BPH: terazosin, doxazosin, tamsulosin, and alfuzosin. All are well tolerated and have comparable dose-dependent effectiveness. Tamsulosin and alfuzosin SR do not require dose titration. Alfuzosin, terazosin, and doxazosin have all been shown to be effective in relieving LUTS/BPH independent of prostate size.     

Diabetes, growth hormone-insulin-like growth factor pathways and association to benign prostatic hyperplasia

Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH.     

5-alpha-Reductase Inhibitors Prevent the Progression of Benign Prostatic Hyperplasia

Lower urinary tract symptoms (LUTS) associated with clinical benign prostatic hyperplasia (BPH) are a common occurrence in aging men, causing bother and interference with daily activities and affecting disease-specific quality of life. There is increasing evidence to suggest that, in many patients, the signs and symptoms of BPH are progressive. Progression can be measured as continued growth of the prostate gland; worsening of symptoms, bother, or quality of life; deterioration of urinary flow rate; episodes of acute urinary retention (AUR); and need for prostate-related surgery. Furthermore, it has become clear that the risk of disease progression increases with age as well as with increasing prostate volume and serum prostate-specific antigen (PSA) level. The 5-alpha-reductase inhibitor finasteride has been shown not only to improve symptoms, bother, and quality of life but also to prevent progression to AUR and surgery, with a relative risk reduction of over 50%. As the risk for such progression is higher in patients with larger glands or higher serum PSA values at baseline, it is in those patients that finasteride induces an even greater risk reduction, making it a cost-effective treatment choice for patients with LUTS associated with prostatic enlargement.     

Benign prostatic hyperplasia: does prostate size matter?

Recent studies and analyses have confirmed that baseline prostate volume is related to progression of benign prostatic hyperplasia (BPH) as well as to negative outcomes related to BPH, such as acute urinary retention (AUR) and need for surgery, and can also predict response to therapy. Other investigations have determined that prostate-specific antigen (PSA) level has good predictive value for assessing prostate volume. Strong evidence exists that baseline serum PSA level, like baseline prostate volume, predicts future prostate growth. Randomized placebo-controlled finasteride trials have shown that men with larger prostate volumes and higher PSA levels experience a clinically significant response to therapy compared with those with smaller prostate volumes and lower PSA levels. It has also been demonstrated that men with larger prostate glands and higher PSA levels are at increased risk for AUR and BPH-related surgery but that finasteride reduces these risks. Moreover, doxazosin and finasteride, alone and in combination, have been shown to significantly reduce BPH clinical progression.     

Long-Term Experience with 5-alpha-Reductase Inhibitors

Finasteride, a 5-alpha-reductase inhibitor, dramatically suppresses the production of dihydrotestosterone in men; thus, attention has turned to this agent for the treatment of benign prostatic hyperplasia (BPH). A number of randomized clinical trials have studied finasteride's effects on prostate size, BPH symptoms, flow rate, and prostate-specific antigen (PSA) level. Although the decrease in symptoms with finasteride therapy has been modest compared with more invasive treatments, its use has resulted in sustained reductions in prostatic volume and PSA level with minimal adverse effects. Fewer surgeries for BPH, as well as a decreased incidence of acute urinary retention, have also been seen with finasteride therapy. More research is needed to maximize the effectiveness of such medical therapy for BPH.     

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

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated with alpha(1) adrenergic receptor antagonists. Unfortunately, currently marketed alpha(1) blockers produce CV-related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that an alpha(1a/1d) subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective alpha(1a/1d) ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human alpha(1)-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both alpha(1a), and alpha(1d) subtypes, with 14- to 47-fold selectivity versus the alpha(1b) subtype and >15-fold selectivity versus dopamine D(2).     

The Role of Minimally Invasive Surgical Techniques in the Management of Large-gland Benign Prostatic Hypertrophy

Lower urinary tract symptoms (LUTS) secondary to benign prostatic hypertrophy (BPH) are among the most common medical issues for aging men. Population-based studies suggest that 13.8% of men in their 40s and more than 40% of men over age 60 have BPH. When LUTS are refractory to medical therapy and bothersome enough to warrant surgical intervention, transurethral resection of the prostate and open simple prostatectomy have been the historical reference-standard procedures for decades. Both procedures are highly effective and offer durable improvements in urinary functional outcomes. However, they also have the potential for considerable perioperative complications and morbidity. In an effort to limit surgical morbidity, a variety of minimally invasive surgical techniques to treat BPH have been introduced. Herein we present a comprehensive, evidence-based review of the efficacy and safety profile of modern minimally invasive treatments for large-gland BPH.Key words: Benign prostatic hypertrophy, Lower urinary tract symptoms, GreenLight photovaporization, Holmium laser enucleation of the prostate (HoLEP), Robotic simple prostatectomyLower urinary tract symptoms (LUTS) secondary to benign prostatic hypertrophy (BPH) are among the most common medical issues for aging men. Population-based studies suggest that 13.8% of men in their 40s and more than 40% of men over age 60 have BPH.¹ When LUTS are refractory to medical therapy and bothersome enough to warrant surgical intervention, transurethral resection of the prostate (TURP) and open simple prostatectomy (SP) have been the historical reference-standard procedures for prostates < 80 g and ≥ 80 to 100 g, respectively, for decades.²Both procedures are highly effective and offer durable improvements in urinary functional outcomes.^3–5 However, they also have the potential for considerable perioperative complications and morbidity. A recent prospective study of more than 10,654 patients undergoing TURP reported an overall short-term morbidity rate of 11.1%. Among the most common complications reported were surgical reoperation (5.6%), transfusions (2.9%), and transurethral resection syndrome (1.4%).⁶ Furthermore, the risks of both complications and mortality increased with gland size.⁶ The morbidity of open SP is even higher, with 7.5% of patients requiring transfusions and 3.7% requiring surgical intervention for severe bleeding, even in contemporary series.⁷In an effort to limit surgical morbidity, a variety of minimally invasive surgical techniques to treat BPH have been introduced. Although a large body of research exists investigating the overall safety and efficacy of such procedures, there remains a paucity of evidence regarding the safety and efficacy of these procedures in the management of large prostates ≥ 80 g in size (Figure 1).Open in a separate windowFigure 1Example of large-gland benign prostatic hyperplasia on computed tomography scan in the axial (above) and coronal (below) planes.     

A Comparison of Varying alpha-Blockers and Other Pharmacotherapy Options for Lower Urinary Tract Symptoms

alpha(1)-Adrenoceptor antagonists are now well established as the most common treatment for lower urinary tract symptoms (LUTS) suggestive of bladder outflow obstruction associated with benign prostatic hyperplasia. Both alpha(1)-adrenoceptor antagonists and 5alpha-reductase inhibitors are accepted treatments for LUTS, but with finasteride this applies only to patients with clinically enlarged prostates, whereas alpha(1)-adrenoceptor antagonists are considered to be appropriate treatment for all patients, irrespective of prostate size. Systematic analyses of placebo-controlled studies show that commonly used alpha(1)-blockers are significantly superior to placebo in improving urinary flow and reducing symptoms. Efficacy of alpha-blockers appears to be well maintained over time, and there is no evidence of tolerance or tachyphylaxis to alpha(1)-blockade after 6-12 months' usage. Direct comparative trials show that, in the short term, alpha(1)-adrenoceptor antagonists are more effective than finasteride in reducing symptom score. For alpha(1)-adrenoceptor antagonists, the most commonly reported adverse effects are dizziness, asthenia, postural hypotension, and syncope. Alfuzosin has a more pronounced effect on blood pressure than does tamsulosin, especially in elderly patients. Tamsulosin is well tolerated and has minimal effects on blood pressure; tamsulosin 0.4 mg has the lowest potential to reduce blood pressure and causes less symptomatic orthostatic hypotension than terazosin.     

(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.     

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.     

La dysfonction érectile associée à une hypertrophie bénigne de prostate (HBP) symptomatique: son lien avec le stade évolutif de l’HBP, et son évolution sous différentes thérapeutiques

Introduction

Although the relationship between the lower urinary tract symptoms (LUTS) and the erectile dysfunction (ED) is no more debated, its underlying mechanism remains obscure so far. Several studies emphasized the correlation between the severity of LUTS and the sexual function, and the impact of the different medications used. This study is the first to highlight the association between the stage of evolution of BPH (complicated and noncomplicated BPH) and the severity of the ED.

Objectives

To assess the correlation between ED and the stage of evolution of BPH, and to evaluate the impact of different medications on ED.

Patients and methods

This is a prospective trial relating of 100 patients admitted for urologic consultation, in the Universitary Hospital Center of Fez in Morocco, in a period of 12 months. To evaluate the severity of ED, we used International Index of Erectile Function (IIEF). In our patients, it was not possible to use the International Prostate Symptom Score (IPSS) to assess the severity of urinary symptoms, and it was not possible to date exactly the beginning of LUTS. Hence, we studied patients’ age, the stage of evolution of BPH (complicated or noncomplicated BPH) and the response of the ED to different treatments.

Results

The average man age was 64.3 years. Forty patients had complicated BPH and 60 patients had noncomplicated BPH. Thirty patients (75%) among 40 with complicated BPH had severe ED, whereas an ED rate of 33% (20 patients) was noticed in patients presenting with noncomplicated BPH. Alpha-blockers (tamsulosin) improved erectile function in 12 patients (20%) among those with noncomplicated BPH. Patients presenting with complicated BPH underwent surgical procedure (either transurethral resection of the prostate or open prostatectomy). Erectile function was not statistically improved in this group of patients.

Conclusion

ED showed a correlation with the stage of evolution of symptomatic BPH. Indeed, the risk of ED is higher in patients with complicated BPH. The alphablockers improved the erectile function in the group of noncomplicated BPH, contrary to the surgical approach.     

Characterization of Fibrillar Collagens and Extracellular Matrix of Glandular Benign Prostatic Hyperplasia Nodules

Objective

Recent studies have associated lower urinary tract symptoms (LUTS) in men with prostatic fibrosis, but a definitive link between collagen deposition and LUTS has yet to be demonstrated. The objective of this study was to evaluate ECM and collagen content within normal glandular prostate tissue and glandular BPH, and to evaluate the association of clinical parameters of LUTS with collagen content.

Methods

Fibrillar collagen and ECM content was assessed in normal prostate (48 patients) and glandular BPH nodules (24 patients) using Masson''s trichrome stain and Picrosirius red stain. Second harmonic generation (SHG) imaging was used to evaluate collagen content. Additional BPH tissues (n = 47) were stained with Picrosirius red and the association between clinical parameters of BPH/LUTS and collagen content was assessed.

Results

ECM was similar in normal prostate and BPH (p = 0.44). Total collagen content between normal prostate and glandular BPH was similar (p = 0.27), but a significant increase in thicker collagen bundles was observed in BPH (p = 0.045). Using SHG imaging, collagen content in BPH (mean intensity = 62.52; SEM = 2.74) was significantly higher than in normal prostate (51.77±3.49; p = 0.02). Total collagen content was not associated with treatment with finasteride (p = 0.47) or α-blockers (p = 0.52), pre-TURP AUA symptom index (p = 0.90), prostate-specific antigen (p = 0.86), post-void residual (PVR; p = 0.32), prostate size (p = 0.21), or post-TURP PVR (p = 0.51). Collagen content was not associated with patient age in patients with BPH, however as men aged normal prostatic tissue had a decreased proportion of thick collagen bundles.

Conclusions

The proportion of larger bundles of collagen, but not total collagen, is increased in BPH nodules, suggesting that these large fibers may play a role in BPH/LUTS. Total collagen content is independent of clinical parameters of BPH and LUTS. If fibrosis and overall ECM deposition are associated with BPH/LUTS, this relationship likely exists in regions of the prostate other than glandular hyperplasia.