Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia

Context

This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies.

Objective

We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS.

Evidence acquisition

We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction.

Evidence synthesis

We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH.

Conclusions

Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some α-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of α-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and α1-adrenergic blockers seems superior to PDE5-I monotherapy.     

Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: sexual function

Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), and sexual dysfunction, are common, highly bothersome conditions in older men, and the prevalence of both disorders increases with age. Sexual dysfunction manifests mainly as erectile dysfunction (ED), ejaculatory disorders, or decreased libido/hypoactive sexual desire (HSD). Whereas both reduced rigidity and reduced ejaculate volume are highly prevalent in ageing men, reduced rigidity and pain on ejaculation are considered to be most bothersome. Sexual dysfunction is much more prevalent in patients with LUTS/BPH than in men with no LUTS/BPH, even after controlling for confounding variables such as age or comorbidities. Hence LUTS/BPH is considered an independent risk factor for sexual dysfunction. Whether this is because of a common underlying pathology, or whether the considerable bother associated with LUTS/BPH leads to reduced sexual functioning, remains to be elucidated. Despite a decline in the frequency of sexual intercourse, as well as in overall sexual functioning, most ageing men report regular sexual activity and consider their sex life as an important dimension of their quality of life (QoL). However, most patients with LUTS/BPH experience a negative effect of their LUTS on their sex life. Hence, treatment of LUTS/BPH should aim to at least maintain or, if possible, improve sexual function. Current medical treatment of LUTS/BPH consists of monotherapy with alpha1-adrenoceptor (AR) antagonists, 5alpha-reductase inhibitors (RIs) or a combination of these. Whereas 5alpha-RIs increase the risk of ED, ejaculatory disorders and HSD, alpha1-AR antagonists can induce ejaculatory disorders, but do not provoke HSD or ED. Combined therapy carries the cumulative risk for sexual dysfunction associated with either type of drug. As already indicated, ED is generally perceived as more bothersome than ejaculatory disorders. In addition, alpha1-AR antagonists slightly improve overall sexual function, possibly by increasing blood flow in the penis through alpha1-AR blockade and/or to an increased overall QoL from the relief of LUTS. It can be concluded that alpha1-AR antagonists constitute a first-line therapy for LUTS/BPH because they combine good treatment efficacy with very few adverse effects on sexual function.     

Correlation between lower urinary tract symptoms and urethral function in benign prostatic hyperplasia

AIM: To examine the potential correlation between urethral function and lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). METHODS: Thirty-one patients with clinical BPH, who were confirmed to have benign prostatic enlargement (BPE) of 20 ml or more, were enrolled into the study. A mark-sheet questionnaire was used for obtaining the LUTS history. Multichannel pressure-flow urodynamic studies were performed and external urethral sphincter pressure (PEUS), intravesical pressure (PVES), and bladder neck pressure (PBN) were recorded both at maximum cystometric capacity and during voiding with 5-microtip transducers, for the purpose of detecting BPE-specific urodynamic findings at different levels within the urethra. RESULTS: There was a positive correlation between hesitancy and detrusor bladder neck dyssynergia (DBND) (P = 0.0011) and between incomplete emptying and low PBN at maximum cystometric capacity (P = 0.0425). The hesitancy proved to have no correlation with bladder neck opening time (TBNO). CONCLUSION: Urodynamic evaluation of urethral function was beneficial for attributing LUTS to clinical BPH. Among various parameters, DBND was the most specific to clinical BPH, suggesting it to be a situation where a steep rise in PBN or prostatic urethral pressure remains greater than the increasing PVES, resulting in sustained difficulty in opening the bladder neck and subsequently the subjective sensation of hesitancy.     

Phosphodiesterase 5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review

Study Type – Therapy (systematic review)
Level of Evidence 1a What’s known on the subject? and What does the study add? Phosphodiesterase 5 inhibitors improve lower urinary tract symptoms (LUTS), however the maximum urinary flow rate is not significantly affected. Also, the underlying mechanism of action of these drugs on LUTS is not well understood. This systematic review confirms the findings of the individual studies included; however the high heterogeneity between them precluded meta‐analysis and further recommendations.

OBJECTIVE

? To review the evidence in support of the effectiveness of phosphodiesterase 5 inhibitors in lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH).

METHODS

? Relevant studies were identified by performing a literature search using MEDLINE® and The Cochrane Library®. The criteria used during the search included randomized, placebo‐controlled trials of treatment for LUTS secondary to BPH using the International Prostate Symptom Score as an outcome measure.

RESULTS

? Four trials that included a total of 1928 patients met the inclusion criteria. All four studies showed a statistically significant difference in the International Prostate Symptom Score, quality of life and erectile function in favour of phosphodiesterase 5 inhibitors. ? No study showed a statistically significant improvement of the maximum urinary flow. ? Meta‐analysis of the results was not possible because of heterogeneity across the studies.

CONCLUSIONS

? Phosphodiesterase 5 inhibitors used in the clinical setting can significantly improve LUTS secondary to BPH, erectile function and quality of life. Maximum urinary flow improvement is not statistically significant. ? Future research should focus on pathophysiological principles and cost analysis.     

Activity of phosphodiesterase type 5 inhibitors in patients with lower urinary tract symptoms due to benign prostatic hyperplasia

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Phosphodiesterase type 5 inhibitors (PDE 5Is) improve erectile function and lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH), however the exact effects on prostate tissue and its underlying mechanisms remain unclear. PDE 5Is enhanced the production of cyclic nucleotides in the plasma and prostate, and the distribution of PDE 5Is in the prostate was higher than in the plasma.

OBJECTIVE

? To evaluate the impact and distribution of a single phosphodiesterase type 5 inhibitor (PDE5 I) dose (udenafil or tadalafil) in prostate tissue and plasma in patients with benign prostatic hyperplasia (BPH).

PATIENTS AND METHODS

? Thirty BPH patients complaining of erectile dysfunction along with moderate‐to‐severe lower urinary tract symptoms (LUTS) who underwent transurethral resection of the prostate (TURP) were enrolled in the present study. ? The patients were randomly divided into the three groups: group 1, TURP without PDE5 Is; group 2, 200 mg of udenafil given 1 h before TURP; and group 3, 20 mg of tadalafil given 1 h before TURP. ? We evaluated the concentrations of PDE5‐I, cAMP and cGMP in prostate tissues and plasma, and calculated the prostate tissue‐to‐plasma (T/P) ratio.

RESULTS

? The concentration of udenafil in prostate tissue and plasma was 2028.6 ± 360.8 ng/g and 463.7 ± 39.1 ng/mL, respectively, and the resulting T/P ratio was 4.4. The tadalafil concentration in prostate tissue and plasma was 385.7 ± 83.8 ng/g and 305.8 ± 41.1 ng/mL, respectively, and the T/P ratio was 1.3. ? Udenafil and tadalafil significantly increased the cAMP and cGMP levels in plasma and prostate tissues.

CONCLUSIONS

? Udenafil and tadalafil significantly increased cAMP and cGMP levels and were more highly distributed in the prostate than plasma. The T/P ratio of udenafil was higher than tadalafil. ? These findings may help in the assessment of the feasibility of using PDE5 Is to concurrently treat both LUTS and erectile dysfunction.     

Sustained beneficial effects of intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia

OBJECTIVE: To present a comprehensive experience with intraprostatic botulinum toxin-type A (BoNT-A) injection in men with symptomatic benign prostatic hyperplasia (BPH) and to assess the efficacy on lower urinary tract symptoms (LUTS) and quality of life (QoL). PATIENTS AND METHODS: In all, 41 men (mean age 69.1 years, sd 7.1 ) with an International Prostate Symptom Score of > or = 8, peak flow rate of < 12 mL/s, and who were refractory to medical treatment were injected with BoNT-A (Botox, Allergan, Inc., CA, USA) at 100 U (21 men, for prostate volume < 30 mL) or 200 U (20, for prostate volume > 30 mL) into the prostate transperineally under transrectal ultrasonography guidance. Study exclusion criteria were confirmed or suspected malignancy, previous pelvic surgery or trauma and previous invasive treatment for BPH. The clinical effects were evaluated at baseline and at 1, 3 and 6 months after treatment. RESULTS: There were no significant local or systemic side-effects in any men. LUTS and QoL indices improved by > 30% in 31 of the 41 men (76%), and four of five men with urinary retention for > 1 month could void spontaneously at 1 week to 1 month after the BoNT-A injection. In 12 of 41 men (29%) there was no change in prostate volume, yet seven of these men still had a > 30% improvement in maximum flow rate, LUTS and QoL. The efficacy was sustained at 12 months. CONCLUSION: BoNT-A injected into the prostate is safe and effective for men with symptomatic BPH. The mechanisms of relief of symptoms might not depend totally on the volume shrinkage; the inhibitory effect on the smooth muscle tone and aberrant sensory function might also be important.     

Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in relation to the patient's risk profile for progression

Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) is a slowly progressing disease, with some patients progressing more rapidly than others. In 80% of patients who progress this is caused by the worsening of symptoms. The physician can predict the risk of progression from the patient's clinical profile; increased symptom severity, a poor maximum urinary flow rate (Qmax), and a high postvoid residual urine volume (PVR), are major risk factors for overall clinical progression of LUTS/BPH. A large baseline prostate volume and a high serum prostate-specific antigen (PSA) level are the predominant risk factors for developing acute urinary retention. After predicting risk, the most appropriate treatment should be established by balancing the benefits of treatment against the possible risks and bother resulting from adverse events. From the Medical Therapy Of Prostatic Symptoms study it can be concluded that monotherapy with an alpha1-adrenoceptor (AR) antagonist is an appropriate treatment for many patients with LUTS/BPH. However, for those at high risk of progression (those with a large prostate volume and high PSA level), it appears more appropriate to add a 5alpha-reductase inhibitor to the alpha1-AR antagonist to obtain maximum relief of symptoms, and ideally to halt the progression of the disease. This was confirmed by the RAND Appropriateness Method study, in which 12 urologists determined the most appropriate treatment for patients with LUTS/BPH based on their clinical profile, combination of clinical variables and/or risk factors. This study also indicates that patients at very high risk of progression, with severe obstruction (poor Qmax and high PVR), are potential candidates for immediate surgery.     

Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms

Study Type – Prevention (individual cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Statin medications reduce inflammation. Inflammation may be important in causing prostate enlargement and lower urinary tract symptoms in aging men. Therefore, statin use may decrease inflammation and help prevent prostate enlargement and lower urinary tract symptoms. Men who took statin medications were less likely to develop an enlarged prostate or lower urinary tract symptoms compared to men who did not take statins. Additionally, men who took statins for the longest period of time had the lowest risk of developing these urological problems. These results suggest that statin use may help prevent common urological problems in aging men.

OBJECTIVE

• ? To determine whether statin use is associated with a decreased risk of developing benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS).

SUBJECTS AND METHODS

• ? We conducted a retrospective, population‐based cohort study of 2447 men, 40–79 years of age, residing in Olmsted County, MN, USA, in 1990, and followed these men biennially through 2007.
• ? Cox proportional hazard models were used to assess associations between statin use and new onset of moderate/severe LUTS (American Urological Association Symptom Index score >7), a decreased maximum urinary flow rate (<12 mL/s) or BPE (prostate volume >30 mL).

RESULTS

• ? Statin use was inversely associated with new onset of LUTS (Hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.31–0.49), a decreased maximum flow rate (HR 0.53; 95% CI 0.34–0.82) and BPE (HR 0.40; 95% CI 0.23–0.69) after adjustment for baseline age and body mass index, diabetes, hypertension, coronary heart disease, smoking, alcohol use, activity level and non‐steroidal anti‐inflammatory use.
• ? The longest duration of statin use was associated with the lowest risk of developing each outcome (all tests for trend: P < 0.001).

CONCLUSION

• ? In this study, statin use was associated with a 6.5‐ to 7‐year delay in the new onset of moderate/severe LUTS or BPE.
• ? While men typically take statin medications to prevent coronary heart disease events and related outcomes, these data suggest that men who use statins may also receive urologic benefits.

     

Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects

OBJECTIVE: To evaluate the efficacy and adverse effects of doxazosin for treating lower urinary tract symptoms (LUTS) compatible with benign prostatic obstruction (BPO). METHODS: Randomized controlled trials were included in the meta-analysis if: the study duration was > or = 1 month; the study involved men with symptomatic BPO; and doxazosin was compared with placebo or active controls. Study and patient characteristics and outcome data were extracted in duplicate onto standardized forms using a prospectively developed protocol. RESULTS: Thirteen studies involving 6033 men with (mean age 64 years) met the inclusion criteria; 10 were placebo-controlled, including two with combined doxazosin/finasteride therapy and finasteride monotherapy arms. Three trials were a comparison with other alpha-blockers. The study duration was 1-54 months. The mean baseline symptom scores and peak urinary flow (PUF) rates were indicative of moderate BPO. Doxazosin gave significant improvements in LUTS, assessed by symptom scores, vs placebo and finasteride in the short- to long-term. Two long-term studies (1 and 4 years) reported mean changes from baseline for the International Prostate Symptom Score of - 8.3 and - 6.6 points (-49% and - 39%) for doxazosin and - 5.7 and - 4.9 points (-33% and - 29%) for placebo, respectively. Doxazosin significantly increased PUF rates vs placebo. In pooled results from three studies, the weighted mean difference in the mean change from baseline vs placebo was 1.6 mL/s (95% confidence interval 1.2-2.1). Efficacy was comparable with other alpha1-blockers. In the long-term (>4 years) doxazosin was no better then finasteride in improving PUF. Combined doxazosin and finasteride significantly reduced the risk of overall clinical progression of BPO vs each drug separately in men followed for >4 years. Absolute risk reductions vs placebo were 11.3%, 6.9% and 6.4% for combined therapy, doxazosin and finasteride, respectively (P < 0.001). Improvements in symptom scores and PUF were also significantly greater with combined than monotherapy, and the former reduced the need for invasive treatment for BPO and the risk of long-term urinary retention, although the absolute reductions in risk vs placebo were small (<4%). Dizziness and fatigue were significantly more common with doxazosin than placebo (11% vs 7%, and 6% vs 3%, respectively). Adverse events reported for combined therapy were similar to those with each monotherapy. CONCLUSION: The evidence indicates that doxazosin is effective and generally well tolerated for improving LUTS and PUF in men with symptomatic BPO. Combined therapy was better than doxazosin alone in reducing the risk of clinical progression of BPO and other long-term complications related to BPO.     

Effects of tadalafil on storage and voiding function in patients with male lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A urodynamic‐based study

Objective

To investigate the effects of tadalafil on storage and voiding function in treatment‐naïve patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia, based on a urodynamic study.

Methods

This was an open‐labeled, single‐center, prospective study. A total of 80 untreated outpatients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia received tadalafil 5 mg/day for 12 weeks. Subjective symptoms and objective findings on voiding and storage function obtained through urodynamic studies, including cystometry and pressure flow study, were evaluated before and after treatment.

Results

A total of 71 patients with a mean age of 70.2 years and a mean prostate volume of 45.6 mL were included in the analysis. In the International Prostate Symptom Score and Overactive Bladder Symptom Score, mean total scores significantly improved from 18.2 to 13.4 (P < 0.001) and 6.5 to 4.7 (P < 0.001), respectively, after treatment. Mean maximum bladder capacity significantly increased by approximately 35 mL (P < 0.001). Detrusor overactivity disappeared in 15 (39.5%) of 38 patients with detrusor overactivity at baseline (P < 0.001). Mean maximum flow rate on pressure flow study significantly increased from 7.1 to 9.1 mL/s (P < 0.001) and mean bladder outlet obstruction index significantly decreased from 61.3 to 47.1 (P < 0.001).

Conclusions

Treatment with tadalafil 5 mg once daily effectively relieves lower urinary tract symptoms based on objective improvement of storage and voiding function, such as detrusor overactivity and bladder outlet obstruction, in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.     

Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on alpha-adrenoceptor antagonists

An update of a systematic review of alpha1-adrenoceptor (AR) antagonists in the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) showed that these agents have comparable efficacy. The total symptom score is improved by 30-45% and maximum urinary flow rate by 15-30% vs baseline. alpha1-AR antagonists that can be started at their therapeutic dose have a more rapid onset of action than alpha1-AR antagonists that have to be titrated. alpha1-AR antagonists can be differentiated according to their tolerability. Alfuzosin (especially the 10 mg once daily dose) and tamsulosin (especially the 0.4 mg once daily dose) are better tolerated than doxazosin and terazosin. However, alfuzosin might induce more cardiovascular adverse events (AEs) in the elderly and/or patients with cardiovascular comorbidity and/or comedication. Tamsulosin tends to interfere less with blood pressure regulation and induce less vasodilatory AEs than alfuzosin, especially in the elderly, and is well tolerated in patients with cardiovascular comorbidity and/or comedication. Cardiovascular AEs might lead to potentially serious complications such as falls, fractures and institutionalization. Abnormal ejaculation has mainly been reported in placebo-controlled trials with tamsulosin but in direct comparative trials its rate with tamsulosin 0.4 mg was similar to, or only slightly higher than, the rate with alfuzosin. In addition, abnormal ejaculation is not reported as bothersome by the patient or associated with serious complications. It can be concluded that an alpha1-AR antagonist with a low potential to interfere with blood pressure regulation and to induce cardiovascular AEs, also in patients with cardiovascular comorbidity and/or comedication, can be considered a first-choice treatment option in LUTS/BPH.     

An Asian multinational prospective observational registry of patients with benign prostatic hyperplasia, with a focus on comorbidities, lower urinary tract symptoms and sexual function

OBJECTIVE

To examine the characteristics, management practices and outcomes of patients presenting with symptoms of benign prostatic hyperplasia (BPH) in Asia, with a focus on comorbidities and sexuality.

PATIENTS AND METHODS

In this multinational prospective observational registry, eligible patients with BPH attending a urology clinic for the first time were enrolled. Details of comorbidities, sexuality and symptoms of BPH were collected through the International Prostate Symptom Score (IPSS), International Index of Erectile Dysfunction‐5 (IIEF‐5) and the Danish Prostate Symptom Score (DAN‐PSS‐1) questionnaires. The follow‐up was scheduled at 1–3 or 3–6 months, depending on the treatment.

RESULTS

In 994 men aged 40–88 years the most common comorbidities were hypertension (38%) and obesity (36%). Nocturia was the most common symptom for consultation. A previous episode of acute urinary retention (AUR) was recorded in 12%. About 90% of the men had moderate‐to‐severe lower urinary tract symptoms (LUTS), and the severity increased with age. Sexual dysfunction was reported by 82%, and it correlated with the severity of LUTS. Of 918 sexually active men, only 20% had normal erectile function; 36%, 19% and 25% reported severe, moderate and mild erectile dysfunction (ED), respectively. BPH medication was started in 78%, 9% had surgery, and in 13% an approach of watchful waiting was adopted. In all, 89% of patients completed the follow‐up. The symptoms of BPH resolved in 93% after surgery, in 83% on BPH medication and in 34% of those on ‘watchful waiting’. Surgery, which led to a mean reduction of 17.0 IPSS points, was the most effective in improving LUTS. Improvement on the DAN‐PSS‐1 items of reduced erection and reduced ejaculation was higher with medication, while surgery led to better outcomes on the DAN‐PSS‐1 item of pain/discomfort on ejaculation. For ED, from baseline to after treatment, the mean IIEF‐5 scores changed from 19.1 to 18, from 14.2 to 14.8, and from 4.5 to 5.5 for those with mild, moderate and severe ED at baseline, respectively. Only 2.3% of patients had an episode of AUR while on treatment. About 5.5% of patients on BPH medication and 6% of surgical patients reported adverse events.

CONCLUSION

Asian patients with BPH usually present with LUTS; sexual dysfunction is also very common. BPH medication is the most frequent treatment approach, followed by watchful waiting and surgery. Medication and surgery resulted in a greater reduction of LUTS and improvement in sexual dysfunction than watchful waiting. As Asian men remain sexually active even at advanced ages, sexual function should be assessed and discussed with the patient before deciding the management strategy for LUTS associated with BPH.