Common approach to managing lower urinary tract symptoms and erectile dysfunction

The present paper serves as a review of the associations between lower urinary tract symptoms （LUTS） and erectile dysfunction （ED）, with a focus on common and combined pathways for treatment. LUTS and ED are common conditions seen in general urologic practice. Research has started to establish epidemiologic and pathophysiologic links between the two conditions and a strong association confirmed across multiple studies. Men seeking care for one condition should always be interviewed for complaints of the other condition. Proposed common pathways include α-1 adrenergic receptor imbalance, Rho-kinase overactivity, endothelial cell dysfunction and atherosclerosis-induced ischemia. Medical therapy has replaced surgery as the first-line treatment for LUTS in most patients, with the incorporation of α-adrenergic receptor antagonists （α-ARAs） and 5-α-reductase inhibitors （5-ARIs） into everyday practice. Treatment with α-ARAs contributes to some improvement in ED, whereas use of 5-ARIs results in worsened sexual function in some patients. Phosphodiesterase-5 （PDE-5） inhibitors have revolutionized the treatment of ED with a simple oral regimen, and new insights demonstrate a benefit of combined use of PDE-5 inhibitors and α-ARAs. The mechanisms of action of these medications support these observed benefits, and they are being studied in the basic science and clinical settings. In addition, novel mechanisms for therapy have been proposed based on clinical and research observations. The minimally invasive and surgical treatments for LUTS are known to have adverse effects on ejaculatory function, while their effects on erectile function are still debated. Much remains to be investigated, but it is clear that the associations between LUTS and ED lay the foundation for future therapies and possible preventative strategies.     

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.     

Combination of phosphodiesterase‐5 inhibitors and α‐blockers in patients with benign prostatic hyperplasia: treatments of lower urinary tract symptoms,erectile dysfunction,or both?

As the prevalence of both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) increases with age, physicians could be in the position to manage these two conditions simultaneously. Moreover, medical therapies for either one of these conditions can affect the other and this should be carefully considered when making treatment decisions. Pharmacotherapy for benign prostatic hyperplasia (BPH)/LUTS can cause side-effects affecting sexual function. Hence, 5alpha-reductase inhibitors such as finasteride and dutasteride are associated with a greater risk of ED, ejaculatory disorders (EjD) and decreased libido than is placebo. Among alpha1-adrenergic blockers, tamsulosin is associated with an increased risk of EjD. However, some alpha1-adrenergic blockers can also have a positive impact on erection. This is the case for alfuzosin, which has been shown to enhance erectile function in experimental models, probably by reducing the sympathetic tone and thus relaxing corpus cavernosum smooth muscle cells. Phosphodiesterase 5 (PDE-5) inhibitors are commonly used to treat ED. There is increasing evidence that they might also have a beneficial effect on LUTS, probably through the nitric-oxide pathway. Nitric oxide is an important mediator of the relaxation of isolated bladder and urethral smooth muscle, and could modulate prostatic smooth muscle tone. Alpha1-adrenergic blockers and PDE-5 inhibitors can therefore have a positive impact on both ED and LUTS. Although placebo-controlled studies are needed to confirm the impact of these drugs, alone or combined, on both ED and LUTS, this reinforces the need for a common approach to managing these two highly prevalent and bothersome conditions.     

Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms

OBJECTIVE: To evaluate the potential of sildenafil, vardenafil and tadalafil, all phosphodiesterase-5 (PDE-5) inhibitors used for treating erectile dysfunction, for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: The mRNA expression of the PDE-5 was determined in rat LUT tissues. The PDE-5 inhibitors were also tested in organ-bath experiments and in a partial bladder outlet obstruction (BOO) rat model in vivo. RESULTS: The highest PDE-5 mRNA expression was in the bladder, followed by the urethra and prostate. PDE-5 inhibitors dose-dependently reduced the contraction of the isolated bladder, urethral and prostate strips. The rank order of potency was vardenafil > sildenafil > tadalafil. In human prostate stromal cells vardenafil inhibited cell proliferation and was more effective than tadalafil and sildenafil. In the BOO model, there was a reduction in the non-voiding contractions after bolus intravenous administration of 3 mg/kg sildenafil and vardenafil. CONCLUSION: These results show that PDE-5 is expressed in LUT tissues. PDE-5 inhibitors induced significant relaxation of these tissues, inhibited the proliferation of human prostate stromal cells and reduced the irritative symptoms of BPH/LUTS in vivo. Therefore, PDE-5 inhibitors could be used as an effective treatment for BPH/LUTS.     

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.     

Future drugs for the treatment of benign prostatic hyperplasia

For at least a decade, no new drug principles have been added to the therapeutic armamentarium for the treatment of lower urinary tract symptoms (LUTS) associated with or suggestive of benign prostatic hyperplasia (BPH). Theoretically, there seem to be several possibilities to improve the current treatment, which is based mainly on alpha1-adrenoceptor (AR) antagonists, 5alpha-reductase inhibitors and phytotherapy. It cannot be dismissed that subtype selective alpha1-AR antagonists can further improve treatment, but convincing evidence is still lacking. Muscarinic receptor antagonists are currently evaluated in BPH patients, but their eventual place in therapy, as a single treatment or in combination with alpha1-AR antagonists, has to be established. Endothelin receptor antagonists, alone or together with alpha1-AR antagonists, seem to offer a new attractive approach; however, proof of concept studies are lacking. The L-arginine/NO/cGMP pathway awaits further exploration; nitric oxide (NO) donors or phosphodiesterase (PDE) inhibitors may be clinically useful. Purinoceptors are currently the focus of interest as treatment targets in the lower urinary tract and inhibitors of P2X3 (and P2X1) subtypes may offer new opportunities. If a treatment based on desensitising C-fibres in the bladder and urethra is effective, not only in neurogenic bladders, but also for treating LUTS, it would be a viable option. For new treatments of LUTS, targets within the central nervous system (CNS) may offer exciting opportunities.     

Urodynamic Effects of Once-Daily Tadalafil in Men with LUTS Secondary to Clinical BPH

Lower urinary tract symptoms (LUTS) are common and increase with age in men with benign prostatic hypertrophy (BPH). Erectile dysfunction (ED) also increases with age and is often a comorbid condition with BPH. Treatment with phosphodiesterase type 5 (PDE5) inhibitors aimed at decreasing breakdown of nitric oxide (NO) is a mainstay of treatment for ED. Because NO has been found to mediate male prostatic and urinary function in multiple ways, there is increasing interest in PDE5 inhibitors addressing concomitant LUTS. Several studies have shown significant improvement in LUTS after treatment with PDE5 inhibitors; however, concern exists that PDE5 inhibitors exert their beneficial effects through impairment of bladder function. Because limited invasive urodynamic data exist to address these queries, tadalafil’s impact on bladder function was recently evaluated. Results indicate that tadalafil treatment had no negative impact on bladder function, as measured by detrusor pressure at maximum flow or any other urodynamic parameter assessed.     

The use of PDE-5 Inhibitors in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia

The relationship between lower urinary tract symptoms secondary to BPH and ED has recently been the subject of significant research due to the prevalence of both conditions concomitantly existing in older men. Many large-scale studies have demonstrated an association between erectile dysfunction and lower urinary tract symptoms. Although the mechanisms underlying the relationship between LUTS and ED are not fully elucidated, several theories are currently proposed in literature: the nitric oxide/cGMP pathway, RhoA/Rho-kinase signaling, pelvic atherosclerosis associated with chronic hypoxia, and autonomic adrenergic hyperactivity. The mechanisms by which these pathways affect the bladder, prostate, pelvic vasculature and spinal cord are also the subject of current research. In this chapter, we examine the randomized, placebo-controlled trials that have evaluated the use of PDE-5Is in LUTS, as well as randomized, controlled trials (RCTs) researching combination PDE-5Is and alpha blockers.     

Influences of neuroregulatory factors on the development of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction in aging men

As men age, there is an increase in the frequency of pathologic diseases affecting the genitourinary tract. Most notable among these changes are the rising prevalence of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). The pathogenesis of these conditions seems to be multifactorial and includes age-related changes in the nervous system and neuroregulatory factors, such as nitric oxide and RhoA/Rho-kinase. Various pharmacologic agents that target these pathways, such as α-blockers and PDE-5is, underscore the contribution of neuroregulatory factors on the development of LUTS/BPH and ED.     

Sexual dysfunction and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

Sexuality is an essential aspect of a couple's relationship and has a significant impact on life satisfaction. Benign prostatic hyperplasia (BPH) is a condition that commonly affects older men and is often associated with lower urinary tract symptoms (LUTS) and sexual dysfunction. Men with moderate-to-severe LUTS are at increased risk for sexual dysfunction, including moderate-to-severe erectile dysfunction (ED), ejaculatory dysfunction (EjD), and hypoactive desire (HD). The results of several recent large-scale studies have shown a consistent and strong relationship between LUTS and both ED and EjD. It appears that the pathophysiological mechanisms of LUTS and the related prostatic enlargement of BPH as well as certain treatments for this condition may have an impact on both the erection and ejaculation components of the sexual response. Validated questionnaires that assess sexual function provide clinicians with valuable information to help guide treatment selection decisions. Effective medical therapies for LUTS associated with BPH include alpha(1)-adrenergic receptor antagonists (i.e., alfuzosin, doxazosin, tamsulosin, and terazosin) and 5alpha-reductase inhibitors (i.e., finasteride and dutasteride). The side effects of these medications, including sexual dysfunction, are important distinguishing features. The successful management of patients with LUTS associated with BPH should include assessments of sexual function and monitoring of medication-related sexual side effects. For men with LUTS and sexual dysfunction, an appropriate integrated management approach, based on each patient's symptoms and outcome objectives, is warranted.     

PDE-5 inhibitors: current status and future trends

Phosphodiesterase-5 (PDE-5) inhibitors are a well-established, first-line therapy for erectile dysfunction (ED). Extensive clinical trials and clinical experience established the highly significant efficacy and the safety of this class of drugs in the treatment of ED.Furthermore, the efficacy of PDE-5 inhibitors has been established in men with ED with a broad range of etiologies and comorbidities. The future of PDE-5 inhibitors includes the expansion of indications such as the treatment of pulmonary hypertension and the potential of treatment of symptomatic BPH.     

Physician perceptions of sexual dysfunction related to benign prostatic hyperplasia (BPH) symptoms and sexual side effects related to BPH medications

In a large-scale epidemiology study, 50% of aging men reported erectile dysfunction (ED) or ejaculatory dysfunction (EjD), with lower urinary tract symptoms (LUTS) an independent risk factor for each of these conditions. In light of the shift from urologists (UROs) to primary care/internal medicine physicians (PCPs) for the initial management of men with LUTS associated with benign prostatic hyperplasia (BPH), a survey was conducted to assess the perceptions of UROs and PCPs regarding sexual dysfunction (SD) in men with LUTS/BPH and the effects of BPH treatments (alpha(1)-adrenergic receptor antagonists (alpha-blockers) and 5alpha-reductase inhibitors (5ARIs)) on sexual function. The survey was mailed to 7500 UROs and 2500 PCPs, with 1275 (13%) surveys returned (1087 by UROs, 177 by PCPs and 11 by other specialty). Alpha-blocker monotherapy was the most common medication prescribed by both UROs (56%) and PCPs (47%). UROs estimated that 19% of their patients with LUTS/BPH experienced SD owing to their symptoms compared with the estimate of 27% by PCPs. UROs estimated that 19% of their patients experienced SD owing to their BPH medication compared with the PCP estimate of 24%. The incidence of EjD owing to BPH medications estimated by UROs (32%) was higher than that estimated by PCPs (22%); the rate of ED estimated by PCPs (34%) was higher than that estimated by UROs (23%). UROs were more aware than PCPs of the specific sexual side effects caused by alpha-blockers versus 5ARIs. These results suggest that physicians are underestimating the prevalence of SD in men with LUTS/BPH. As men with LUTS/BPH are at increased risk for SD, physicians should be especially cognizant of BPH treatment-related sexual side effects.     

When to Treat the Prostate,the Bladder,or Both?

ContextPharmacological therapy for relieving lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) has evolved during the past years. The possible benefits of combination therapies to prevent disease progression or to treat LUTS/BPH with concomitant overactive bladder (OAB) or erectile dysfunction (ED) are currently studied.ObjectivesTo review the evidence provided in clinical trials and to assess the current medical practice concerning the pharmacological treatment of men suffering from LUTS/BPH.Evidence acquisitionThis paper is based on a presentation during the symposium “The future of LUTS/BPH: management beyond the prostate” at the European Association of Urology's 2008 annual meeting. The results of a Web survey evaluating the opinion of urologists about treatment of LUTS/BPH patients were discussed and an update lecture on medical therapy for LUTS/BPH was given.Evidence synthesisMen who are highly bothered by their symptoms but with a low risk of disease progression can achieve fast relief of symptoms with α₁-adrenoceptor (α₁-AR) antagonist monotherapy. Those patients at risk for LUTS/BPH progression can benefit from additional 5α-reductase inhibitor therapy. Concomitant OAB symptoms in LUTS/BPH patients can be treated with a combination of an α₁-AR antagonist and an antimuscarinic agent. An α₁-AR antagonist combined with a phosphodiesterase-5 inhibitor might improve symptoms in men with lower urinary tract symptoms (LUTS) and concomitant ED.ConclusionsThe pharmacological treatment of LUTS/BPH patients should be adapted to their individual risk of progression and their individual symptom profile.     

Transient global amnesia after intake of tadalafil, a PDE-5 inhibitor: a possible association?

Inhibitors of phosphodiesterase type 5 (PDE-5) are well established as an oral treatment for the majority of patients with erectile dysfunction (ED). PDE-5 is found in high concentration in smooth muscle cells of the corpora cavernosa. However, enzymes of the PDE family are also expressed in various other tissues, including the brain. Little is known about its effects on the central nervous system (CNS), although it has been suggested that PDE-5 inhibitors might cross the blood-brain barrier. Side effects, such as headache, nasal congestion, flushing, nausea, are much more common. We describe a patient who had a transient global amnesia (TGA) after his first-ever use of tadalafil, a potent PDE-5 inhibitor. Despite the fact that the aetiology of TGA has not entirely been clarified at present, we consider the hypothesis of a causal relationship as tempting with respect to the current hypotheses of TGA pathophysiology. This case, together with others, suggests that PDE-5 inhibitors might be capable of exerting adverse effects in the CNS. Physicians should be aware of the possibility of neurological disturbances when prescribing PDE-5 inhibitors for ED.     

Protecting Bladder Function and Reducing Disease Progression

Infravesical obstruction impairs bladder function, and α₁-adrenoceptor (AR) antagonists can relieve such dysfunction in part due to their moderate deobstructing effects. Moreover, α₁-AR antagonists may also have beneficial effects on bladder function via mechanisms independent from those regulating bladder outlet resistance. Such beneficial effects have repeatedly been reported from various animal models of bladder outlet obstruction, and preliminary data indicate that this may perhaps also occur in lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) patients. The contribution of such effects on the bladder in the long-term treatment of LUTS/BPH remains to be assessed. The recently completed Medical Therapy Of Prostatic Symptoms (MTOPS) study has demonstrated that α₁-AR antagonists have beneficial effects on the progression of LUTS/BPH which are quantitatively similar to but qualitatively different from those of 5α-reductase inhibition. Due to this differential mode of action, long-term combination treatment was significantly more effective than either treatment alone. Since combination therapy is at least associated with the side effects of both the α₁-AR antagonist and 5α-reductase inhibitor, great care should be taken to identify patients at high risk in whom the benefits of combination treatment outweigh its risk. Use of an α₁-AR antagonist with very high tolerability may facilitate the use of combination treatment.     

Beneficial effects of extended-release doxazosin and doxazosin standard on sexual health

The prevalence of benign prostatic hypertrophy (BPH) and erectile dysfunction (ED) both increase with age, and increasing evidence suggests a common cause rather than independent age-related changes. Arterial hypertension often accompanies these urological disorders, suggesting the possibility that increased alpha-adrenoceptor activity may be causal in all three conditions. As evidence for this model, alpha-adrenoceptor antagonists such as doxazosin produce therapeutically beneficial effects in lowering blood pressure, reducing prostate growth and BPH symptoms, and relieving ED. At postjunctional alpha(1)-receptors in the corpus cavernosa, noradrenaline causes vascular smooth muscle cell contraction, restricting blood flow, resulting in penile detumescence. Just as alpha-adrenoceptor antagonism results in systemic vasorelaxation to lower blood pressure, the same mechanism in the penis modulates the effects of noradrenaline to favour vasodilatation, resulting in improved erectile function. Increasing clinical evidence attests to the effectiveness of doxazosin in relieving ED, even in patients refractory to ED-specific treatment, as well as in reducing BPH symptoms and elevated blood pressure.     

Synergetic effect of testosterone and phophodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: A systematic review

Testosterone deficiency seems to impair the clinical response to phophodiesterase-5 (PDE-5) inhibitors in patients with erectile dysfunction (ED). In hypogonadal men, testosterone repletion was associated with enhanced sexual function in patients who failed initial treatment with sildenafil or tadalafil. We conducted a systematic review of studies that evaluated combination therapy of testosterone and PDE-5 inhibitors in patients with ED and low, low-normal testosterone levels who failed monotherapy. The studies we examine are heterogeneous with several methodological drawbacks and that, overall, the addition of testosterone to PDE-5 inhibitors might benefit patients with ED associated with testosterone <300 ng/dL (10.4 nmol/L) who failed monotherapy. Further studies, with a randomized placebo-controlled and double blind design, are needed to describe the appropriate target patient group, testosterone cut-off and to define the optimal dose and duration of combination therapy.     

Medikamentöse Therapie der benignen Prostatahyperplasie

The majority of men with benign prostatic hyperplasia (BPH) seek medical help because of lower urinary tract symptoms (LUTS). Pharmacological treatment of BPH is indicated if the patient has no absolute indications for prostate surgery or benign prostatic obstruction (BPO), but LUTS with a decrease of quality of life. Plant extracts can be prescribed in men with mild to moderate symptoms. α-Blockers can quickly and effectively decrease LUTS and symptomatic disease progression. If patients have predominantly bladder filling symptoms and a small prostate, muscarinic receptor antagonists are a viable treatment option. The combination of an α-blocker plus a muscarinic receptor antagonist is more effective than single drugs used alone. Especially in men with larger prostates, 5α-reductase inhibitors can decrease LUTS and the probability of acute urinary retention as well as need for prostate surgery. The combination of α-blocker plus 5α-reductase inhibitor can reduce LUTS and disease progression more effectively than single drugs.