Correspondence: Osamu Yamaguchi M.D., Ph.D., Division of Bioengineering and LUTD Research, Nihon University School of Engineering, Koriyama 963-8642, Japan. Email: email@example.com
Recent studies suggest that antimuscarinics might suppress bladder afferent activity by blocking muscarinic receptors in the urothelium, myofibroblasts and detrusor, thereby improving overactive bladder symptoms. β3-Adrenoceptors are predominantly expressed in the human bladder and mediate relaxation of detrusor muscle. β3-Adrenoceptor agonists increase bladder capacity and prolong micturition interval. It is assumed that β3-adrenoceptor agonists could exert an inhibitory effect on bladder afferent through β3-adrenoceptors in the urothelium and detrusor, which eventually improve the symptom of urgency. Mirabegron is a potent and selective β3-adrenoceptor agonist. A Japanese phase 3 study showed that mirabegron has excellent efficacy and safety for treating overactive bladder. α1-Adrenoceptor antagonists (α1-blockers) have become a mainstay of male lower urinary tract symptoms treatment. The α1A subtype is known to mediate functional obstruction as a result of benign prostatic enlargement. Recent studies have suggested that α1A-adrenoceptors are additionally involved in the generation of storage symptoms. The α1D subtype is thought to play a role in the facilitation of voiding reflex; that is; storage symptoms. α1-Blockers often fail to alleviate overactive bladder symptoms. In this context, combination therapy with α1-blockers and antimuscarinics has been recommended. Treatment with 5α-reductase inhibitor for 1 year improves urinary symptoms and flow rate by reducing prostatic volume in men with benign prostatic enlargement. A pooled analysis showed that the long-term (2 or 4 years) treatment with 5α-reductase inhibitor reduced the rate of progression to acute urinary retention and surgery. Combination therapy with 5α-reductase inhibitor and α1-blocker was shown to provide a rapid improvement in lower urinary tract symptoms, and reduce the relative risk of acute urinary retention and benign prostatic hyperplasia-related surgery. Phosphodiesterase inhibitors might target a nitric oxide–cyclic guanosine monophosphate pathway in the prostate, urethra and bladder. Phosphodiesterase-5 inhibitors (sildenafil or tadalafil) were shown to provide clinically relevant improvements in both male lower urinary tract symptoms and erectile dysfunction.
LUTS comprise storage symptoms, voiding symptoms and postmicturition symptoms. OAB, the most bothersome subset of LUTS, has been defined by the ICS as urgency, with or without urgency incontinence, usually with frequency and nocturia. According to this definition, urgency is an essential component for a diagnosis of OAB, and it is the cornerstone symptom that drives all other symptoms of OAB. Therapeutic agents, such as antimuscarinics, are known to improve the symptom of urgency. As urgency is an abnormal or pathological bladder sensation, these therapeutic agents might influence the sensory (afferent) part of the micturition reflex. This has created a renewed interest in the mechanism of action for drugs used for the treatment of LUTS.
The management of male LUTS has been disproportionately dominated in the past by an emphasis on prostatic pathology, such as BOO and prostatic enlargement. Medical treatment of the male LUTS, thus, has been based on mainly two types of agents, α1-AR antagonists and 5αRI. However, Irwin et al. showed that LUTS were highly prevalent in both men and women, and a similar extent in both sexes, suggesting that male LUTS cannot be attributable exclusively to prostate because of a similar prevalence in women. Thus, the focus has shifted from the prostate to the bladder as the source of some of the male LUTS, and as a therapeutic target.
The present article reviews pharmacotherapy for OAB and male LUTS, with a particular emphasis on the mechanism of action for therapeutic agents. In addition, some combinations of drugs for the treatment of male LUTS are also considered.
Antimuscarinics are considered first-line treatment for patients with OAB. Oxybutynin and tolterodine ER are widely prescribed in Europe and the USA. Newer compounds, such as solifenacin, darifenacin and fesoterodine, are also available. Propiverine was the most widely prescribed agent in Japan, until solifenacin and tolterodine were launched in 2006. Imidafenacin was also available in Japan. These antimuscarinics are known to improve OAB symptoms, including urgency.
Muscarinic mechanisms for afferent activation
The common view regarding the main mechanism of action of antimuscarinics is that antimuscarinics block MR on the efferent in the detrusor muscle and reduce the ability of the detrusor to contract. However, in the dose recommended for treatment of OAB, there is little evidence for a significant reduction of the voiding contraction. The issue is whether there are other mechanisms of action of antimuscarinics at the dose used for treatment of OAB.
Recent evidence suggests a role for MR mediated mechanism in urothelial sensory function, as well as in local contractions of the bladder wall, both of which contribute to generating afferent signals.
Recently, the roles of the urothelium and suburothelial myofibroblasts in afferent activation have become the focus of intense interest. The bladder urothelium is known to release many signaling molecules (ATP, prostaglandins, etc.) that can activate C-fiber afferent in the suburothelial layer of the bladder wall.[8-13] In addition, a suburothelial layer of myofibroblasts (interstitial cells) has been identified in the bladder wall.[14, 15] These myofibroblasts make close appositions to unmyelinated nerves (afferent C-fiber nerves), which might allow for an amplification of the afferent system in response to stimulatory mediators.
Ach is one of these urothelial signaling molecules.[17, 18] Several studies showed the presence of Ach-synthesizing enzymes in the urothelium.[17, 18] Yoshida et al. found by microdialysis technique that there is a basal Ach release in the human bladder and that the released Ach is of non-neuronal origin, generated at least partly by the urothelium. This non-neuronal release of Ach was shown to increase when bladder strips were stretched, suggesting that bladder distension during the storage phase causes a release of Ach from the urothelium.
All five MR subtypes (mRNA and protein levels) are detected in the bladder urothelium.[19-23] Recent studies showed that the human urothelium carries multiple MR subtypes, with predominant expression of M2 receptors.[19, 21] Furthermore, Mukerji et al. showed M2 and M3 receptor immunoreactivity on suburothelial myofibroblast-like cells in the human bladder. In addition to MR, nicotinic receptors are also found in the human urothelium.
Ach release from the urothelium activates MR and nicotinic receptors in the urothelium in an autocrine fashion. Activation of MR and nicotinic receptors in the urothelium can release ATP, which, in turn, activates P2X3 receptors on afferent nerve terminals to evoke a neural discharge[26, 27] (Fig. 1). Furthermore, Ach and ATP released from the urothelium can activate MR and P2Y receptors, respectively, on myofibroblasts (Fig. 1).
Upregulation of these urothelium-related mechanisms might increase afferent nerve activity, and contribute to the development of OAB symptoms and DO. It is therefore likely that antimuscarinics can decrease bladder afferent activity by blocking MR in the urothelium and suburothelial myofibroblasts, thereby improving OAB symptoms (Fig. 1).
Brading and Turner have emphasized that myogenic change (regardless of etiology) can contribute to the pathophysiology of idiopathic DO.[28, 29] On the basis of observation that denervation is consistently found in detrusor biopsy specimens from patients with various forms of non-neurogenic detrusor overactivity, they have proposed that partial denervation of the detrusor might alter the properties of smooth muscle, leading to increased sensitivity to Ach (denervation supersensitivity).
In pathological conditions, such as OAB, Ach release from both neuronal and non-neuronal sources (urothelium) might increase.[7, 17] Thus, together with an increase in sensitivity of the detrusor smooth muscle to Ach, the increase in Ach release could be expected to induce local contractions of small units of the detrusor. These contractions are called a micromotion and do not necessarily lead to an increase in intravesical pressure. However, local contractions in the bladder wall were shown to generate afferent signals, which would precipitate a feeling of urgency and detrusor overactivity.[31, 33, 34]
Antimuscarinics might suppress these local contractions through MR in the detrusor, which eventually reduces bladder afferent activity (Fig. 1). This might lead to improvement of OAB symptoms.
There have been several animal studies investigating the effect of antimuscarinics on bladder afferents. Yokoyama et al., using a rat model of neurogenic detrusor overactivity, showed that tolterodine at low doses significantly increased bladder capacity without increasing residual volume, but no effect on bladder capacity in RTX-treated rats. These results suggest that tolterodine at low doses exerts an inhibitory effect on C-fiber afferent nerves, thereby improving bladder storage function.
Hedlund et al. showed that tolterodine also increased the micturition interval and the bladder capacity in normal rats. Similar effects were seen with the same dose in RTX-treated rats, suggesting that these effects were exerted independently of RTX-sensitive afferents.
Haga et al. showed that a long-term administration of low-dose oxybutynin significantly increased the micturition interval and bladder capacity, but it did not affect micturition pressure. Low-dose oxybutynin also decreased c-Fos expression in the spinal cord, which was induced by continuous infusion of saline into the rat bladder. This finding suggests that oxybutynin might suppress afferent input from the bladder.
Recently, studies using an electrophysiological technique provided direct evidence that systemic administration of antimuscarinics decreased afferent spike rate for C- and A-delta fibers during bladder filling in anesthetized rats.[38, 39] These studies, thus, suggest that the efficacy of antimuscarinics for OAB might be partly a result of bladder afferent desensitization.
The urinary bladder is innervated by both sympathetic and parasympathetic nervous systems. Activation of sympathetic nerves contributes to urine storage by relaxing the detrusor muscle through activation of β-AR. β-AR are currently classified into β1-, β2- and β3- subtypes. This section describes the expression and function of β3-AR subtype in the bladder and suggests the therapeutic potential of β3-AR agonist for treatment of the OAB. In addition, some clinical data of β3-AR agonist (mirabegron) are also described.
Expression of β-AR subtypes in the bladder
The identification of β-AR at the protein level is typically based on binding studies with various radioligands. However, the radioligands used in these studies have much a lower affinity for β3- than for β1- and β2-AR.[41, 42] The characterization and cloning of a β3-AR gene from the human genomic library, mouse genomic library and rat brown adipose complementary DNA library has been accomplished. Thus, instead of binding assays, the β-AR subtypes can be discriminated by evaluating mRNA encoding the three subtypes.
The expression of β1-AR, β2-AR and β3-AR in mRNA in the rat bladder has been reported.[46-48] Studies in the human bladder have also detected mRNA for all three β-AR subtypes.[46, 49, 50]
There is only one study that has determined the relative abundance of β-AR subtypes in the human bladder at the mRNA level. Using a real-time quantitative reverse transcription polymerase chain reaction, this study has shown that of all β-AR mRNA, 97% was represented by the β3-AR and just 1.5% and 1.4% for the β1-AR and β2-AR, respectively. If the amount of subtype mRNA reflects the population of receptor protein, then the β3-AR is the most abundant subtype in human detrusor muscle.
Studies in various species have used agonist and antagonist potency to identify the functional involvement of β-AR subtypes in bladder relaxation. It has been suggested that the relaxation induced by β-AR agonists in detrusor muscle might be mediated mainly through β2-AR in rabbits,[52-54] through both β2- and β3-AR in rats,[52-56] through β2-AR and possibly β3-AR in pigs, but predominantly through β3-AR in dogs.[54, 58]
In human detrusor muscle, neither dobutamine (a β1-AR agonist) nor procaterol (a β2-AR agonist) produced significant relaxation. In contrast, the selective β3-AR agonists, BLR37344, CL316243 and CGP12177A, all produced concentration-dependent relaxation.[49, 50] Furthermore, isoproternol-induced relaxation was inhibited by the selective β3-AR antagonists (SR58894A), but not by the selective β1-AR antagonists atenolol and CGP20712A, nor by the selective β2-AR antagonists butoxamine. In all, these findings suggest that the relaxation induced by β-adrenergic stimulation of the human detrusor is mediated mainly through β3-AR activation. Thus, this subtype is the most important for bladder relaxation during the storage phase of the micturition cycle.
Therapeutic potential for β3-AR agonists
Antimuscarinic agents are widely used for the treatment of OAB. However, these agents have various disadvantages, including adverse events derived from antimuscarinic effects, such as dry mouth, constipation and voiding difficulty with significant amounts of residual urine. Thus, the development of new drugs other than anticholinergics has been considered, and β3-AR agonist has been a potential candidate among those drugs.
Effect of β3-AR agonists on bladder function
The in vivo effects of β3-AR agonists on bladder function have been studied in conscious rat models of bladder hyperactivity. These studies[46, 60-62] have shown that β3-AR agonists (FK175, CL316243) significantly increased bladder capacity and prolonged micturition interval without affecting voiding pressure or post-void residual volume. In addition, β3-AR agonist CL316243 did not produce significant cardiovascular side-effects.[60, 61] Similarly, cystometry in urethane-anesthetized rats showed that when compared with other agents (isoproterenol, verapamil and atropine), CL316243 also increased bladder capacity and did not change the residual volume. Of the compounds tested, CL316243 had the weakest cardiovascular side-effects, as assessed by changes in heart rate and blood pressure.
The aforementioned studies show that the activation of β3-ARs increases bladder capacity without influencing bladder contraction during the voiding phase or without affecting post-void residual urine volume. This can be explained by functional coupling between β-AR and postjunctional muscarinic M2 receptors in detrusor muscle. Thus, during the voiding phase, Ach released from parasympathetic nerves activates muscarinic M3 receptors in the bladder, leading to detrusor contraction. At the same time, Ach also activates muscarinic M2 receptors, which inhibits adenylyl cyclase activity that is increased by stimulation of β-AR. In this respect, muscarinic M2 receptors were shown to mediate the cancellation of β-AR-induced detrusor relaxation in rat bladder. Therefore, under the administration of β3-AR agonist, the relaxation of detrusor muscle in the voiding phase might be canceled by muscarinic M2 receptor activation, suggesting that β3-AR agonist have little risk of causing the urinary retention noted with antimuscarinic agents. However, it needs to be considered whether this concept obtained from the rat study might also apply to the β3-AR system in the human bladder.
Effect of β3-AR agonists on bladder sensation (afferent)
Recently, Thomas et al. have identified the presence of β1-AR, β2-AR and β3-AR mRNA in the urothelium of the human bladder. It was also shown that β-AR activation by isoproterenol in rat urothelial cells can trigger production and release of NO as a result of an increase in intracellular Ca2+ after activation of the adenylyl cyclase pathway in the urothelial cells. Because NO has only minimal relaxing effects on bladder smooth muscle, it is suggested that NO can depress bladder overactivity by suppressing excitability of the bladder afferent nerves.[66, 67] Thus, activation of β3-AR in the urothelium could have inhibitory effects on bladder afferent activity (Fig. 2).
As a myogenic basis for OAB, Brading and Turner[28, 29] have proposed that partial denervation of the detrusor might alter the properties of smooth muscle (denervation supersensitivity), leading to local contractions of small units of the detrusor (micromotion). It has been shown that these local contractions in the bladder wall precipitate a feeling of urgency and detrusor overactivity.[31, 33, 34] Thus, β3-AR agonists might suppress myogenic local contractions through β3-AR in the detrusor, which eventually improve the symptom of urgency (Fig. 2).
Clinical trials of mirabegron (selective β3-AR agonist)
Mirabegron, a potent and selective β3-AR agonist, was first launched in Japan in 2011. In a Japanese phase 3 study, the outcome of the primary efficacy analysis was that mirabegron treatment (50 mg once-daily) resulted in a statistically significant baseline to end-point reduction of 1.67 micturitions per 24 h compared with a reduction of 0.86 episodes for patients receiving placebo. When assessing secondary efficacy end-points, mirabegron treatment also resulted in statistically significant baseline to end-point reductions in urgency episodes (1.85/day) and urge incontinence episodes (1.01/24 h) compared with reductions of 1.37/day and 0.60/day, respectively, for patients receiving placebo. In addition, mirabegron significantly increased voided volume by 24.3 mL as compared with placebo (9.72 mL).
Mirabegron was well tolerated in patients with OAB and showed a low incidence of adverse events. In particular, the incidence of dry mouth was very low (2.6%) and similar in the placebo group (2.9%).
The aforementioned clinical data show that selective β3-AR agonists can provide a new option for the medical treatment of OAB.
A large number of randomized, double-blind and placebo-controlled studies have been carried out to evaluate the efficacy and safety of α1-AR antagonists (terazosin, doxazosin, alfuzosin, tamsulosin and naftopidil) in the treatment of male LUTS associated with BPH. Obviously, all α1-AR antagonists (α1-blockers) improve LUTS in men to a similar extent. They have become a mainstay of male LUTS treatment. These agents possess favorable tolerability profiles and treat both storage and voiding symptoms.
Role of α1-AR subtypes in pathophysiology of male LUTS
α1-AR are subdivided into α1A, α1B and α1D subtypes. Of the three subtypes, the α1A and α1D AR subtypes contribute to the mechanisms for LUTS relieved by α1-AR antagonists.
The α1A-AR subtype predominates in the smooth muscle of the prostate and male proximal urethra. Moriyama et al. also showed that expression of total α1-AR mRNA increased in the BPH tissue, and that of all α1-AR mRNA, 85% was represented by the α1A-AR, and 14% and 1.0% for the α1D-AR and α1B-AR, respectively. Thus, α1A-AR in the prostate and urethra are thought to be responsible for the dynamic component of BPO and voiding symptoms.
Now, a highly selective α1A-AR antagonist (silodosin) is available. The phase 3 studies of silodosin showed that not only voiding symptoms, but also storage symptoms were significantly improved by this agent in patients with BPH. These studies thus suggest that α1A-AR are also involved in the generation of storage symptoms, although this subtype has been believed to mediate only BPO.
The role for α1D-AR was investigated using the relevant receptor KO mice. Chen et al. showed that α1D-AR KO mice have a larger bladder capacity and voided volumes than their wild-type control, supporting an important role for α1D-AR in the facilitation of the voiding reflex. However, it was not possible to draw any conclusions from their data about the location of α1D-AR involved in micturition control.
Male OAB symptoms and DO are often associated with BOO and BPH. Several studies[73, 74] implied that α1D-AR in the detrusor muscle are responsible for DO and storage symptoms secondary to BOO. However, Nomiya and Yamaguchi showed that in human detrusor muscle, there was no upregulation of any of the α1-AR subtypes with outflow obstruction. They also found a small response to phenylephrine at high drug concentrations, with no difference between normal and obstructed bladder, although these findings were challenged by Bouchelouche et al., who showed an increased response of detrusor muscle to α1-AR stimulation in human obstructed bladder.
With regard to other locations of α1D-AR, Smith et al. reported that in the human spinal cord, α1D-AR mRNA predominated overall. Ishihama et al. showed the expression of α1D-AR in the rat bladder urothelium, suggesting that these α1D-AR might mediate the release of ATP from the urothelium, which activates bladder C-fiber afferent nerves.
The exact role of α1D-AR in the generation of LUTS cannot be determined until a drug with appropriate subtype selectivity becomes available.
Bladder ischemia and α1-AR antagonists
Recent evidence has suggested that chronic bladder ischemia might underlie male DO and OAB symptoms. The animal model of BOO showed that BOO is associated with a reduction of bladder blood flow and repeated episodes of prolonged detrusor ischemia.[78, 79] Koritsiadis et al. showed that the number of cells immunoreactive to hypoxia-inducible factor-1α significantly increased in the biopsy specimen from obstructed human bladder, suggesting the possible involvement of bladder ischemia in the pathogenesis of DO secondary to BOO (Fig. 3).
Bladder ischemia might play a role in the pathogenesis of DO and OAB symptoms, regardless of which BOO is present. A number of cardiovascular, metabolic and endocrine factors were shown to be associated with the development of LUTS.[81, 82] More interestingly, Ponholzer et al. have investigated the association between LUTS and vascular risk factors (hypertension, hyperlipemia, diabetes mellitus and nicotine use). They reported that the IPSS increased significantly in both men and women with two or more risk factors, suggesting the potential role of atherosclerosis in the development of LUTS, including OAB symptoms. Many studies using animal models also showed that atherosclerosis and subsequent ischemia/oxidative stress induce the expression of NGF and COX2 in the bladder, which cause functional and structural alteration of the detrusor, leading to DO.[84-86] Masuda et al. have suggested that oxidative stress mediates DO through sensitization of afferent pathway in the bladder of rats. Extrapolating these observations to humans would suggest that long-term arterial insufficiency, consequent to atherosclerosis, might cause DO and OAB through ischemia, hypoxia and oxidative stress in the bladder (Fig. 3).
Pinggera et al. measured lower urinary tract perfusion using transrectal color Doppler ultrasound, and observed that blood flow in the bladder and prostate decreased significantly in men with LUTS. They also showed that α1-AR antagonist tamsulosin (comparatively selective for α1A-AR) increased blood flow in the lower urinary tract. Thus, the therapeutic effect of α1-blockers on BPH/LUTS would be a result of the improvement of chronic bladder ischemia.
Combination therapy with α1-blocker and antimuscarinic
Most male LUTS patients (50–75%) reported OAB symptoms. A first-choice pharmacotherapy for male LUTS is an α1-blocker, because α1-blockers can alleviate not only voiding symptoms, but also storage symptoms.[90-92] However, pharmacotherapy using an α1-blocker alone often fails to improve OAB symptoms. Lee et al. have suggested that in patients with both BOO and DO, doxazosin alone was not able to alleviate LUTS sufficiently. Therefore, combination therapy of α1-blocker plus antimuscarinic has been recommended.
There is the well-known study named the Tolterodine and Tamsulosin In Men with LUTS Including OAB: Evaluation of Efficacy and Safety (TIMES) study. This large-scaled trial was designed to investigate the efficacy of combination therapy using tamsulosin and tolterodine ER in a population of men with LUTS, including OAB. The results showed that some men bothered by LUTS and OAB might not respond to monotherapy with either α1-blockers or antimuscarinics. Treatment with tamsulosin plus tolterodine ER resulted in statistically and clinically significant treatment benefits compared with placebo treatment.
In daily clinical practice, a majority of these patients have already been treated with α1-blocker. Thus, for residual OAB symptoms, a number of studies reported the efficacy of antimuscarinic add-on therapy to α1-blocker.[93, 95-98] Chapple et al. showed that Patient Perception of Bladder Condition improvement from baseline to week 12 was reported by 63.6% and 61.6% of patients receiving tolterodine ER plus α1-blocker and placebo plus α1-blocker, respectively. This treatment difference, which was the primary end-point, was not statistically significant. However, diary variables (24-h micturition, 24-h urgency episode, etc.), IPSS storage score and symptom bother were significantly improved when receiving additional tolterodine ER versus placebo plus α1-blocker. The results of this study are generally consistent with those of the Vesicare in Combination with Tamsulosin in Overactive Bladder Residual Symptoms (VICTOR) study, which assessed safety and tolerability of solifenacin add-on therapy to α1-blocker treated men with residual urgency and frequency.
As a similar clinical study, MacDiarmid et al. evaluated efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of male LUTS. Nishizawa et al. also showed that compared with the tamsulosin (0.2 mg) group, tamsulosin plus propiverine (10 mg) patients experienced significantly fewer micturitions, urgencies per 24 h, lower IPSS storage scores and lower IPSS urgency subscores, suggesting that combining tamsulosin and a low dose of propiverine provides added benefit for men with BPH and OAB.
The Add-on therapy of Solifenacin Succinate In men for BPH with OAB Symptoms treated by Tamsulosin hydrochloride (ASSIST) was the first study to examine the efficacy of tamsulosin (0.2 mg) and solifenacin (2.5 mg or 5.0 mg) add-on therapy by assessing urgency, which represents OAB as the primary end-point in male LUTS patients with residual OAB symptoms despite α1-blocker treatment. The results showed a statistically significant reduction of overactive bladder symptom score (OABSS) urgency score in the tamsulosin plus solifenacin 2.5 mg group, as well as in the tamsulosin plus solifenacin 5.0 mg group compared with the tamsulosin plus placebo, whereas significant reduction of urgency episodes from a bladder diary was shown in only tamsulosin plus solifenacin 5 mg.
There are two isozymes of 5α-reductase – type 1 and type 2. Finasteride is an inhibitor of type 2 5α-reductase. Dutasteride is a dual inhibitor of type 1 and type 2 5α-reductase, which is available in Japan.
In a placebo-controlled double-blind study, Gormley et al. evaluated the effect of finasteride (5 mg) given once daily for 12 months in men with symptomatic BPH. They showed that compared with the men in the placebo group, the men treated with finasteride had a significant decrease in total urinary symptom score, an increase in the maximum flow rate (1.6 mL/s) and a 19% decrease in PV. Boyle et al. identified prostate size as a pretreatment predictor of finasteride therapy outcomes expressed by symptoms or urinary flow rate.
A pooled analysis of all available randomized trials with 2-year follow-up data with finasteride and placebo showed that finasteride use significantly reduced AUR and BPH-related surgical intervention. Similarly, treatment with finasteride for 4 years was shown to reduce the risk of surgery and AUR.[103, 104]
Dutasteride also improve male LUTS and flow rate. Randomized, placebo-controlled, large-scale studies showed that in patients with moderate-to-severe LUTS and prostatic enlargement, dutasteride reduced PV, provided continuous symptom improvements, and reduced the rate of progression to AUR and surgery.[105-107]
Combination therapy with α1-blocker and 5αRI
α1-Blockers are effective for short-term improvements of LUTS in men with BPE, whereas 5αRI can reduce the risk of underlying disease progression.
The 1-year results from three studies showed a combination therapy with finasteride and α1-blocker was not more significantly effective than α1-blocker monotherapy.[108-110] The Medical Therapy of Prostatic Symptoms (MTOPS) study showed significant benefit for finasteride and doxazosin combination therapy versus either monotherapy in reducing the relative risk of overall clinical progression of BPH, AUR and the need for invasive therapy during mean follow up of 4.5 years.
The Combination of Avodart and Tamsulosin (CombAT) study aimed to investigated the effect of dutasteride (0.5 mg), tamsulosin (0.4 mg) and their combination on LUTS in men with total IPSS > 12, PV > 30 cc and prostate-specific antigen levels 1.5–10 ng/mL. After 2 years, combination treatment achieved significantly greater reductions in both voiding and storage symptoms than monotherapy. The 4-year CombAT study also showed that dutasteride and tamsulosin combination therapy significantly reduced symptom deterioration and the relative risk of AUR or BPH-related surgery compared with tamusulosin monotherapy. However, no significant difference was observed between combination therapy and dutasteride monotherapy.
A current area of interest in male LUTS centers around a role for the NO/cGMP signaling in the prostate and urinary bladder. Recent studies suggest that similar mechanisms might underlie the generation of male LUTS and erectile dysfunction.[114-119] Based on these suggestions, it has been proposed that PDE inhibitors might target this signaling pathway to relax bladder, urethral and prostate smooth muscle, thereby alleviating LUTS.[120-122] Evidence also suggests that bladder ischemia might play a role in the pathogenesis of male DO and OAB symptoms. In this respect, PDE-5 inhibitors might produce vasodilatation in the bladder, leading to an improvement of bladder ischemia (ICI,37).
Randomized, controlled trials have shown that treatment with PDE-5 inhibitors, for example sildenafil and tadalafil,[124-127] results in clinically relevant and significant improvement in both LUTS and erectile dysfunction, although there was no improvement in urinary flow rate. Furthermore, combination therapy with an α1-AR antagonist and sildenafil has been shown to be superior to monotherapy in treating male LUTS, with an associated improvement in urinary flow rate.