Secondary Logo

Journal Logo

MALE LOWER URINARY TRACT SYMPTOMS: Edited by Oliver Reich

New concepts for the treatment of male lower urinary tract symptoms

Füllhase, Claudius; Hakenberg, Oliver

Author Information
doi: 10.1097/MOU.0000000000000126
  • Free

Abstract

INTRODUCTION

That our understanding what causes micturition problems in men is changing is illustrated by the ongoing change of terminology; whereas in 2005, the European Association of Urology (EAU) guidelines were named ‘guidelines on BPH’, those guidelines were renamed as ‘guidelines on the treatment of non-neurogenic male lower urinary tract symptoms (LUTS)’ in 2010, and redefined to ‘guidelines on the management of male LUTS, including benign prostatic obstruction’ in 2012. This change of terminology from an organ restricted term benign prostatic hyperplasia (BPH) to a nonorgan confined umbrella term (LUTS) is based on insights that symptoms of the LUT do not relate to any specific pathophysiology, and that, vice versa, not all BPH will result in symptoms.

It has long been known, is well established, and undoubted until today that in men, the prostate gland grows large with increasing age [1]. In the past, it was believed that prostatic enlargement leads to urinary symptoms, which could be treated by removal of the prostatic obstruction [2]. However, it became apparent that there is a poor correlation between prostate size and symptoms and that not all men with symptoms suggestive for BPH will benefit from a surgical therapy [3]. In addition, it was found that the overactive bladder (OAB) syndrome, which was historically believed to only affect women, is also prevalent in men [4]. At the same time, more and more scientific reports pointed to a seminal role of the bladder as originator of LUTS in BPH [5,6]. All this evidence cumulated during the last decade in publications, which not only made the point to consider the bladder as symptomatic key player in BPH/LUTS, but also voted to use drugs, commonly used to target the bladder, in the treatment of male LUTS [7–9].

There is now sufficient evidence to link male LUTS to the bladder. BPH induces structural and functional changes within the bladder urothelium, detrusor, and adjacent neuronal structures, all of which subdue to be possible pharmacological targets [10]. As such, our new understanding how LUTS are generated enables us to increase our therapeutic armamentarium by drugs which act on micturition-controlling pathways in the bladder. It should be kept in mind that even though the bladder is nowadays considered the generator of LUTS, there is still a correlation between BPH and LUTS (as undoubtedly, many patients experience LUTS relief through BPH surgery). New concepts why the prostate grows large with age have been reported recently. Whereas drug therapies targeting the bladder seem to be rather symptomatic, targeting prostatic growth might be rather causal or prophylactic.

Box 1
Box 1:
no caption available

NEW CONCEPTS REGARDING PROSTATIC GROWTH

Classical concepts on BPH rely mostly on disturbances of androgen levels [11–13]. However, as already Wilson stated [12], ‘The growth of the prostate is mediated by testicular hormones. This assumption does not imply that endocrine factors are primary in the cause, only that a permissive role for the hormones is essential’. New concepts on prostate growth suggest a genetic, metabolic, or inflammatory cause.

Genetic origin

The term ‘familial BPH’ illustrates well the old knowledge that there exists a hereditary component of BPH [14]. Twin studies estimated a heritability for BPH of 49% [15]. The Olmsted County Study [16] reported an increased risk of BPH-related symptoms if a family history was present [odds ratio (OR): 1.3; 95% confidence interval (CI): 1.1–1.7]. Despite this knowledge, and despite recent advances in the field of genetic research, there seems to be a surprising lack of genetic studies regarding BPH/LUTS. There exist no genome-wide association studies for male LUTS, but only candidate gene approach studies. In a meta-analysis, Cartwright et al. assessed all genetic LUTS association studies up to January 2013. Quantitative analysis was possible for 35 polymorphisms in 24 genes [17▪▪]. Out of those, only five achieved statistical significance: polymorphisms within the genes for the angiotensin-converting enzyme, rs4340; for the zinc phosphodiesterase protein 2 (ELAC2), rs5030739; for the glutathione S-transferase M1, null allele; for the telomerase reverse transcriptase, rs2736098; and for the vitamin D receptor (VDR), rs731236. However, out of those five only the single-nucleotide polymorphism, rs731236, within the VDR gene, was assigned ‘epidemiological credibility’. rs731236 is associated with increased vitamin D levels, and has a protective effect in association with LUTS (OR: 0.64; 95% CI: 0.49–0.83) [17▪▪]. In an epidemiological study [18], vitamin D deficiency was linked to LUTS. In a clinical trial [19], elocalcitol (BXL628), a vitamin D3 analogue, was not able to improve symptomatic LUTS, but was able to arrest prostatic growth [−2.9% of prostate volume vs. +4.8% (placebo) within 12 weeks]. Hence, targeting the vitamin D pathway might be worth to be further explored in the prevention of BPH/LUTS.

In general, it should be said that studies assessing genetic associations with BPH and/or LUTS, particularly genome-wide association studies, contain the prospects to fundamentally extend our understanding of what causes BPH/LUTS and to identify completely new pharmacological targets unthought-of today. A similar potential might inhere studies assessing epigenetic mechanisms in regards to BPH/LUTS. None of such studies exist so far.

Metabolic origin

There is epidemiological evidence suggesting that LUTS are associated with the metabolic syndrome (MetS) [20▪,21]. Lifestyle modifications can positively influence MetS, and hence might be able to influence LUTS. The impact of lifestyle on LUTS is discussed elsewhere in this journal's issue. However, if MetS is associated with LUTS, drugs used for the treatment of MetS might be used as well to tackle LUTS. To assess this issue, Gacci et al.[22▪▪] performed a meta-analysis. According to their calculations, MetS, as defined by the American Heart Association, is clearly associated with an increased prostate size (+1.8 ml prostate volume; 95% CI: 0.74–2.87), but not with different International Prostate Symptom Score (IPSS). Referring to this high level of evidence data, it might be speculated that treating MetS could prevent development or progression of BPH, and hence act prophylactically in avoiding BPH-related LUTS. Accordingly, observational studies did not report any benefit of statins (drugs used for the lowering of blood lipids) in regards to LUTS [23]. But, evenly in accordance, a retrospective study [24] reported a beneficial impact of statins on prostate size (−1.8% of prostate volume over 1 year statin intake). Even though the latter data need to be confirmed in further studies, it just might be stated that, particularly regarding further potential, beneficial effects of statins in urology [14], the role of lipid level modifying drugs seems worth being further explored in preventing BPH/LUTS.

Inflammatory origin

In health, the prostate is populated by a small number of primarily T-cell receptor lymphocytes (T-cells) [25]. In BPH, T-cells were reported to be upregulated and chronically activated [25]. Histologically, it is known that prostate cell hyperplasia does not occur evenly distributed throughout the organ, but occurs concentrated in so-called nodules [26]. Accordingly, it has been reported that the lymphocyte profiles and cytokine expression patterns differ between nodules and regions of normal cell histology in BPH specimen [27,28]. As recently summarized by Gandaglia et al.[29▪], various studies assessed the immune profile in BPH, and all suggest a state of increased chronic T-cell mediated inflammation with a cytokine profile promoting growth factor release and cell proliferation. In consequence, it was concluded that a persistent process of immune cell-mediated stimulation of prostatic cells results in BPH. In a just published autopsy study [30▪], it was shown that men with chronic inflammation had a 6.8-fold higher risk of BPH than those without chronic inflammation. Despite the strong correlation between BPH and inflammation, there seems to be only a week relationship between histological signs of chronic inflammation and LUTS severity. In the Reduction by Dutasteride of Prostate Cancer Events Trial (REDUCE) trial [31], assessing 8151 men, chronic inflammation and IPSS showed only a correlation coefficient of 0.036, whereas 1 would indicate complete correlation, and 0, no correlation.

As such, it could be assumed that drugs reducing inflammation, for example, NSAIDs, should affect BPH and prostatic growth, but might have only minor effects on LUTS. Regrettably, high-quality data on this field are scarce, and reported outcomes are controversial. In a recently published meta-analysis, out of 381 initially identified articles, only 33 were eligible, and out of those only three, as good quality randomized controlled trials, could be included in the analysis [32▪▪]. According to this report, the mean difference was a −2.89 IPSS point reduction (95% CI: −3.83–−1.95) for a 4–6 week NSAID intake compared to placebo. Prostate size and growth was not assessed in the meta-analysis. However, long-term observational data, as for example in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, report no beneficial use of NSAIDs in regards to BPH and/or LUTS. In between 1993–2001, the PLCO cancer screening trial prospectively assessed 76 705 men in the USA, out of those, 4771 were eligible for an analysis regarding BPH/LUTS. Out of those 4771 men (aged 55–74 years), all of which had no BPH or LUT dysfunction at baseline (exclusion criterion), 27.4% reported a daily use of aspirin, and 7.0% a daily use of ibuprofen. Over an observation period of 5–13 years, 1536 of the 4771 men (30.6%) reported the diagnosis of BPH. Hereby, the risk of BPH diagnosis was not associated with any regular NSAID intake [33]. Despite those controversial data, regarding the clear involvement of inflammation in histological BPH development but a lacking effect of NSAIDs in protecting from BPH development, as well as inconsistent data on LUTS, it seems worthwhile to further explore the role between inflammation and BPH/LUTS – particularly as modern drug development might provide us with new and better-to-be-tolerated NSAIDs.

Researchwise, it should be emphasized that, apart from the clear role of chronic inflammation in BPH development, the truly intriguing question seems to be ‘what initiates chronic inflammation in the prostate’. Bacterial infections, virus infections, autoimmune mechanisms, local hypoxia, oxidative stress, and MetS, all of which have been discussed in the context of chronic prostatic inflammation; but summing up, none of which has yielded so far in a convincing and proven hypothesis [29▪,34–39].

NEW CONCEPTS REGARDING LOWER URINARY TRACT SYMPTOMS

Our new understanding that LUTS are not only related to an increase in prostate size, but rely on a whole sequelae of pathophysiological changes within the bladder, as well as the bladder blood supply, and the bladder innervation, opens up a whole new arena of the most various receptors, signaling molecules, and biochemical pathways, all of which might be of value for LUTS treatment. However, it should be said that new revelations about how LUTS are working does not only bear the prospect of potential new drugs, but also challenges our views on how established drugs are acting. It goes beyond the scope of this review to specify all the implications the new concepts of LUTS have on our views how established drugs work. The following part of this review aims only to give an overview about some (not all) potential pharmacological approaches, which occurred in the rise of our new LUTS understanding.

Transient receptor potential cation channel subfamily V member 1 antagonists

Transient receptor potential cation channel subfamily V member 1 (TRPV1) is an ion channel, which is expressed in bladder afferent nerves and in the urothelium. Several basic research studies suggest a beneficial effect of TRPV1 (and TRPV4) antagonists in bladder overactivity [40]. As an example, in one of the most recent reports the TRPV1 antagonist JTS-653 was shown to reduce afferent nerve firing, and micturition frequency in rats. Intravesical instillation of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, significantly increased the number of electrophysiologically measured bladder afferent nerve impulses per second [41]. This increase of nerve discharge by RTX could be prevented when rats were administered JTS-653 intravenously 5 min prior to electrophysiological recording experiments. In urodynamic experiments, JTS-653, given orally 2 h prior to experiments, was able to completely reverse the increase of micturition frequency, which was induced by intravesical RTX instillation. Thus, the authors concluded that JTS-653 (or in general, TRPV1 antagonism) might be a therapeutic approach to treat OAB [41]. To the best of our knowledge, no TRPV1 antagonist has been tested clinically in regards to OAB and/or LUTS. TRPV1 is also involved in nociception, and thus, TRPV1 antagonist might also be useful in alleviating pain. However, most TRPV1 antagonists tested clinically in humans were not further developed because of their hyperthermic effects [42]. However, just recently another TRPV1 antagonist, AZD1386, has been tested successfully in humans. AZD1386, given orally at a single dose to healthy men and women, was well tolerated (no hyperthermia) and resulted in a meaningful pain relief upon third molar extraction [43▪▪]. As the latter compound has already been tested successfully in humans, it seems tempting to evaluate this compound, or other TRPV1 antagonists in clinical development (e.g., SB-705498), in patients with OAB/LUTS.

Fatty acid amide hydrolase inhibitors

The cannabinoid system has been recognized to be involved in the micturition process [44]. In basic research experiments cannabinoid type 1 as well as cannabinoid type 2 receptor agonists showed promising results in reducing bladder overactivity [45▪]. However, the use of cannabinoid agonists seems problematic because of the potential well known central nervous side-effects of cannabinoids. A novel approach to harness the cannabinoid system without inducing central nervous system side-effects might be to inhibit the breakdown of endogenous cannabinoids [46,47]. Fatty acid amide hydrolases (FAAHs) are enzymes degrading endocannabinoids and are expressed in the bladder as well as in bladder controlling neuronal structures [48,49]. Different FAAH inhibitors have been shown to reduce micturition frequency in chemical as well as mechanical (obstruction) models of bladder overactivity [49,50]. FAAH inhibitors were shown to reduce bladder afferent nerve firing in electrophysiological recording experiments [51]. Existing basic research data suggest that FAAH inhibition might be of therapeutic value in obstruction-related (BPH) LUTS as well as in OAB (storage LUTS). To the best of our knowledge, no FAAH inhibitor has been tested in humans so far for urological diseases. However, in pain research a FAAH inhibitor, PF-04457845, has been successfully tested in humans [52]. Even though the clinical outcome in regard to pain relief was disappointing [53], it appears very interesting to evaluate this substance in regards to BPH/LUTS and OAB/LUTS.

Soluble guanylyl cyclase stimulators/activators

Phosphodiesterase type 5 inhibitors are approved for the treatment of male LUTS. Even though the exact mechanism of action is still under debate, there is agreement that the relevant biochemical effect is an inhibition of the cyclic guanosine monophosphate (cGMP) degradation [54]. An alternative way to increase cGMP levels is to boost cGMP synthesis through activation or stimulation of soluble guanylyl cyclase (sGC), the enzyme responsible for cGMP synthesis. BAY 60–2770, an sGC activator, was able to induce beneficial effects on erection in normal rats, and in rats with cavernosal nerve crush injury [55], and was shown to reduce urodynamic signs of bladder overactivity in obese mice [56]. When BAY 60–2770, an sGC activator, and BAY 41–2272, an sGC stimulator, were tested urodynamically in rats with urethral obstruction-related bladder overactivity, they both reduced urodynamic signs of bladder overactivity, which were similar to the urodynamic effects of vardenafil [57]. Hereby, the effects of BAY 60–2770 (activator) were more pronounced than the effects of BAY 41–2272 (stimulator). As sGC stimulators target reduced sGC, and sGC activators target oxidized sGC (hence, in a redox state in which oxidation is promoted), the different efficacy of the compounds was interpreted that in obstruction-related bladder overactivity, the level of oxidative stress is higher (oxidation). Thus explaining the higher efficacy of an sGC activator in obstruction-related bladder overactivity [57]. Neither BAY 60–2770 nor BAY 41–2272 has been tested in humans. However, currently riociguat (BAY 63–2521, an sGC stimulator) undergoes clinical trials for pulmonary hypertension [57], and cinaciguat (BAY 58–2667, an sGC activator) is tested in patients with heart failure [58▪▪]. Both compounds have not been tested yet preclinically in regards to bladder function. Because of the strong effects of sGC stimulators as well as activators on blood pressure, the value of those compounds in BPH/LUTS needs to be awaited.

Rho-kinase inhibitors

Rho-kinases are effectors of the small G-protein Rho, which has a seminal role in transducing signals from membrane-located receptors to intracellular second-messenger systems. Rho-kinases themselves have various substrates, and hence have various effects. Among others, they influence via myosin light-chain kinases contraction of smooth muscle cells. The rationale to use Rho-kinase inhibitors in LUT dysfunction is mainly based upon relaxing effects of Rho-kinase inhibitors on smooth muscle cells within the LUT [59▪▪]. Burmeister et al.[60] had shown in PCR experiments that in rats with partial urethral obstruction, rock1 expression (rock1 = gene of Rho kinase 1) is significantly higher in those animals that showed urodynamic signs of bladder overactivity than in those that showed no BO. In various animal experiments, Rho-kinase inhibitors were shown to reduce urodynamic signs of ischemia-induced or chemical-induced bladder overactivity [61,62]. Rho-kinase inhibition was furthermore shown to reduce prostatic smooth muscle cell contraction in mice [63] and guinea pigs [64]. So far, experimental data suggest a beneficial effect of Rho-kinase inhibiton on BPH and/or LUTS. Currently, Rho-kinase inhibitors, such as fasudil hydrochloride (AT-877) or K-115, are tested in clinics for very special indications, such as pulmonary hypertension or glaucoma (topical) [65,66▪▪]. An evaluation of these compounds in regards to BPH/LUTS might be promising.

Purinergic receptor blockers

Purinergic receptors in the LUT are located on smooth muscle cells, interstitial cells, neurons, as well as urothelium, and are involved in contraction/relaxation of the detrusor, as well as in neuronal control of the micturition on several levels (locally, peripherally, and within the CNS) [67]. In healthy humans, the purinergic component of bladder parasympathetic neurotransmission is estimated to be only 3% (in contrast to the dominating muscarinergic component). However, in disease scenarios, purinergic transmission in the bladder might account for up to 40% of parasympathetic innervation [67]. ATP is a ligand to purinergic P2X and P2Y receptors. In women with OAB, urinary ATP concentrations were elevated, and inversely correlated with the urodynamic ‘first desire to void’ volume [68▪▪]. Latest evidence suggests that bladder stretch released ATP is an important mediator of urgency in the early phase of bladder filling in patients suffering from OAB [69]. As recently reviewed in detail by Burnstock [67], purinergic receptor expression in various components of the LUT, as well as tissue responses to ATP exposure in organ bath experiments, is altered in various voiding disorders, such as neurogenic and idiopathic detrusor overactivity, diabetes, ischemia, and multiple sclerosis-related bladder dysfunctions, as well as in bladder outflow obstruction and BPH. Urothelial tissue from BPH patients was reported to secrete significantly higher amounts of ATP under stretch than control tissue [70▪]. In summary, there is abundant evidence for purinergic transmission in the bladder (particularly P2X1 receptors) and in sensory bladder neurons (particularly P2X3 receptors) [67]. Several P2X1 and P2X3 antagonists are available, but, to our knowledge, none of which has ever been tested clinically in humans.

Others

Several other new approaches might be worth being further explored for a potential therapeutic value in BPH/LUTS. Among these are nerve growth factor blockade [71], HSV vector-mediated gene therapy [72▪,73], targeting of beta1-integrins [74▪], endothelin [75], and many more [76,77]. But, it should also be mentioned that promising basic research evidence might not necessarily result in a successful clinical translation, as to be seen on the ‘failure’ of past promising future drug candidates. For neurokinins as well as for prostaglandins, there was good preclinical evidence that they might be of value in treating LUTS [78–80]. But, recently published clinical data showed no meaningful effect of neither netupitant, a neurokinin receptor antagonist, nor ONO-8539, a prostaglandin (subtype EP1) receptor antagonist, in LUTS [81,82▪▪,83▪▪].

CONCLUSION

New concepts on BPH cause are still in the early stages, but seem to be the most promising in bringing forward a potential causal treatment for BPH-related LUTS. In regards to genetic reasons for BPH development, genome-wide association studies are lacking. BPH and the MetS seem to share common pathophysiological mechanisms, and thus, therapies targeting common mechanisms bear the prospect to treat MetS and prevent BPH-related LUTS at the same time. BPH is nowadays clearly linked with inflammation. So far the use of anti-inflammatory drugs failed to show any convincing evidence justifying their use in clinical routine. However, that might change with the ongoing development of new anti-inflammatory drugs. In addition, the most interesting question to be answered seems to be ‘why the prostate gets inflamed’. Uncovering this relationship might have the biggest potential to result in a causal treatment of BPH-related LUTS.

Based upon our new understanding of LUTS, several new molecular targets have been identified within the last years. Particularly, TRPV1, FAAH, sGC, Rho-kinases, and purinergic receptors appear to be promising candidates for drug targeting. AZD1386, a TRPV1 antagonist, PF-04457845, a FAAH inhibitor, BAY 63–2521 and BAY 58–2667, an sGC stimulator and an sGC activator, respectively, as well as AT-877 and K-115, Rho-kinase inhibitors, are currently tested in early clinical trials for other than urological indications. Initiating clinical trials with one of those substances in patients with LUTS might be worth trying.

Acknowledgements

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

REFERENCES

1. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984; 132:474–479.
2. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. The Veterans Affairs Cooperative Study Group on Transurethral Resection of the Prostate. N Engl J Med 1995; 332:75–79.
3. Abrams P. Benign prostatic hyperplasia. Poorly correlated with symptoms. Bmj 1993; 307:201.
4. Dmochowski RR, Staskin D. Overactive bladder in men: special considerations for evaluation and management. Urology 2002; 60 (5 Suppl 1):56–63.
5. Levin RM, Longhurst PA, Monson FC, et al. Effect of bladder outlet obstruction on the morphology, physiology, and pharmacology of the bladder. Prostate Suppl 1990; 3:9–26.
6. Andersson KE. Emptying against outflow obstruction: pharmacological aspects. Scand J Urol Nephrol Suppl 1997; 184:77–84.
7. Andersson KE. New roles for muscarinic receptors in the pathophysiology of lower urinary tract symptoms. BJU Int 2000; 86 (Suppl 2):36–43.
8. Kaplan SA, Walmsley K, Te AE. Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. J Urol 2005; 174:2273–2276.
9. Chapple CR, Roehrborn CG. A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: focus on the bladder. Eur Urol 2006; 49:651–658.
10. Roosen A, Chapple CR, Dmochowski RR, et al. A refocus on the bladder as the originator of storage lower urinary tract symptoms: a systematic review of the latest literature. Eur Urol 2009; 56:810–819.
11. Bosch RJ. Pathogenesis of benign prostatic hyperplasia. Eur Urol 1991; 20 (Suppl 1):27–30.
12. Wilson JD. The pathogenesis of benign prostatic hyperplasia. Am J Med 1980; 68:745–756.
13. Untergasser G, Madersbacher S, Berger P. Benign prostatic hyperplasia: age-related tissue-remodeling. Exp Gerontol 2005; 40:121–128.
14. Solomon KR, Freeman MR. The complex interplay between cholesterol and prostate malignancy. Urol Clin North Am 2011; 38:243–259.
15. Partin AW, Page WF, Lee BR, et al. Concordance rates for benign prostatic disease among twins suggest hereditary influence. Urology 1994; 44:646–650.
16. Roberts RO, Rhodes T, Panser LA, et al. Association between family history of benign prostatic hyperplasia and urinary symptoms: results of a population-based study. Am J Epidemiol 1995; 142:965–973.
17▪▪. Cartwright R, Mangera A, Tikkinen KA, et al. Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men. Eur Urol 2014; 66:752–768.

As a meta-analysis, providing the highest level of evidence regarding current knowledge about genetic reasons for BPH/LUTS.

18. Vaughan CP, Johnson TM 2nd, Goode PS, et al. Vitamin D and lower urinary tract symptoms among US men: results from the 2005–2006 National Health and Nutrition Examination Survey. Urology 2011; 78:1292–1297.
19. Colli E, Rigatti P, Montorsi F, et al. BXL628, a novel vitamin D3 analog arrests prostate growth in patients with benign prostatic hyperplasia: a randomized clinical trial. Eur Urol 2006; 49:82–86.
20▪. Kupelian V, McVary KT, Kaplan SA, et al. Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston area community health survey. J Urol 2013; 189 (1 Suppl):S107–S116.

Good epidemiological data to support the association between MetS and LUTS.

21. Rohrmann S, Smit E, Giovannucci E, Platz EA. Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes (Lond) 2005; 29:310–316.
22▪▪. Gacci M, Corona G, Vignozzi L, et al. Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis. BJU Int 2014; [Epub ahead of print].

As a meta-analysis, providing the highest level of evidence regarding current knowledge about the association between MetS and LUTS.

23. Mondul AM, Giovannucci E, Platz EA. A prospective study of statin drug use and lower urinary tract symptoms in older men. Am J Epidemiol 2013; 178:797–803.
24. Lee SH, Park TJ, Bae MH, et al. Impact of treatment with statins on prostate-specific antigen and prostate volume in patients with benign prostatic hyperplasia. Korean J Urol 2013; 54:750–755.
25. Steiner G, Gessl A, Kramer G, et al. Phenotype and function of peripheral and prostatic lymphocytes in patients with benign prostatic hyperplasia. J Urol 1994; 151:480–484.
26. McNeal J. Pathology of benign prostatic hyperplasia. Insight into etiology. Urol Clin North Am 1990; 17:477–486.
27. Steiner GE, Stix U, Handisurya A, et al. Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Invest 2003; 83:1131–1146.
28. Steiner GE, Djavan B, Kramer G, et al. The picture of the prostatic lymphokine network is becoming increasingly complex. Rev Urol 2002; 4:171–177.
29▪. Gandaglia G, Briganti A, Gontero P, et al. The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH). BJU Int 2013; 112:432–441.

Good review summarizing our current knowledge about the association between inflammation and BPH/LUTS.

30▪. Zlotta AR, Egawa S, Pushkar D, et al. Prevalence of inflammation and benign prostatic hyperplasia on autopsy in Asian and Caucasian men. Eur Urol 2014; 66:619–622.

Important study showing in autopsies the relevance of prostatic inflammation in the development of BPH.

31. Nickel JC, Roehrborn CG, O’Leary MP, et al. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol 2008; 54:1379–1384.
32▪▪. Kahokehr A, Vather R, Nixon A, Hill AG. Nonsteroidal anti-inflammatory drugs for lower urinary tract symptoms in benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. BJU Int 2013; 111:304–311.

As a meta-analysis providing the highest level of evidence regarding current knowledge about the use of NSAIDs in LUTS.

33. Sutcliffe S, Grubb Iii RL, Platz EA, et al. Nonsteroidal anti-inflammatory drug use and the risk of benign prostatic hyperplasia-related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. BJU Int 2012; 110:1050–1059.
34. Hochreiter WW, Duncan JL, Schaeffer AJ. Evaluation of the bacterial flora of the prostate using a 16S rRNA gene based polymerase chain reaction. J Urol 2000; 163:127–130.
35. Madigan AA, Sobek KM, Cummings JL, et al. Activation of innate antiviral immune response genes in symptomatic benign prostatic hyperplasia. Genes Immun 2012; 13:566–572.
36. Berger AP, Kofler K, Bektic J, et al. Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia. Prostate 2003; 57:57–65.
37. Pace G, Di Massimo C, De Amicis D, et al. Oxidative stress in benign prostatic hyperplasia and prostate cancer. Urol Int 2010; 85:328–333.
38. Kasturi S, Russell S, McVary KT. Metabolic syndrome and lower urinary tract symptoms secondary to benign prostatic hyperplasia. Curr Urol Rep 2006; 7:288–292.
39. Chughtai B, Lee R, Te A, Kaplan S. Inflammation and benign prostatic hyperplasia: clinical implications. Curr Urol Rep 2011; 12:274–277.
40. Soler R, Andersson KE, Chancellor MB, et al. Future direction in pharmacotherapy for nonneurogenic male lower urinary tract symptoms. Eur Urol 2013; 64:610–621.
41. Kitagawa Y, Wada M, Kanehisa T, et al. JTS-653 blocks afferent nerve firing and attenuates bladder overactivity without affecting normal voiding function. J Urol 2013; 189:1137–1146.
42. Gavva NR, Treanor JJ, Garami A, et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 2008; 136:202–210.
43▪▪. Quiding H, Jonzon B, Svensson O, et al. TRPV1 antagonistic analgesic effect: a randomized study of AZD1386 in pain after third molar extraction. Pain 2013; 154:808–812.

Clinical study to show well tolerability of a TRPV1 antagonist in humans.

44. Ruggieri MR Sr. Cannabinoids: potential targets for bladder dysfunction. Handb Exp Pharmacol 2011; 425–451.
45▪. Hedlund P. Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 2014; 33:46–53.

Good review providing an overview about the (endo-)cannabinoid system in LUT control.

46. Apostolidis A. Taming the cannabinoids: new potential in the pharmacologic control of lower urinary tract dysfunction. Eur Urol 2012; 61:107–111.
47. Benigni F, Hedlund P. Reply from Authors re: Apostolos Apostolidis. Taming the cannabinoids: new potential in the pharmacologic control of lower urinary tract dysfunction. Eur Urol 2012; 61:107–109.
48. Strittmatter F, Gandaglia G, Benigni F, et al. Expression of fatty acid amide hydrolase (FAAH) in human, mouse, and rat urinary bladder and effects of FAAH inhibition on bladder function in awake rats. Eur Urol 2012; 61:98–106.
49. Fullhase C, Russo A, Castiglione F, et al. Spinal cord FAAH in normal micturition control and bladder overactivity in awake rats. J Urol 2013; 189:2364–2370.
50. Gandaglia G, Strittmatter F, La Croce G, et al. The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats. Neurourol Urodyn 2013; [Epub ahead of print].
51. Aizawa N, Hedlund P, Fullhase C, et al. Inhibition of peripheral FAAH depresses activities of bladder mechanosensitive nerve fibers of the rat. J Urol 2014; 192:956–963.
52. Li GL, Winter H, Arends R, et al. Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br J Clin Pharmacol 2012; 73:706–716.
53. Huggins JP, Smart TS, Langman S, et al. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain 2012; 153:1837–1846.
54. Giuliano F, Uckert S, Maggi M, et al. The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Eur Urol 2013; 63:506–516.
55. Lasker GF, Pankey EA, Frink TJ, et al. The sGC activator BAY 60-2770 has potent erectile activity in the rat. Am J Physiol Heart Circ Physiol 2013; 304:H1670–H1679.
56. Leiria LO, Silva FH, Davel AP, et al. The soluble guanylyl cyclase activator BAY 60-2770 ameliorates overactive bladder in obese mice. J Urol 2014; 191:539–547.
57. Füllhase C, Hennenberg M, Sandner P, et al. Reduction of obstruction related bladder overactivity by the guanylyl cyclase modulators BAY 41-2272 and BAY 60-2770 alone or in combination with a phosphodiesterase type 5 inhibitor. Neurourol Urodyn 2014 [Epub ahead of print]. doi: 10.1002/nau.22665.
58▪▪. Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation 2013; 128:502–511.

Clinical study to show well tolerability of an sGC stimulator in humans.

59▪▪. Erdmann E, Semigran MJ, Nieminen MS, et al. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. Eur Heart J 2013; 34:57–67.

Clinical study to show well tolerability of an sGC activator in humans.

60. Christ GJ, Andersson KE. Rho-kinase and effects of Rho-kinase inhibition on the lower urinary tract. Neurourol Urodyn 2007; 26 (6 Suppl):948–954.
61. Burmeister D, AbouShwareb T, D’Agostino R Jr, et al. Impact of partial urethral obstruction on bladder function: time-dependent changes and functional correlates of altered expression of Ca(2)(+) signaling regulators. Am J Physiol Renal Physiol 2012; 302:F1517–F1528.
62. Inoue S, Saito M, Takenaka A. Hydroxyfasudil ameliorates bladder dysfunction in male spontaneously hypertensive rats. Urology 2012; 79:1186e9–1186e11.
63. Masago T, Watanabe T, Saito M, et al. Effect of the rho-kinase inhibitor hydroxyfasudil on bladder overactivity: an experimental rat model. Int J Urol 2009; 16:842–847.
64. White CW, Short JL, Ventura S. Rho kinase activation mediates adrenergic and cholinergic smooth muscle contractile responses in the mouse prostate gland. Eur J Pharmacol 2013; 721:313–321.
65. Lam M, Kerr KP, Exintaris B. Involvement of Rho-kinase signaling pathways in nerve evoked and spontaneous contractions of the guinea pig prostate. J Urol 2013; 189:1147–1154.
66▪▪. Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J 2013; 77:2619–2625.

Clinical study to show well tolerability of a Rho-kinase inhibitor in humans.

67. Tanihara H, Inoue T, Yamamoto T, et al. Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115. JAMA Ophthalmol 2013; 131:1288–1295.
68▪▪. Burnstock G. Purinergic signalling in the urinary tract in health and disease. Purinergic Signal 2014; 10:103–155.

Excellent review providing an overview on purinergic receptors in the LUT.

69. Cheng Y, Mansfield KJ, Allen W, et al. Does adenosine triphosphate released into voided urodynamic fluid contribute to urgency signaling in women with bladder dysfunction? J Urol 2010; 183:1082–1086.
70▪. Cheng Y, Mansfield KJ, Allen W, et al. ATP during early bladder stretch is important for urgency in detrusor overactivity patients. Biomed Res Int 2014; 2014:204604.

Interesting study providing information about the role of ATP (purinergic receptor ligand) in urgency.

71. Sun Y, MaLossi J, Jacobs SC, Chai TC. Effect of doxazosin on stretch-activated adenosine triphosphate release in bladder urothelial cells from patients with benign prostatic hyperplasia. Urology 2002; 60:351–356.
72▪. Kashyap M, Kawamorita N, Tyagi V, et al. Down-regulation of nerve growth factor expression in the bladder by antisense oligonucleotides as new treatment for overactive bladder. J Urol 2013; 190:757–764.

Interesting study about the idea to target nerve growth factor as a treatment for storage LUTS.

73. Yokoyama H, Oguchi T, Goins WF, et al. Effects of herpes simplex virus vector-mediated enkephalin gene therapy on bladder overactivity and nociception. Hum Gene Ther 2013; 24:170–180.
74▪. Funahashi Y, Oguchi T, Goins WF, et al. Herpes simplex virus vector mediated gene therapy of tumor necrosis factor-alpha blockade for bladder overactivity and nociception in rats. J Urol 2013; 189:366–373.

Interesting study about the idea of gene therapy in LUTS treatment.

75. Kanasaki K, Yu W, von Bodungen M, et al. Loss of beta1-integrin from urothelium results in overactive bladder and incontinence in mice: a mechanosensory rather than structural phenotype. Faseb J 2013; 27:1950–1961.
76. Schroder A, Tajimi M, Matsumoto H, et al. Protective effect of an oral endothelin converting enzyme inhibitor on rat detrusor function after outlet obstruction. J Urol 2004; 172:1171–1174.
77. Hennenberg M, Stief CG, Gratzke C. Prostatic alpha1-adrenoceptors: new concepts of function, regulation, and intracellular signaling. Neurourol Urodyn 2014; 33:1074–1085.
78. Andersson KE. Future therapies: early trials and basic science. Can Urol Assoc J 2013; 7 (9–10 Suppl 4):S179–S180.
79. Arms L, Vizzard MA. Neuropeptides in lower urinary tract function. Handb Exp Pharmacol 2011; 395–423.
80. Yamauchi H, Akino H, Ito H, et al. Urinary prostaglandin E(2) was increased in patients with suprapontine brain diseases, and associated with overactive bladder syndrome. Urology 2010; 76:1267 e13–1267 e19.
81. Aoki K, Hirayama A, Tanaka N, et al. A higher level of prostaglandin E2 in the urinary bladder in young boys and boys with lower urinary tract obstruction. Biomed Res 2009; 30:343–347.
82▪▪. Haab F, Braticevici B, Krivoborodov G, et al. Efficacy and safety of repeated dosing of netupitant, a neurokinin-1 receptor antagonist, in treating overactive bladder. Neurourol Urodyn 2014; 33:335–340.

Clinical study on the (vain) use of a neurokinin receptor blocker in patients with storage LUTS.

83▪▪. Chapple CR, Abrams P, Andersson KE, et al. Phase II study on the efficacy and safety of the EP1 receptor antagonist ONO-8539 for nonneurogenic overactive bladder syndrome. J Urol 2014; 191:253–260.
Keywords:

drug therapy; lower urinary tract symptoms; prostatic hyperplasia; urinary bladder

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.