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New medical treatments for lower urinary tract symptoms due to benign prostatic hyperplasia and future perspectives | BMC Urology
        

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# New medical treatments for lower urinary tract symptoms due to benign prostatic hyperplasia and future perspectives

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  * Published: 15 September 2016


  * Volume 16, article number 58, (2016) 
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New medical treatments for lower urinary tract symptoms due to benign prostatic hyperplasia and future perspectives 

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  * Simone Albisinni [ORCID: orcid.org/0000-0001-5529-3064](http://orcid.org/0000-0001-5529-3064)1, 
  * Ibrahim Biaou1, 
  * Quentin Marcelis1, 
  * Fouad Aoun1, 
  * Cosimo De Nunzio2 &
  * …
  * Thierry Roumeguère1

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  * 6835 Accesses

  * 17 Citations

  * 1 Altmetric

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## Abstract

### Background

Lower Urinary Tract Symptoms (LUTS) in men are a common clinical problem in urology and have been historically strictly linked to benign prostatic hyperplasia (BPH), which may lead to bladder outlet obstruction (BOO). New molecules have been approved and have entered the urologists’ armamentarium, targeting new signaling pathways and tackling specific aspects of LUTS. Objective of this review is to summarize the evidence regarding the new medical therapies currently available for male non-neurogenic LUTS, including superselective α1-antagonists, PDE-5 inhibitors, anticholinergic drugs and intraprostatic onabotulinum toxin injections.

### Methods

The National Library of Medicine Database was searched for relevant articles published between January 2006 and December 2015, including the combination of “BPH”, “LUTS”, “medical” and “new”. Each article’s title, abstract and text were reviewed for their appropriateness and their relevance. One hundred forty eight articles were reviewed.

### Results

Of the 148 articles reviewed, 92 were excluded. Silodosin may be considered a valid alternative to non-selective α1-antagonists, especially in the older patients where blood pressure alterations may determine major clinical problems and ejaculatory alterations may be not truly bothersome. Tadalafil 5 mg causes a significant decrease of IPSS score with an amelioration of patients’ QoL, although with no significant increase in Qmax. Antimuscarinic drugs are effective on storage symptoms but should be used with caution in patients with elevated post-void residual. Intraprostatic injections of botulinum toxin are well-tolerated and effective, with a low rate of adverse events; however profound ameliorations were seen also in the sham arms of RCTs evaluating intraprostatic injections.

### Conclusion

New drugs have been approved in the last years in the medical treatment of BPH-related LUTS. Practicing urologists should be familair with their pharmacodynamics and pharmacokinetics.

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## Background

Lower Urinary Tract Symptoms (LUTS) in men are a common clinical problem in urology, and have been historically strictly linked to benign prostatic hyperplasia (BPH). These are classified into storage, voiding and post micturition symptoms [[1](/article/10.1186/s12894-016-0176-0#ref-CR1 "Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Am J Obstet Gynecol. 2002;187:116–26.")]. However, BPH does not describe symptoms, but is instead a histologic diagnosis, characterized by a micronodular hyperplasia evolving into a macroscopic nodular enlargement, which in turn may determine bladder outlet obstruction (BOO). Although BOO as a consequence of BPH may be responsible for a part of male LUTS, studies have found that the prostate is not the only actor in the complex play of male LUTS. The bladder and it’s articulated neuronal control has been found to be another main character in this plot [[2](/article/10.1186/s12894-016-0176-0#ref-CR2 "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;49:651–8.")]. To support this theory, also women suffer from storage LUTS, with overactive bladder (OAB) being the most frequent cause. Moreover, although voiding LUTS are the most common symptoms in BPH, storage are the most bothersome with great impact on the patients’ quality of life (QoL) [[3](/article/10.1186/s12894-016-0176-0#ref-CR3 "Peters TJ, Donovan JL, Kay HE, Abrams P, de la Rosette JJ, Porru D, et al. The International Continence Society “Benign Prostatic Hyperplasia” Study: the botherosomeness of urinary symptoms. J Urol. 1997;157:885–9.")]. As such, today it is insufficient and inappropriate to consider the prostate as the only therapeutic target in the management of LUTS in men, even when BOO is present. Rather, the entire lower urinary tract, from the afferent sensory nerves to the urethra, must be seen as a whole and in this direction research is moving [[4](/article/10.1186/s12894-016-0176-0#ref-CR4 "Soler R, Andersson K-E, Chancellor MB, Chapple CR, de Groat WC, Drake MJ, et al. Future direction in pharmacotherapy for non-neurogenic male lower urinary tract symptoms. Eur Urol. 2013;64:610–21.")].

Historically, the standard medical treatment for LUTS in men with BPH included α1-antagonists, 5α-reductase inhibitors and phytotherapy. These agents remain indeed today the mainstay of BPH treatment. Nonetheless, albeit full dose treatment, some patients remain symptomatic or may experience BPH progression, defined as the onset of acute urinary retention (AUR), urinary infection (UI) or the need of BPH-related surgery [[5](/article/10.1186/s12894-016-0176-0#ref-CR5 "Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192–202.")]. In addition, the drugs routinely used in the management of LUTS carry potential adverse effects (AE), which in turn may be the cause of non-compliance of patients [[6](/article/10.1186/s12894-016-0176-0#ref-CR6 "Masumori N, Hashimoto J, Itoh N, Tsukamoto T, Group TSMUNS. Short-term efficacy and long-term compliance/treatment failure of the alpha1 blocker naftopidil for patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Scand J Urol Nephrol. 2007;41:422–9.")]. Therefore, research is progressing in order to expand and optimize medical strategies in the management of BPH-related LUTS. Selective α1-antagonists, phosphodiesterase 5 (PDE5) inhibitors, and anticholinergics have been tested and have entered our armamentarium for the management of male LUTS. These agents, their pharmacodynamics, pharmacokinetics and AEs should be well known to the practicing urologist. Furthermore, our knowledge of bladder and prostatic molecular anatomy is constantly growing, and in parallel new biomolecular targets are being identified and explored as new candidates in BPH management. Objective of this systematic review is to summarize the evidence regarding the new medical therapies currently available for BPH-related LUTS, and to give an overview on current research and agents which may enter our everyday clinical practice in the close future.

## Methods

The National Library of Medicine Database was searched for relevant articles published between January 2006 and December 2015. A wide search was performed including the combination of following words: “BPH”, “LUTS”, “medical” “new”. Although recent articles were prioritized, manuscripts with relevant historical findings were referenced if necessary. Publications in English language were preferred, though if necessary data was extrapolated even from manuscripts in other languages. Evidence was not limited to human data; results from animal and in vitro experiments were also included in the review. Helsinki declaration principles were respected and informed consent was obtained. Each article’s title, abstract and text were reviewed for their appropriateness and their relevance. The initial list of selected papers was enriched by individual suggestions of the authors of the present review. Overall, 148 articles were reviewed. Of these, 92 were excluded after screening by the authors, leaving 56 articles eligible for the review (Fig. [1](/article/10.1186/s12894-016-0176-0#Fig1)).

**Fig. 1**

[![figure 1](//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12894-016-0176-0/MediaObjects/12894_2016_176_Fig1_HTML.gif)](/article/10.1186/s12894-016-0176-0/figures/1)

Flowchart of literature search

[Full size image](/article/10.1186/s12894-016-0176-0/figures/1)

## Results and Discussion

### Selective α1-antagonists

α1-receptors are highly concentrated along the urinary and ejaculatory tracts [[7](/article/10.1186/s12894-016-0176-0#ref-CR7 "Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006;147 Suppl 2:S88–119.")], and non-selective α1-antagonists, alfuzosin, doxazosin, terazosin and tamsulosine are today the first line medical treatment in men with moderate to severe symptoms of BPH [[8](/article/10.1186/s12894-016-0176-0#ref-CR8 "Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64:118–40.")]. There are three main subtypes of α1-receptors expressed in the human organism: α1A, α1B and α1D-receptors. These are all composed of seven transmembrane domains and are coupled with G proteins, and their stimulation results in the activation of phospholipase C with consequent increase in intracellular Ca2+, which in turn stimulates contraction in smooth muscular cells [[7](/article/10.1186/s12894-016-0176-0#ref-CR7 "Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006;147 Suppl 2:S88–119.")]. While α1B-receptors are typically found in vascular tissue, where they mediate arterial contraction, α1A and α1D are more specific of the lower urinary tract [[7](/article/10.1186/s12894-016-0176-0#ref-CR7 "Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol. 2006;147 Suppl 2:S88–119.")]. Kojima et al. explored the expression of these two subtypes in the transitional zone of 28 prostatic tissue of men affected by BPH, and found that 43 % were α1A dominant, whereas 57 % α1Ddominant [[9](/article/10.1186/s12894-016-0176-0#ref-CR9 "Kojima Y, Kubota Y, Sasaki S, Hayashi Y, Kohri K. Translational pharmacology in aging men with benign prostatic hyperplasia: molecular and clinical approaches to alpha1-adrenoceptors. Curr Aging Sci. 2009;2:223–39.")]. These receptors are found also in the human detrusor muscle and in the spinal cord, although the role of these localizations in the pathology of LUTS remains controversial. Moreover, in a rat model, α1-receptors stimulation determined an increase in bladder vascular resistance, with doxazosin determining an increase in bladder blood flow [[10](/article/10.1186/s12894-016-0176-0#ref-CR10 "Das AK, Leggett RE, Whitbeck C, Eagen G, Levin RM. Effect of doxazosin on rat urinary bladder function after partial outlet obstruction. Neurourol Urodyn. 2002;21:160–6.")].

Non-selective α1-antagonists act on the dynamic component of BPH, counteracting smooth muscle contraction in the prostate, which is augmented in BPH, with a consequent increase in urinary flow, reduction of LUTS and improvement in QoL [[11](/article/10.1186/s12894-016-0176-0#ref-CR11 "Yamanishi T, Mizuno T, Tatsumiya K, Watanabe M, Kamai T, Yoshida K-I. Urodynamic effects of silodosin, a new alpha 1A-adrenoceptor selective antagonist, for the treatment of benign prostatic hyperplasia. Neurourol Urodyn. 2010;29:558–62."), [12](/article/10.1186/s12894-016-0176-0#ref-CR12 "Matsukawa Y, Gotoh M, Komatsu T, Funahashi Y, Sassa N, Hattori R. Efficacy of silodosin for relieving benign prostatic obstruction: prospective pressure flow study. J Urol. 2009;182:2831–5.")]. A recent metanalysis has demonstrated the reduction of bladder outlet obstruction index of −30.45 for silodosin, effect which was higher than all other available α1-antagonists [[13](/article/10.1186/s12894-016-0176-0#ref-CR13 "Rossi M, Roumeguère T. Silodosin in the treatment of benign prostatic hyperplasia. Drug Des Devel Ther. 2010;4:291–7.")]. However, due to their concurrent action on α1B-receptors, their use is associated with vascular AE, notably orthostatic hypotension, headaches and dizziness [[8](/article/10.1186/s12894-016-0176-0#ref-CR8 "Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64:118–40.")].

Silodosin is the most recently developed, highly selective antagonist of α1A-receptors. Its selectivity towards α1A-receptor blockade was reported to be 38 times higher than tamsulosin [[13](/article/10.1186/s12894-016-0176-0#ref-CR13 "Rossi M, Roumeguère T. Silodosin in the treatment of benign prostatic hyperplasia. Drug Des Devel Ther. 2010;4:291–7.")]. It has been shown that in vitro silodosin possesses an elevated α1A/α1B binding ratio of 162/1 [[14](/article/10.1186/s12894-016-0176-0#ref-CR14 "Tatemichi S, Kobayashi K, Maezawa A, Kobayashi M, Yamazaki Y, Shibata N. Alpha1-adrenoceptor subtype selectivity and organ specificity of silodosin \(KMD-3213\). Yakugaku Zasshi. 2006;126\(Spec no\):209–16.")], and in vivo experiments have demonstrated its higher affinity for the urinary tract compared to the vascular system [[15](/article/10.1186/s12894-016-0176-0#ref-CR15 "Akiyama K, Noto H, Nishizawa O, Sugaya K, Yamagishi R, Kitazawa M, et al. Effect of KMD-3213, an alpha1A-adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs. Int J Urol Off J Jpn Urol Assoc. 2001;8:177–83.")]. Kobayashi et al. demonstrated that in dogs, while tamsulosin inhibits intraurethral pressure in a dose dependent manner with a concurrent reduction of blood pressure (especially in old dogs), silodosin determines similar effects on intraurethral pressures without altering blood pressure [[16](/article/10.1186/s12894-016-0176-0#ref-CR16 "Kobayashi S, Tomiyama Y, Tatemichi S, Hoyano Y, Kobayashi M, Yamazaki Y. Effects of silodosin and tamsulosin on the urethra and cardiovascular system in young and old dogs with benign prostatic hyperplasia. Eur J Pharmacol. 2009;613:135–40.")]. The recommended dosage is 8 mg once –daily, which has been found to be non-inferior to 4 mg twice-daily in a double-blind randomized controlled trial (RCT) [[17](/article/10.1186/s12894-016-0176-0#ref-CR17 "Choo M-S, Song M, Kim JH, Lee K-S, Kim JC, Kim SW, et al. Safety and efficacy of 8-mg once-daily vs 4-mg twice-daily silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia \(SILVER Study\): a 12-week, double-blind, randomized, parallel, multicenter study. Urology. 2014;83:875–81.")]. After administration, Silodosin is quickly absorbed and has a bioavailability of 32 % at 8 mg/day (therapeutic dose) [[18](/article/10.1186/s12894-016-0176-0#ref-CR18 "Keating GM. Silodosin: a review of its use in the treatment of the signs and symptoms of benign prostatic hyperplasia. Drugs. 2015;75:207–17.")]. Tmax is reached in 2.6 h and half life of the drug is 13.3 h. The drug is then eliminated via fecal (55 %) and renal (45 %) route [[18](/article/10.1186/s12894-016-0176-0#ref-CR18 "Keating GM. Silodosin: a review of its use in the treatment of the signs and symptoms of benign prostatic hyperplasia. Drugs. 2015;75:207–17.")].

On this pharmacologic basis, silodosin has been tested in order to evaluate its non-inferior effect on BPH, while minimizing peripheral vasodilatation and cardiovascular effects which may be cause of falls and fractures, especially in the elderly [[19](/article/10.1186/s12894-016-0176-0#ref-CR19 "Welk B, McArthur E, Fraser L-A, Hayward J, Dixon S, Hwang YJ, et al. The risk of fall and fracture with the initiation of a prostate-selective α antagonist: a population based cohort study. BMJ. 2015;351:h5398.")]. Chapple et al. have explored the efficacy of silodosin in a prospective, placebo controlled trial [[20](/article/10.1186/s12894-016-0176-0#ref-CR20 "Chapple CR, Montorsi F, Tammela TLJ, Wirth M, Koldewijn E, Fernández Fernández E, et al. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011;59:342–52.")]. Nine hundred ninety five European men were randomized to receive either 8 mg silodosin, 0,4 mg tamsulosin or placebo on a daily basis for 12 weeks. The authors found a significant improvement of voiding and storage LUTS after treatment with silodosin compared to placebo (Δ IPSS: 2.3, 95%CI 1.4-3.2, _p_ < 0.001)*, similar to that of tamsulosin, with a significant amelioration of patients’ QoL. Furthermore, silodosin determined a reduction of nycturia (Change from baseline silodosin vs placebo: −0.9 vs-0.7, _p_ = 0.013), effect which was non-significant (_p_ = 0.095) for tamsulosin vs placebo. Silodosin also caused an increase in urinary flow of3.77 ml/s, though this was not significantly higher compared to placebo (_p_ = 0.089). Kawabe et al. reported results of a RCT which included 457 Japanese men treated by silodosin, tamsulosin or placebo, and found a significant decrease in total IPSS in the silodosin arm compared to placebo [[21](/article/10.1186/s12894-016-0176-0#ref-CR21 "Kawabe K, Yoshida M, Homma Y, Silodosin Clinical Study Group. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006;98:1019–24.")]. Similarly, Marks et al. found that 8 mg daily silodosin caused a significant reduction of both storage and voiding LUTS compared to placebo (Δ total 1.9, _p_ < 0.0001; Δ storage 0.5, _p_ = 0.0002; Δ voiding 1.4 _p_ < 0.0001) [[22](/article/10.1186/s12894-016-0176-0#ref-CR22 "Marks LS, Gittelman MC, Hill LA, Volinn W, Hoel G. Rapid efficacy of the highly selective alpha1A-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol. 2009;181:2634–40.")]. Finally, it appears that Silodosin may decrease nycturia, especially in patients >65 years old in which desmopressin therapy may be problematic: in a pooled analysis of three RCTs, Eisenhardt et al. found that silodosin, compared to placebo, determined a significant nicturia improvement (53.4 vs. 42.8 %, _p_ < 0.0001) [[23](/article/10.1186/s12894-016-0176-0#ref-CR23 "Eisenhardt A, Schneider T, Cruz F, Oelke M. Consistent and significant improvement of nighttime voiding frequency \(nocturia\) with silodosin in men with LUTS suggestive of BPH: pooled analysis of three randomized, placebo-controlled, double-blind phase III studies. World J Urol. 2014;32:1119–25.")], making it an interesting drug in the elderly population.

Most studies reported that truly silodosin determines less peripheral vascular AE compared to non-selective α1-antagonists, as it does not determine significant effects on supine or orthotopic blood pressure [[20](/article/10.1186/s12894-016-0176-0#ref-CR20 "Chapple CR, Montorsi F, Tammela TLJ, Wirth M, Koldewijn E, Fernández Fernández E, et al. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011;59:342–52."), [24](/article/10.1186/s12894-016-0176-0#ref-CR24 "Bozkurt O, Demir O, Sen V, Esen A. Silodosin causes impaired ejaculation and enlargement of seminal vesicles in sexually active men treated for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology. 2015;85:1085–9.")]. However, silodosin caused in most trials a higher rate of anejaculation compared to non-selective α1-antagonists or tamsulosin, with rates between 14.2 and 20.9 %: this has been hypothesized to be a consequence of its selectivity for α1A-receptors, which are highly expressed along the vas deferens, with a consequent reduction of their contractility [[20](/article/10.1186/s12894-016-0176-0#ref-CR20 "Chapple CR, Montorsi F, Tammela TLJ, Wirth M, Koldewijn E, Fernández Fernández E, et al. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011;59:342–52.")]. In 30 young sexually active patients, Bozkurt et al. have found impaired ejaculation in 27/30 men, with significant enlargement of seminal vesicles [[24](/article/10.1186/s12894-016-0176-0#ref-CR24 "Bozkurt O, Demir O, Sen V, Esen A. Silodosin causes impaired ejaculation and enlargement of seminal vesicles in sexually active men treated for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology. 2015;85:1085–9.")]. A long-term analysis following 104 men for 6 years found a quite high discontinuation of silodosin (75 %), mostly due to progression of disease and need for surgery or to unknown causes; only 9/78 stopped treatment due to side effects [[25](/article/10.1186/s12894-016-0176-0#ref-CR25 "Yamanishi T, Kaga K, Fuse M, Shibata C, Kamai T, Uchiyama T. Six-year follow up of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: What are the factors for continuation or withdrawal? Int. J Urol Off J Jpn Urol Assoc. 2015;22:1143–8.")].

As such, silodosin may be considered a valid alternative to non-selective α1-antagonists, especially in the older patients where blood pressure alterations may determine major clinical problems and ejaculatory alterations may be not truly bothersome.

### Phosphodiesterase 5 Inhibitors

In addition to adrenergic fibers, key actors in micturition are the nonadrenergic-noncholinergic fibers. This neural system is implicated in the release and increase of nitric oxide (NO), a cardinal molecule for intracellular signaling which causes an increase of cyclic guanosine monophosphate (cGMP), consequently catabolized by the enzyme PDE. After its fundamental discovery in the cavernous tissue and the development of PDE5 inhibitors in the treatment of erectile dysfunction (ED), researchers have demonstrated the presence of PDE-5 isoenzymes all along the lower urinary tract: they are in fact expressed in the detrusor, the prostate, the urethra and in pelvic vessels [[26](/article/10.1186/s12894-016-0176-0#ref-CR26 "Giuliano F, Ückert S, Maggi M, Birder L, Kissel J, Viktrup L. 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;63:506–16.")]. Here PDE-5 inhibition determines intracellular cGMP increase, which in turn may promote micturition via different though yet unclear mechanisms of action [[27](/article/10.1186/s12894-016-0176-0#ref-CR27 "Roumeguere T, Aoun F, Marcelis Q. Minimally invasive devices for treating lower urinary tract symptoms in benign prostate hyperplasia: technology update. Res Rep Urol. 2015;7:125.")]. First, cGMP phosphorylates and inactivates a protein kinase G (ρ-kinase) to promote smooth muscle cells relaxation [[28](/article/10.1186/s12894-016-0176-0#ref-CR28 "Rees RW, Foxwell NA, Ralph DJ, Kell PD, Moncada S, Cellek S. Y-27632, a Rho-kinase inhibitor, inhibits proliferation and adrenergic contraction of prostatic smooth muscle cells. J Urol. 2003;170:2517–22.")]. In addition, this ρ-kinase stimulates endothelin-1, which is a potent vasoconstrictor which can mediate muscle contraction [[28](/article/10.1186/s12894-016-0176-0#ref-CR28 "Rees RW, Foxwell NA, Ralph DJ, Kell PD, Moncada S, Cellek S. Y-27632, a Rho-kinase inhibitor, inhibits proliferation and adrenergic contraction of prostatic smooth muscle cells. J Urol. 2003;170:2517–22.")]. Therefore, PDE-5 inhibition, via a cGMP increase, reduces ρ-kinase activity and thus increases relaxation in the lower urinary tract. Additionally, PDE inhibition enhances smooth muscle cell relaxation increasing NO activity as observed in the bladder neck, where nitrergic innervation is prominent [[26](/article/10.1186/s12894-016-0176-0#ref-CR26 "Giuliano F, Ückert S, Maggi M, Birder L, Kissel J, Viktrup L. 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;63:506–16.")], in the prostate, were PDE inhibition determines a dose-dependent tissue relaxation [[29](/article/10.1186/s12894-016-0176-0#ref-CR29 "Uckert S, Sormes M, Kedia G, Scheller F, Knapp WH, Jonas U, et al. Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue. Urology. 2008;71:526–30.")], and in urethral tissue [[30](/article/10.1186/s12894-016-0176-0#ref-CR30 "Lee JG, Moon DG, Kang SH, Cho DY, Park HS, Bae JH. Relaxation effect of phosphodiesterase-5 inhibitor on the animal bladder and prostatic urethra: in vitro and in vivo study. Urol Int. 2010;84:231–5.")]. Finally, PDE-5 inhibition leads to increased perfusion of pelvic organs with the hypothesis that pelvic atherosclerosis with consequent ischaemia may have a role in male LUTS [[31](/article/10.1186/s12894-016-0176-0#ref-CR31 "Azadzoi KM, Babayan RK, Kozlowski R, Siroky MB. Chronic ischemia increases prostatic smooth muscle contraction in the rabbit. J Urol. 2003;170:659–63.")], the vasodilatation and increased end-organ perfusion determined by PDE-5 inhibitors on blood vessels may be beneficial for LUTS. Of note, Bertolotto et al. demonstrated increased prostatic perfusion on contrast-enhanced ultrasound after administration of tadalafil 20 mg [[32](/article/10.1186/s12894-016-0176-0#ref-CR32 "Bertolotto M, Trincia E, Zappetti R, Bernich R, Savoca G, Cova MA. Effect of Tadalafil on prostate haemodynamics: preliminary evaluation with contrast-enhanced US. Radiol Med \(Torino\). 2009;114:1106–14.")]. Moreover, soluble cGMP plays a key role in the NO-mediated inhibition of leukocyte rolling, and PDE5 inhibition may reduce atherosclerotic damage and overall inflammation by reducing leukocyte recruitment. Tadalafil was shown to attenuate in vitro the expression of the inflammatory cytokines TNF-α and IL-1βin pulmonary arteries [[33](/article/10.1186/s12894-016-0176-0#ref-CR33 "Tsai BM, Turrentine MW, Sheridan BC, Wang M, Fiore AC, Brown JW, et al. Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg. 2006;81:272–8.")] and of TNF-α and IL-8 in endothelial cells [[34](/article/10.1186/s12894-016-0176-0#ref-CR34 "Roumeguère T, Zouaoui Boudjeltia K, Babar S, Nuyens V, Rousseau A, Van Antwerpen P, et al. Effects of phosphodiesterase inhibitors on the inflammatory response of endothelial cells stimulated by myeloperoxidase-modified low-density lipoprotein or tumor necrosis factor alpha. Eur Urol. 2010;57:522–8.")]. Finally, cGMP modulates afferent nerve fibers from the bladder and urethra, and PDE inhibitors may decrease the sensation of bladder filling, thus reducing urgency [[26](/article/10.1186/s12894-016-0176-0#ref-CR26 "Giuliano F, Ückert S, Maggi M, Birder L, Kissel J, Viktrup L. 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;63:506–16."), [35](/article/10.1186/s12894-016-0176-0#ref-CR35 "Minagawa T, Aizawa N, Igawa Y, Wyndaele J-J. Inhibitory effects of phosphodiesterase 5 inhibitor, tadalafil, on mechanosensitive bladder afferent nerve activities of the rat, and on acrolein-induced hyperactivity of these nerves. BJU Int. 2012;110:E259–66.")]. In this context Minagawa et al. found that tadalafil significantly decreased afferent activity from the bladder in response to bladder filling in a rat model [[35](/article/10.1186/s12894-016-0176-0#ref-CR35 "Minagawa T, Aizawa N, Igawa Y, Wyndaele J-J. Inhibitory effects of phosphodiesterase 5 inhibitor, tadalafil, on mechanosensitive bladder afferent nerve activities of the rat, and on acrolein-induced hyperactivity of these nerves. BJU Int. 2012;110:E259–66.")] and Behr-Roussel et al. reported a reduction of afferent signaling in rats with spinal cord injury in response to bladder filling after treatment with vardenafil [[36](/article/10.1186/s12894-016-0176-0#ref-CR36 "Behr-Roussel D, Oger S, Caisey S, Sandner P, Bernabé J, Alexandre L, et al. Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord-injured rats. Eur Urol. 2011;59:272–9.")].

Randomized, placebo-controlled clinical trials have demonstrated that daily treatment with 5 mg tadalafil improves safely BPH-related LUTS [[37](/article/10.1186/s12894-016-0176-0#ref-CR37 "McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177:1401–7.")–[39](/article/10.1186/s12894-016-0176-0#ref-CR39 "Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012;61:917–25.")]. McVary et al. found that tadalafil determined a decrease of total IPSS of −3.8 compared to −1.7 with placebo after 12 weeks of treatment (_p_ < 0.0001) [[37](/article/10.1186/s12894-016-0176-0#ref-CR37 "McVary KT, Roehrborn CG, Kaminetsky JC, Auerbach SM, Wachs B, Young JM, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177:1401–7.")]. QoL also significantly improved (−0.7 vs −0.3, _p_ = 0.008), while no significant differences were observed for peak urinary flow (Qmax). Roehrborn et al. confirmed these findings, and noted in their trial that the dose of tadalafil with the best risk-benefit profile was 5 mg, determining a reduction of IPSS of −4.87 vs −2.27 with placebo (_p_ < 0.001) [[38](/article/10.1186/s12894-016-0176-0#ref-CR38 "Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180:1228–34.")]. Similarly, also QoL was significantly improved with tadalafil 5 mg. On post hoc analysis, the authors found that although tadalafil caused a numerically superior increase in Qmax compared to placebo, this increase was non-significant [[40](/article/10.1186/s12894-016-0176-0#ref-CR40 "Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, Viktrup L. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int. 2010;105:502–7.")]. Oelke et al. reported an amelioration of total IPSS after 12 weeks of tadalafil 5 mg (Δ IPSS vs placebo: −2.1, _p_ = 0.001) and of QoL (−0.3, _p_ = 0.022) [[39](/article/10.1186/s12894-016-0176-0#ref-CR39 "Oelke M, Giuliano F, Mirone V, Xu L, Cox D, Viktrup L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012;61:917–25.")]. Moreover, these investigators described a significant increase in Qmax: +2.4 ml/s (tadalafil) vs +1.2 ml/s (placebo), _p_ = 0.009: although this result is not consistent with those previously reported [[41](/article/10.1186/s12894-016-0176-0#ref-CR41 "Laydner HK, Oliveira P, Oliveira CRA, Makarawo TP, Andrade WS, Tannus M, et al. Phosphodiesterase 5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review. BJU Int. 2011;107:1104–9.")], it must be kept in mind that Qmax is intra individually variable and influenced by age, sexual activity and baseline Qmax severity [[40](/article/10.1186/s12894-016-0176-0#ref-CR40 "Roehrborn CG, Kaminetsky JC, Auerbach SM, Montelongo RM, Elion-Mboussa A, Viktrup L. Changes in peak urinary flow and voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int. 2010;105:502–7.")]. In a meta-analysis, Gacci et al. synthesized that tadalafil determines a significant −2.85 decrease in overall IPSS compared to placebo and a significant −1.85 decrease in association with α1-inhibitors compared to α1-inhibitors alone [[42](/article/10.1186/s12894-016-0176-0#ref-CR42 "Gacci M, Corona G, Salvi M, Vignozzi L, McVary KT, Kaplan SA, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61:994–1003.")]. Clearly, tadalafil also significantly improves erectile function with a net increase of the International Index of Erectile Function. Indeed, a point of controversy is whether the amelioration of IPSS and QoL, which are subjective measurements, is a direct consequence of tadalafil’s pharmacologic effect on the lower urinary tract or if the results observed are confounded by the fact that the patients, having an improved potency, are more sexually active and thus more satisfied. It appears however that the amelioration seen in IPSS and QoL is observed both in potent and impotent patients [[43](/article/10.1186/s12894-016-0176-0#ref-CR43 "Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75:1452–8.")] and pooled data analyses determined that the LUTS amelioration was largely (92.5 %) determined by a direct effect of the drug [[44](/article/10.1186/s12894-016-0176-0#ref-CR44 "Brock GB, McVary KT, Roehrborn CG, Watts S, Ni X, Viktrup L, et al. Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies. J Urol. 2014;191:405–11.")]. Tadalafil is also being tested in combination therapy with tamsulosin [[45](/article/10.1186/s12894-016-0176-0#ref-CR45 "Singh DV, Mete UK, Mandal AK, Singh SK. A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. J Sex Med. 2014;11:187–96.")] or finasteride [[46](/article/10.1186/s12894-016-0176-0#ref-CR46 "Glina S, Roehrborn CG, Esen A, Plekhanov A, Sorsaburu S, Henneges C, et al. Sexual function in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: results of a 6-month, randomized, double-blind, placebo-controlled study of tadalafil coadministered with finasteride. J Sex Med. 2015;12:129–38.")], demonstrating a more pronounced amelioration of LUTS and ED symptoms in the combination arms. Concerning AE, the vast majority of manuscripts reported mild to moderate grade AE (dyspepsia and flushing), with a low rate (2–4 %) of discontinuation of the therapy secondary to AE [[42](/article/10.1186/s12894-016-0176-0#ref-CR42 "Gacci M, Corona G, Salvi M, Vignozzi L, McVary KT, Kaplan SA, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61:994–1003."), [47](/article/10.1186/s12894-016-0176-0#ref-CR47 "Donatucci CF, Brock GB, Goldfischer ER, Pommerville PJ, Elion-Mboussa A, Kissel JD, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011;107:1110–6.")].

In conclusion, tadalafil 5 mg is an effective and well tolerated treatment for BPH-related LUTS, and is of cardinal importance when treating patients with concomitant ED. Tadalafil causes a significant decrease of IPSS score with an amelioration of patients’ QoL, although with no significant increase in Qmax.

Great caution is advised when prescribing iPDE5. As a consequence of systemic vasodilation, reduced venous blood flow to the heart may trigger cardiac failure in patients with preexisting cardiac insufficiency [[42](/article/10.1186/s12894-016-0176-0#ref-CR42 "Gacci M, Corona G, Salvi M, Vignozzi L, McVary KT, Kaplan SA, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61:994–1003.")]. As such, before prescribing iPDE5, the clinician must always exclude signs of cardiac insufficiency as dyspnea, lower extremity oedema, chest pain. Moreover, for the same pharmacologic reasons, concomitant treatment with nitroderivates is an absolute contraindication to iPDE5 utilisation [[8](/article/10.1186/s12894-016-0176-0#ref-CR8 "Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64:118–40.")].

### Antimuscarinics

Two main subtypes of muscarinic receptor (MR) are expressed in the lower urinary tract: M2 and M3 receptors. Their proportions in detrusor membranes are respectively evaluated at 71 % and 22 % [[48](/article/10.1186/s12894-016-0176-0#ref-CR48 "Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Br J Pharmacol. 2005;144:1089–99.")]. While M3 are mainly responsible for detrusor contraction in both healthy and pathologic conditions, M2 are predominant in the urothelium and may be associated with pathologic changes in the bladder [[49](/article/10.1186/s12894-016-0176-0#ref-CR49 "Mukerji G, Yiangou Y, Grogono J, Underwood J, Agarwal SK, Khullar V, et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol. 2006;176:367–73.")]. It has been commonly and reasonably thought that the main mechanism of action of antimuscarinics in the treatment of LUTS is mediated by a reduction of detrusor contractility. Specimens from patients with bladder overactivity are consistently denervated, and as such it has been hypothesized that possible denervation supersensibility to acetylcholine may be crucial in OAB physiopathology [[50](/article/10.1186/s12894-016-0176-0#ref-CR50 "Yoshida M, Inadome A, Maeda Y, Satoji Y, Masunaga K, Sugiyama Y, et al. Non-neuronal cholinergic system in human bladder urothelium. Urology. 2006;67:425–30.")]. However MR are also present in the urothelium and are here involved in urothelial sensory function. The urothelium in fact releases multiple signal molecules, including acetylcholine, which activate unmyelinated afferent C-fibers present in the suburothelial layer of the bladder wall, and this release of acetylcholine is increased by bladder overstretching . This, associated to the denervation supersensitivity of the detrusor to acetylcholine, may induce disorganized contraction of small muscular units in the detrusor, generating pathologic afferent signals which in turn may determine urgency symptoms [[51](/article/10.1186/s12894-016-0176-0#ref-CR51 "Drake MJ, Harvey IJ, Gillespie JI, Van Duyl WA. Localized contractions in the normal human bladder and in urinary urgency. BJU Int. 2005;95:1002–5.")].

Antimuscarinics have been prevalently used in female patients with OAB: however today it is clear that in men with BPH, storage symptoms are partially caused by the bladder, with urodynamically proven OAB being a common cause [[52](/article/10.1186/s12894-016-0176-0#ref-CR52 "Lee JY, Kim HW, Lee SJ, Koh JS, Suh HJ, Chancellor MB. Comparison of doxazosin with or without tolterodine in men with symptomatic bladder outlet obstruction and an overactive bladder. BJU Int. 2004;94:817–20.")]. As such antimuscarinic therapy has emerged as a new option in male LUTS management [[8](/article/10.1186/s12894-016-0176-0#ref-CR8 "Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64:118–40.")]. Chun-Hou Liao et al. have studied the predictors of therapeutic success with a first line antimuscarinic treatment in BPH men with predominant storage symptoms. In their 197 patients group, receiving tolterodine in monotherapy, higher baseline IPSS, higher baseline Qmax and lower prostate volume were each associated with a better response [[53](/article/10.1186/s12894-016-0176-0#ref-CR53 "Liao C-H, Kuo Y-C, Kuo H-C. Predictors of successful first-line antimuscarinic monotherapy in men with enlarged prostate and predominant storage symptoms. Urology. 2013;81:1030–3.")]. Treatment with antimuscarinics alone is still felt as dangerous in patients with BOO by many urologists, due to the possible increased risk of AUR. Abrams et al. reported that in men with mild to moderate BOO, the antimuscarinic tolterodine 2 mg twice daily for 12 weeks caused a significant increase in post void residual (PVR) urine compared to placebo (49 ml vs 16 ml): however, rates of AUR (3 %) and Qmax were equal across both groups [[54](/article/10.1186/s12894-016-0176-0#ref-CR54 "Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol. 2006;175:999–1004. discussion 1004.")]. This is probably a consequence of the action of antimuscarinics on the storage phase of micturition and not on voiding, as there is little evidence that these agents, at the therapeutic recommended doses, determine a significant reduction of voiding contraction [[55](/article/10.1186/s12894-016-0176-0#ref-CR55 "Andersson K-E. Antimuscarinics for treatment of overactive bladder. Lancet Neurol. 2004;3:46–53.")]. Nonetheless, in daily clinical practice, the majority of patients is already under treatment with an α1-antagonist, and present with persisting storage symptoms. In this context, several trials have explored the efficacy and safety of the addition of an antimuscarinic to the α1-antagonist in these patients [[56](/article/10.1186/s12894-016-0176-0#ref-CR56 "Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006;296:2319–28.")–[58](/article/10.1186/s12894-016-0176-0#ref-CR58 "Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety and tolerability of solifenacin add-on therapy to alpha-blocker treated men with residual urgency and frequency. J Urol. 2009;182:2825–30.")]. The TIMES study included 879 men with symptoms of BPH and OAB [[56](/article/10.1186/s12894-016-0176-0#ref-CR56 "Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006;296:2319–28.")]. Patients were randomized to receive either tolterodine 4 mg ER + tamsuloin, one of the two drugs alone or placebo. After 12 weeks, in the combination arm the patients reported significant decrease in urgency incontinence episodes (−0.88 vs −0.31, _p_ = 0.005), frequency (−2.54 vs −1.41, _p_ < 0.001) and an amelioration of QoL. Although higher than for placebo and for tamsulosin alone, the rate of AUR was low for the combination (0.4 %) and the tolterodine arm alone (0.5 %). MacDiarmid et al. reported significant amelioration of both storage and voiding symptoms (_p_ = 0.006) in men affected by BPH treated with tamsulosin + oxybutinin 10 mg, with a non-significant increase in PVR in treated patients compared to placebo [[57](/article/10.1186/s12894-016-0176-0#ref-CR57 "MacDiarmid SA, Peters KM, Chen A, Armstrong RB, Orman C, Aquilina JW, et al. Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc. 2008;83:1002–10.")]. Similarly, in the VICTOR study, 398 men were randomized to receive tamsulosin plus either solifenacin 5 mg or placebo. In the solifenacin group, patients showed a significant reduction of urgency episodes (−2.18 vs −1.10, _p_ = 0.001) but a non-significant reduction of frequency (−1.05 vs −0.67, _p_ = 0.135) [[58](/article/10.1186/s12894-016-0176-0#ref-CR58 "Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety and tolerability of solifenacin add-on therapy to alpha-blocker treated men with residual urgency and frequency. J Urol. 2009;182:2825–30.")]. In most trials the most frequent AE associated with antimuscarinics is xerostomia [[56](/article/10.1186/s12894-016-0176-0#ref-CR56 "Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006;296:2319–28."), [57](/article/10.1186/s12894-016-0176-0#ref-CR57 "MacDiarmid SA, Peters KM, Chen A, Armstrong RB, Orman C, Aquilina JW, et al. Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc. 2008;83:1002–10.")]. Increase in PVR urine, though statistically significant in many studies, frequently did not determine a significant increase in the risk of AUR requiring catheterization [[56](/article/10.1186/s12894-016-0176-0#ref-CR56 "Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA. 2006;296:2319–28."), [57](/article/10.1186/s12894-016-0176-0#ref-CR57 "MacDiarmid SA, Peters KM, Chen A, Armstrong RB, Orman C, Aquilina JW, et al. Efficacy and safety of extended-release oxybutynin in combination with tamsulosin for treatment of lower urinary tract symptoms in men: randomized, double-blind, placebo-controlled study. Mayo Clin Proc. 2008;83:1002–10.")]. However, as recommended by current EAU guidelines, antimuscarinics are therefore medications which can be prescribed in men with BPH with residual storage symptoms after treatment with α1-antagonists. Before to start a treatment with an antimuscarinic, BPH patients should be monitored for PVR and then closely followed [[8](/article/10.1186/s12894-016-0176-0#ref-CR8 "Oelke M, Bachmann A, Descazeaud A, Emberton M, Gravas S, Michel MC, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64:118–40.")]. Some authors have been questioning the compliance to bi-therapy, considering the fact that the common chronic combination of antimuscarinics and αl-antagonists could be a burden for the patients. Barkin et al. reported a retrospective analysis based on patients prescriptions reimbursement data. They concluded that patients treated in combination therapy showed an improved persistence over a year period, compared to those on αl-antagonists monotherapy [[59](/article/10.1186/s12894-016-0176-0#ref-CR59 "Barkin J, Diles D, Franks B, Berner T. Alpha blocker monotherapy versus combination therapy with antimuscarinics in men with persistent LUTS refractory to alpha-adrenergic treatment: patterns of persistence. Can J Urol. 2015;22:7914–23.")].

Concerning anticholinergic drugs, great care is necessary when prescribing these drugs in the elderly, as cognitive deterioration may be a serious consequence and one must bear in mind that 16 % of patients >70 years show some form of cognitive impairment [[60](/article/10.1186/s12894-016-0176-0#ref-CR60 "Petersen RC, Roberts RO, Knopman DS, Geda YE, Cha RH, Pankratz VS, et al. Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging. Neurology. 2010;75:889–97.")]. Indeed, encephalic cholinergic activity, and in particular M1 and M2 receptors which represent over 60 % of the brains cholinergic receptors, are vital in cognitive function [[61](/article/10.1186/s12894-016-0176-0#ref-CR61 "Jiang S, Li Y, Zhang C, Zhao Y, Bu G, Xu H, et al. M1 muscarinic acetylcholine receptor in Alzheimer’s disease. Neurosci Bull. 2014;30:295–307.")]. The only antimuscarinic which was accorded a beneficial safety profile in the elderly is Fesoterodine, as this drug was studied specifically in the ageing population [[62](/article/10.1186/s12894-016-0176-0#ref-CR62 "Wagg A, Khullar V, Marschall-Kehrel D, Michel MC, Oelke M, Darekar A, et al. Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. J Am Geriatr Soc. 2013;61:185–93.")–[64](/article/10.1186/s12894-016-0176-0#ref-CR64 "Sand PK, Heesakkers J, Kraus SR, Carlsson M, Guan Z, Berriman S. Long-term safety, tolerability and efficacy of fesoterodine in subjects with overactive bladder symptoms stratified by age: pooled analysis of two open-label extension studies. Drugs Aging. 2012;29:119–31.")]. In the SOFIA trial 581 patients >65, of which 33 % were >75 years old and frequently on polypharmacy, completed a 3 month double-blind randomized trial of Fesoterodine versus placebo [[62](/article/10.1186/s12894-016-0176-0#ref-CR62 "Wagg A, Khullar V, Marschall-Kehrel D, Michel MC, Oelke M, Darekar A, et al. Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. J Am Geriatr Soc. 2013;61:185–93.")]. At 12 weeks, patients in the treatment arm demonstrated reduced urgency (−3.8 episodes), pollakiuria and nycturia (−0.55 episodes) (all _p_ < 0.001) compared to placeebo. Fesoterodine determined a similar rate of adverse events compared to placebo (39.8 % vs 36.1 %), mostly mild xerostomia. Of note, no clinically relevant changes in cognitive function (evaluated through the mini-mental status examination) were observed throughout the study in both arms. This may be attributed to the high affinity of Fesoterodine for the M3 receptor and its inability to pass the blood–brain barrier [[65](/article/10.1186/s12894-016-0176-0#ref-CR65 "Chancellor MB, Staskin DR, Kay GG, Sandage BW, Oefelein MG, Tsao JW. Blood–brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drugs Aging. 2012;29:259–73.")]. In any case, great care is advised with anticholinergic drugs and a high level of suspiciousness in case of cognitive deterioration while receiving treatment.

### Intraprostatic agents

In addition to classic oral therapy, medical agents may be injected directly in the prostate [[66](/article/10.1186/s12894-016-0176-0#ref-CR66 "Andersson K-E. Treatment of lower urinary tract symptoms: agents for intraprostatic injection. Scand J Urol. 2013;47:83–90.")]. This is a promising minimally invasive approach in patients who are unresponsive to medical treatment, who experience debilitating AE or who are poor candidates for surgery. The rationale for this therapy is the ability of some agents to determine prostatic involution and promote apoptosis, thus shrinking prostatic volume and ameliorating LUTS [[66](/article/10.1186/s12894-016-0176-0#ref-CR66 "Andersson K-E. Treatment of lower urinary tract symptoms: agents for intraprostatic injection. Scand J Urol. 2013;47:83–90.")]. In addition, these agents may modulate prostatic afferent nerves, reducing nociception and improving BPH-related symptoms. However, it must be remembered that profound ameliorations were seen also in the sham arms of RCTs evaluating intraprostatic injections [[67](/article/10.1186/s12894-016-0176-0#ref-CR67 "Welliver C, Kottwitz M, Feustel P, McVary K. Clinically and statistically significant changes seen in sham surgery arms of randomized, controlled benign prostatic hyperplasia surgery trials. J Urol. 2015;194:1682–7.")]: as such, the results of such trials must always be redimensioned and relativized to the sham-control arm, rather than considering the absolute results.

Ethanol has been explored as agent for intraprostatic administration, with favorable results. Investigators found a significant reduction of IPSS and an amelioration of Qmax and QoL [[68](/article/10.1186/s12894-016-0176-0#ref-CR68 "El-Husseiny T, Buchholz N. Transurethral ethanol ablation of the prostate for symptomatic benign prostatic hyperplasia: long-term follow-up. J Endourol Endourol Soc. 2011;25:477–80."), [69](/article/10.1186/s12894-016-0176-0#ref-CR69 "Grise P, Plante M, Palmer J, Martinez-Sagarra J, Hernandez C, Schettini M, et al. Evaluation of the transurethral ethanol ablation of the prostate \(TEAP\) for symptomatic benign prostatic hyperplasia \(BPH\): a European multi-center evaluation. Eur Urol. 2004;46:496–501. discussion 501–2.")]. However results are seldom durable, and patients frequently require re-treatment, which has been reported necessary in over 40 % of patients [[70](/article/10.1186/s12894-016-0176-0#ref-CR70 "Goya N, Ishikawa N, Ito F, Kobayashi C, Tomizawa Y, Toma H. Transurethral ethanol injection therapy for prostatic hyperplasia: 3-year results. J Urol. 2004;172:1017–20.")]. Intraprostatic botulinum toxin injection is a very promising and is being throughout fully explored. This neurotoxin exists in seven different subtypes, and the most widely used has been Onabotulinum toxin A. Though yet unclear, it has been hypothesized that this may enhance prostatic apoptosis, down-regulate α-receptors and modulate afferent signaling in the prostate [[71](/article/10.1186/s12894-016-0176-0#ref-CR71 "Chuang Y-C, Huang C-C, Kang H-Y, Chiang P-H, Demiguel F, Yoshimura N, et al. Novel action of botulinum toxin on the stromal and epithelial components of the prostate gland. J Urol. 2006;175:1158–63.")]. Investigators have reported positive and significant improvement of LUTS in men with BPH treated by Onabotulinum toxin injection [[72](/article/10.1186/s12894-016-0176-0#ref-CR72 "Crawford ED, Hirst K, Kusek JW, Donnell RF, Kaplan SA, McVary KT, et al. Effects of 100 and 300 units of onabotulinum toxin a on lower urinary tract symptoms of benign prostatic hyperplasia: a phase II randomized clinical trial. J Urol. 2011;186:965–70.")]. Generally, doses between 100U and 300U have been used during most trials but Arnouk et al. reported similar functional and safety results after injection of 100U and 200U [[73](/article/10.1186/s12894-016-0176-0#ref-CR73 "Arnouk R, Suzuki Bellucci CH, Benatuil Stull R, de Bessa J, Malave CA, Mendes Gome C. Botulinum neurotoxin type A for the treatment of benign prostatic hyperplasia: randomized study comparing two doses. Sci World J. 2012;2012:463574.")]. To date the largest trial testing botulinum in BPH was recently published by Marberger et al. in a phase II placebo-controlled trial, enrolling 380 men [[74](/article/10.1186/s12894-016-0176-0#ref-CR74 "Marberger M, Chartier-Kastler E, Egerdie B, Lee K-S, Grosse J, Bugarin D, et al. A randomized double-blind placebo-controlled phase 2 dose-ranging study of OnabotulinumtoxinA in men with benign prostatic hyperplasia. Eur Urol. 2013;63:496–503.")]. Patients were randomized to receive 100U, 200U or 300U Onabotulinum toxin A or 0.9 % saline, and were followed for 72 weeks. The investigators found a meaningful improvement of BPH parameters after botulinum injection, including IPSS (Δ IPSS: 5.6 to 6.6, according to dose), Qmax(Δ = 2.0 to 2.4 ml/s, according to dose) and QoL. However, a pronounced placebo effect was observed, with patients in the control arm experiencing a similar symptom amelioration, yielding non-significant differences in outcomes across the treatment and control arm. Overall, intraprostatic injections of botulinum toxin are well-tolerated, with a low rate of AE mainly associated with the administration of the drug (2 % prostatitis) [[74](/article/10.1186/s12894-016-0176-0#ref-CR74 "Marberger M, Chartier-Kastler E, Egerdie B, Lee K-S, Grosse J, Bugarin D, et al. A randomized double-blind placebo-controlled phase 2 dose-ranging study of OnabotulinumtoxinA in men with benign prostatic hyperplasia. Eur Urol. 2013;63:496–503.")] and not the compound itself. Moreover, no sexual AEs are reported, with full conservation of sexual potency [[75](/article/10.1186/s12894-016-0176-0#ref-CR75 "Silva J, Pinto R, Carvalho T, Botelho F, Silva P, Silva C, et al. Intraprostatic botulinum toxin type A administration: evaluation of the effects on sexual function. BJU Int. 2011;107:1950–4.")].

### Future perspectives in the medical treatment of BPH

Research in the field of BPH therapy is continuously progressing. As our molecular understanding of bladder, prostatic, urethral anatomy and pathophysiology advances, so do the experimental studies and clinical trials exploring new drugs in this domain. In particular there is growing interest in the role of inflammation, the vitamin D receptor signaling pathway and the activity of β3-receptors in BPH-mediated LUTS.

Inflammation has been associated with BPH pathogenesis and progression, with multiple cytokines and inflammatory cells responsible for the increased risk of BPH determined by prostatic inflammation [[76](/article/10.1186/s12894-016-0176-0#ref-CR76 "De Nunzio C, Kramer G, Marberger M, Montironi R, Nelson W, Schröder F, et al. The controversial relationship between benign prostatic hyperplasia and prostate cancer: the role of inflammation. Eur Urol. 2011;60:106–17.")]. The COX pathway leads to the production of free radicals and consequent oxidative stress: as such, a possible therapeutic effect of non-steroidal anti-inflammatory drugs has been hypothesized [[77](/article/10.1186/s12894-016-0176-0#ref-CR77 "Di Silverio F, Bosman C, Salvatori M, Albanesi L, Proietti Pannunzi L, Ciccariello M, et al. Combination therapy with rofecoxib and finasteride in the treatment of men with lower urinary tract symptoms \(LUTS\) and benign prostatic hyperplasia \(BPH\). Eur Urol. 2005;47:72–8. discussion 78–9."), [78](/article/10.1186/s12894-016-0176-0#ref-CR78 "Altavilla D, Minutoli L, Polito F, Irrera N, Arena S, Magno C, et al. Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia. Br J Pharmacol. 2012;167:95–108.")]. Di Silverio et al. found that the combination of finasteride and a COX-2 inhibitor, rofecoxib 25 mg/die, caused a significant improvement in IPSS score (_p_ = 0.0001) and of Qmax (_p_ = 0.03) compared to finasteride alone [[77](/article/10.1186/s12894-016-0176-0#ref-CR77 "Di Silverio F, Bosman C, Salvatori M, Albanesi L, Proietti Pannunzi L, Ciccariello M, et al. Combination therapy with rofecoxib and finasteride in the treatment of men with lower urinary tract symptoms \(LUTS\) and benign prostatic hyperplasia \(BPH\). Eur Urol. 2005;47:72–8. discussion 78–9.")]. Moreover flavocoxid, an inhibitor of COX and 5-lipoxygenase enzymes, reduced prostate weight, increased the expression of Bax and caspase-9 mRNA (pro-apoptotic) and decreased that of Bcl-2 (anti-apoptotic) in mice with induced BPH [[78](/article/10.1186/s12894-016-0176-0#ref-CR78 "Altavilla D, Minutoli L, Polito F, Irrera N, Arena S, Magno C, et al. Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia. Br J Pharmacol. 2012;167:95–108.")]. Although COX inhibitors could have a future role in the management of BPH, clinical evidence is still lacking and their application in BPH must be considered experimental.

The vitamin D receptor (VDR) signaling pathway could be associated with BPH and LUTS [[79](/article/10.1186/s12894-016-0176-0#ref-CR79 "Colli E, Rigatti P, Montorsi F, Artibani W, Petta S, Mondaini N, et al. BXL628, a novel vitamin D3 analog arrests prostate growth in patients with benign prostatic hyperplasia: a randomized clinical trial. Eur Urol. 2006;49:82–6."), [80](/article/10.1186/s12894-016-0176-0#ref-CR80 "Penna G, Fibbi B, Amuchastegui S, Corsiero E, Laverny G, Silvestrini E, et al. The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappaB pathways. Prostate. 2009;69:480–93.")]. Investigators have found that VDR agonists, notably elocalcitol, a synthetic derivative of vitamin D3 that regulates cell proliferation and apoptosis may inhibit the androgen-dependent and androgen-independentprostatic cell proliferation [[81](/article/10.1186/s12894-016-0176-0#ref-CR81 "Crescioli C, Ferruzzi P, Caporali A, Scaltriti M, Bettuzzi S, Mancina R, et al. Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia. Eur J Endocrinol Eur Fed Endocr Soc. 2004;150:591–603.")]. It can also reduce IL-8 secretion by inflammatory cells in the prostate by targeting the NF-kB pathway [[80](/article/10.1186/s12894-016-0176-0#ref-CR80 "Penna G, Fibbi B, Amuchastegui S, Corsiero E, Laverny G, Silvestrini E, et al. The vitamin D receptor agonist elocalcitol inhibits IL-8-dependent benign prostatic hyperplasia stromal cell proliferation and inflammatory response by targeting the RhoA/Rho kinase and NF-kappaB pathways. Prostate. 2009;69:480–93.")]. Elocalcitol modulates bladder contractility by inhibiting the calcium-sensitizing RhoA/ROCK with a potential interest in storage symptoms control [[82](/article/10.1186/s12894-016-0176-0#ref-CR82 "Adorini L, Penna G, Amuchastegui S, Cossetti C, Aquilano F, Mariani R, et al. Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 \(elocalcitol\). J Steroid Biochem Mol Biol. 2007;103:689–93.")]. In a phase II RCT, Colli et al. treated 57 men with prostate volumes ≥40 ml with elocalcitol for 12 weeks, finding a significant reduction of prostate growth compared to placebo (−2.90 vs +4.32, _p_ < 0.0001) [[79](/article/10.1186/s12894-016-0176-0#ref-CR79 "Colli E, Rigatti P, Montorsi F, Artibani W, Petta S, Mondaini N, et al. BXL628, a novel vitamin D3 analog arrests prostate growth in patients with benign prostatic hyperplasia: a randomized clinical trial. Eur Urol. 2006;49:82–6.")]. However until now in humans, elocalcitol was demonstrated with a very good safety profile but only exhibited limited efficacy on LUTS in patients with BPH and overactive bladder. Recent data in animals reported the interest of association of elicalcitol with tolterodine [[83](/article/10.1186/s12894-016-0176-0#ref-CR83 "Streng T, Andersson K-E, Hedlund P, Gratzke C, Baroni E, D’Ambrosio D, et al. Effects on bladder function of combining elocalcitol and tolterodine in rats with outflow obstruction. BJU Int. 2012;110:E125–31.")]. Clinical experimentation is continuing to evaluate its potential role in LUTS due to BPH and OAB management.

In the bladder the predominant form of β-adrenoceptor is the β3-receptor subtype. Its activation is associated with increased bladder capacity without change in micturition pressure, residual volume, or voiding contraction [[84](/article/10.1186/s12894-016-0176-0#ref-CR84 "Tyagi P, Tyagi V. Mirabegron, a β3-adrenoceptor agonist for the potential treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder. IDrugs Investig Drugs J. 2010;13:713–22.")]. Mirabegron is a β3-receptor agonist that has been successfully tested in male and female patients suffering from OAB without BOO [[85](/article/10.1186/s12894-016-0176-0#ref-CR85 "Herschorn S, Barkin J, Castro-Diaz D, Frankel JM, Espuna-Pons M, Gousse AE, et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology. 2013;82:313–20."), [86](/article/10.1186/s12894-016-0176-0#ref-CR86 "Nitti VW, Khullar V, van Kerrebroeck P, Herschorn S, Cambronero J, Angulo JC, et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract. 2013;67:619–32.")] and is now being evaluated also in men with associated BOO. Nitti et al. in a randomized, double-blind, phase II study, treated 200 men affected by BOO with mirabegron 50, 100 mg or placebo. Mirabegron 50 mg was effective in reducing urgency and frequency, without impairing Qmax and with a non-significant increase in PVR urine [[87](/article/10.1186/s12894-016-0176-0#ref-CR87 "Nitti VW, Rosenberg S, Mitcheson DH, He W, Fakhoury A, Martin NE. Urodynamics and safety of the β3-adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol. 2013;190:1320–7.")]. Otsuki et al. studied the response to mirabegron 50 mg in two groups of patient, newly diagnosed OAB and BPH related OAB unresponsive to antimuscarinics [[88](/article/10.1186/s12894-016-0176-0#ref-CR88 "Otsuki H, Kosaka T, Nakamura K, Mishima J, Kuwahara Y, Tsukamoto T. β3-Adrenoceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men. Int Urol Nephrol. 2013;45:53–60.")]. They showed a significant improvement of OAB Symptom Score and IPSS –QOL index, voiding symptoms with no significant difference on post-void residual, supporting the use of Mirabegron in second line after failure of antimuscarinics. A recent randomized controlled trial tested the add-on of Mirabegron 50 mg to 0.2 mg tamsulosine compared to tamsulosine alone, with a significant benefit on urgency, daytime frequency and quality of life index after 2 months of therapy [[89](/article/10.1186/s12894-016-0176-0#ref-CR89 "Ichihara K, Masumori N, Fukuta F, Tsukamoto T, Iwasawa A, Tanaka Y. A randomized controlled study of the efficacy of tamsulosin monotherapy and its combination with mirabegron for overactive bladder induced by benign prostatic obstruction. J Urol. 2015;193:921–6.")]. Although the increase in post-void residual urine volume was significantly greater in the add-on group, AUR was observed only in one man. The results of these trials suggest that Mirabegron may be effective in reducing storage LUTS and safe in patients affected by BOO.

Ion channel transient receptor potential subtype melastatin 8 (TRPM8) is an important factor in the mechanism of detection of bladder filling, whose activation can activate the initiation of micturition. Ito et al. described their activity in a rat model, finding [[90](/article/10.1186/s12894-016-0176-0#ref-CR90 "Ito H, Aizawa N, Sugiyama R, Watanabe S, Takahashi N, Tajimi M, et al. Functional role of the transient receptor potential melastatin 8 \(TRPM8\) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat. BJU Int. 2016;117:484–94.")] that administration of the TRPM8 antagonist RQ-00203078 significantly increased bladder capacity and voided volume. Moreover, the activation of TRPM8 is enhanced by cold temperatures, as found by Uvin et al. [[91](/article/10.1186/s12894-016-0176-0#ref-CR91 "Uvin P, Franken J, Pinto S, Rietjens R, Grammet L, Deruyver Y, et al. Essential role of transient receptor potential M8 \(TRPM8\) in a model of acute cold-induced urinary urgency. Eur Urol. 2015;68:655–61.")], demonstrating the known empirical finding that cold temperatures worsen urgency. Although these findings represent important steps in the understanding of the physiology of micturition, their clinical relevance to date remains limited: TRPM8 antagonists (PF-05105679) have been tested in phase 1 trials, however given the generalized expression of these receptors, significant side effects were recorded including hypothermia [[92](/article/10.1186/s12894-016-0176-0#ref-CR92 "Winchester WJ, Gore K, Glatt S, Petit W, Gardiner JC, Conlon K, et al. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther. 2014;351:259–69.")], thus limiting their possible clinical application.

PRX302 is a PSA-activated bacterial protoxin which has the ability to bind to cellular membranes, where it creates transmembrane channels with consequent lytic cell death. After intriguing results in animal models where intraprostatic injection of PRX302 caused extensive, organ-confined prostatic shrinkage [[93](/article/10.1186/s12894-016-0176-0#ref-CR93 "Williams SA, Merchant RF, Garrett-Mayer E, Isaacs JT, Buckley JT, Denmeade SR. A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease. J Natl Cancer Inst. 2007;99:376–85.")], this molecule has been tested in humans with favorable preliminary results. In a phase II trial, 18 men received intraprostatic injections of PRX302 [[94](/article/10.1186/s12894-016-0176-0#ref-CR94 "Denmeade SR, Egerdie B, Steinhoff G, Merchant R, Abi-Habib R, Pommerville P. Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2011;59:747–54.")]. After one year there was an average change from baseline IPPS of −9.7 and of +2.8 ml/s inQmax. Moreover, 12/18 (67 %) patients showed a ≥20 % reduction inprostate volume at day 90. Of note, no patient experienced sexual AEs. Clearly, though these results appear very encouraging, the small sample size limits their interpretation and PRX302 is still considered experimental.

NX-1207 is another protein for intraprostatic injection currently under evaluation in preliminary studies. This molecule promotes focal apoptosis, with significant reductions of prostate volumes in animal models [[95](/article/10.1186/s12894-016-0176-0#ref-CR95 "Shore N. NX-1207: a novel investigational drug for the treatment of benign prostatic hyperplasia. Expert Opin Investig Drugs. 2010;19:305–10.")]. Human phase II studies found that intraprostatic injection of NX-1207 determined a reduction of AUA Symptom Score, maintained during 6 months follow-up, with no significant AE [[95](/article/10.1186/s12894-016-0176-0#ref-CR95 "Shore N. NX-1207: a novel investigational drug for the treatment of benign prostatic hyperplasia. Expert Opin Investig Drugs. 2010;19:305–10.")]. Two phase III trials are underway and their results are awaited to better analyze the true potential of this drug in BPH management.

## Conclusions

Today, BPH should not be considered a strictly prostatic disease, as it has been demonstrated that the entire lower urinary tract is involved in a complex pathophysiology. New medical treatments are available and the right drugs should be prescribed t the correct patients. Silodosin has similar efficacy compared to tamsulosin, with a lower risk of cardiovascular AE, making it a good choice for older patients requiring α1-antagonists. Tadalafil improves BPH symptoms in men with and without ED, and could be considered especially when ED and BPH coexist. Antimuscarinics are effective on residual storage symptoms after α1-antagonist therapy and appears to be safe even in men with moderate BOO, though these patients should be strictly monitored with regular PVR measurements. Intraprostatic injections of onabotulinum toxin A are a promising minimally invasive option for LUTS management, although their true efficacy is still object of evaluation. Finally, research in the field of BPH medical treatment is actively progressing, with new agents as elocalcitol and mirabegron being tested. Future basic research and prospective clinical trials must continue in order to increase our pharmacologic armamentarium for men suffering from LUTS, in order to reduce BPH progression, improve QoL and decrease AEs.

## Abbreviations

AE:
    

Adverse effects

AUR:
    

Acute urinary retention

BOO:
    

Bladder outlet obstruction

BPH:
    

Benign prostatic hyperplasia

cGMP:
    

Cyclic guanosine monophosphate

ED:
    

Erectile dysfonction

IPSS:
    

International prostatic symptom score

LUTS:
    

Lower urinary tract symtoms

NO:
    

Nitric oxide

OAB:
    

Overactive bladder

PDE5:
    

Phosphodiesterase 5

QoL:
    

Quality of Life

UI:
    

Urinary infection

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## Acknowledgements

None.

### Funding

No funding was obtained for the present study.

### Availability of data and materials

All articles analysed are available to the public on PudMed.

### Authors’ contributions

Study concept and design: SA, CDN, TR. Acquisition of data: SA, IB, QM, FA. Analysis and interpretation of data: SA, FA, CDN, TR. Drafting of the manuscript: SA, IB, QM, FA. Critical revision of the manuscript for important intellectual content: FA, CDN, TR. All authors read and approved the final manuscript.

### Competing interest

The authors declare that they have no competing interests.

### Consent for publication

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### Ethics approval and consent to participate

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## Author information

### Authors and Affiliations

  1. Urology Department, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium

Simone Albisinni, Ibrahim Biaou, Quentin Marcelis, Fouad Aoun & Thierry Roumeguère

  2. Department of Urology, Ospedale Sant’Andrea, University “La Sapienza”, Roma, Italy

Cosimo De Nunzio




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Albisinni, S., Biaou, I., Marcelis, Q. _et al._ New medical treatments for lower urinary tract symptoms due to benign prostatic hyperplasia and future perspectives. _BMC Urol_ **16** , 58 (2016). https://doi.org/10.1186/s12894-016-0176-0

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  * Received: 06 April 2016

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  * Published: 15 September 2016

  * DOI: https://doi.org/10.1186/s12894-016-0176-0




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REVIEW article 

Front. Pharmacol. , 08 May 2020

Sec. Drugs Outcomes Research and Policies 

Volume 11 - 2020 |  [ https://doi.org/10.3389/fphar.2020.00658 ](https://doi.org/10.3389/fphar.2020.00658)

This article is part of the Research Topic Drug Prevention and Treatment of Benign Prostatic Diseases: from Clinical Original to Translational Research [View all 8 articles](https://www.frontiersin.org/research-topics/10303/drug-prevention-and-treatment-of-benign-prostatic-diseases-from-clinical-original-to-translational-research/articles)

# Efficacy and Side Effects of Drugs Commonly Used for the Treatment of Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia

[![Zhao-Jun Yu,](https://loop.frontiersin.org/images/profile/818672/74)Zhao-Jun Yu](https://loop.frontiersin.org/people/818672)1,2[![Hai-Lan Yan](https://loop.frontiersin.org/images/profile/960391/74)Hai-Lan Yan](https://loop.frontiersin.org/people/960391)3![Fang-Hua Xu](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Fang-Hua Xu4[![Hai-Chao Chao](https://loop.frontiersin.org/images/profile/960695/74)Hai-Chao Chao](https://loop.frontiersin.org/people/960695)5![Lei-Hong Deng](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Lei-Hong Deng6![Xiang-Da Xu](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Xiang-Da Xu2![Jian-Biao Huang](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Jian-Biao Huang2![Tao Zeng*](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Tao Zeng1*

  * 1Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
  * 2Medical Department of Graduate School, Nanchang University, Nanchang, China
  * 3Department of Clinical Medicine, Xi'an Jiao Tong University Health Science Center, Xi'an, China
  * 4Department of Pathology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
  * 5Institute of Clinical Medicine, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, China
  * 6Department of Ultrasound, The First Affiliated Hospital of Nanchang University, Nanchang, China



Benign prostatic hyperplasia (BPH) is the most common benign disease of the prostate gland and is caused by benign hyperplasia of the smooth muscle cells and stromal cells in this important gland. BPH is also the most common disease underlying lower urinary tract symptoms (LUTS). The incidence of BPH increases with age and affects more than half of all men 50 years or older. BPH mainly exerts effects on urinary function and can seriously reduce a patient's quality of life. At present, treatment for BPH aims primarily to improve the quality of life and reduce the risk of BPH-related complications. Pharmacological therapy is recommended for moderate-to-severe cases of LUTS that are suggestive of BPH. A range of drugs is currently available to treat this condition, including α1-adrenoceptor antagonists, 5α-reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitors (PDE5Is), muscarinic receptor antagonists (MRAs), β3-adrenoceptor agonists, and plant extracts. Of these, the most commonly used drugs in the clinic are α1-adrenoceptor antagonists, 5-ARIs, and combination therapy. However, these drugs exert their effects _via_ various mechanisms and are associated with adverse reactions. The purpose of this review is to provide current comprehensive perspectives on the mechanisms of action, efficacy, and adverse reactions associated with the drugs most commonly used for the treatment of BPH.

## Introduction

Benign prostatic hyperplasia (BPH) is one of the most common benign diseases of the urinary system in middle-aged and elderly men. The prostate is an almond-shaped organ located at the junction of the bladder and the urethra, and comprises the central zone, peripheral zone, and transitional zone. BPH is an irregular benign hyperplasia of smooth muscle cells and stromal cells in the transitional area of the prostate gland that compresses the urethra, and can result in a series of lower urinary tract symptoms (LUTS) (Lee et al., 1997). LUTS involves voiding symptoms, such as a sensation of incomplete bladder emptying, straining to void, urinary hesitancy, and a weak urinary stream. Other problems include storage symptoms, such as nocturia, frequent urination, dysuria, and urinary urgency. Of these symptoms, the most common is nocturia; this is followed by a weak urinary stream, a sensation of incomplete bladder emptying, urgency, and urinary incontinence (Homma et al., 2017; Langan, 2019). In addition to LUTS, BPH can cause further complications including sexual dysfunction, urinary incontinence, renal insufficiency, urinary tract infection, and acute urinary retention (AUR) (Juliao et al., 2012). Although BPH is not lethal, it can seriously affect a patient's quality of life (QOL) by causing anxiety, sleep disorders, and sexual disharmony.

The morbidity of BPH can exceed 50% in men older than 50 years and can exceed 80% in men who are 70 years of age and above; evidence clearly shows that the morbidity of BPH increases with age (Egan, 2016). In addition, BPH can be induced by a range of risk factors, including obesity, hyperlipidemia, type 2 diabetes, and certain hormonal disorders (Calogero et al., 2019; Yoo et al., 2019). Interestingly, recent a meta-analysis found that the periodontal disease may be positively associated with an increased risk of BPH (Wu et al., 2019). In addition, research has shown that the long-term excessive consumption of alcohol, diuretics, dicyclomine, and caffeine may also contribute to LUTS, although moderate levels of alcohol intake have been shown to reduce the incidence of BPH (Bradley et al., 2017). At present, BPH can be treated by both non-pharmacological and pharmacological treatments. Over the past few decades, a wide variety of drugs have been developed to prevent the progression of BPH and improve the QOL. Many BPH patients achieve satisfactory treatment outcomes after receiving such treatments. This review focuses on the mechanism of actions, therapeutic efficacy, and major side effects of the drugs that are commonly used to treat BPH and shows newer perspectives about these drugs.

## Methodology

We conducted an extensive literature search of PubMed for articles relating to the drugs used to treat BPH or LUTS. We also searched several official websites for specific drug information or guidelines relating to BPH or LUTS, including the United States Food and Drug Administration (FDA), the European Association of Urology (EAU), and the American Urological Association (AUA). The following search terms were used: benign prostatic hyperplasia, BPH, lower urinary tract symptoms, LUTS, drug, treatment, therapy, safety, efficacy, side effect, adverse reaction, mechanism, α1-adrenergic antagonists, α1-blockers, 5α-reductase inhibitors (5-ARIs), muscarinic receptor antagonists (MRAs), β3-adrenoceptor agonists, beta-3 agonists, phosphodiesterase5 inhibitors (PDE5Is), plant extracts, and combination therapy. We also used the names of specific drugs as search terms, including tamsulosin, silodosin, doxazosin, alfuzosin, terazosin, tadalafil, mirabegron, tolterodine, and fesoterodine.

## Current Therapies for BPH

At present, the primary goals of BPH treatment are to ameliorate LUTS, improve QOL, inhibit disease progression, and reduce complications. The treatment of BPH involves three different stages: watchful waiting, drug therapy, and surgical treatment (Kim et al., 2016). Watchful waiting is recommended by the AUA for patients in whom QOL has not been influenced by mild LUTS; this strategy includes the implementation of dietary changes, exercise, education, and regular review (Mcvary et al., 2011). However, for patients with severe LUTS, watchful waiting is often ineffective and may delay optimal treatment; such patients need to be administered appropriate medication. A range of drugs are currently available for the treatment of BPH, including α1-blockers, 5-ARIs, MRAs, PDE5Is, β3-adrenoceptor agonists, and plant extracts. Of these, the most commonly used drugs are α1-blockers, 5-ARIs, and a combination treatment featuring both α1-blockers and 5-ARIs (Kim et al., 2016).

Several potential drugs have recently been developed for the treatment of BPH, including RS17503 (an α-adrenoceptor antagonist), RONO2 (an endogenous organic nitrate), SR49050 (an antagonist of the vasopressin receptor subtype V1A), and BXL-628 (a vitamin D3 agonist). RS-17503 has a high affinity for α1a-adrenoceptor and is a promising drug for the treatment of BPH. RONO2 has been used in several _in vitro_ experiments and has been shown to increase Q-max and mean voided urine volume while reducing postvoid residual volume (PVR), and International Prostate Symptom Score (IPSS). Because vasopressin plays a physiological role in the contraction of the smooth musculature in both the prostate and urethra, there is considerable speculation that SR49059, a drug that targets the vasopressin receptor, might represent a potential candidate for the treatment of BPH (Uckert et al., 2019). However, as yet, none of these drugs have been tested in clinical studies, except for BXL-628. The clinical efficacy of BXL-628 in the treatment of BPH was not satisfactory; consequently, the clinical development of this drug was terminated (Colli et al., 2006). None of the other agents listed herein have been approved by the FDA for the treatment of BPH.

According to AUA guidelines, surgery is a potential option for BPH patients with severe LUTS or other complications, including recurrent urinary tract infections, AUR, renal insufficiency, recurrent bladder stones, gross hematuria due to BPH, or those who are unwilling to receive drug treatments (Foster et al., 2019). Although the standard surgical treatment for BPH is still transurethral resection of the prostate (TURP), other less invasive surgical therapies are available for patients with severe LUTS, including transurethral incision of the prostate, transurethral laser prostatectomy, transurethral microwave therapy of the prostate, and prostatic urethral lift (Foster et al., 2019).

## Drugs for BPH

### α1 Adrenergic Antagonists (α1-Blockers)

#### Mechanisms Underlying the Action of α1-Adrenergic Antagonists in the Treatment of BPH

α1-adrenoceptors are highly expressed in the smooth muscle cells of the prostate gland, bladder neck, and urethra. When stimulated by α-adrenergic nerve fibers, these cells cause strong contractions, resulting in increased levels of urethral resistance (Akinaga and Garcia-Sainz, 2019). Based on this physiological mechanism, α1-adrenergic antagonists bind to α1-adrenoceptors on the smooth muscle cells of the urethra and cause relaxation in smooth muscle tone, thereby reducing urethral resistance and relieving LUTS (Andersson and Gratzke, 2007). The α1-adrenoceptors can be classified into three different subtypes (α1a, α1b, and α1d); these subtypes are distributed across various anatomical sites (Akinaga and Garcia-Sainz, 2019). Consequently, α1-blockers can cause a range of side effects when used for the treatment of BPH, including postural hypotension, dizziness, asthenia, abnormal ejaculation, and intraoperative floppy iris syndrome (IFIS) (Andersson and Gratzke, 2007). Several α1-blockers have been approved by the FDA for the treatment of BPH, including alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin.

#### The Efficacy of α1-Blockers in the Treatment of BPH

α1-blockers have become the most common form of drug prescribed by urologists to treat BPH, and can lead to obvious improvements in patients with LUTS. Previous clinical trials have reported that α1-blockers reduced IPSS by 50%, and increased the maximum urinary flow rate (Q-max) by 40% (Michel et al., 1998; Djavan et al., 2004). α1-blockers can significantly improve the urinary symptoms of patients, including voiding symptoms and storage symptoms. Moreover, these effects can be achieved within only a few weeks. Several clinical trials have reported that α1-blockers can be efficacious over both the short and long terms, and in some cases, can exert effect in a rapid manner (Masumori et al., 2013; Manjunatha et al., 2016). These drugs target only α-adrenoceptors and do not induce changes in the size of the prostate, particularly within the transition zone (Roehrborn, 2006).

Interestingly, BPH patients who have a smaller prostate volume (PV) appear to represent optimal candidates for treatment with α1-blockers alone, while BPH patients with a larger PV are more suitable for treatment with 5α-reductase inhibitors (e.g., dutasteride) or combination therapy (e.g., dutasteride with tamsulosin). A previous prospective study, conducted in a single center, investigated the effects of silodosin monotherapy on LUTS, with specific reference to prostate size. In this previous study, 140 outpatients were equally divided into two groups: a small prostate group (SP, PV < 40 ml) and a large prostate group (LP, PV≥40 ml). Both groups were given silodosin (8 mg/day) for two years. The authors recorded IPSS, overactive bladder symptoms score (OABSS), bladder outlet obstruction index (BOOI), and detrusor overactivity at baseline, 3 months, and 24 months after treatment. Both groups showed significant improvements in IPSS and parameters related to the function of the lower urinary tract (storage function parameters and voiding function parameters), particularly in the SP group (PV < 40 ml). Although voiding function declined over time, the benefits in storage function were maintained for 2 years in the LP group. It is possible that the increase in bladder flow caused by α1-adrenoceptor antagonists led directly to an improvement in storage function, and that the greater structural changes taking place in the prostate stroma in BPH patients with a larger PV resulted in an improvement in BOOI (Matsukawa et al., 2018). Similarly, a randomized controlled intervention study reported that α1-blockers worked better in men with a PV ≤ 35 ml compared with those with larger PV (Joo et al., 2012).

In addition to patients with a small PV, α1-blockers appear to be more appropriate for BPH patients with lower baseline PSA levels; BPH patients with higher PSA levels appear to be more suitable for treatment with 5-ARIs or a combination of 5-ARIs and α1-blockers. In a parallel controlled trial, there was no remarkable improvement in terms of IPSS when compared between tamsulosin (an α1-blocker) and dutasteride (a type of 5-ARI) in patients with a baseline PSA level < 3.5 ng/ml; however, patients with baseline PSA levels > 3.5 ng/ml and treated with dutasteride showed significant improvement in IPSS compared to those treated with tamsulosin (Roehrborn et al., 2009).

#### Potential Side Effects Associated With the Use of α1-Blockers in BPH Treatment

In general, different α1-blockers appear to have similar effects on patients with LUTS; however, there is considerable variation in terms of side effects. Based on their binding affinity to α1-adrenoceptor subtypes, α1-blockers can be divided into selective α1-blockers and nonselective α1-blockers. The nonselective α1-blockers include terazosin, doxazosin, and alfuzosin; these drugs can block all α1-adrenoceptor subtypes equally. Selective α1-blockers include silodosin and tamsulosin. However, alfuzosin appears to be an exception. When we consider affinity to α1-adrenoceptor subtypes, alfuzosin can be referred to as a nonselective α1-blocker; however, this drug is clinically uroselective and has no significant effect on vascular α-adrenoceptors (Lowe, 2004).

α1-blockers are associated with three major side effects. Firstly, α1-blockers are associated with cardiovascular events such as postural hypotension, asthenia, and dizziness. The mechanism underlying these cardiovascular side effects might involve the reduction of blood pressure caused by α1-blocker-induced vasodilatation in smooth muscle cells and endothelial cells (Akinaga and Garcia-Sainz, 2019). However, De Mey and colleagues report that asthenia and dizziness reported in patients taking α1-blockers were not associated with blood pressure changes, but more likely to be associated with the central nervous system, which is also known to express α1-adrenoceptors (De Mey, 2000). Almost all α1-blockers, but particularly terazosin and doxazosin, can cause these side effects, although those related to selective α1-blockers are relatively weaker (Oelke et al., 2014a). Therefore, it is important to evaluate cardiovascular function in patients with BPH before considering the use of α1-blockers.

The second side effect is ejaculatory dysfunction (EjD). α1-blockers are known to cause retrograde ejaculation, but do not affect libido. Several meta-analyses have reported that tamsulosin and silodosin have the most significant association with retrograde ejaculation; other α1-blockers, such as alfuzosin, doxazosin, and terazosin, have a far smaller impact on ejaculatory function (Rosen et al., 2009; Gacci et al., 2014; Jung et al., 2017). In a previous randomized controlled trial, analysis of covariance (ANCOVA) was used to compare a group of patients taking silodosin with controls in order to analyze changes in Q-max, IPSS, and treatment efficacy. Over the short term, silodosin treatment led to a rapid improvement in urinary symptoms and a reduced risk of postural hypotension; however, the most common side effect related to silodosin treatment was retrograde ejaculation (Marks et al., 2013). Several other meta-analyses have shown that silodosin is stronger than tamsulosin when considering the improvement of urinary symptoms, particularly with regards to voiding symptoms; however, these studies also reported that silodosin was associated with a much higher risk of retrograde ejaculation (Wu et al., 2013; Gacci et al., 2014). The difference between these two α1-blockers with regards to their respective efficacy in patients with LUTS may be attributable to the significantly higher affinity between silodosin and α1a-adrenoceptors (Tatemichi et al., 2006). In general, silodosin had the strongest effects with regards to the side effect of retrograde ejaculation, followed by tamsulosin and nonselective α1-blockers. Interestingly, a very recent systematic review featuring data from 1,371 patients in six cohort studies provided evidence that alfuzosin could improve ejaculatory function (Yeung et al., 2020). It is possible that the blockade of adrenoceptors located in spermatic ducts and seminal vesicles may be associated with EjD in BPH patients receiving α1-blockers (Hisasue et al., 2006). The specific mechanisms underlying these observations may include insufficient contraction of the seminal vesicles, insufficient rhythmic contraction of the muscles of the pelvic floor, and the loss of seminal emission (Kobayashi et al., 2008; Nagai et al., 2008).

The third side effect that is commonly associated with α1-blockers is IFIS. This side effect often occurs in patients taking α-blockers who undergo cataract surgery; the risk of IFIS, however, is relatively low. It has been reported that most α1-blockers have the ability to cause IFIS, and that the highest level of risk is associated with tamsulosin (Srinivasan et al., 2007). IFIS also occurs in patients that have discontinued α-blockers (Nguyen et al., 2007). It is not yet known how α-blockers can induce IFIS. However, it is possible that the blockade of α-adrenoceptors could lead to contraction of the iris dilator muscle, or that the interaction between α-blockers and melanin induces atrophy in the dilator muscle (Oelke et al., 2014a). Therefore, prior to cataract surgery, it is important that ophthalmologists include previous α-blocker use in their patient history, and, if necessary, prohibit the use of α-blockers, especially tamsulosin, during cataract surgery.

α1-blockers have become the first-line clinical treatment for BPH and are commonly used worldwide. However, these drugs are mainly suitable for patients with moderate-to-severe LUTS, and are particularly useful for patients with a small PV and low baseline PSA levels. However, α1-blockers have a range of side effects; consequently, alfuzosin may be the most appropriate drug to prescribe to younger LUTS-BPH patients who are sexually active. This is because alfuzosin has been proven to improve ejaculatory function, while both silodosin and tamsulosin are contraindicated. Nonselective α1-blockers would not be appropriate for patients experiencing postural hypotension, asthenia, dizziness, and other risk factors associated with cardiovascular events. Patients scheduled to undergo cataract surgery should not be administered α-blockers, particularly tamsulosin.

### 5α-Reductase Inhibitors (5-ARIs)

#### Mechanisms Underlying the Action of 5-ARIs in the Treatment of BPH

It is commonly known that testosterone and dihydrotestosterone (DHT) promote the development of BPH. DHT plays a primary role in the development of BPH and amplify androgen-related activities in the prostate. 5α-reductase inhibitors (5-ARIs) were developed to treat BPH on the basis that testosterone can be converted into DHT by the enzyme 5α-reductase. The 5-ARIs can inhibit the conversion of testosterone and reduce the levels of DHT, thereby shrinking an enlarged prostate and preventing the progression of disease into BPH (Drobnis and Nangia, 2017). 5α-reductases can be divided into two subtypes, with very different patterns of biodistribution: type I and type II. The type I 5α-reductases are widely expressed in the skin, sebaceous glands, liver, and prostate epithelial cells. Type II 5α-reductases are mainly expressed in the stromal cells of the prostate, and, to a lesser extent, the epithelial cells (Cilotti et al., 2001). There are two inhibitors of 5α-reductase: finasteride and dutasteride. Finasteride is specific to type II 5α-reductase, while dutasteride inhibits both type I and type II 5α-reductase (Drobnis and Nangia, 2017).

#### The Efficacy of 5-ARIs in the Treatment of BPH

It is known that 5-ARIs can significantly reduce PV and serum levels of PSA. In a previous study, Na et al. investigated the safety and efficacy of dutasteride treatment in Chinese BPH patients using a double-blind, parallel placebo-controlled clinical trial. This study specifically recruited patients with a total prostate volume (TPV) of 30 ml or more; Q-max ranged from 5 ml/s to 15 ml/s; and the American Urology Association Symptom Index (AUA-SI) score was 12 units or higher. The research subjects were randomly classified into a dutasteride group or a placebo group. The dutasteride group was administered 0.5 mg of dutasteride on a daily basis, while the placebo group was given the placebo. After six months, the total PV had reduced by an average of 17.14% and 3.71% in the dutasteride group and the placebo group, respectively. Patients in the placebo group were given 0.5 mg of dutasteride on a daily basis for six months; the mean TPV had fallen by 11.75% when assessed at 12 months, and by 14.65% when assessed at 18 months. The dutasteride group also showed greater mean reductions in TPV at 12 months (18.83%) and 18 months (22.85%). This study provided strong evidence that 5-ARIs can reduce PV over the long term in men with BPH (Na et al., 2012).

Another clinical study examined the effect of 5-ARIs on serum PSA levels and PV. In this study, all 166 BPH patients were administered 5 mg of finasteride on a daily basis for six months. Researchers then measured the median percentage change in serum PSA levels in the entire study cohort, and measured PV by transrectal ultrasonography and prostate-specific antigen density (PSAD) in 86 men with BPH. In another study, Chiu and Yong reported that the median percentage changes in PSA level, PV, and PSAD, were −44.26%, −17.80%, and −38.67%, respectively (Chiu and Yong, 2004). Other studies have shown that 5-ARIs can also significantly improve Q-max, QOL, LUTS, and nocturia in men with BPH (Na et al., 2012; Oelke et al., 2014b).

Patients with enlarged prostates and higher baseline PSA levels are usually at greater risk of prostatic hyperplasia progression. In addition, LUTS deterioration, AUR, and BPH-related surgery are all closely associated with the clinical progression of BPH (Roehrborn, 2008). Several reports have confirmed that the long-term treatment of BPH patients with 5-ARIs, finasteride, and dutasteride can lead to reductions in the risk of developing AUR, and a reduction in the need for BPH-related surgery (Roehrborn and Ray, 2006; Kaplan et al., 2011). It is particularly evident that 5-ARIs can significantly prevent the progression of BPH.

The 5-ARIs are most suitable for patients with moderate-to-severe LUTS-BPH and an enlarged prostate. It is also evident that the baseline PV is closely associated with the outcome of BPH patients treated with 5-ARIs. In a four-year clinical trial, Roehrborn et al. compared the influence of baseline PV and PSA on the incidence of AUR, BPH-related surgery, and overall clinical progression in 4844 men treated with tamsulosin, dutasteride, or a combination of both drugs. Analysis showed that there was a greater reduction in the risk of AUR or BPH-related surgery in patients with a baseline PV ≥ 40 mL and receiving dutasteride than in patients with a smaller PV (Roehrborn et al., 2011). Kaplan et al. also reported that LUTS-BPH patients with a PV > 30 ml are ideal candidates for finasteride therapy (Kaplan et al., 2011). However, neither of these two clinical studies observed any significant improvement in terms of clinical progression in patients with a smaller PV. In addition, total serum PSA represents a significant predictor for evaluation of the efficacy of 5-ARIs in BPH patients. Several studies have reported that BPH patients with higher baseline PSA levels are more suitable for treatment involving 5-ARIs (Roehrborn et al., 2009; Roehrborn et al., 2011). These two previous studies showed that remarkable therapeutic effects can be achieved in men who receive 5-ARIs over long periods of time. Interestingly, 5-ARIs have been shown to cure androgenetic alopecia; dutasteride has been shown to be more effective than finasteride in the treatment of androgenetic alopecia (Gubelin Harcha et al., 2014).

#### Potential Side Effects Associated With the Use of 5-ARIs in the Treatment of BPH

5-ARI treatments are associated with a range of side effects in BPH patients, including decreased libido, gynecomastia, and erectile dysfunction (ED). There are also reports that dutasteride can improve the prognosis of patients with prostate cancer, especially in low-risk prostate cancer (Fleshner et al., 2012; Schroder et al., 2013). Similarly, the Prostate Cancer Prevention Trial (PCPT) provided evidence that finasteride had similar effects to dutasteride in terms of reducing the incidence of prostate cancer, although finasteride can also increase the risk of high-grade Gleason prostate tumors (Thompson et al., 2003). For this reason, it appears that the genetic instability created by alteration in the androgen milieu results in an invasive prostate cancer phenotype (Tso et al., 2000). Generally, there are no obvious differences between dutasteride and finasteride in terms of efficacy and safety, although finasteride has fewer sexual side effects and breast complications than dutasteride when used in the treatment for BPH (Kaplan et al., 2012).

### Muscarinic Receptor Antagonists (MRAs)

#### Mechanisms Underlying the Use of MRAs in the Treatment of BPH

Abundant M2 and M3 cholinergic receptors are distributed on the smooth muscle cells of the bladder, urothelium, and afferent nerves. The detrusor contracts when these cholinergic receptors are stimulated, resulting in frequent micturition and an increased urgency to urinate (Eglen, 2005). Although the M2 receptor subtype is far more abundant in the bladder than the M3 receptor subtype, the M3 subtype is more crucial to bladder contractions than the M2 subtype (Chapple et al., 2002). It is clear that M2/M3 cholinergic receptors play significant roles in the urethra and bladder. Consequently, MRAs were developed to ameliorate storage symptoms in BPH patients. MRAs exert action by blocking muscarinic cholinergic receptors, although the exact mechanisms and sites of action have yet to be established (Sellers and Chess-Williams, 2012). Thus far, several MRAs have been approved by the FDA, including oxybutynin, tolterodine, fesoterodine, darifenacin, solifenacin, and trospium. This class of drugs is primarily used to treat the storage symptoms associated with LUTS and overactive bladder (OAB), such as frequent micturition, urgency of urination, and urgent urinary incontinence (UUI) (Yamada et al., 2018).

#### The Efficacy of MRAs in the Treatment of BPH

The most significant strength of MRAs is their ability to improve storage in patients with LUTS. Lee et al. described a prospective, randomized, multicenter, study in which 156 patients (IPSS ≥14, voiding subscore ≥ 8, storage subscore ≥ 6) were randomized into two groups. In group 1 (n=80), the patients were received 0.2 mg of tamsulosin each day for four weeks, and then received 0.2 mg of tamsulosin plus 5 mg of solifenacin on a daily basis for 8 weeks. In group 2, all patients received a combination of 0.2 mg of tamsulosin and 5 mg of solifenacin on a daily basis for 12 weeks. The authors assessed changes from baseline in a range of parameters, including total IPSS, IPSS storage sub-score, IPSS voiding sub-score, OABSS, and urgency symptoms between the two groups over the twelve weeks of treatment. Analysis showed that the IPSS storage sub-score was obviously lower in the group of patients receiving a daily combination of 0.2 mg tamsulosin plus 5 mg solifenacin than in the group receiving 0.2 mg of tamsulosin each day over a period of 4 weeks. However, there were no striking differences with regards to total IPSS or IPSS voiding sub-score between the two groups at four weeks. After 12 weeks of treatment, there were no significant differences between the two groups with regards to storage symptoms (Lee et al., 2014). In another meta-analysis, Gong et al. also provided strong evidence to support the efficacy of a combination therapy featuring MRAs and α1-blockers when used for patients with LUTS (Gong et al., 2015).

Interestingly, it appears that LUTS patients with a smaller PV or a lower baseline PSA level would achieve better benefits from antimuscarinic therapy than those with a larger PV or higher PSA level (Roehrborn et al., 2008; Liao and Kuo, 2015). Liao and Kuo found that, among in patients with a TPV > 40 ml, there were no significant differences between patients treated with tolterodine and those treated with doxazosin with regards to IPSS improvement (76.5% _vs._ 78.0%, p = 0.871). In contrast, there was a significant improvement in IPSS in the group treated with tolterodine compared with that in the group treated with doxazosin (73.3% _vs._ 57.6%, p = 0.040) among patients with a TPV < 40 ml (Liao and Kuo, 2015). In addition, a randomized, double-blind, research study reported that the efficacy of antimuscarinic drugs in BPH patients was closely related to the serum PSA level. Roehrborn et al. found that tolterodine could significantly improve 24-h frequency, frequency-urgency sum, and IPSS storage sub-score in patients with serum PSA levels < 1.3 ng/ml in comparison with those receiving placebo (Roehrborn et al., 2008).

The specific formulations of anti-muscarinic drugs are also associated with their relative efficacies. For example, tolterodine is available in two drug formulations: extended-release (ER) and immediate-release (IR). The ER formulation of tolterodine is more effective than the IR formulation when used for the treatment of OAB symptoms, and is also associated with a lower incidence of side effects (Van Kerrebroeck et al., 2001).

#### Side Effects of MRAs in the Treatment of BPH

There are several side effects associated with MRAs, including dry mouth, pruritus, constipation, micturition difficulties, nasopharyngitis, and dizziness. A previous meta-analysis showed that the most common side effect is dry mouth (Chapple et al., 2008). An open trial showed that oxybutynin is more likely to cause dry mouth than tolterodine, and that although there were similarities between the two agents in terms of other side effects, oxybutynin is more effective than tolterodine for reducing micturition (Diokno et al., 2003). Interestingly, a clinical study found that the combination of tolterodine with pilocarpine led to an effective reduction in the risk of dry mouth and did not simultaneously influence the efficacy of tolterodine in the treatment of OAB (Dmochowski et al., 2014).

However, the most serious side effect of antimuscarinic drugs is AUR. Because of their effect on the bladder (detrusor flaccidity), antimuscarinics are closely associated with AUR. A retrospective cohort study suggested that patients receiving antimuscarinic treatment for one month had a higher incidence of AUR than patients receiving long-term treatment (8.3 _vs._ 2.0) (Martin-Merino et al., 2009). The risk of AUR also seems to be higher during the early stages of antimuscarinic treatment. In terms of the risk of AUR, another meta-analysis, involving randomized controlled trials (RCTs) and observation studies, 365 men, and a 12-week follow-up period, suggested that the incidence of AUR was only small (0.3%) (Blake-James et al., 2007). According to the AUA Guidelines on the Management of Benign Prostatic Hyperplasia, LUTS-BPH patients with a PVR > 250 to 300 ml should only receive antimuscarinic treatment with caution. The AUA guideline also recommends that MRAs should only be prescribed after investigating a patient's PVR (Mcvary et al., 2011). Another meta-analysis investigated the relationship between age and the safety of antimuscarinics in older adults. It appears that the treatment of LUTS patients with antimuscarinics increases the risk of side effects in patients aged 65 or older when compared with patients younger than 65 years of age (Vouri et al., 2017). This result may be associated with drug metabolism and the fact that elderly individuals generally exhibit lower rates of metabolism, thus prolonging the drug residence time.

Several newer antimuscarinics have been developed for use in LUTS-BPH patients; these include tarafenacin, imidafenacin, vaginal oxybutynin, and tolenix (a combination therapy involving 2 mg of tolterodine IR and 9g of ER pilocarpine 9 mg). Although these drugs have been demonstrated to reduce the side effects of traditional MRAs in clinical trials, including dry mouth and constipation, their ability to relieve storage symptoms remains invariant, or slightly better, in LUTS-BPH patients (Thiagamoorthy et al., 2016). However, these drugs are still not approved by the FDA for BPH treatment, although imidafenacin has been licensed in Japan.

### β3-Adrenoceptor Agonists (Beta-3 Agonists)

#### Mechanisms Underlying the Use of β3-Adrenoceptor Agonists in BPH Treatment

β-adrenoceptors are ubiquitously expressed in the bladder, urethra, and prostate. Furthermore, the expression levels of the β3-adrenoceptor subtype are far higher than those of the other two subtypes (β1-adrenoceptor and β2-adrenoceptor) in the bladder (Michel and Vrydag, 2006). β3-adrenoceptor agonists were first developed to reduce detrusor tone and promote urine storage on the basis that activation of the β-adrenoceptors relaxes the smooth muscle and detrusor in both the urethra and bladder (Yang and Tao, 2019). Mirabegron is currently the only selective β3-adrenoceptor agonist that has been approved by the FDA.

#### The Efficacy of β3-Adrenoceptor Agonists in BPH Patients

Mirabegron has been shown to significantly improve OAB symptom-frequency, urgency, nocturia, and UUI-in patients with LUTS or/and OAB, but has little effect on voiding urodynamics, particularly maximum urinary flow and detrusor pressure at maximum urinary flow, compared with a placebo, over a period of 12 weeks (Nitti et al., 2013). Mirabegron is commonly used for the treatment of OAB syndrome induced by BPH owing to its pharmacological activity, although currently AUA does not recommend its use for BPH treatment. This drug is often used as a second-line medicine for LUTS treatment. Because of the similarity between β3-adrenoceptor agonists and muscarinic antagonists in terms of pharmacological action, mirabegron is regarded as a well-tolerated alternative to MRAs for the treatment of LUTS (Tubaro et al., 2017).

#### The Side Effects of β3-Adrenoceptor Agonists in BPH Treatment

The most common side effects induced by mirabegron treatment include headache, constipation, nasopharyngitis, hypertension, and urinary tract infection, with the latter three being the most common among these (Chapple et al., 2014). A previous meta-analysis investigated the tolerability of mirabegron in comparison with antimuscarinics and combination therapy, and suggested that 50 mg of mirabegron had a lower risk of side effects than antimuscarinic monotherapy, but with similar efficacy (Kelleher et al., 2018). Aside from having fewer side effects than antimuscarinics, mirabegron is also associated with greater levels of persistence than antimuscarinics. A retrospective and observational study provided evidence that patients with OAB showed greater levels of persistence and adherence when treated with mirabegron than those treated with tolterodine (Chapple et al., 2017). It is also worth noting that uncontrolled hypertension is a contraindication due to the risk of severe hypertension (Michel and Gravas, 2016). Therefore, it is important that urologists review the cardiovascular disease history of their patients and monitor blood pressure when prescribing mirabegron for the treatment of OAB.

### Plant Extracts

Plant extracts are a class of herbal medicines that remain somewhat controversial and are not yet recommended by the EAU or AUA for the treatment of BPH. Such treatments predominantly include extracts from _Saw palmetto_ , _Cucurbita pepo_ L., _Prunus africana_ , _Urtica dioica_ L, and _Secale cereale_ L. (Sharma et al., 2017). Phytotherapies have not yet been accepted by the EAU and AUA because of methodological problems and heterogeneity in the clinical trials carried out thus far. However, plant extracts have already been prescribed in clinical practice for BPH patients who were unwilling to accept standard medical treatments in the United States and numerous European countries, including Hungary, Germany, Poland, and France (Cornu et al., 2010). The prescription of plant extracts is therefore dependent on the guidelines adopted by individual nations and their health systems.

Extracts from _S. palmetto_ and _C. pepo_ L. are the most frequently used. Over the past few decades, increasing clinical evidence has demonstrated the effects of these extracts in patients with BPH. One meta-analysis, which included data extracted from 15 RCTs and 12 observational studies, suggested that Permixon, a hexanic extract of _S. palmetto_ , had similar levels of efficacy to α1-blockers with regards to improvements in the IPSS, QOL, and Q-max (Vela-Navarrete et al., 2018). This previous study also showed that Permixon treatment led to an improvement in LUTS symptoms, and an inhibition in the progression of BPH, that was equivalent to that achieved with a 6-month treatment with 5-ARIs (Vela-Navarrete et al., 2018). A 15-year open observation study investigated the changes in PV, Q-max, QOL, and IPSS, in BPH patients treated with a daily dose of _S. palmetto_ extract (320 mg), and found that this extract was able to prevent the progression of BPH (Vinarov et al., 2019).

The _C. pepo_ L. extract has also been reported to be efficacious for the treatment of BPH patients. In a pilot study, Leibbrand et al. assigned 60 BPH patients with an IPSS of 14.8 (95% confidence interval [CI]: 13.5-16.1) to a group that received an oil-free hydroethanolic _C. pepo_ L. extract once daily for 12 weeks, and investigated the consequent changes in IPSS, frequency of nocturia, and PVR. Analysis showed that this treatment led to an average reduction of 30.1% (95% CI: 23.1-37.1) for total IPSS. There was also an obvious reduction in PVR (baseline: 83.67 mL [95% CI: 58.02-109.3]; after 12 weeks: 63.11 mL [95% CI: 45.37-80.85]), and a significant reduction in the frequency of nocturia (Leibbrand et al., 2019). Although the precise mechanisms underlying the effects of plant extracts on BPH patients have yet to be elucidated, several studies suggest that plant extracts may exert pharmacological action through anti-androgenic, anti-proliferative, anti-inflammatory, and anti-edema activities (Buck, 2004; Gandaglia et al., 2017; Paterniti et al., 2018).However, the mechanisms underlying these effects may involve the action of multiple active ingredients present in the plant extract.

The existing literature clearly suggests that plant extracts are effective for the treatment of BPH. However, some clinical trials have reported contradictory results. A double-blind trial investigating the efficacy of _S. palmetto_ in 225 BPH patients with moderate-to-serve LUTS found no obvious difference between the control group and the treated patients (Bent et al., 2006). More recently, Russo et al. used surface under the cumulative ranking curve (SUCRA) analysis to compare the relative effects of alfuzosin, tamsulosin, silodosin, _S. palmetto_ , and placebo, with regards to improvements in LUTS and peak flow. This research found that the score for _S. palmetto_ in terms of the improvement of LUTS and peak flow in BPH patients was the lowest, and even lower than that of the placebo group. These results indicated that _S. palmetto_ had no clinical effect in terms of improving LUTS and peak flow in BPH patients (Russo et al., 2020). To date, however, no other studies have indicated that _C. pepo_ L. has no clinical effect as a form of treatment for BPH.

It is possible that the different clinical outcomes evident in the literature for the same plant extract may be related to the differences in brands from which the extracts were prepared, methods of extraction, environments in which the plants were grown, or time at which they were harvested. It is also possible that different parts or concentrations, of the plants were used to extract the active compounds (Habib and Wyllie, 2004). It is also worth noting that several studies have suggested that _S. palmetto_ appears to have few negative impacts on sexual function; similar levels of activity have also been recorded for _Crocus sativus_ L (Cai et al., 2013; Vela-Navarrete et al., 2018). At the time of writing this article, plant extracts have still not been approved by the FDA, EAU, or the AUA because of the associated drug heterogeneity, a limited regulatory framework, and the methodological limitations of the trials and meta-analyses published thus far (Mcvary et al., 2011).

### Phosphodiesterase 5 Inhibitors (PDE5Is)

#### Mechanisms Underlying the Use of PDE5Is in BPH Treatment

Phosphodiesterase 5 is distributed throughout the urinary tract, including the bladder detrusor, vascular smooth muscle, prostate tissue, and ureter. PDE5Is relax the urinary smooth muscle and the bladder detrusor, and can therefore improve LUTS by increasing the concentration of intracellular cyclic guanosine monophosphate (cGMP) (Fibbi et al., 2010). It is also worth noting that the nitric oxide (NO) pathway is the underlying signaling mechanism by which PDE5Is exert their pharmacological action on urinary smooth muscle (Kedia et al., 2008).

#### The Efficacy of PDE5Is in BPH Patients

Although several PDE5Is (sildenafil, tadalafil, and vardenafil) have been reported to exert efficacy on LUTS-BPH patients, only tadalafil has been approved by the FDA to treat patients with BPH (Hiramatsu et al., 2020). PDE5Is were initially developed to treat ED. Many reports have suggested that tadalafil is a highly effective option for the treatment of LUTS related to BPH. A previous meta-analysis, featuring 3214 patients with BPH, demonstrated that PDE5Is can significantly improve IPSS and International Index of Erectile Function (IIEF) scores, but have no effect on Q-max (Gacci et al., 2012). In a clinical trial, Porst et al. also demonstrated that tadalafil treatment resulted in significant improvements to the IPSS and IIEF scores, but had no impact on Q-max in LUTS-BPH patients (Porst et al., 2011). Therefore, tadalafil appears to be a good option for the treatment of sexually active LUTS-BPH patients with or without ED.

#### Side Effects of PDE5Is in BPH Treatment

The use of PDE5Is is associated with numerous side effects, including flushing, indigestion, headache, back pain, gastroesophageal reflux, and nasal congestion (Gacci et al., 2012). A previous meta-analysis revealed that headache, dyspepsia, and backpain were the most common side effect associated with PDE5Is, and that there were no significant differences between various types of PDE5Is in this respect (Yuan et al., 2013). Yuan et al. also found that the form of PDE5I with the highest risk of headache was avanafil; the PDE5I with the highest risk of indigestion was tadalafil; and the PDE5I with the highest risk of backpain was vardenafil; while tadalafil was associated with a higher risk of myalgia than sildenafil. (Yuan et al., 2013). Another meta-analysis assessed the effect of a daily 15 mg dose of tadalafil for the treatment of BPH and ED, and suggested that a 5-mg tadalafil, given once daily, was well tolerated due to the low risk of discontinuation resulting from related side effects (Wang et al., 2018). The side effects associated with PDE5Is appear to be moderate and well tolerated by BPH patients, although contraindications should be considered by urologists. When combined with nitrates, PDE5Is can increase the risk of life-threatening symptomatic hypotension (Chrysant, 2013); therefore, it is important that nitrates should not be used in combination therapies with PDE5Is. According to a clinical study, the interval of time between the intake of nitrates and the intake of long-acting PDE5I tadalafil should be at least 48 h (Abrams, 2004). The α1-blockers, doxazosin and terazosin, can have similar effects on patients taking PDE5Is. In addition to the drugs described above, diuretics can also exert influence on the efficacy of tadalafil. Among the population of patients with BPH, there is a sub-population who are elderly and have hypertension. A previous integrated analysis of data from four RCTs investigated the influence of cardiovascular risk factors and antihypertension drugs on a daily dose of oral tadalafil (5 mg) in patients with BPH. Among the patients taking antihypertensive drugs on a daily basis, the placebo-adjusted least squares (LS) mean improvement in total IPSS in patients taking diuretics was −0.2 (95% CI: −2.1 to 1.7), the placebo-adjusted LS mean improvement in total IPSS in patients taking other forms of antihypertension medicine was −2.8 (95% CI, −3.7 to −1.9), and the placebo-adjusted LS mean improvement in total IPSS in patients not taking any antihypertension medicine was −2.3 (95% CI, −3.2 to −1.5). These data indicate that diuretics have a negative influence on the efficacy of tadalafil treatment in LUTS-BPH patients who take daily doses of antihypertensive medication (Vlachopoulos et al., 2015). Serious cardiovascular events are another problematic contraindication that should be considered carefully when prescribing this drug (Chrysant, 2013). Urologists should evaluate the general health of BPH patients before prescribing tadalafil, particularly with regards to cardiovascular disease.

## Combination Therapies for BPH

In LUTS-BPH patients, it is often difficult to achieve satisfactory efficacy with a single drug, and patients often discontinue treatment because of side effects. Consequently, there is an urgent need to develop novel combination therapies with satisfactory efficacy and inhibition of disease progression as well as improved patient adherence to treatment. The combination of different drugs may result in additional side effects, however. Currently, the most common combination therapies include the combination of α1-blockers with 5-ARIs and with MRAs. The most commonly used combination therapy is α1-blockers combined with 5-ARIs; furthermore, this is the only combination therapy recommended by the AUA (Mcvary et al., 2011). A previous clinical trial investigated the efficacy and safety of tamsulosin, dutasteride, and combination therapy, in the long-term treatment of patients with BPH over a four-year period. Results from this study showed that the combination of tamsulosin-dutasteride significantly reduced LUTS, delayed the disease progression of BPH, and reduced the risk of developing AUR and the need for surgery compared with a single-drug therapy; however, the incidence of side effects increased for the combination therapy (Roehrborn et al., 2010). According to AUA recommendations, the combination of an α1-blocker and a 5-ARI is more appropriate for patients with cases of LUTS that are associated with demonstrable prostatic enlargement (Mcvary et al., 2011). In addition, another meta-analysis, featuring data from 3,063 patients and seven articles, showed that treatment with a combination of tamsulosin and solifenacin achieved good efficacy in male LUTS-BPH patients, especially those with severe symptoms relating to urinary storage. However, attention should be paid to the PVR of patients when considering combination therapies in order to avoid increasing the risk of AUR (Gong et al., 2015). In addition to these common combination treatments, the combination of tadalafil with tamsulosin can also improve the IPSS, QOL, IIEF score, Q-max, and reduce the PVR more effectively than tamsulosin or tadalafil alone; however, this combination therapy also increases the risk of severe hypotension (Singh et al., 2014). The combination of PDE5Is with 5-ARIs may additionally represent a promising form of therapy (Roehrborn et al., 2015).

## Conclusion

Herein, we summarize the most commonly used drugs used to treat BPH. The most common forms of clinical treatment include α1-blockers, 5-ARIs, and the combination of these two drug types. The mechanism of action for each type of drug, along with its specific target, can vary widely. Furthermore, the drugs used to treat BPH exhibit a wide range of clinical applications, pharmacological actions, and side effects. It is also possible that the efficacy and side effects of each BPH drug may vary within the same patient population, and that the sensitivity of different BPH patient populations to the same BPH drug may also vary. Consequently, there is no universal therapy for LUTS-BPH patients, and individualized treatment plans are required to ensure the judicious use of medical resources. Before making decisions to choose the best available treatment for BPH patients, urologists should consider the severity of storage or voiding symptoms, the risk of disease progression (PV, baseline serum PSA level), patient characteristics (age, health condition, concomitant disease, current medication status, and the need for sexual function), individual preferences, and the acceptance of potential side effects.

## Author Contributions

Z-JY reviewed the literature and wrote the first draft of the manuscript. Figure 1 and Table 1 were created by F-HX, H-CC, and L-HD. H-LY checked and revised the draft manuscript. All authors contributed read, revised, and approved the submitted version.

FIGURE 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/528249/fphar-11-00658-HTML/image_m/fphar-11-00658-g001.jpg) ](https://www.frontiersin.org/files/Articles/528249/fphar-11-00658-HTML/image_m/fphar-11-00658-g001.jpg)

**Figure 1** The classification of the most common drugs used for the clinical treatment of LUTS/BPH, showing α1-blockers (α1 adrenergic antagonists), 5α-reductase inhibitors (5-ARIs), muscarinic receptor antagonists (MRAS), β3-adrenoceptor agonists (beta-3 agonists), and phosphodiesterase 5 inhibitors (PDE5Is).

TABLE 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/528249/fphar-11-00658-HTML/image_m/fphar-11-00658-t001.jpg) ](https://www.frontiersin.org/files/Articles/528249/fphar-11-00658-HTML/image_m/fphar-11-00658-t001.jpg)

**Table 1** The efficacy and safety of several common drugs approved by the FDA for the treatment of LUTS/BPH.

## Funding

This research was supported by the National Nature Science Foundation of China (grants: 81760464 and 81860455).

## Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Abbreviations

ANCOVA, analysis of covariance; AUA, American Urological Association; AUA-SI, American Urology Association Symptom Index; AUR, Acute urinary retention; 5-ARIs, 5α-reductase inhibitors; BPH, Benign prostatic hyperplasia; BOOI, Bladder outlet obstruction index; cGMP, Cyclic guanosine monophosphate; DHT, Dihydrotestosterone; EAU, European Association of Urology; ED, Erectile dysfunction; EjD, Ejaculation dysfunction; ER, Extended-release; FDA, Food and Drug Administration; IFIS, Intraoperative floppy iris syndrome; IIEF, International Index of Erectile Function; IPSS, International Prostate Symptom Score; IR, Immediate-release; LS, Least squares; LUTS, Lower urinary tract symptoms; MRAs, Muscarinic receptor antagonists; OAB, Overactive bladder; OABSS, Overactive Bladder Symptoms Score; PCPT, Prostate Cancer Prevention Trial; PDE5Is, Phosphodiesterase type 5 inhibitors; PV, Prostate volume; PVR, Post-void residual volume; PSA, Prostate-specific antigen; PSAD, Prostate-specific antigen density; Q-max, Maximum urinary flow rate; QOL, Quality of life; RCT, Randomized controlled trial; TPV, Total prostate volume; TURP, Transurethral resection of the prostate; UI, Urge urinary incontinence.

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Keywords: lower urinary tract symptoms, benign prostatic hyperplasia, efficacy, side effect, drug

Citation: Yu Z-J, Yan H-L, Xu F-H, Chao H-C, Deng L-H, Xu X-D, Huang J-B and Zeng T (2020) Efficacy and Side Effects of Drugs Commonly Used for the Treatment of Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia. _Front. Pharmacol._ 11:658. doi: 10.3389/fphar.2020.00658

Received: 20 January 2020; Accepted: 22 April 2020;  
Published: 08 May 2020.

Edited by:

[Hao Hu](https://loop.frontiersin.org/people/605473), University of Macau, China

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[Lingfan Xu](https://loop.frontiersin.org/people/894216), Duke University, United States  
[Natasa Duborija-Kovacevic](https://loop.frontiersin.org/people/713946), University of Montenegro, Montenegro

Copyright (C) 2020 Yu, Yan, Xu, Chao, Deng, Xu, Huang and Zeng. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Tao Zeng, dGFvemVuZzQwNzA5QHNpbmEuY29t

Disclaimer:  All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 

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Table of contents

  * Abstract
  * Introduction
  * Methodology
  * Current Therapies for BPH
  * Drugs for BPH
  * Combination Therapies for BPH
  * Conclusion
  * Author Contributions
  * Funding
  * Conflict of Interest
  * Abbreviations
  * References



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SYSTEMATIC REVIEW article 

Front. Med. , 12 October 2021

Sec. Geriatric Medicine 

Volume 8 - 2021 |  [ https://doi.org/10.3389/fmed.2021.744012 ](https://doi.org/10.3389/fmed.2021.744012)

This article is part of the Research Topic Advances on Pathogenesis and Treatment of Lower Urinary Tract Symptoms and Pelvic Floor Dysfunction Diseases [View all 22 articles](https://www.frontiersin.org/research-topics/18688/advances-on-pathogenesis-and-treatment-of-lower-urinary-tract-symptoms-and-pelvic-floor-dysfunction-diseases/articles)

# Efficacy and Safety of 12-week Monotherapy With Once Daily 5 mg Tadalafil for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: Evidence-based Analysis

[![\\nJianwei Cui&#x;](https://loop.frontiersin.org/images/profile/1328351/74)Jianwei Cui](https://loop.frontiersin.org/people/1328351)†[![Dehong Cao&#x;](https://loop.frontiersin.org/images/profile/1067744/74)Dehong Cao](https://loop.frontiersin.org/people/1067744)†![Yunjin Bai](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Yunjin Bai![Jiahao Wang](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Jiahao Wang[![Shan Yin](https://loop.frontiersin.org/images/profile/1171291/74)Shan Yin](https://loop.frontiersin.org/people/1171291)![Wuran Wei](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Wuran Wei![Yunfei Xiao](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Yunfei Xiao[![Jia Wang
](https://loop.frontiersin.org/images/profile/1407492/74)Jia Wang](https://loop.frontiersin.org/people/1407492)*[![Qiang Wei
](https://loop.frontiersin.org/images/profile/831767/74)Qiang Wei](https://loop.frontiersin.org/people/831767)*

  * Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, China



**Background:** Tadalafil has been approved for the treatment of benign prostatic hyperplasia (BPH) for nearly 10 years. However, there are insufficient evidence-based studies of the efficacy and safety of tadalafil in treating lower urinary tract symptoms of BPH (LUTS/BPH).

**Objective:** To evaluate the therapeutic effect and clinical safety of tadalafil monotherapy (5 mg once daily for 12 weeks) for LUTS/BPH.

**Methods:** A total of 13 studies (15 randomized clinical trials [RCTs]) were extracted from the following databases: PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science for the period up to July 2021. The quality of the included RCTs was evaluated independently by two authors, who, respectively, extracted data according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses principles. Conflicts were settled by a discussion with two-third of senior authors. All data analyses were conducted by the Review Manager, version 5.4.

**Results:** Regarding efficacy, 12-week trials indicated that 5 mg once daily tadalafil showed a significantly lower and, consequently, better total International Prostate Symptom Score (IPSS) than the placebo did (mean difference [MD]: −1.97, 95% CI: −2.24 to −1.70; _P_ < 0.00001). In addition, significant differences were found between the tadalafil regimen and the placebo in the IPSS voiding subscore (MD: −1.30, 95% CI: −1.48 to −1.11; _P_ < 0.00001), the IPSS storage subscore (MD: −0.70, 95% CI: −0.82 to −0.58; _P_ < 0.00001), the IPSS quality of life (MD: −0.29, 95% CI: −0.35 to −0.22; _P_ < 0.00001), and BPH impact index (MD: −0.58, 95% CI: −0.76 to −0.40; _P_ < 0.00001). The safety analysis did not show a significant difference in serious adverse events between the two groups (risk ratio: 1.27, 95% CI: 0.80-2.01; _P_ = 0.31), although the adverse events occurred at a higher incidence in the tadalafil group than in the placebo.

**Conclusions:** This study demonstrates that once daily 5 mg tadalafil is a potentially effective and safe treatment choice with excellent tolerability for patients with LUTS/BPH.

**Systematic Review Registration:** Identifier (CRD42021228840).

## Introduction

Benign prostatic hyperplasia (BPH), which is caused by the proliferation of epithelial and stromal cells in the transition zone of the prostate, is characteristic of nonmalignant hyperplasia of prostatic tissue and is highly prevalent in older men (1). Lower urinary tract symptoms (LUTS) associated with BPH include storage or irritative (mainly including urinary frequency, urgency, and nocturia), voiding or obstructive (mainly including urinary hesitancy, straining, retention, and a decreased force of urination), and postmicturition symptoms, which can significantly and negatively affect the quality of life (QoL) of the elderly (2, 3). More than 50% of men > 50 years and over 80% of men > 80 years old experience LUTS/BPH (4).

In addition to surgical intervention, alpha-blockers (ABs), 5-alpha reductase inhibitors (5ARIs), and phytotherapies (monotherapy or cotherapy) have been prescribed for the treatment of LUTS related to BPH for decades (5, 6). Although these drug treatments are effective, they can cause troublesome adverse reactions, such as hypotension, dizziness, and sexual dysfunction (7, 8). Tadalafil, one of the phosphodiesterase type 5 inhibitors (PDE5Is) used to improve the symptoms of erectile dysfunction (ED), has been increasingly investigated and gained approval for the treatment of BPH in many countries since 2011 (9).

This is mainly because PDE5Is are believed to likely act mainly by increasing the concentration of nitric oxide (NO), which improves the activity of intracellular cyclic guanosine monophosphate (cGMP) (10). This system is collectively called the NO-cGMP signaling pathway, and its activation could lead to the relaxation of smooth muscle in the detrusor, bladder neck, and prostate (10). In addition, PDE5Is not only ameliorate intraprostatic inflammation-associated BPH but also improve tissue oxygenation and blood supply and thereby playing a vital part in alleviating LUTS (9, 11).

Recent meta-analyses comparing the effect of tamsulosin as a monotherapy and a cotherapy with tadalafil in improving LUTS/BPH, have concluded that cotherapy might be more suitable for patients than monotherapy (12, 13). However, analyses of tadalafil 5 mg monotherapy administered once daily for the treatment of LUTS/BPH are rare. Despite the use of tadalafil monotherapy, LUTS/BPH has been reported to improve significantly following treatment with this strategy (14). Therefore, in this study, we conducted the latest and high-quality synthesis of current worldwide evidence to evaluate the therapeutic effect and clinical safety of tadalafil 5 mg once daily monotherapy for 12 weeks in men with LUTS/BPH.

## Materials and Methods

### Study Protocol

The study registration application has been submitted to the International Prospective Register of Systematic Reviews (CRD42021228840) and the report was prepared using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

### Information Sources and Literature Search

A comprehensive and systematic search of PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science databases was performed for the period up to July 2021 by using the following key terms: [("Prostatic Hyperplasia"[Mesh]) OR (Benign Prostatic Hyperplasia) OR (Hyperplasia, Prostatic) OR (Prostatic Hypertrophy) OR (Adenoma, Prostatic) OR (Adenomas, Prostatic) OR (Prostatic Adenomas) OR (Prostatic Adenoma) OR (Prostatic Hyperplasia, Benign) OR (Prostatic Hypertrophy, Benign) OR (Benign Prostatic Hypertrophy) OR (Hypertrophy, Benign Prostatic) OR ("lower urinary tract symptoms"[Mesh]) OR (lower urinary tract symptom)] AND [("Tadalafil"[Mesh]) OR (Pyrazino (1′,2′:1,6) pyrido (3,4-b)indole-1,4 -dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-) OR (IC-351) OR (IC 351) OR (Cialis)]. Reference lists of relevant articles were also manually searched and the "related articles" function was used to identify additional articles in PubMed. The subsequent document filtration and data extraction were performed independently by the two authors (JW Cui, DH Cao), and conflicts on suitable articles were settled by discussion and consultation with two-third senior authors (Q Wei, J Wang).

### Study Selection

Trials included in our study met the following criteria according to the population, intervention, comparator, outcome, and study design (PICOS) approach: (P) male patients were diagnosed as LUTS/BPH; (I) taking medication: 12-week monotherapy with once daily 5 mg tadalafil; (C) treatment with an oral isodose placebo in the same way; (O) evaluating the following outcomes: changes in the total International Prostate Symptom Score (IPSS), IPSS storage (or irritative) subscore, IPSS voiding (or obstructive) subscore, IPSS quality of life (IPSS QoL), adverse events (AEs), and serious adverse events (SAEs); and (S) randomized controlled trials (RCTs). In addition, we excluded reviews, case reports, meeting abstracts, comments, letters to the editor, and animal research.

### Statistical Analysis

The outcome indicators were the QoL affected by LUTS/BPH scored using the IPSS, IPSS storage subscore, IPSS voiding subscore, BPH impact index (BII), IPSS QoL, the maximum flow rate (_Q_ max), and the postvoid residual (PVR). Furthermore, safety-related findings assessed based on AEs and SAEs were additional indicators. Efficacy was evaluated by analyzing index changes from baseline to 12 weeks, whereas safety was assessed by comparing AE-related data. The analyses were mainly conducted using the Review Manager, version 5.4 (Cochrane Collaboration, Oxford, the UK). Specifically, heterogeneity was evaluated with Cochrane's Q-statistic test and the _I_ 2 tests. The random-effects model was used when heterogeneity was accepted at a _P_ _Q_ < 0.10 or _I_ 2 > 50%, otherwise, the fixed-effects model was used. The risk of bias was independently assessed by two authors using the Jadad scale (≥3 scores represented high-quality studies), funnel plot, and _the Cochrane Collaboration 's tool for assessing the risk of bias_, and conflicts were resolved by reaching a consensus through discussions. Sensitivity analysis was performed in the outcome indicators, respectively, by sequentially excluding each study. To find out more information about the ideal candidate for tadalafil monotherapy, several linear regressions were performed. Continuous variables reported as a mean and SD in the original articles were converted from standard error into SD for this study: SD = standard error *(sample size)1/2. A 95% CI was chosen whether mean difference (MD) was used to express the continuous data or risk ratio (RR) was used for dichotomous data.

## Result

### Search Results and Quality Assessments

A total of 1,425 relevant articles were extracted from the databases through systematical and manual search strategies. Eventually, 13 articles (15-27) involving 9,525 participants were identified, of which 15 trials that met the eligibility criteria were included in this study. While the follow-up period was different in each study, we pooled data of the change from baseline to 12 weeks from the studies.

Figure 1 illustrates the literature search process used and Table 1 shows the mean baseline characteristics. The symmetrical funnel plot roughly revealed no selection biases or no small sample studies with poor methodological quality (Figure 2A). The risk of biases was presented further in the risk of bias graph summary and risk of bias graph, which illustrated that the probability of each bias in every study is quite small (Figure 2B). Apart from _Q_ max, the rest of the indicators have reached the insubstantial heterogeneity standard (_P_ _Q_ > 0.10 or _I_ 2 < 50% in forest plots) in Cochrane Reviewers' Handbook. In addition, no significant differences from the original analysis were found after sensitivity analysis.

FIGURE 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g001.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g001.jpg)

**Figure 1**. Flow diagram of literature searches.

TABLE 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-t001.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-t001.jpg)

**Table 1**. Participant demographic and baseline characteristics of the included studies.

FIGURE 2

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g002.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g002.jpg)

**Figure 2**. **(A)** Funnel plot of the studies represented in our meta-analysis; **(B)** risk of bias graph summary and risk of bias graph.

### Efficacy

#### Total IPSS

The total IPSS, IPSS voiding subscore, and IPSS storage subscore were reported in all the trails we selected. The data pooled from 15 studies (15-27) including 9,525 participants (4,937 and 4,588 in the tadalafil and placebo groups, respectively), and provided the necessary information for this study. The subsequent analysis result revealed a significantly larger total IPSS change from the baseline to 12 weeks in the tadalafil group (MD: −1.97 95% CI: −2.24 to −1.70, _P_ < 0.00001, Figure 3A) than in the placebo group.

FIGURE 3

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g003.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g003.jpg)

**Figure 3**. Forest plot of **(A)** the total IPSS; **(B)** the IPSS voiding subscore; **(C)** the IPSS storage subscore; **(D)** the IPSS QoL; **(E)** BII; **(F)** _Q_ max; and **(G)** PVR. IPSS, International Prostate Symptom Score; PVR, postvoid residual; QoL, quality of life.

#### IPSS Voiding Subscore and IPSS Storage Subscore

A total of 15 studies (15-27) included in the analysis recorded the change in the IPSS voiding and storage subscores from baseline to 12 weeks. The analysis of the combined data showed that tadalafil significantly reduced the IPSS voiding and storage subscores more than the placebo did, and the MD of the change in the two subscores was −1.30 (95% CI: −1.48 to −1.11, _P_ < 0.00001, Figure 3B) and −0.70 (95% CI: −0.82 to −0.58, _P_ < 0.00001, Figure 3C), respectively.

#### The IPSS Quality of Life

A total of 14 studies (15-26) including 9,423 participants (4,886 and 4,537 in the tadalafil and placebo groups, respectively) investigated the IPSS QoL improvement data. The fixed-effects estimate of the MD was −0.29 (95% CI: −0.35 to −0.22, _P_ < 0.00001, Figure 3D).

#### BPH impact Index

Eight studies (15-18, 21-23) including 3,682 participants (1,852 and 1,830 in the tadalafil and placebo groups, respectively) compared the effect of the treatments on the BII. Overall, the pooled MD was −0.58 (95% CI: −0.76 to −0.40, _P_ < 0.00001, Figure 3E) in the fixed-effect model, which indicated the BII was significantly lower in patients administered tadalafil therapy than in those who received the placebo.

These results suggested that tadalafil oral monotherapy (5 mg once daily for 12 weeks) significantly improved LUTS/BPH in the treated patients. Interestingly, the better improvement in IPSS seemed to be in connection with the younger age, the high BMI, and the high baseline IPSS (Figure 4).

FIGURE 4

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g004.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g004.jpg)

**Figure 4**. Influence of **(A)** the baseline of the total International Prostate Symptom Score (IPSS), **(B)** age, and **(C)** body mass index on IPSS improvement.

#### The Maximum Flow Rate (Qmax)

The mean change in the _Q_ max was calculated from pooled data from seven studies (15, 16, 18-21, 23) including 2,891 participants (1,458 and 1,433 in the tadalafil and placebo groups, respectively). The results showed an insignificant difference between tadalafil and the placebo, with an MD of 0.11 (95% CI: −0.41 to 0.63, _P_ = 0.68, Figure 3F).

#### Postvoid residual

Five studies (16, 18, 19, 21, 23) including 2,188 participants (1,106 and 1,082 in the tadalafil and placebo groups, respectively), provided information about the change in the PVR from baseline to 12 weeks. The results indicated that the decrease in PVR was similar between these two groups, with an MD of −0.89 (95% CI: −5.53 to 3.76, _P_ = 0.71, Figure 3G).

#### Safety

In our study, the most common AEs were headache (3.59%), nasopharyngitis (3.21%), dyspepsia (2.92%), and back pain (2.29%). The results of meta-analyses showed that a higher incidence of headache, dyspepsia, and back pain was associated with tadalafil monotherapy (Table 2).

TABLE 2

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-t002.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-t002.jpg)

**Table 2**. Most common reported treatment-related adverse events.

The AEs and SAEs that occurred in the tadalafil and placebo groups were compared in this review. All the studies included (15-27) in the analysis reported the incidence of AEs, which showed a significant difference between the tadalafil and placebo groups with a RR of 1.27 (95% CI: 1.19-1.36, _P_ < 0.00001, Figure 5A). However, the comparison of incidences of SAE did not show any significant difference between the two groups (RR: 1.27, 95% CI: 0.80-2.01, _P_ = 0.31, Figure 5B) in the 13 studies including 8,436 participants (4,393 and 4,043 in the tadalafil and placebo groups, respectively).

FIGURE 5

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g005.jpg) ](https://www.frontiersin.org/files/Articles/744012/fmed-08-744012-HTML/image_m/fmed-08-744012-g005.jpg)

**Figure 5**. Forest plot of **(A)** AE and **(B)** SAE. AE, adverse event; SAE, serious adverse event.

## Discussion

This systematic review and meta-analysis have demonstrated comprehensively the therapeutic effect and clinical safety of 12-week monotherapy with once daily 5 mg tadalafil for LUTS/BPH. In our study, the total IPSS improvement was clinically meaningful after a tadalafil monotherapy, which significantly improved the IPSS voiding and storage subscores, IPSS QoL, and BII, whereas no statistically significant difference was found in terms of _Q_ max and PVR. In addition, the result shows that tadalafil and placebo were similar in the matter of the incidence of SAEs, although the difference in AEs was statistically significant.

Medicinal management has become the standard of therapy in patients diagnosed with moderate to severe LUTS/BPH, whereas surgery is performed in those who fail to respond to medication. Tamsulosin is regarded as an effective treatment for LUTS/BPH because it selectively blocks α1 receptors to induce smooth muscle relaxation in the bladder, neck, and prostate (28). Furthermore, tamsulosin 0.4 mg administered once daily is used in Western countries and is the safest AB in combination with PDE5Is (12). As a recommended medicine, tamsulosin could improve the symptom score by 4-6 points in the European Association of Urology guidelines. Likewise, the total IPSS was reduced by an average of 4.7-6.4 points with tadalafil monotherapy in the studies we included. Coincidentally, the study by Oelke (19), comparing with tamsulosin, monotherapy with tadalafil seemed to be a similar therapeutic effect in improving moderate to severe LUTS/BPH. All these make it necessary to test whether tadalafil is effective in LUTS/BPH with more sufficient evidence.

Tadalafil, the only PDE5I used for the treatment of BPH, was initially prescribed for the treatment of ED in 2003 but later proved to be effective in LUTS/BPH. Consequently, this agent was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of symptoms of BPH especially when accompanied by ED (29). A dose-finding study was conducted with a sample size of 1,058 patients experiencing LUTS/BPH who were randomly assigned to receive tadalafil (2.5, 5, 10, or 20 mg) or a placebo once daily. The results showed that tadalafil administered at all the tested doses significantly improved the symptoms more than the placebo did, and tadalafil 5 mg daily showed a more positive risk-benefit profile (15). In fact, an oral dose of 5 mg per day is the standard for tadalafil (12). Dong et al. (30) performed a meta-analysis of studies reporting the use of monotherapy for LUTS in 2012, whereas Wang et al. (31) conducted a similar study in 2016. However, the tadalafil dose used in the included trials in the article by Dong et al. (30) was not unified in the analysis of the comprehensive effect of four different doses, and the number of studies included was small in the latter passage (30, 31). Furthermore, three related literature reports (25-27) (four RCTs) have been published over the last 5 years. Therefore, the latest and largest pooled analysis and systematic review are urgently required to evaluate the therapeutic effect and clinical safety of tadalafil with a unified dose (5 mg once daily) and a uniform endpoint (12 weeks) in patients with LUTS/BPH.

The reduced indexes, including the total IPSS, IPSS voiding and storage subscores, IPSS QoL, and BII, showed the relief of symptoms of BPH and the improvement of QoL. As we all know, IPSS QoL indicates the view of the patient if always accompanied by current LUTS/BPH in a future life, among which are six options: from 0 (pleasurable) to 3 (acceptable), to 6 points (terrible), in turn. Therefore, although the score of QoL was only reduced by about one point, it meant a qualitative leap in the satisfaction of patients with the improvement of urination symptoms and reflected the need of the patient for treatment. Storage symptoms, especially the relief in nocturia, made a greater contribution to the improvement in QoL (32). These statistically significant results illustrated a great therapeutic effect of tadalafil in improving LUTS, but the specific mechanisms of action remain unclear. The PDE5 enzyme is expressed in the bladder, urethra, corpora cavernosa, prostate, ureter, and kidney (33). Matsukawa et al. (34) conducted a urodynamic-based study that demonstrated that tadalafil significantly improved bladder outlet obstruction and bladder storage function. In addition, _in vitro_ studies showed that a PDE5I relaxed the smooth muscle of the bladder, neck, and prostate, and decreased detrusor muscle overactivity (35). The relaxant effect of PDE5Is on the bladder neck and urethra mediated by the NO-cGMP signaling pathway might result in symptom relief in patients with LUTS/BPH. Other related mechanisms include decreased activation of the RhoA/Rho kinase pathway, improvement of oxygenation, regulation of proliferation and transdifferentiation, modulation of the afferent nerves of the bladder and the prostate along with autonomic nervous system overactivity, and anti-inflammatory effects (7, 36). These mechanisms identified by our results might mediate the effective alleviation of the symptoms of BPH by this agent.

The corpus cavernosum, bladder, and prostate have similar pathophysiological pathways, and, therefore, LUTS/BPH and ED are often comorbid in the older population and have a higher incidence in older men (37). More importantly, LUTS is considered a risk factor for ED (38). Although many PDE5Is have similar mechanisms of action, tadalafil is the only PDE5I approved for the treatment of BPH because of its safety, tolerability, and longer duration of action (7). Nevertheless, a study of more than 1,000 men conducted by Broderick et al. (39) reported that tadalafil exhibited a similar efficacy in improving LUTS/BPH in men with or without comorbid ED. Moreover, Dong et al. (30) performed a subgroup analysis and reported that tadalafil showed a more significant improvement in BPH symptoms in men without ED than in those with ED. The effect of tadalafil on LUTS does not appear to mainly involve its mechanism of action on ED. However, the inhibitory effects of tamsulosin on neurogenic contractions have been reported to be enhanced by tadalafil in the human bladder, neck, and prostate. Those findings along with the study showing that cotreatment with ABs and tadalafil produces an additional relaxation effect on the corpus cavernosum _in vitro_ (40, 41), suggests there might exist synergistic effects among tadalafil and tamsulosin accounting for the better effect in patients who are suffering from LUTS/BPH and ED. Thus, when an ABs or tadalafil alone does not show sufficient efficacy, cotherapy with both agents may be considered.

No statistically significant difference was found in _Q_ max and PVR in this study, which is consistent with the finding by Liu et al. (42). However, trials studying cotreatment with ABs and PDE5Is demonstrated that it increased the urinary flow rate (43, 44). The relaxant effect of PDE5Is on the bladder neck and prostate, which should have increased the urinary flow, might be counteracted by the concomitant relaxation of the detrusor muscle. Nevertheless, cotherapy may exert a synergistically positive effect on the detrusor muscle, thereby improving the urinary flow rate (12). More studies are required to elucidate the mechanism.

Although the difference in AEs was statistically significant, the side effects were mild and sustainable, such as headache, dyspepsia, and back pain. Furthermore, the difference in the incidence of SAEs was not significant. Interestingly, one patient reported an SAE in the tadalafil group whereas six participants reported in the placebo group of the study by Roehrborn (15) reported SAEs, suggesting that some AEs might be caused by psychological effects. Moreover, Wada et al. (45) demonstrated that the main reason for withdrawal of tadalafil was insufficient efficacy, followed by AEs and improvement of symptoms (45). In addition, calculated finally to be 2.5% on average, the incidence of discontinuation was low. Therefore, tadalafil 5 mg daily had no obvious adverse effects and is highly effective in improving LUTS/BPH.

Previous trials have reported that a higher baseline IPSS score correlates with a better therapeutic effect of ABs (46), which is consistent with our present observation (Figure 4A). Moreover, the improvement in IPSS appeared to be related to age and obesity (Figures 4B,C). These results suggested that younger, more obese men with more severe urinary symptoms may be the ideal candidates for tadalafil monotherapy. This could be explained by the changes in metabolism and hormonal levels that accompany aging and obesity. Testosterone levels decrease with increasing age and the hormonal dependency of PDE5 expression has been found in the animal models (47). Additional research is needed to further verify these results and explore the underlying mechanisms of action.

There are some limitations to our study that should be recognized. We were restricted to studies comparing tadalafil with placebo, rather than other pharmacological treatments recommended in guidelines to manage LUTS. Nonetheless, we focus on whether tadalafil is effective and safe in treating LUTS/BPH, rather than assessing which is better after comparing tadalafil and other drugs. In addition, relatively few experiments reported _Q_ max and PVR, and those that did were conducted before 2013, which may have caused the lack of statistical significance observed. More large-scale, well-designed, and long-term prospective clinical studies using comprehensive indicators should be conducted to further confirm the effectiveness and safety of tadalafil monotherapy in improving LUTS/BPH vs. active control.

Despite the several limitations to this study, we have reported the latest and most comprehensive evidence-based medical proof to demonstrate that 5 mg once daily tadalafil was effective and safe for the treatment of LUTS/BPH. All the studies in our analysis were RCTs and the follow-up deadline of 3 months was long enough, and the heterogeneity of our forest plots was also calculated to be low, except for the _Q_ max (_I_ 2 = 52%). These findings indicate the reliability of the curative effect of tadalafil. As the population ages, more and more aging men are being troubled with LUTS/BPH together with ED. As an effective treatment for ED, tadalafil, shown in our study, has also a therapeutic effect in relieving LUTS/BPH. So, tadalafil is a better choice for men suffering from both LUTS/BPH and ED. What is more, due to its safety and tolerable AEs, tadalafil may provide another option for those who are intolerant to the side effects of ABs or 5ARIs. This study could provide a more meaningful reference for clinicians and researchers, and provide more concrete evidence for future guidelines for the treatment of BPH.

## Conclusion

Treatment with 5 mg tadalafil once daily effectively improved total IPSS, IPSS voiding subscore, IPSS storage subscore, IPSS QoL, and BII. Moreover, monotherapy with tadalafil appeared to be well tolerated and safe because no significant difference was detected in SAEs between the tadalafil- and placebo-treated patients. Finally, 5 mg tadalafil administered once daily could be a therapeutic option for patients with LUTS/BPH.

## Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

## Author Contributions

Conception and design, and administrative support by JW and QW. Provision of study materials or patients were administered by JC and DC. Collection and assembly of data were administered by JC, DC, YB, WW, and YX. Data analysis and interpretation were administered by JC, DC, and YB. Manuscript writing and final approval of manuscript were done by all the authors.

## Funding

This work was funded by the National Natural Science Foundation of China (Grant no. 82000721 and no. 81770756); the Post-Doctor Research Project, West China Hospital, Sichuan University (Grant no. 2019HXBH089); and the Health Commission of Sichuan Province (Grant no. 20PJ036).

## Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## Acknowledgments

We would like to thank Editage ([www.editage.cn](http://www.editage.cn)) for the English language.

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Keywords: benign prostatic hyperplasia (BPH), lower urinary tract symptoms (LUTS), tadalafil, efficacy, safety

Citation: Cui J, Cao D, Bai Y, Wang J, Yin S, Wei W, Xiao Y, Wang J and Wei Q (2021) Efficacy and Safety of 12-week Monotherapy With Once Daily 5 mg Tadalafil for Lower Urinary Tract Symptoms of Benign Prostatic Hyperplasia: Evidence-based Analysis. _Front. Med._ 8:744012. doi: 10.3389/fmed.2021.744012

Received: 19 July 2021; Accepted: 06 September 2021;  
Published: 12 October 2021.

Edited by:

[Xiulin Zhang](http://loop.frontiersin.org/people/1032585/overview), Second Hospital of Shandong University, China

Reviewed by:

[Hui Ding](http://loop.frontiersin.org/people/984706/overview), Lanzhou University Second Hospital, China  
[Zhangqun Ye](http://loop.frontiersin.org/people/1073673/overview), Huazhong University of Science and Technology, China

Copyright (C) 2021 Cui, Cao, Bai, Wang, Yin, Wei, Xiao, Wang and Wei. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Qiang Wei, d2VpcWlhbmc5MzNAMTI2LmNvbQ==; Jia Wang, d2FuZ2ppYXdjaEAxNjMuY29t

†These authors have contributed equally to this work and share first authorship

Disclaimer:  All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 

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[![Xiulin Zhang](https://loop.frontiersin.org/images/profile/1032585/32) Xiulin Zhang  The Second Hospital of Shandong University, China ](https://loop.frontiersin.org/people/1032585/overview)

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[![Zhangqun Ye](https://loop.frontiersin.org/images/profile/1073673/32) Zhangqun Ye  Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China ](https://loop.frontiersin.org/people/1073673/overview)[![HUI DING](https://loop.frontiersin.org/images/profile/984706/32) HUI DING  Department of Urology, Lanzhou University Second Hospital, China ](https://loop.frontiersin.org/people/984706/overview)

Table of contents

  * Abstract
  * Introduction
  * Materials and Methods
  * Result
  * Discussion
  * Conclusion
  * Data Availability Statement
  * Author Contributions
  * Funding
  * Conflict of Interest
  * Publisher's Note
  * Acknowledgments
  * References



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