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Editorial: Exercise, diet and weight loss before therapy for LUTS/BPH?

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In recent decades we have had access to an increasing body of evidence evoking a strong relationship between metabolic syndrome and the development of LUTS/BPH. This relationship suggests that metabolic syndrome might be responsible not only for putting patients at higher risk of developing LUTS/BPH but also for influencing the response and outcome of therapy. In a study in the present issue of BJUI [1] it has been observed that patients with a greater waist circumference, a sign of metabolic syndrome, are at a higher risk of experiencing persistent LUTS after either TURP or open prostatectomy for BPH. Likewise, in a recent systematic review and meta-analysis, a strong relationship between metabolic syndrome and prostatic enlargement was observed, underlining the exacerbating role of this syndrome in inducing the development of benign prostate enlargement as obese, dyslipidaemic and aged men have a higher risk of metabolic syndrome being a determinant factor of their prostate enlargement [2].

Metabolic syndrome is a constellation of clinical findings characterizing patients affected by a combination of abdominal obesity, elevated serum triglyceride levels, lowered HDL cholesterol levels, increased blood pressure or a high level of plasma glucose. It has also been considered an important risk factor for the eventual development of a number of diseases including type 2 diabetes, coronary vascular disease, fatty liver disease, chronic kidney disease and hyperuricaemia [3]. Furthermore metabolic syndrome has been recently associated with an increased risk of clinical progression of LUTS/BPH in men with moderate to severe LUTS, reinforcing this syndrome as a factor for progression in addition to IPSS score, prostate volume, PSA, maximum urinary flow rate and post-void residual urine volume [4]. Several studies have recently shown that patients with LUTS/BPH and metabolic syndrome have a higher prostate volume than those without, and express a worse response to pharmacological therapy, suggesting the need to consider this at the time of selecting patients with LUTS/BPH for drug therapy [5, 6]. Check these leptitox reviews for harmless and natural weight loss treatment.

Several factors in the development of metabolic syndrome have been elucidated, including hyperinsulinaemia and autonomic hyperactivity, increased adiposity, ischaemia and hypoxia, chronic proinflamatory state and abnormal androgen levels. These factors are probably inter-related. A lack of exercise, together with obesity, may lead to insulin resistance, exerting a detrimental effect on lipid ratios decreasing blood levels of HDL cholesterol and increasing blood levels of triglycerides and LDL cholesterol. These undesirable levels of cholesterol may lead to deposits of atheromatous plaques in artery walls, increasing the risk of cardiovascular disease. In addition, hyperinsulinaemia may lead to sodium retention, causing hypertension.

The implications for clinical practice are that, if metabolic syndrome is related to the development of BPH/LUTS, lifestyle interventions including weight loss (you can check resurge reviews and find how this supplement heal you losing weight), a healthy diet, and physical activity would have a positive effect in both symptom relief and disease progression. As a consequence we should develop management strategies to address both the symptoms and the underlying processes, not only because men with LUTS/BPH and metabolic syndrome respond worse than those without metabolic syndrome, but also because lifestyle change, a healthy diet and exercise might be enough to achieve symptom improvement and decrease the risk of cardiovascular disease, prevent most obesity related conditions just by reading these meticore reviews.

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David Castro-Diaz
Department of Urology, University Hospital of the Canary Islands, University of La Laguna, Tenerife, Spain

Video: Central obesity is predictive of persistent storage LUTS after surgery for BPE

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Central obesity is predictive of persistent storage LUTS after surgery for Benign Prostatic Enlargement: results of a multicenter prospective study

Mauro Gacci, Arcangelo Sebastianelli, Matteo Salvi, Cosimo De Nunzio*, Andrea
Tubaro*, Linda Vignozzi†, Giovanni Corona‡, Kevin T. McVary§, Steven A. Kaplan¶, Mario Maggi†, Marco Carini and Sergio Serni

 

Department of Urology, Careggi Hospital, University of Florence, Florence, *Department of Urology, Sant’Andrea Hospital, University ‘La Sapienza’, Rome, †Department of Clinical Physiopathology, University of Florence, Florence , ‡Endocrinology Unit, Medical Department, Maggiore-Bellaria Hospital, Bologna, Italy, §Department of Urology, Southern Illinois University School of Medicine, Springfield, IL , and Department of Urology, Weill Cornell Medical College, Cornell University, New York, NY, USA

 

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OBJECTIVE

To evaluate the impact of components of metabolic syndrome (MetS) on urinary outcomes after surgery for severe lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE), as central obesity can be associated with the development of BPE and with the worsening of LUTS.

PATIENTS AND METHODS

A multicentre prospective study was conducted including 378 consecutive men surgically treated for large BPE with simple open prostatectomy (OP) or transurethral resection of the prostate (TURP), between January 2012 and October 2013. LUTS were measured by the International Prostate Symptom Score (IPSS), immediately before surgery and at 6–12 months postoperatively. MetS was defined according the USA National Cholesterol Education Program-Adult Treatment Panel III.

RESULTS

The improvement of total and storage IPSS postoperatively was related to diastolic blood pressure and waist circumference (WC). A WC of >102 cm was associated with a higher risk of an incomplete recovery of both total IPSS (odds ratio [OR] 0.343, P = 0.001) and storage IPSS (OR 0.208, P < 0.001), as compared with a WC of <102 cm. The main limitations were: (i) population selected from a tertiary centre, (ii) Use exclusively of IPSS questionnaire, and (iii) No inclusion of further data.

CONCLUSIONS

Increased WC is associated with persistent postoperative urinary symptoms after surgical treatment of BPE. Obese men have a higher risk of persistent storage LUTS after TURP or OP.

 

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Could Urolift stand the test of time for LUTS management?

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july15urojc1Several new surgical technologies have been assessed during the last decades in order to improve the management of LUTS (Lower Urinary Tract Symptoms): HoLEP (Holmium laser enucleation of the prostate), HoLAP (Holmium laser ablation of the prostate), TUMT (transurethral microwave therapy), TUNA (transurethral needle ablation), HIFU (high-intensity frequency ultrasound) and more recently Greenlight laser vaporization. All these techniques have been compared to TURP (transurethral resection of the prostate), which it is currently considered as the surgical standard procedure for men with mid-size prostate gland associated with moderate-severe LUTS and obstruction.
This month, the #urojc tribe discussed a multicentric randomized trial of a new surgical treatment option for LUTS caused by prostate enlargement: the Prostatic Urethral Lift (PUL), which supposedly reduces the negative effects of other surgical therapies on sexual function. One important controversy of the article is the use of a composite end-point, the BPH6 that includes the assessment of 1) LUTS relief, 2) postoperative recovery experience, 3) erectile function, 4) ejaculatory function, 5) urinary continence preservation and 6) safety, a concept that may resemble the Pentafecta from the surgical treatment of prostate cancer.
The PUL vs TURP – BPH6 study seems to be a well done RCT that accurately follows the CONSORT
statement. july15urojc2

Despite of this, #urojc participants showed reluctance to accept the main outcomes of the study. Interestingly, comments about COI (conflict of interest) and the impact of the industry in manuscripts were mentioned…

july15urojc3july15urojc4

july15urojc5july15urojc6july15urojc7People were not completely convinced about using a novel endpoint to compare TURP and PUL… the BPH6 seems to balance the impact of the 6 elements… or perhaps it gave more magnitude to the sexual side effects…

Jul15urojc8-15

As usual in this #urojc, urologists mentioned specific details about the design and methods of the study…

july15urojc16july15urojc17july15urojc18 july15urojc19And participants questioned about why authors emphasized in the manuscript specific points that may favor PUL over TURP…

july15urojc20july15urojc21 july15urojc22july15urojc23

Good discussion went throughout the 48 hours session, constructive comments about the study, and some other tweets revealed skepticism at this new technique….

july15urojc24And then, @sivanrij evoked the truth about LUTS (by the way, one of the most retweeted/favorited comments)…july15urojc25

Despite being something completely related to the type of health care system, and the specific conditions of each continent or region, costs were compared…july15urojc26

Some experts in PUL shared their thoughts…july15urojc27july15urojc28
Final thoughts were mentioned…july15urojc29

Only time will determine the real success of this novel therapy…july15urojc30 july15urojc31 july15urojc32

But some questions remain unanswered…july15urojc33july15urojc34 july15urojc35

… And helpful references were mentioned…july15urojc36

https://www.bmj.com/content/326/7400/1167


https://www.ncbi.nlm.nih.gov/pubmed/?term=25885560

 


https://www.ncbi.nlm.nih.gov/pubmed/7563343

At this time we do not have any treatment options for LUTS/BPO that preserves the ejaculatory function, and PUL may be an option in selected cases; we should accept that it is another option to increase our therapeutic armamentarium…
#urojc demonstrates that Twitter is a powerful tool to share our scientific thoughts all over the world. #urojc gives the opportunity to discuss articles with world-wide experts and authors of the published articles. Following and participating in these discussing definitely opens our minds, expands our medical knowledge and contributes to offer better health care to our patients.

 

op

Daniel Olvera-Posada (@OlveraPosada) is a Mexican Urologist, trained at @incmnszmx, currently in his second year of the Endourology Fellowship (@EndourolSoc) at @westernu, in London Ontario, Canada.

Article of the Week: Evaluating Silodosin in the Treatment of LUTS Associated with BPE

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Naeem Bhojani, discussing his accompanying editorial to the Article of the Week. 

If you only have time to read one article this week, it should be this one.

Individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH): subgroup analyses of efficacy and safety data

Giacomo Novara, Christopher R. Chapple* and Francesco Montorsi
‡Department of Oncological, Surgical, and Gastroenterological Sciences, Urology Clinic, University of Padua, Padua,Italy, ‡Deprtment of Urology, Vita-Salute University, San Raffaele Hospital, Milan, Italy, and *Department of Urology, Royal Hallamshire Hospital, Sheffield, UK
Read the full article
OBJECTIVE

To evaluate efficacy and safety of silodosin in a pooled analysis of individual patient data from three registrational randomised controlled trials (RCTs) comparing silodosin and placebo in patients with lower urinary tract symptoms (LUTS).

PATIENTS AND METHODS

A pooled analysis of 1494 patients from three 12-week, multicentre, double-blind, placebo-controlled phase III RCTs was performed. Efficacy and safety data were assessed across patients with different baseline characteristics. Vertigo is one of the most common health problems in adults. It is a symptom, not a disease and is usually associated with a problem in the inner ear balance mechanisms (vestibular system), in the brain, or with the nerve connections between the two organs. Vertigo can also be brought on suddenly through various actions or incidents, such as sudden changes in blood pressure or as a symptom of motion sickness while sailing, on amusement rides, airplanes or in an automobile. It can be acute and severe, lasting for days, or it may be recurrent, with attacks that last for minutes to hours. Vertigo los angeles associated with panic attacks can sometimes be caused by hyperventilating.  For the best treatment for vertigo, do visit us.

Patients often describe balance problems, dizziness, light headedness, and motion sickness. They may also describe an intense or severe sensation of movement, tilting, or imbalance; the sensation is aggravated by movement and improved by remaining stationary. Patients may say that they are having continuous vertigo, when in reality, they are having repeated episodes (with each episode lasting less than a minute). Those with persistent vomiting or intractable vertigo may require admission for hydration and vestibular suppressant medication. These disorders are the ninth most common complaint that leads people to visit their physicians. It is important to not use general terms when describing balance problems. To put it another way, it is best to simply describe the sensation they feel without using general terms like dizziness or vertigo. The cause is often revealed by the patient’s history and physical examination. In migraine-associated vertigo for instance, the patient may report a history of acute-onset vertigo that lasts minutes, a few hours, many hours, or days.

 RESULTS

Silodosin was significantly more effective than placebo in improving all International Prostate Symptom Score (IPSS)-related parameters, and maximum urinary flow rate (Qmax) regardless of patients age (P < 0.041). Comparing the efficacy of silodosin in the different age groups, there were no differences for all the IPSS-related parameters, whereas Qmax improvement was slightly higher in patients aged <65 years (P = 0.009). Silodosin was significantly more effective than placebo in reducing all IPSS-related parameters regardless of baseline IPSS (P ≤ 0.001). Similarly, silodosin was more effective than placebo in improving IPSS-related parameters regardless of baseline Qmax (P ≤ 0.02). Silodosin was associated with significantly higher adverse event (AE) rates, compared with placebo, in all patient subgroups, with retrograde ejaculation being the most common. Prevalence of dizziness, orthostatic hypotension, and discontinuation rate was similar with silodosin and placebo in most patient subgroups.

CONCLUSIONS

We analysed the efficacy and safety of silodosin in several patient subgroups, showing that silodosin was more effective than placebo in improving all IPSS-related parameters in all patient subgroups, whereas AEs were similar. Notably, cardiovascular AEs were not higher in patients taking antihypertensive drugs or with mild renal function impairment. Discontinuation rates due to AEs were lower in elderly patients.

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Editorial: Selecting the right α-blocker – is silodosin your best option?

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A significant proportion of aging men will have bothersome LUTS and will eventually seek help for this problem. Various medical therapies are available to help aleviate these symptoms. Amongst the various treatments, α-blockers are some of the most widely used drugs. Novara et al. [1] recently published a report on the efficacy and safety of silodosin in a pooled analysis of individual patient data from three registrational randomized controlled trials comparing silodosin and placebo in patients with LUTS. Their study contributes pertinent information to aid the clinician in determining which α-blocker is best suited for specific patients with LUTS.

In the current study, patients were subdivided into groups in order to better understand which patient would benefit most from the use of silodosin [2]. In addition, the article examines the safety of silodosin in these same distinct patient groups. With regard to efficacy, silodosin was significantly more effective than placebo in improving all IPSS-related variables and maximum urinary flow rate, regardless of the patient’s age. When comparing the efficacy of silodosin in different age groups, no difference was observed for any of the IPSS variables, whereas patients aged <65 years had a statistically significantly greater maximum urinary flow rate.

With regard to safety, silodosin was associated with a significantly higher adverse event (AE) rate compared with placebo. When comparing the safety of silodosin in patients aged <65 years and >65 years, the overall AE rate, ejaculatory dysfunction and discontinuation rate attributable to AEs were all higher in the younger age group. Interestingly, in patients with concomitant use of antihypertensive drugs, the use of silodosin was not associated with a higher risk of either dizziness or orthostatic hypotension.

In a previous study by the same authors, no clinically relevant or statistically significant differences with regard to diastolic blood pressure, systolic blood pressure or heart rate in patients taking silodosin as compared to placebo were found [3]; however, a minor statistically significant difference vs placebo was observed with tamsulosin. The present study by Novara et al. [2] further supports the belief that silodosin is a safe drug from a cardiovascular standpoint.

From a sexual standpoint, silodosin does not seem to perform as well. In the present study, patients in the silodosin group had significantly more adverse events as compared with the placebo group. Retrograde ejaculation was by far the most common side effect affecting 32.8% of patients aged <65 years vs 0.9% in the placebo group. Similarly, in a study by Chapple et al. [3], as many as 14.2% of patients in the silodosin treatment group had ejaculatory dysfunction, compared with 2.1 and 1.1% of patients in the tamsulosin and placebo treatment groups, respectively. Although the percentage of patients who discontinued treatment because of treatment-emergent AEs in the present study was small and not significantly different among all treatment groups, one might hypothesize that over a longer follow-up period, such a prevalent side effect could be responsible for a higher discontinuation rate. Consequently, it should be kept in mind that for patients desiring to maintain antegrade ejaculation, or who are bothered by treatment-onset ejaculatory dysfunction, especially younger patients, silodosin might not be the best treatment option. Furthermore, it should be recognized that some patients would potentially accept a reduction in treatment efficacy to preserve ejaculation [4].

With regard to clinical outcomes, few published papers comparing tamsulosin with silodosin are available [5, 6]. One article found no clinically significant difference between the two α-blockers [5] whereas the other, which was a post hoc analysis, found a marginal clinical benefit for silodosin over tamsulosin [4]. Unfortunately, head-to-head trials are not forthcoming, so it will not be possible to determine if one α-blocker is clinically better than the other. Furthermore, the present study, because it lacked an active control arm, did not compare silodosin with tamsulosin, which leaves something to be desired.

In conclusion, careful consideration should be given to specific patient characteristics such as age and comorbidities, along with personal preferences towards sexual function when offering patients α-blockers for treatment of LUTS.

Read the full article
Hugo Lavigueur-Blouin and Naeem Bhojani

 

Department of Urology, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada

 

References

 

1 Novara G, Chapple CR, Montorsi F. A pooled analysis of individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). BJU Int 2014; 114: 427–33

 

2 Novara G, Chapple CR, Montorsi F. Individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH): subgroup analyses of efficacy and safety data. BJU Int 2015; 115: 802–4

 

3 Chapple CR, Montorsi F, Tammela TL 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

 

4 Sturch P, Woo HH, McNicholas T, Muir G. Ejaculatory dysfunction after treatment for lower urinary tract symptoms: retrograde ejaculation or retrograde thinking? BJU Int 2014. doi: 10.1111/bju.12868

 

5 Montorsi F. Profile of Silodosin. Eur Urol Suppl 2010; 9: 491–5

 

6 Novara G, Tubaro A, Sanseverino R et al. Systematic review and meta-analysis of randomized controlled trials evaluating silodosin in the treatment of non-neurogenic male lower urinary tract symptoms suggestive of benign prostatic enlargement. World J Urol 2013; 31: 997–1008

 

Video: Is silodosin your best option when selecting the right α-blocker?

/by

A significant proportion of aging men will have bothersome LUTS and will eventually seek help for this problem. Various medical therapies are available to help aleviate these symptoms. Amongst the various treatments, α-blockers are some of the most widely used drugs. Novara et al. [1] recently published a report on the efficacy and safety of silodosin in a pooled analysis of individual patient data from three registrational randomized controlled trials comparing silodosin and placebo in patients with LUTS. Their study contributes pertinent information to aid the clinician in determining which α-blocker is best suited for specific patients with LUTS.

In the current study, patients were subdivided into groups in order to better understand which patient would benefit most from the use of silodosin [2]. In addition, the article examines the safety of silodosin in these same distinct patient groups. With regard to efficacy, silodosin was significantly more effective than placebo in improving all IPSS-related variables and maximum urinary flow rate, regardless of the patient’s age. When comparing the efficacy of silodosin in different age groups, no difference was observed for any of the IPSS variables, whereas patients aged <65 years had a statistically significantly greater maximum urinary flow rate.

With regard to safety, silodosin was associated with a significantly higher adverse event (AE) rate compared with placebo. When comparing the safety of silodosin in patients aged <65 years and >65 years, the overall AE rate, ejaculatory dysfunction and discontinuation rate attributable to AEs were all higher in the younger age group. Interestingly, in patients with concomitant use of antihypertensive drugs, the use of silodosin was not associated with a higher risk of either dizziness or orthostatic hypotension.

In a previous study by the same authors, no clinically relevant or statistically significant differences with regard to diastolic blood pressure, systolic blood pressure or heart rate in patients taking silodosin as compared to placebo were found [3]; however, a minor statistically significant difference vs placebo was observed with tamsulosin. The present study by Novara et al. [2] further supports the belief that silodosin is a safe drug from a cardiovascular standpoint.

From a sexual standpoint, silodosin does not seem to perform as well. In the present study, patients in the silodosin group had significantly more adverse events as compared with the placebo group. Retrograde ejaculation was by far the most common side effect affecting 32.8% of patients aged <65 years vs 0.9% in the placebo group. Similarly, in a study by Chapple et al. [3], as many as 14.2% of patients in the silodosin treatment group had ejaculatory dysfunction, compared with 2.1 and 1.1% of patients in the tamsulosin and placebo treatment groups, respectively. Although the percentage of patients who discontinued treatment because of treatment-emergent AEs in the present study was small and not significantly different among all treatment groups, one might hypothesize that over a longer follow-up period, such a prevalent side effect could be responsible for a higher discontinuation rate. Consequently, it should be kept in mind that for patients desiring to maintain antegrade ejaculation, or who are bothered by treatment-onset ejaculatory dysfunction, especially younger patients, silodosin might not be the best treatment option. Furthermore, it should be recognized that some patients would potentially accept a reduction in treatment efficacy to preserve ejaculation [4].

With regard to clinical outcomes, few published papers comparing tamsulosin with silodosin are available [5, 6]. One article found no clinically significant difference between the two α-blockers [5] whereas the other, which was a post hoc analysis, found a marginal clinical benefit for silodosin over tamsulosin [4]. Unfortunately, head-to-head trials are not forthcoming, so it will not be possible to determine if one α-blocker is clinically better than the other. Furthermore, the present study, because it lacked an active control arm, did not compare silodosin with tamsulosin, which leaves something to be desired.

In conclusion, careful consideration should be given to specific patient characteristics such as age and comorbidities, along with personal preferences towards sexual function when offering patients α-blockers for treatment of LUTS.

Read the full article
Hugo Lavigueur-Blouin and Naeem Bhojani

 

Department of Urology, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada

 

References

 

1 Novara G, Chapple CR, Montorsi F. A pooled analysis of individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). BJU Int 2014; 114: 427–33

 

2 Novara G, Chapple CR, Montorsi F. Individual patient data from registrational trials of silodosin in the treatment of non-neurogenic male lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH): subgroup analyses of efficacy and safety data. BJU Int 2015; 115: 802–4

 

3 Chapple CR, Montorsi F, Tammela TL 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

 

4 Sturch P, Woo HH, McNicholas T, Muir G. Ejaculatory dysfunction after treatment for lower urinary tract symptoms: retrograde ejaculation or retrograde thinking? BJU Int 2014. doi: 10.1111/bju.12868

 

5 Montorsi F. Profile of Silodosin. Eur Urol Suppl 2010; 9: 491–5

 

6 Novara G, Tubaro A, Sanseverino R et al. Systematic review and meta-analysis of randomized controlled trials evaluating silodosin in the treatment of non-neurogenic male lower urinary tract symptoms suggestive of benign prostatic enlargement. World J Urol 2013; 31: 997–1008

 

Article of the Month: Have TRP channels fulfilled their promise in LUTS?

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Every Month the Editor-in-Chief selects the Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Month heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Wouter Everaerts, discussing his paper. 

If you only have time to read one article this week, it should be this one.

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶ and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, ‡University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

Read the full article

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.
Read more articles of the week

Editorial: TRP channel – a reality that still requires many years of scientific efforts

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Seventeen years have elapsed since the capsaicin receptor was first cloned by Caterina et al. [1] and the excellent review with an unusual provocative title by Deruyver et al. [2] was written. The capsaicin channel, re-named transient receptor potential (TRP) vanilloid receptor subtype 1 (TRPV1), is now commonly referred to as the founding member of the TRP family, as it currently includes 28 related channels, a number difficult to foresee in those early years [3].

TRP channels have been extensively studied in the lower urinary tract (LUT) with the aim of clarifying their role in micturition control and in the generation of LUTS. It is well accepted that TRP receptors have neuronal and non-neuronal expression [3, 4]. TRPV1 is fundamental to bladder hyperactivity and pain associated with LUT inflammation [3], while TRPV4 may participate in the generation of the normal sensation to void [5]. Another group of TRP receptors may even participate in bladder oncogenesis, which seems to be a role of TRPV2 [3]. The main substance of all this information is not a myth; rather it represents a large body of very solid scientific data.

There are certainly still many obscure areas. The distribution of TRP receptors in the bladder is certainly one of them. However, I disagree that a substantial part of available technical and financial resources have been allocated to study this matter. One should not forget that other matters, like the role of many TRP channels for bladder function, remain elusive. Broadly speaking, in my opinion, future key studies should tackle three very relevant but still unclear points. The importance of most TRP channels for bladder function is difficult to predict at the moment [3]. Just as an example, TRPA1 and TRPM8, which are sensitive to cold temperatures, are expressed in the bladder. However, the bladder, as all internal organs, is conserved at very constant physiological temperatures, making it difficult to understand the relevance of cold receptors to its function. Then, we need to find what the endogenous agonists for TRP receptors are in the LUT. Anandamide has been largely explored as an endogenous agonist for TRPV1 in the bladder [6], a fruitful observation as drugs able to manipulate endogenous levels of anandamide are currently being explored in clinical trials. The same holds true for the other members of the TRP family. TRPA1 may respond to infections due to its capacity to react to hydrogen sulphide [3]. But for the large majority of the TRP family endogenous agonists remain unknown. Finally, TRP antagonists that are simultaneously effective and safe must be generated. Most available TRPV1 antagonists, produced to date, although able to control bladder dysfunction in models of cystitis and spinal cord injury [3], cause hyperthermia and have been associated with an enlargement of ischaemic areas of the heart after coronary artery obstruction [3]. TRPV4 antagonists look very promising for controlling frequency but a compound safe for human use is still eagerly awaited [2]. Eventually the combination of antagonists for more than one of these receptors may prove effective at very low doses, so low that they do not generate serious adverse effects [7].

In conclusion, TRP receptors are a reality that still needs an enormous amount of work and dedication before becoming therapeutically useful. And that may take more time than we anticipate at the moment.

 

Read the full article
Francisco Cruz
Department of Urology, Al. Hernani Monteiro, Porto, Portugal

 

References

 

1 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389: 816–24

 

2 Deruyver Y, Voets T, De Ridder D, Everaerts W. Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms: myth or reality? BJU Int 2015; 115: 686–97

 

3 Avelino A, Charrua A, Frias B et al. Transient receptor potential channels in bladder function. Acta Physiol (Oxf) 2013; 207: 110–122

 

4 Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci U S A 2001; 98: 13396–401

 

5 Gevaert T, Vriens J, Segal A et al. Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding. J Clin Invest 2007; 117: 3453–62

 

6 Dinis P, Charrua A, Avelino A et al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosci 2004; 24: 11253–63

 

7 Charrua A, Cruz C, Jansen K, Rozenberg B, Heesakkers J, Cruz F. Co- administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiates the effect of each drug in a rat model of cystitis. BJU Int 2014; [Epub ahead of print] doi: 10.1111/bju.12861

 

Video: TRP channel modulators as pharmacological treatments for LUTS – myth or reality?

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Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, ‡University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

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Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.
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Article of the Week: Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis

Mauro Gacci, Giovanni Corona*, Linda Vignozzi†, Matteo Salvi, Sergio Serni, Cosimo De Nunzio‡, Andrea Tubaro‡, Matthias Oelke§, Marco Carini and Mario Maggi†

Department of Urology, University of Florence, Careggi Hospital, Florence, *Endocrinology Unit, Maggiore-Bellaria Hospital, Bologna, †Department of Clinical Physiopathology, University of Florence, Florence, ‡Department of Urology, Sant’Andrea Hospital, University ‘La Sapienza’, Rome, Italy; and §Department of Urology, Hannover Medical School, Hannover, Germany

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OBJECTIVE

To summarise and meta-analyse current literature on metabolic syndrome (MetS) and benign prostatic enlargement (BPE), focusing on all the components of MetS and their relationship with prostate volume, transitional zone volume, prostate-specific antigen and urinary symptoms, as evidence suggests an association between MetS and lower urinary tract symptoms (LUTS) due to BPE.

METHODS

An extensive PubMed and Scopus search was performed including the following keywords: ‘metabolic syndrome’, ‘diabetes’, ‘hypertension’, ‘obesity’ and ‘dyslipidaemia’ combined with ‘lower urinary tract symptoms’, ‘benign prostatic enlargement’, ‘benign prostatic hyperplasia’ and ‘prostate’.

RESULTS

Of the retrieved articles, 82 were selected for detailed evaluation, and eight were included in this review. The eight studies enrolled 5403 patients, of which 1426 (26.4%) had MetS defined according to current classification. Patients with MetS had significantly higher total prostate volume when compared with those without MetS (+1.8 mL, 95% confidence interval [CI] 0.74–2.87; P < 0.001). Conversely, there were no differences between patients with or without MetS for International Prostate Symptom Score total or LUTS subdomain scores. Meta-regression analysis showed that differences in total prostate volume were significantly higher in older (adjusted r = 0.09; P = 0.02), obese patients (adjusted r = 0.26; P < 0.005) and low serum high-density lipoprotein cholesterol concentrations (adjusted r = −0.33; P < 0.001).

CONCLUSIONS

Our results underline the exacerbating role of MetS-induced metabolic derangements in the development of BPE. Obese, dyslipidaemic, and aged men have a higher risk of having MetS as a determinant of their prostate enlargement.

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