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Article of the Week: Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis

January 21, 2015/by admin Z.9

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

Read the full article

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.

Editorial: The Prostate – The gateway to men’s health

January 21, 2015/by Jonathan Rees

We have been told for many years that the management of men with LUTS due to BPH was, for most, about treating the impact of those symptoms on their quality of life. However, evidence has been accumulating over recent years to suggest that BPH may be associated with the various components of the metabolic syndrome – a combination of central obesity, impairment of glucose tolerance, dyslipidaemia and hypertension. Hammarsten et al. [1] examined the link between BPH and 22 individual aspects of the metabolic syndrome and found that BPH was linked to 21 of these factors, including increased body mass index (BMI) and waist circumference, hypertension, type 2 diabetes, dyslipidaemia and atherosclerosis, lending support to the hypothesised association with metabolic syndrome as a whole.

In this issue of BJUI, Gacci et al. [2] report the results of a meta-analysis of eight studies examining this link between BPH and metabolic syndrome, including >5000 patients, of which over a quarter had metabolic syndrome. They report a higher prostate volume (and transitional zone volume) in men with metabolic syndrome than in those without, particularly in older and obese patients and those with low high-density lipoprotein (HDL)-cholesterol levels. Interestingly however, no difference was seen between the groups in terms of LUTS, as measured by total IPSS or the storage/voiding sub-scores, although other studies have reported this in the past [1]. They conclude that modification of lifestyle and cardiovascular risk factors, by weight loss, increased exercise, dietary improvements etc., may have a role to play in improving LUTS. In addition, further exploration of the role of medication, such as statins, in the management of LUTS due to BPH is recommended. These conclusions are supported in the literature by observational studies, showing for instance a decrease in the severity of LUTS with increasing exercise, an increased risk of LUTS with obesity, and a delay in the onset of LUTS for patients taking long-term statins of up to 7 years [3, 4].

BPH is not the only urological condition that appears to have links with metabolic syndrome [1]. It is well established that erectile dysfunction has strong associations with type 2 diabetes mellitus, cardiovascular disease, obesity and sedentary lifestyle. Less well known links are also seen with prostate cancer, renal calculi, hypogonadism and overactive bladder [5]. We are familiar with carrying out cardiovascular risk assessment, screening for diabetes and giving lifestyle advice to men with erectile dysfunction. Given the evidence suggesting that erectile dysfunction and BPH are closely associated, with many men suffering from both conditions [6], it would suggest that perhaps we should be doing the same for men presenting with symptomatic BPH.

An awareness and understanding of the connection between BPH and metabolic syndrome should encourage all physicians to assess patients with LUTS/BPH for underlying cardiovascular risk. It suggests that as a minimum, a number of baseline investigations should be carried out: blood pressure measurement, a fasting lipid profile (and formal cardiovascular risk profile using established algorithms, such as QRISK®), assessment for diabetes using fasting glucose or glycated haemoglobin (HbA1c), measurement of weight and BMI, or ideally the measurement of abdominal circumference (as central obesity is a far more sensitive marker of risk than BMI). Identification of features of the metabolic syndrome allows for tailored lifestyle intervention, in terms of increasing exercise, dietary changes, weight loss, smoking cessation advice and alcohol moderation. Medical management of hypertension, diabetes, dyslipidaemia and cardiovascular disease may be required according to national guidelines.

Huge numbers of men die prematurely from cardiovascular disease and complications of type 2 diabetes, and men are renowned for poor engagement with primary preventive strategies to decrease this risk. Men presenting to their GP or Urologist with symptoms from BPH are therefore presenting us with an opportunity to intervene and potentially save lives in the process – the prostate can be considered a gateway to wider aspects of men’s health, far beyond the quality-of-life impact of LUTS.

Read the full article

Jonathan Rees

Backwell & Nailsea Medical Group, North Somerset, UK

References

1 Hammarsten J, Peeker R. Urological aspects of the metabolic syndrome. Nat Rev Urol 2011; 8: 483–94

2 Gacci M, Corona G, Vignozzi L et al. Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis. BJU Int 2015; 115: 24–31

3 Parsons JK, Messer K, White M et al. Obesity increases and physical activity decreases lower urinary tract symptom risk in older men: the Osteoporotic Fractures in Men Study. Eur Urol 2011; 60: 1173–80

4 St Sauver J, Jacobsen SJ, Jacobson DJ et al. Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms. BJU Int 2011; 107: 443–50

5 Rees J, Kirby M. Metabolic syndrome and common urological conditions: looking beyond the obvious. Trends in Urology and Men’s Health 2014; 5: 9–14

6 Rosen R, Altwein J, Boyle P et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 2003; 44: 637–49

Ejaculatory Function and Treatment for Male LUTS due to BPH

May 12, 2014/1 Comment/by Ben Jackson

This month’s twitter-based international urology journal club discussed “Impact of Medical Treatments for Male LUTS due to BPH on Ejaculatory Function: A Systematic Review and Meta-analysis”, published online in the Journal of Sexual Medicine. The discussion was enriched by the participation of Asst. Prof. Giacomo Novara (@giacomonovara) of the University of Padua, the senior author of the paper.

There was general consensus that this was a well constructed paper addressing an important and sometimes neglected side-effect of a group of medications that most urologists use commonly. The principal messages of the paper were:

Ejaculatory dysfunction (EjD) was significantly more common with alphablockers (ABs) in general than placebo
This effect was mainly seen with selective ABs (tamsulosin and sildosin). Non-selective ABs (doxazosin and terazosin) had similar rates of EjD to placebo.
Finasteride and dutasteride both cause EjD, and to a similar extent as each other.
Combination therapy (5ARI + AB) resulted in a three-fold increase in EjD compared to either monotherapy

The authors were congratulated on the amount of work that had obviously gone into the analysis. There was a discussion of some of the technical aspects of how to conduct a systematic review (SR) and meta-analysis. The PRISMA guidelines are a mandatory standard, and are recommended to anyone considering undertaking one. @LoebStacy also recommended the Cochrane handbook as a useful source of info. @DrHWoo asked whether Jadad scores had been used to rate RCT quality. They were not used in this study, but are one method of assessing RCT quality for an SR. @chrisfilson and @jleow advocated the Cochrane Collaboration’s tool for risk of bias assessment (found in Section 8.5 of the handbook), as an alternative.

After the technical aspects, discussion focussed on how best to avoid EjD in men who are concerned about it. @linton_kate asked whether PDE5 inhibitors were an option in this regard. General consensus was that they are an option, especially where LUTS and erectile dysfunction (ED) coexist, but concerns were expressed about the cost (which varied country by country, but is generally far in excess of the cost of ABs) and by @nickbrookMD about the uncertainty surrounding their mechanism of action for LUTS improvement.

Several correspondants were using PDE5Is in clinical practice for this indication however, including @VMisrai. It was pointed out however, that alfuzosin also offers a reduced risk of EjD compared to other ABs, and is substantially less expensive than PDE5Is. Alfuzosin was not evaluated in this paper, however @giacomonovara agreed that it was an option in men with LUTS who wish to avoid EjD, especially where ED is not a concern. @DrHWoo pointed out the Rosen data demonstrating the correlation between increasing LUTS and decreasing erectile function, but indeed (as suggested by @JCLinMD) treatment of LUTS, e.g. with an AB, may in itself improve erectile function.

Discussion moved on to 5ARIs. @giacomonovara stated that these agents had a broad spectrum of potential effects on ejaculatory/erectile function. @shomik_S raised the issue of whether 5ARIs could cause irreversible sexual side-effects. This is certainly a medicolegal concern, and undoubtedly some men report persistent effects on libido and sexual function, although a firm causal link has not been established.

The medicolegal theme was further explored with a discussion on what to warn patients of when commencing these medications. All were agreed that patients commencing ABs/5ARIs, including those undergoing medical expulsive therapy for stones should be warned about EjD. There was some discussion however, about whether patients commencing a 5ARI should be warned about the increased rates of high-grade prostate cancer seen in the PCPT and REDUCE trials. This increase may be an artefact of more effective cancer detection, but none-the-less @loebStacy was of the opinion that it should be included in pre-treatment counselling.

But is all the concern about sexual side-effects justified? It was pointed out that many patients are prepared to tolerate sexual side-effects in return for improvement in their LUTS.

Regardless, this paper from @giacomonovara and co-authors provided useful insight and stimulated a valuable discussion. Undoubtedly, some patients are very concerned about EjD and this paper will help all urologists who treat male LUTS to address these concerns.

Winner of the Best Tweet Prize was David Gillatt for his response to the discussion regarding the needs of various nationalities for PDE5I. Special thanks to the SIU for offering a prize of free registration to the 2014 SIU Congress in Glasgow. Also special thanks to Wiley for allowing open access of the article for the May #urojc discussion.

Ben Jackson has completed urological training in the East Midlands, and is now undertaking a fellowship at St. Vincent’s Hospital, Sydney. His principal clinical interest is urologic oncology.
Twitter @Ben_L_Jackson

UroLift Takes Off From Down Under. The Potential Rewards When Engineers Bring You Into Their Inner Circle

September 17, 2013/2 Comments/by Henry Woo

At the American Urological Association meeting in San Antonio in May 2005, I was introduced to a four engineers from a small start up company called NC2 (New Company 2). It had at that time been recently spun off from the medical device incubator company Exploramed. They had no product and not even a prototype of a product that could possibly be used in humans but what they did have was a passion to make a difference, incredible ideas and a laptop computer.

They had thought about the failings of existing mechanical treatments for LUTS/ BPH and the first that comes to your mind is prostatic stents. No stent conforms perfectly to the shape of the prostatic urethra and there were the issues of encrustation of any elements of stent material that were exposed to the urine. Rather than throw the baby out with the bathwater, they harnessed what was good about stents, which was the potentially immediate effects they could have on urinary function without associated destruction of tissue and that perhaps tailoring the radial expansion to just a few critical points rather than the entire length of the prostatic urethra could do the trick.

The original idea was that some sort of metallic disc could be placed outside the prostate capsule and one on the urethral side and between them, a non absorbable suture could be placed under tension and therefore draw open the prostatic urethra and defined sites. How these engineers were to find a way of designing a delivery tool to do this had me a little skeptical at first but there seemed to be no doubt in their minds, even thought they had not yet worked it out, were going to find a way. Their confidence, intellect and enthusiasm was infectious and you just felt like you wanted to be a part of this project. It so turned out that the metallic discs would be replaced by linear metallic tabs which logically make for easier delivery.

So why involve Australians? It is difficult to keep things under the radar and one way of doing so is to take the idea where it is less likely to be visible. Additionally, the data needed to be trustworthy and in a place where strong ethic committee governance structures exist. We make no illusion that for once, being Australian, gave us a clinical research opportunity from a company based in the US that would rarely be directed our way.

My Australian colleague, Dr Peter Chin was also brought in on the project. Over the next few months, we did not hear anything but there was then an urgent call that ‘California was the place we ought to be’ so we literally dropped everything and headed over to Silicon Valley where we had the opportunity to use the first prototype of the device on human cadavers. Whilst our travel costs were covered by NC2, we received no payment for our time spent during these exercises but remuneration was the last thing on our minds given the exciting path that the idea could potentially take. Simultaneously, animal studies were being conducted and these demonstrated that the internal metallic tabs of the prosthesis would become covered by urothelium and in combination with the cadaveric work, provided a convincing argument to move forward with human clinical trials.

Putting on a brave face doing the first human Urolift case at Westmead Hospital in Sydney in December 2005

By December 2005, we were ready to conduct the first human trials. We measured everything that could possibly move and it probably took close to 2 hours to perform the first case. The initial prototype device used looked like it was literally built in somebody’s garage workshop but it was functional and confirmed proof in principle that a transurethral delivery system could deploy metallic tabs on the capsular side of the prostate and within the urethra that was connected by a tensioned suture. Through this, it created mechanical alteration to the anatomy of the prostatic urethra with positive influence on lower urinary tract symptoms. From here, multiple clinical trials have been performed by the company that became known as Neotract Inc and as of 13 September 2013, the device received FDA approval.

It is enormous privilege to have played a role in product development from inception of an idea through to FDA approval. These opportunities are rare and whilst healthy skepticism and caution should be applied to all ideas presented to you, if you are offered such an opportunity to take a side project, it could be a rewarding diversion from your daily clinical practice. Financially, you will never recoup your time investment but the rewards of making a difference is priceless.

Shared passion for a project can go a long way. This experience emphasizes the value of engineers interacting with clinicians to achieve a desired outcome and there is certainly room for of such interactions. Opportunities to embrace these relationships are out there and perhaps a good place to start is to become active in the Engineering and Urology Society which as a section of the Endourological Society meets each year at the AUA Annual Meeting.

Henry Woo is an Associate Professor of Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney in Australia. He has been appointed as the inaugural BJUI CME Editor. He is currently the coordinator of the International Urology Journal Club on Twitter. Follow him on Twitter @DrHWoo

Disclosure: Henry Woo has formerly been an investigator and advisor to Neotract Inc. He holds a small stock investment in the company.

Radiotherapy for Leukaemic infiltration of Prostate

December 15, 2010/by admin Z.9

We present an 81 year old gentleman with haematuria and LUTS who had TURP for his outflow symptoms. Radiotherapy is an excellent option for local symptom control as evidenced in this patient.

Authors: Venugopal S, Das.S, Hamid BN, Doyle.G, Leggat H, Powell CS. Countess of Chester Hospital NHS Foundation Trust

Corresponding Author: Suresh Venugopal, Countess of Chester Hospital NHS Foundation Trust Email: [email protected]

Abstract

Haemopoietic malignant infiltration of the prostate is unusual. When present, it brings about the dilemma on the best approach to manage it. Usually, chronic lymphocytic leukaemia is an indolent process that waxes and wanes in its course and when present with lymphadenopathy and clinical symptoms would warrant treatment with chemotherapy. When organ confined, it has a more favourable course and would be amenable to local treatments.

We present an 81 year old gentleman with haematuria and LUTS who had TURP for his outflow symptoms. The histology had confirmed a malignant lymphocytic infiltration of the prostate and he had elevated lymphocytic count and peripheral blood marker study confirming chronic lymphocytic leukaemia. He was treated with radiotherapy of his prostate. His presenting WBC count was 19.2 and PSA was 4.41 and presently his white count is 10.3 and PSA is 1.77. He was treated with 24 Gray external beam radiotherapy to the prostate.

As we encounter an aging population, we will be seeing more of these cancers with higher incidence in the elderly. Radiotherapy is an excellent option for local symptom control as evidenced in this patient.

Case Report

Presentation

An 81 year old gentleman had simultaneous referral to the haematologist for low haemoglobin and raised white count and the urologist for visible haematuria and LUTS. A digital rectal examination revealed a smooth, benign-feeling prostate with a normal age-specific PSA. A CT scan done to evaluate his haematuria had picked up a large mass in the pelvis. It was difficult to differentiate whether it was of bladder or prostate origin (Figure-1).

Figure 1: CT scan showing pre treatment pelvic mass (left) and post treatment pelvic mass (right).

Trans-urethral resection of the mass showed diffuse infiltration of the prostate gland by a malignant B-cell type lymphoid infiltrate. His peripheral blood markers for chronic lymphocytic leukaemia were positive. He did not have generalised lymphadenopathy, splenomegaly or B type symptoms of leukaemia.

Pathology

The trans-urethral resection chippings of prostate showed large foci of basal cell hyperplasia and extensive infiltration with monotonous population of small lymphoid cells (Figure-2).

Figure 2: Prostate tissue infiltrated by lymphocytes staining strongly for CD20 (left) and H&E staining showing sheets of monotonous lymphocytic infiltration of prostate (right).

The abnormal lymphoid infiltrate stained positively for CD5, CD20, CD79a but was negative for CD3, CD10, BCL2 and BCL6. This is keeping in with a picture of Chronic Lymphocytic Leukaemia of Prostate. There was no evidence of high grade PIN or adenocarcinoma of prostate.

Radiotherapy

In view of his symptomatic haematuria and potential for the lesion to cause local symptoms of persistence of haematuria and possible obstruction of adjacent structures, he was considered for radiotherapy after due discussion at the multidisciplinary team meeting. The pros and cons of the treatment was discussed with the patient and he opted to have the treatment. He received standard 24 Gray in 12 fractions for low grade lymphoma of the prostate (1).

Follow-up

He has since been regularly followed up at the urology clinic for his lower urinary tract symptoms with a flow rate and rectal examination on the six monthly visits as well as a yearly PSA test. He does not have any lower urinary tract symptoms. His six monthly follow-up in the haematology clinic for his Chronic Lymphocytic Leukaemia involves assessing the presence or absence of B symptoms of leukaemia as well as a peripheral blood smear assessment. At the end of three years a re-biopsy of the prostate revealed the presence of a residual malignant lymphomoid infiltrate (Figure 3).

Figure3: Core biopsy specimen showing lymphocytes staining strongly for CD 20 (left) and H&E staining showing monotonous lymphocytic infiltration of the core biopsy specimen of prostate (right).

A rescan showed the persistence of the pelvic mass but without increase in size and without any accompanying symptomatic haematuria or obstructive features.

Discussion

Infiltration of prostate by Chronic Lymphocytic Leukaemia is not an uncommon finding in patients with CLL. Autopsy studies have revealed CLL as the commonest secondary tumour of the prostate. Leukemic infiltration is symptomatic in only 1% of them (2). They usually present with outflow obstructive features. Chronic lymphocytic leukaemia has an indolent course with waxing and waning of the white cell count. As a haemopoietic malignancy involving the prostate, it cannot be cured by local therapies, though this has been claimed on short term follow-up in literature (3,4,5).

The prostatic component of the disease is best dealt with by radiotherapy if local problems are anticipated. Chemotherapy is reserved for patients who have systemic disease progression. Outflow obstruction is best relieved by Trans-urethral resection of the prostate. Though various doses have been cited for curative treatment of this disease, this claim is to be disputed. We currently recommend a dose of 24 Gray in 12 fractions for palliative control of symptoms as per the recommendation for a low-grade non Hodgkin’s lymphoma.

Urological follow-up of these patients is as that of other patients with outflow symptoms, who generally get a flow rate and rectal examination assessment. In addition they need to have continuous follow-up at a haematology clinic for monitoring their systemic symptoms, which may dictate the need for further intervention.

Lesson learnt:

• Leukaemic infiltration is not uncommon.

• It usually presents as bladder outflow obstruction requiring TURP.

• Radiotherapy is indicated only if local complications are anticipated and is not always curative.

References

1) https://www.rcr.ac.uk/docs/oncology/pdf/DoseFract_49_Lymphoma.pdf

2) E. H. Eddes et al, Urinary symptoms due to leukemic infiltration of the prostate A case report, Ann Haematol 1993, 66:323 – 324.

3) Mitch Jr et al, Leukemic infiltration of the prostate: A reversible form of urinary obstruction, Cancer 1970, 26: 1361-1365.

4) Belis JA, Lizza EF, Kim JC, Raich PC, Acute leukemic infiltration of the prostate. Successful treatment with radiation, Cancer 1983, 51: 2164–2167.

5) Belhiba H et al, Prostatic involvement in leukemia. Report of a case Progrès en Urologie 1992, Aug-Sep;2(4):650-2.

Date added to bjui.org: 15/12/2010

DOI: 10.1002/BJUIw-2010-063-web