Management of benign prostate enlargement

The prostate gland in most men will become enlarged with age. Although this growth is in itself harmless, hence the term benign prostatic hyperplasia and benign prostate enlargement, it can cause lower urinary tract symptoms.

Lower urinary tract symptoms (LUTS) are a common occurrence in ageing males and frequently impact on quality of life (QoL). The symptoms can be further classified as those resulting from a failure to store urine-storage LUTS (urinary frequency, urgency, nocturia and incontinence)-often called “overactive bladder syndrome”; a failure to void-voiding LUTS (hesitancy, intermittency, weak stream and terminal dribble); or post-micturition symptoms (post-micturition dribble and a feeling of incomplete bladder emptying).

It is estimated that 72.3% of men suffer from one or more of the symptoms on at least one occasion whereas in 47.9% this occurs frequently.¹ Most patients will complain of both storage and voiding LUTS. Traditionally used terms like “prostatism”, “voiding dysfunction” or “clinical BPH” highlight a failure to consider the contribution of bladder dysfunction to the symptoms and are not recommended in contemporary practice.

Benign prostatic hyperplasia (BPH) or benign prostate enlargement is the expansion of both epithelial and stromal components of the prostate gland and is now considered a purely histological diagnosis. A multitude of autopsy studies have demonstrated that BPH increases with age, occurring in 42% of men aged 50 to 59 years increasing to 88% in the over 80s.² When BPH results in a clinical enlargement of the prostate gland, as occurs in approximately 50% of cases,³ the term benign prostatic enlargement (BPE) is applied.

This enlargement may lead to encroachment on the urethra causing bladder outlet obstruction (BOO) and the voiding symptoms such as hesitancy straining and poor stream. It is of note that BOO is a urodynamic, which can be suspected to be present from a flow rate and post-voiding residual measurement but can only be confirmed by the use of a synchronous pressure/flow urodynamic study with the findings of a low urinary flow and high detrusor muscle pressure. It is estimated that BOO occurs in only half of men over the age of 60 years presenting with LUTS and it is worth remembering that a poorly contracting bladder may cause similar symptoms, therefore using the term “LUTS suggestive of BOO” is more accurate in men with predominately voiding symptoms and BPE.

Storage LUTS are less common than voiding LUTS, but typically more bothersome and include urinary urgency, frequency, nocturia and incontinence. Urinary urgency is defined as “a sudden and compelling desire to void that is difficult to defer”⁴ and is the essential component of overactive bladder syndrome (OAB) in which it is usually accompanied by frequency, nocturia with or without urgency incontinence.⁴ OAB is also a common age related phenomenon in men with significant ramifications for quality of life and is often associated with involuntary contractions of the detrusor muscle. This, in some cases, may be attributable to BOO but can also occur independently, highlighting the importance of considering the bladder as the originator of LUTS in men.

The initial assessment entails focused history taking enquiring into the nature and frequency of symptoms as well as the impact on quality of life.  It is particularly important to determine which group of symptoms the patient is most bothered by so as to tailor treatment and assess response. Storage symptoms are more bothersome for patients, especially nocturia, which may be fragmenting the sleep cycle and adversely affecting QoL. An often-overlooked but frequent cause of this symptom is nocturnal polyuria, which may be caused by a variety of conditions such as peripheral oedema, obstructive sleep apnoea and diabetes insipidus.

Attention should be paid to lifestyle factors such as fluid, alcohol and caffeine intake. A wider enquiry into general health should identify potential contributory comorbidities such as diabetes mellitus and medications with diuretic effects including over the counter and herbal medicines.

An examination focusing on the urinary tract comprises abdominal examination looking for a palpable bladder indicative of chronic urinary retention.  Examination of the external genitalia allows assessment of the urethral meatus, which may be obstructed by an inflammatory stenosis or tight foreskin resulting in voiding LUTS. Enlargement of the prostate is generally discernable by digital rectal examination (DRE) and identification of abnormalities such as a nodule which may be indicative of prostate cancer.  Urine dipstick testing should be performed in all patients to identify urinary tract infections (UTI), haematuria and the presence of glycosuria, which all require further consideration.

A urinary frequency volume chart (FVC) whereby the patients documents the times of voiding and volumes passed is completed typically over three days and is invaluable in getting a realistic picture of symptom severity.  Additionally it identifies patients with polyuria and nocturnal polyuria and may also provide useful insights into drinking habits. The FCV is recommended in all male patients with LUTS in all major guidelines including the NICE guidelines on male LUTS. It will identify the large proportion of men where there is a systemic pathophysiology responsible for the LUTS and where therapy directed at the lower urinary tract will not be effective.

Further investigative measures are not routine and are largely guided by positive findings in the initial assessment. PSA testing should be offered to men after counselling in case they have an abnormal DRE, they request the test or their LUTS are suggestive of BOO due to BPE. Men with suspected prostate cancer should be managed and referred according to local guidelines, which in addition to rectal examination should include a serum prostate specific antigen (PSA) estimation after appropriate counselling of the patient as to the potential consequences of this testing and taking into account other relevant factors such as age and other medical conditions.

Serum urea and creatinine measurement is appropriate in patients with suspected chronic urinary retention (palpable bladder, nocturnal enuresis) and recurrent UTIs. Other investigations such as ultrasonography and cystoscopy are generally considered in the specialist setting, even then not on a routine basis.

Initially, men with LUTS should be reassured and given lifestyle advice that may improve their symptoms such as avoiding caffeine or excessive evening fluid intake that may alleviate urinary frequency and nocturia respectively.  Conservative management is appropriate in those not bothered by symptoms. In the case of those with significant storage symptoms, bladder training may be helpful.  If incontinence is present containment products in the form of pads or urine collection devices will aid in preserving social continence until the cause is established and management instituted.

Prostate

Should patients be significantly bothered and inclined to treatment, medical therapy may be offered (Box 2). Symptom scores, such as the International Prostate Symptom Score (IPSS), are useful, allowing an objective assessment of change in symptoms.

Alpha-blockers are widely used as first-line medical therapy in men with LUTS regardless of prostate size. They act upon the “dynamic” component of BOO due to BPE by inducing smooth muscle relaxation through blockade of the alpha-1 adrenoceptors. The result is a reduction in outflow resistance and improvement in around 70% of patients. An advantage of alpha-blockers is the rapidity of action, usually within 48 hours. There is no effect upon prostatic volume, risk of acute urinary retention or need for outflow surgery. Alpha-blockers are distinguished by their selectivity for the alpha-1a adrenoceptor over other subtypes. Non-selective alpha-blockers more commonly have cardiovascular side effects owing to effects on the alpha-1b adrenoceptor, such as postural hypotension, than their alpha-1a adrenoceptor subtype selective counterparts where ejaculatory disturbance is more likely.

5-alpha-reductase inhibitors decrease the production of di-hydrostestrone, a driver of cell growth in BPH. They have been shown to reduce disease progression and the incidence of acute urinary retention and outflow surgery in patients with enlarged glands and so are particularly useful in those at risk of disease progression. The speed of action is significantly slower than alpha-blockers, taking six months or more before any improvement in symptoms and treatment must be continued for the effect to be sustained. Side-effects including ejaculatory problems, loss of libido, erectile  dysfunction and gynaecomastia can have a significant impact on sexual function and self-image and this needs to be borne in mind when treating younger patients.  Combination treatment with both classes of drug has been shown to provide the most rapid treatment response and the greatest risk reduction in disease progression, acute urinary retention and need for surgery.

Bladder

A relatively new approach in the management of men with BPE and bothersome storage LUTS is the use of anti-muscarinics, which until recently were avoided due to the worry of causing urinary retention. Recent evidence suggests this is unlikely, provided the residual urine volume is <200ml. They act through antagonism of the muscarinic receptors in the detrusor muscle as well as potentially also affecting sensory mechanisms, reducing the strength and frequency of non-voiding contractions, thereby improving bladder storage function. Anti-muscarinics may be used as sole therapy in those with OAB or as an add-on to alpha-blocker in those who also have voiding LUTS. The main concern is poor tolerability due to side effects such as dry mouth and constipation.

New pharmacotherapies

Recently two new classes of drug have become licensed for the treatment of LUTS. The B3 agonists (Mirabegron, first in class) enhance urine storage through agonism of the B3 adrenoreceptor present on the detrusor muscle. As such they offer an alternative to the use of anti-muscarincs in patients with storage LUTS without having the bothersome side affects such as dry mouth that often lead patients to discontinue anti-muscarinic therapy. Additionally, there does not appear to be any adverse cardiovascular effects associated with the use of these agents.

The phosphodiestrase inhibitors have traditionally been used for the treatment of erectile dysfunction. Recent evidence has shown these agents to have similar efficacy to alpha-blockers in treating men with LUTS whilst not improving flow rates suggesting a bladder-related mechanism. The exact place of these classes in the treatment algorithm of men with LUTS is yet to be determined.

In 2013 we now have the potential to use combination therapy in the management of male LUTS, as noted earlier the combination of an alpha blocker and a 5-alpha-reductase inhibitor is well established, there is increasing interest in the use of an alpha-blocker and an anti-muscarinic. Potentially, with the introduction of Phosphodiestersae inhibitors and beta-3 agonists for the management of LUTS, in the future, new combinations are likely to become widely used.

LUTS as a consequence of BPE may be a progressive problem, although in a proportion of patients the condition appears to remain static or may even improve with watchful waiting. Deterioration in symptoms, defined as 4 point decrease in IPSS score, is the most common outcome of progression with a cumulative incidence of approximately 15%. Events such as acute urinary retention (2-3%) and outflow surgery (5%) occur less commonly. Predictors of disease progression including age >70, large prostate size (>30cc), serum PSA>1.4ng/ml, IPSS score 7 and failure to respond to alpha-blockers should be kept in mind to identify men at greatest risk of running into trouble. The indications for specialist referral include failure of medical treatment, haematuria, suspected prostate cancer, urinary incontinence, recurrent UTIs, urinary retention, bladder stones and renal impairment, which is caused most commonly by high pressure chronic retention leading to obstructive uropathy.

It is appropriate to review patients managed conservatively on an annual basis or sooner if their symptoms become more bothersome. After drug treatment is commenced, a review appointment should be made to  re-assess symptoms  improvement in quality of life and any side effects of the medication. Those commenced on alpha-blockers or anti-muscarinics should normally be reviewed at 4-6 weeks then 6-12 monthly if symptoms are stable whereas a 3-6 monthly review followed by 6-12 monthly appointments is more appropriate for 5-alpha-reductase inhibitors therapy. It is worth noting that 5-alpha-reductase inhibitors reduce the level of serum PSA by half therefore any subsequent measurements need to be adjusted. Failure of the PSA to reduce in this fashion should always raise the concern that a clinically significant prostate cancer may be present, as should any sign of a persistently rising PSA when taking this therapy.

A 65-year-old retired engineer presents to his GP with a one-year history of LUTS. His symptoms are predominately storage with frequency and nocturia, although he does note that his flow is slower than it used to be. He himself is not particularly bothered but was encouraged to seek treatment by his wife.

His only other medical problem is hyperlipidaemia and he admits to drinking seven cups of coffee in the day. An examination reveals only an enlarged, smooth, clinically benign prostate and urine dipstick testing is negative.  He is reassured and advised to reduce his caffeine intake and return if symptoms worsen.

A year later he returns complaining that he is now straining to pass urine and his stream is deteriorating. He is asked to complete an IPSS questionnaire and scores as moderate in terms of symptom severity (18/35) with a quality of life score of 4. A frequency volume chart shows frequent voiding 11 x /day with low volumes passed each time (<150ml) but no polyuria or nocturnal polyuria (nocturnal volume <33% of 24 hour urinary volume). After counselling, he said he would like treatment and an alpha-blocker is prescribed.

At review six weeks later, he describes an improvement in symptoms, no side effects and would like to continue with the medication. He also has been talking to a friend about the PSA test and would like to have this done. After counselling him, his GP arranges this and the result is 3.4, (reassuringly within the normal range for his age).

After several missed review appointments he presents four years later complaining of having to rush to the toilet and having the occasional “accident”. He is offered incontinence pads but feels these are unnecessary. He is not keen on taking further medications and is given information on bladder training, which he is keen to try.

On review six weeks later his symptoms are only marginally better so he is referred to the local urology department.

A post-voiding residual is 160ml, he is prescribed an anti-muscarinic agent, which provides some relief but is unable to tolerate it due to associated dry mouth.  Urodynamic studies are undertaken which indicate BOO with detrusor over-activity.  Bladder outflow surgery is suggested as an option and the patient agrees to undergo this, after which he has resolution of both his voiding and storage LUTS.

NICE guidelines on the management of LUTS in men-were published in 2010.⁵

This extensive and up-to-date guideline provides an indispensable framework for investigation and management of patients both in primary and secondary care. A major theme is that the majority of men can be managed safely and effectively in primary care without the need for costly or invasive investigations. Additionally it provides clear guidance on “red flag” signs and when to refer to seek specialist advice. Recommendations on assessment, treatment, medical therapy and review can be found on pages 60-64 and useful algorithms are provided for diagnosis (pg 68), management of predominant storage symptoms (pg 70) and predominant voiding symptoms (pg 72).  A published summary of the guidance is also available.⁶

LUTS are a common and bothersome problem in ageing men. They are often caused by BPH but may also occur due to an entirely unrelated bladder dysfunction. Men with LUTS can be adequately managed in primary care using a combination of lifestyle measures and pharmacotherapies.  Pharmacotherapy should be targeted at the likely underlying problem such as BOO or detrusor overactivity.

Patients should be offered regular follow-up to assess the response to treatment and need for further intervention or referral. Several promising new pharmacotherapies are now becoming available but their exact role in the clinical armamentarium is yet to be defined.

Conflict of interest: none declared

References

1.  Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU international 2009; 104: 352-60
2. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. The Journal of Urology 1984; 132: 474-79
3. Abrams P. Benign prostatic hyperplasia has precise meaning. BMJ 2001: 322; 106
4. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourology and Urodynamics 2002; 21: 167-78
5. Gil KM, Somerville AM, Cichowski S, Savitski JL. Distress and quality of life characteristics associated with seeking surgical treatment for stress urinary incontinence. Health and Quality of Life Outcomes. 2009; 7: 8
6. Jones C, Hill J, Chapple C. Management of lower urinary tract symptoms in men: summary of NICE guidance. BMJ 2010; 340: c2354