Our understanding of lower urinary tract symptoms (LUTS) has improved significantly in recent years, yet much remains unknown. Historically, male LUTS were usually attributed to prostatic enlargement but the pathogenesis is much more complicated and often multifactorial. Typically, LUTS suggests pathology in the lower urinary tract, including bladder overactivity (OAB), sphincteric weakness, sensory disorders of the bladder and benign prostatic hyperplasia (BPH). 

The presence or absence of LUTS is probably best defined by their degree of bother and their effect on health-related quality of life (HRQoL). Several publications have concluded that LUTS significantly impacts on HRQoL.¹  In men over the age of 40, prostatic enlargement certainly plays a role in LUTS. Up to 40% of men have histological evidence of BPH in their fifth decade and this becomes virtually universal in the ninth decade.²

Epidemiology and pathophysiology

The recently published EpiLUTS study examined the presence of LUTS in Western society by performing a population-based, cross-sectional study in the US, the UK and Sweden.³ A representative population of 30,000 men and women over 40 years of age was assessed for LUTS using the International Continence Society (ICS) definitions 2002. The mean age of respondents was 56.5 years. The percentage of respondents who reported at least one symptom ‘sometimes’ was 72% in men and 76% in women, and ‘often’ was 47% in men and 52% in women. Regarding nocturia, 69% of men and 75% of women reported waking at least once a night to urinate, and 28% of men and 33% of women reported voiding twice a night or more.³

In relation to male symptoms suggestive of bladder outflow obstruction (BOO), 45% of men noted terminal dribbling, 27% a weak stream, 22% urgency or incomplete emptying, and 21% hesitancy. The most bothersome symptom for men and women was the fear of leaking during sexual activity, physical exercise and at night (enuresis). The prevalence of all LUTS in men increases with age. In women urgency and urge incontinence are most likely to be age-related. 

In order to explain the underlying pathology, prostatic obstruction to the bladder is often considered as dynamic and static. The static obstruction originates from the fixed enlarged prostate, whereas dynamic obstruction derives from the smooth muscle contraction in the prostatic stroma, which leads to increased urethral resistance and obstruction. The bladder reacts to this obstruction in two phases. Initially, through increased detrusor contraction and hypertrophy of detrusor smooth muscle (bladder wall thickening), the bladder maintains flow and storage function. This is called the compensatory phase. As the situation progresses, the detrusor muscle shows signs of decompensation where it can no longer maintain adequate flow and contractions become erratic, leading to frequency, urgency and incomplete emptying. The detrusor blood flow reduces and areas of hypoxia occur. Ultimately, muscle failure occurs and acute or chronic retention occurs, with or without renal impairment.

Clinical presentation

Urinary symptoms are best separated into voiding and storage symptoms, because this also relates to their pathogenesis and thus their investigations and treatment. Voiding symptoms are hesitancy, reduced flow, intermittent flow, terminal dribbling and double voiding, and relates to outflow obstruction, suggestive of BPH. Storage symptoms are nocturia, frequency, urgency and urge incontinence; these relate to bladder function and should lead one to investigate an overactive bladder. There are additional symptoms of dysuria, haematuria and stress incontinence that need to be covered but clearly relate to specific diseases, such as infection or possible tumours.

More advanced disease can present with urinary tract infection due to incomplete emptying, renal impairment due to high pressure chronic retention, bladder calculi or acute urinary retention. High pressure retention exists when detrusor compliance prevents storage at low pressure. This creates a high vesical pressure with transmission of high pressure to the upper tracts, leading to varying degrees of renal failure. Nocturnal enuresis is a key symptom and its presence should make one suspicious of this condition. Management is immediate catheterisation followed by surgical treatment of the obstruction.

Minor symptoms can bother some patients, whereas others may not be bothered by severe symptoms. Without understanding the underlying disease and its progression, it is difficult to advise patients. Although patients can adapt to more serious symptoms, BOO is progressive and, without intervention, detrusor failure may ensue. 

Examination and assessment of men

BPH classically presents with obstructive LUTS, namely hesitancy, straining, slow flow, intermittency, dribbling, incomplete emptying, double voiding and, in extreme cases, nocturnal enuresis. These symptoms should all be assessed during history taking. Furthermore, it is important to establish the duration, extent and impact of the symptoms. The patient’s fluid intake should be evaluated, particularly tea, coffee, alcohol and fizzy drinks. It is also important to enquire about concurrent medications (eg. drugs with possible anticholinergic effects), as well as any history of pelvic injury, surgery or radiotherapy. 

Physical assessment should consist of abdominal, genital and digital rectal examinations (DRE). Abdominal examination is chiefly aimed at looking for signs of a full bladder, eg. lower abdominal distension or tenderness or dullness to percussion. In extremely rare cases, ballotable hydronephrotic kidneys may be palpable. In the context of BPH, genital examination is rarely informative although very occasionally a severe phimosis may be responsible for some obstructive symptoms. Rectal examination is crucial. It is important to ascertain the approximate size of the prostate gland as well as its consistency – a prostate should feel smooth, symmetrical and typically ‘rubbery’. It should not feel hard, irregular or nodular. The gland should be firm but not hard, and smooth without nodules. The median sulcus should be clearly defined. Prostate carcinoma is suggested by a hard, nodular gland and lacks a clear median sulcus.

For GPs and other doctors who refer patients with such symptoms to a urologist, a legitimate source of concern is that a non-specialist may not be able to confidently discriminate between benign and malignant presentations. This is especially relevant given that there are no urinary symptoms that are sufficiently sensitive and specific to distinguish between prostate cancer and BPH. 

However, a Swedish study that subjected 1,163 men to a DRE by both a GP and a urologist ultimately diagnosed (after biopsy on the basis of DRE findings) prostate cancer in 13 men (nine of these had been suspected by the GP) suggesting a good level of clinical discriminatory expertise in this regard.⁴ Patients are also generally comfortable with their GP carrying out a DRE.

Investigations and PSA

A careful medical history should select a neurogenic or non-neurogenic aetiology for LUTS in men. Those of younger age, neurological diseases or prior urological surgical history will require a different approach to investigation and management. A physical examination should specifically look to elicit any underlying neurological causes, an abdominal examination to assess for a palpable bladder and a DRE should always be performed to assess prostate size and consistency which may identify other prostate disorders other than BPH.

The International Prostate Symptom Score (IPSS) (also known as the American Urological Association (AUA) symptom index) has been deemed to be clinically sensible, reliable, valid and responsive. Clinical practice guidelines recommend that patients’ BPH symptoms should be assessed using a validated symptom score, such as the IPSS. The IPSS consists of seven questions, each scored from 0 to 5, based on the extent of symptoms, and a single quality of life (‘bother score’) question to assess how troublesome the symptoms are. Mild symptomatology is defined as a score of 0-7, moderate as a score of 8-19 and severe as a score of 20-35. The quality of life question is scored from 0 to 6. The ‘bother score’ provides a widely-used and statistically valid measure of the need for treatment of BPH. It has been suggested that a diagnosis of BPH is likely when, in conjunction with a history and examination findings, the IPSS is ≥8, and the bother score is ≥3.⁵ Of concern, previous studies have suggested that only a quarter of GPs are performing an IPSS prior to specialist referral.⁶ Literature shows IPSS re-test reliability at 92%.⁷

Useful laboratory tests include renal function and prostate-specific antigen (PSA) tests. Particularly in the setting of chronic retention, BPH may cause upper urinary tract dilatation and renal failure. The minimal requirement to assess the upper urinary tract function in the community setting is a creatinine measurement. PSA is reflective of prostate cellular activity and thus can be elevated in large benign prostates. It can be used as a guide to prostate volume and to evaluate the risk of acute urinary retention and the need for prostatic surgery. A combination of clinical examination using DRE and PSA levels is essential in attempting to differentiate between a benign and malignant prostate. PSA values should be normalised for age. 

In men with benign DREs aged 50-59 years a PSA of ≤3.5 is considered normal, in those aged 60-69 ≤4.5 and in those 70-79 a PSA of <6.5 ng/ml. Serial PSA measurements should also be recorded. PSA of >1.4 and increasing age are associated with IPSS symptom progression. Dipstick urinalysis should always be performed to exclude an alternative cause for LUTS. If available, uroflowmetry can be used to detect abnormal voiding. In order to be considered valid, two or more flows with a voided volume of >150mL each are required. Post-void residual urine indicates bladder dysfunction and large volumes of residual urine (>300mL) predict a less favourable treatment outcome.

Indications for referral for urological assessment recommended by NICE include: acute retention of urine, acute renal failure, visible haematuria, suspicious-feeling prostate on DRE or two successively abnormal PSAs, chronic urinary retention with overflow or night-time incontinence, recurrent UTIs, microscopic haematuria, or failure to respond to treatment in primary care with poor quality of life as assessed by the IPSS.

Medical treatment 

The principles of management are to reduce the patient’s symptoms and improve their quality of life with minimal morbidity. Initially, patients should have their lifestyle and risk factors evaluated for reversible or avoidable factors that improve symptoms. Simply reducing fluid intake in the evenings or double voiding before retiring to bed can help. Carbonated drinks and bladder stimulants such as tea and coffee should be avoided. First-line medical therapy is alpha-1 anti-adrenergic agents, which can be used in combination, in specific circumstances, with anti-cholinergics or 5-alpha reductase inhibitors. 

Alpha-1 adrenergic antagonists

Alpha-1 adrenergic antagonists or alpha blockers, as they are commonly known, are the most common medication in clinical use for the relief of the symptoms of bladder outflow obstruction. By inhibiting the contraction of smooth muscle within the prostatic stroma  (which increases in BPH), urethral resistance to bladder outflow is reduced. This results primarily in an improved urinary flow by reducing the dynamic obstruction. The secondary effects are improved bladder emptying, resulting in reduced nocturia, frequency and urgency. Long-acting alpha blockers include terazosin and alfuzosin. Newer agents include the prostate specific alpha-1A blockers, tamsulosin and silodosin. Most agents are now available as once-a-day, long-acting agents that are well tolerated. Possible side effects of alpha blockers include: dizziness, retrograde ejaculation, drowsiness and a runny/stuffy nose.  

5-alpha reductase inhibitors (5-ARI)

Whereas alpha blockers are indicated in patients with moderate to severe LUTS secondary to BOO, 5-alpha reductase inhibitors must be used only in a specific subset of patients with BOO, if they are to get any benefit. They do not impact significantly on symptoms and are best used as disease modifying agents. Patients who benefit the most from 5-ARIs are those with large prostate glands, in excess of 40cc by volume, and an associated elevated PSA (>1.6ng/ml). The use of 5-ARIs is not indicated in normal or mildly enlarged prostate. Their clinical effect is brought about by a reduction in prostate size, by approximately 27% within six to 12 months. This reduction in the static obstruction leads to the clinical change and change in disease progression. The MTOPS and CombAT trials demonstrated their ability to reduce the probability of surgery (TURP) or acute retention by up to 50%.^8,9

Through reducing prostate volume, 5-ARIs reduce PSA levels by approximately 50%, so levels should be doubled to calculate the true value. 5-ARIs can therefore make assessment of the prostate for prostate cancer difficult. These medications should not be commenced until the possibility of prostate cancer has been assessed by PSA and DRE, and referral to a rapid access clinic has been made if these tests are abnormal. A biopsy may be needed. Manufacturers have recommended that the PSA be measured at six and 12 months so that a nadir is established, and that any rise in the PSA above this should be considered abnormal, and referral for prostate biopsy should be considered.

Possible side effects from 5-alpha reductase inhibitors include reduced libido, impotence, reduced ejaculate volume, and swelling in the hands or feet.

Combination therapy: alpha blocker/5-alpha reductase inhibitor

The combined use of an alpha blocker and a 5-alpha reductase inhibitor is considered maximum medical therapy in BPH. Patients who continue to have symptoms or develop the complications of BPH despite this maximum medical therapy are generally considered for surgical interventions. Generally, a patient is commenced on oral tamsulosin or alfuzosin for symptomatic relief and finasteride or dutasteride are added where indicated (volume >40cc or PSA >1.6ng/ml). A combined once-a-day pill, dutasteride/tamsulosin hydrochloride is available for ease of administration. Four-year data from MTOPS and CombAT showed superiority of the combined medications over either an alpha blocker or 5-ARI alone, with reduced episodes of acute urinary retention and requirements for surgery.

Combination therapy: alpha blocker and anticholinergic

The addition of an anticholinergic (tolterodine, fesoterodine, darifenacin or oxybutynin) to an alpha blocker in patients with storage symptoms in addition to voiding symptoms for symptom control has been demonstrated to be safe and effective. Although there is a very minor increase in post-void residual, the risk of urinary retention is very low (1-3%), with improvements in frequency and urgency. A combination pill will soon be available to simplify administration.

Phosphodiesterase 5 inhibitors (PDE5I) 

This group of medications is currently being tested in trials for uses in LUTs. Already used in the management of erectile dysfunction (ED), tadalafil (5mg is licensed for signs and symptoms of BPH), sildenafil and vardenafil can produce smooth muscle relaxation in the urinary tract. PDE-4 and PDE-5 are the more prominent subtypes within the human transition zone. Alone they appear effective in reducing symptoms in moderate to severe LUTS, and have been tested in combination with alpha blockers with a more dramatic effect than either drug used alone.¹⁰ The doses tested are the same as for ED treatment. Side effects include headache, flushing, dizziness, dyspepsia, nasal congestion, myalgia, hypotension, syncope, tinnitus, conjunctivitis, or altered vision (blurred, discolouration). 

Phytotherapy

The precise mechanism of how plant extracts work is unknown but in vitro experiments have demonstrated several potential advantageous effects. The production of these preparations is not standardised and as a result their clinical effects may differ. They are well tolerated with few side effects so their use is considered low risk. Although they appeal to many patients, their efficacy is subjective and limited, and most trials show no superiority to placebo.

Surgery and other interventions

Transurethral resection of prostate (TURP/TUIP)

This is the gold standard for the management of prostatic outflow obstruction. Criteria include moderate to severe symptoms on IPSS and urodynamic evidence of a reduced urinary flow. As bladder function deteriorates secondary to obstruction, post-void residual amounts increase, and levels above 300ml are associated with worse outcome post TURP. Resection of the prostate causes retrograde ejaculation in over 65% of cases. Thus, in younger men or in smaller prostates, an incision is made from inside the bladder neck, through the prostate to the urethral veru on both sides (transurethral incision of prostate – TUIP) and this has the effect of splaying open the prostate and reducing outflow obstruction with a much lower risk of retrograde ejaculation. A meta-analysis of 29 trials confirmed the excellent results with TURP, with a mean improvement of over 70% in LUTS.¹¹

Laser TURP / TUNA / TUMT

Various energy sources can be used to destroy prostatic tissue, including radio-frequency ablation (transurethral needle ablation – TUNA), microwave energy (transurethral microwave thermoablation – TUMT) and most recently laser TURP (holmium laser enucleation of the prostate – HoLEP and green light laser). Laser procedures allow for day-case procedures and reduced bleeding (even on anticoagulants) even in very large prostates. Results are equivalent to traditional TURP in expert hands. TUMT has not been proven to be as efficacious as TURP but does have less morbidity and does not require anaesthesia so may be appropriate in frail or elderly patients. TUNA is also minimally invasive but retreatment rates are as high as 50%.

Open prostatectomy

Despite being performed less commonly, open (Millin’s or Freyer’s) prostatectomy remains the most definitive surgical procedure with the best long-term results in BPH. However, owing to its invasive nature and length of stay it is used only in those patients who are not candidates for TURP due to the size of the prostate (typically >100cc). It is also useful if there are co-existing bladder stones that may need to be removed.

Newer therapies

• Intra-prostatic ethanol injection: This is a minimally invasive procedure and injections are performed transurethrally. Although long-term follow-up is pending, the re-operation rate appears high and the procedure remains experimental
• Intra-prostatic botulinum injection: Two randomised controlled trials have demonstrated significant improvements with this minimally invasive technique. Botulinum toxin is injected into the prostatic parenchyma along the transurethral route. Although the mechanism of action is poorly understood, this technique appears to be promising, but remains experimental
• Prostatic stents: Both permanent and temporary prostate stents can be used. They are typically placed in frail patients who may not be surgical candidates. The permanent stent epithelialises and the patient will experience improved voiding or, in the case of retention, the ability to void. Stent migration and dysuria can be a problem 
• Selective embolisation of the prostatic artery: This new procedure requires femoral access and the prostatic arteries are embolised with polyvinyl alcohol particles. Short-term follow-up at two years appears reasonable.

References

1. Berges R, Pientka L, Hofner K, Senge T, Jonas U. Male lower urinary btract symptoms and related health care seeking in Germany. J Urol 1996; 15: 1965-70.
2. Berry SJ, Coffey DS, Walsh PC, et al. The development of human benign prostatic hyperplasia with age. J Urol 1984 Sep;132(3):474-9.
3. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: result from the Epidemiology of LUTS study (EpiLUTS). Karin S. Coyne, Chris C. Sexton, Christine L. Thompson, Ian Milsom, Debra Irwin, Zoe S. Kopp, Christopher R. Chapple, Steven Kaplan, Andrea Tubaro, Lalitha P. Aiyer and Alan J. Wein.
4. Pedersen KV, Carlsson P, Varenhorst E, Lofman O, Berglund K (1990)
5. Screening for carcinoma of the prostate by digital rectal examination in a randomly selected population. BMJ 300(6731):1041–1044
6. Flam T, Montauban V (2003) Screening of clinical benign prostatic hypertrophy in general practice: survey of 18, 540 men. Prog Urol 13(3):416–424
7. McGuire BB, O’Brien MF, McLoughlin S, O’Malley KJ, Fitzpatrick JM (2007) Should patients with symptomatic BPH have a trial of medical therapy by their general practitioner prior to referral for urological assessment? Ir Med J 100(4):428–429
8. MJ Barry et al. Indications for treatment of benign prostatic hyperplasia. The American Urological Association Study. Cancer. 1992 Jul 1;70(1 Suppl):280-3.
9. Fwu CW, Eggers PW, Kaplan SA, Kirkali Z, Lee JY, Kusek JW. Long-term effects of doxazosin, finasteride and combination therapy on quality of life in men with benign prostatic hyperplasia. J Urol. 2013 Jul;190(1):187-93. doi:10.1016/j.juro.2013.01.061. Epub 2013 Jan 25.
10. Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorsi F; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010 Jan;57(1):123-31. doi: 10.1016/j.eururo.2009.09.035. Epub 2009 Sep 19.
11. Gacci M, Corona G, Salvi M, Vignozzi L, McVary KT, Kaplan SA, Roehrborn CG, Serni S, Mirone V, Carini M, Maggi M. 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 May;61(5):994-1003. doi: 10.1016/j.eururo.2012.02.033. Epub 2012 Feb 25. Review.
12. Lee SW, Choi JB, Lee KS, Kim TH, Son H, Jung TY, Oh SJ, Jeong HJ, Bae JH, Lee YS, Kim JC. Transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement: a quality and meta-analysis. Int Neurourol J. 2013 Jun;17(2):59-66. doi: 10.5213/inj.2013.17.2.59. Epub 2013 Jun 30.