Lower urinary tract symptoms in men
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4474 (Published 14 August 2014) Cite this as: BMJ 2014;349:g4474
- 1Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA
- 2Center for Healthcare Outcomes and Policy, University of Michigan Medical School, Ann Arbor, MI, USA
- 3Minneapolis VA Center for Chronic Diseases Outcomes Research, Minneapolis, MN 55417, USA
- 4University of Minnesota School of Medicine, Minneapolis, MN, USA
- Correspondence to: T J Wilt tim.wilt{at}va.gov
Abstract
Benign prostatic hyperplasia (BPH) is a highly prevalent and costly condition that affects older men worldwide. Many affected men develop lower urinary tract symptoms, which can have a negative impact on their quality of life. In the past, transurethral resection of the prostate (TURP) was the mainstay of treatment. However, several efficacious drug treatments have been developed, which have transformed BPH from an acute surgical entity to a chronic medical condition. Specifically, multiple clinical trials have shown that α adrenoceptor antagonists can significantly ameliorate lower urinary tract symptoms. Moreover, 5α reductase inhibitors, alone or combined with an α adrenoceptor antagonist, can reverse the natural course of BPH, reducing the risk of urinary retention and the need for surgical intervention. Newer medical regimens including the use of antimuscarinic agents or phosphodiesterase type 5 inhibitors, have shown promise in men with predominantly storage symptoms and concomitant erectile dysfunction, respectively. For men who do not adequately respond to conservative measures or pharmacotherapy, minimally invasive surgical techniques (such as transurethral needle ablation, microwave thermotherapy, and prostatic urethral lift) may be of benefit, although they lack the durability of TURP. A variety of laser procedures have also been introduced, whose improved hemostatic properties abrogate many of the complications associated with traditional surgery.
Introduction
Benign prostatic hyperplasia (BPH) is fundamentally a histologic diagnosis that refers to a non-malignant proliferative process of the cellular elements of the prostate. By age 70 years, nearly 70% of men will have histologic BPH.1 About half of these men will develop prostatic enlargement, with nearly half (17% in total) having associated bladder outlet obstruction and lower urinary tract symptoms.2 Exclusive of pharmacy spending, in the United States the direct costs of medical services for its management exceed $1bn (£0.58bn; €0.74bn) annually and are rising.3
Sources and selection criteria
We searched the English language literature for human studies without any date limits using Medline (through PubMed), Embase (through Ovid), and the Cochrane Database of Systematic Reviews. We incorporated a variety of terms and synonyms for concepts in each of three distinct filters: a disease filter for benign prostatic hyperplasia; a publication type filter to identify observational studies, clinical trials, and systematic reviews; and a treatment filter designed to capture common medical and surgical treatments. Where possible, we used controlled vocabulary (MeSH in PubMed, Emtree in Embase). We summarize the most clinically relevant diagnostic and management information from these studies.
BPH is one of the most common and costly disorders in older men, and the associated lower urinary tract symptoms can affect quality of life.4 In addition, lower urinary tract symptoms, especially nocturia, increase falls and risk of fractures.5 For these reasons, the main aim of treatment is to reduce bothersome lower urinary tract symptoms and prevent disease progression (for example, the development of acute urinary retention).
In the past, treatment was limited to surgical intervention, which was carried out only in men with severe symptoms, acute urinary retention, or other sequelae of bladder outlet obstruction, such as renal insufficiency and recurrent urinary tract infections. However, with the introduction of efficacious drugs, men with less severe symptoms may benefit from identification and treatment. Therefore, lower urinary tract symptoms are now more appropriately viewed as a chronic medical condition for which lifestyle changes and drugs have become the mainstay of initial management.
Since this paradigm shift in treatment, primary care physicians have taken on a much more important role in the care of men with BPH. More than two thirds of incident cases are now seen by primary care physicians.6 This review aims to summarize the literature on lower urinary tract symptoms related to BPH as a way to improve care for this patient population.
Prevalence of BPH
One challenge to studying the epidemiology of BPH is a lack of consensus on what constitutes a case. As mentioned above, the definition of this condition involves histologic assessment. Several studies have used examination at autopsy to determine the prevalence of benign prostatic hyperplasia. Only 8% of men during the fourth decade of life have this condition on autopsy, but this increases to 50% in those aged 51-60 years.1 The prevalence of histologic BPH is similar in the US, Europe, and Asia.7
The prevalence of BPH derived from urinary flow or prostate size has also been defined statistically according to values in population based cohorts of younger men. Although a peak urinary flow rate of 20 mL/s or more is considered statistically “normal,”8 data from the Olmsted County study showed that 6% of men aged 40-44 years had peak flow rates less than 10 mL/s, increasing to 35% in those over 75.9 In the same cohort, prostate size (measured with ultrasound) increased by about 1.6% each year, such that the median prostate volume for men 50 years and older was more than 40 mL.10
Patient self report provides a more clinically relevant assessment of the prevalence of benign prostatic hyperplasia. In general, the greater the severity of lower urinary tract symptoms, the more detrimental they are to a man’s quality of life (the greater the bother) and the greater the desire for (and benefit from) treatment. With the use of a validated urinary symptom scale, 13% of men participating in the Olmsted County study aged 40-49 years and 28% of those older than 70 years had moderate to severe lower urinary tract symptoms.11 It is important to note that prevalence estimates based on symptom scores depend on the cut-off point chosen to define a case and can therefore vary substantially in a population.12
In addition, although lower urinary tract symptoms are associated with urinary flow and prostate size, there is substantial evidence that men can have symptoms even in the absence of BPH, enlarged prostate on physical examination, or abnormal urinary flow rates. This is partly because lower urinary tract symptoms can be caused by multiple mechanisms, including prostate and bladder smooth muscle tone and contractility.13 Moreover, the prevalence of lower urinary tract symptoms in women is not too dissimilar to that in men.14 Thus, although lower urinary tract symptoms in older men are often attributed to BPH, clinicians should consider other causes in their diagnosis and evaluation (such as neurogenic bladder dysfunction, drug induced lower urinary tract symptoms, and heart diseases with nocturnal polyuria).
Diagnosis and evaluation
At presentation the diagnosis of BPH is typically based on clinical features: an enlarged prostate, bothersome lower urinary tract symptoms, and no other identified causes for the urinary problems. Most primary care physicians arrive at this diagnosis on the basis of patient reported voiding (feelings of incomplete emptying, intermittency, weak stream, and hesitancy) or storage symptoms (frequency, urgency, and nocturia) and possibly the finding of prostate enlargement on digital rectal examination. In particular, nocturia is an important factor associated with urinary symptom bother and request for evaluation and treatment. Urine analysis can help identify treatable conditions (such as urinary tract infection) that may contribute to these symptoms.
Prostate specific antigen (PSA) testing to screen for prostate cancer in men with suspected BPH is controversial. Although patients and clinicians may worry that lower urinary tract symptoms are caused by prostate cancer, BPH is not a risk factor for prostate cancer.15 Thus, use of PSA testing in most men presenting with typical lower urinary tract symptoms in the primary care setting should be considered to be screening, rather than part of the diagnostic evaluation. Furthermore, prostate enlargement can increase PSA levels, reducing test specificity.16 These limitations should be factored into testing decisions. No organization or guideline group recommends PSA screening in those over 70 years or in younger men with limited life expectancy.
The clinical value of determining post-void residual urine in men with lower urinary tract symptoms is not well established. Similar to urinary flow rates, definitions of chronic urinary retention as determined by the post-void residual urine vary greatly. In addition, there are few data on the importance of using post-void residual urine in management decisions. Therefore, for most men, post-void residual urine evaluation, like uroflowmetry, is not necessary, and management strategies should be based on symptoms.
Risk factors
Increasing age is the primary risk factor for BPH, and there is no known association with family history. Other patient factors have been implicated in its development and progression, including metabolic disorders. Specifically, data from the Health Professionals Follow-Up study highlight an association between obesity and lower urinary tract symptoms.17 These findings were corroborated by two population based studies of Chinese and Norwegian men.18 19 Furthermore, data from the Baltimore Longitudinal Study of Aging showed higher odds of prostate enlargement among obese men.20
Type 2 diabetes also seems to be a risk factor for BPH. In addition to urinary frequency as a result of glycosuria, insulin can bind to the insulin-like growth factor receptor in prostate cells, leading to activation of the receptor and the induction of prostate cell growth and proliferation.21 A study on community dwelling men in Massachusetts found that men with type 2 diabetes were 50% more likely to have clinical BPH (diagnosed by a physician or treated with surgery), even after accounting for weight.22 Moreover, a cohort study of Swedish men found that men with diabetes had the highest median prostate growth.23
Unlike obesity and diabetes, exercise may protect against BPH. Moderate long term exercise reduces sympathetic nervous system activity at rest and decreases firing of sympathetic adrenergic neurons.24 This may dampen prostatic smooth muscle tone. Results from the Health Professionals Follow-Up study show that increasing levels of physical activity were associated with a lower risk of lower urinary tract symptoms independent of weight control.17 Data from the Massachusetts Male Aging study found a similar inverse association between a man’s exercise habits and his odds of clinical BPH.22
Initial assessment and management
Initial assessment and management are dictated by a man’s symptom severity and urinary bother. Validated symptom and bother scales are often used in urology practices and research settings. The most popular are the American Urological Association symptom index (AUASI) and the international prostate symptom score (IPSS) (fig 1⇓)).25 Both include a seven item questionnaire that measures the presence and severity of voiding and storage symptoms. Scores range from 0 to 35, with moderate and severe symptoms exceeding 7 and 19 points, respectively. A clinically meaningful difference involves at least a 3 point change.26
Fig 1 International prostate symptom score (IPSS). Use the interactive symptom score tool at http://www.bmj.com/content/349/bmj.g4474/infographic
Although use of these symptom scales is recommended, it may not always be practical in the primary care setting. At the very least, a brief assessment of a man’s degree of bother (none, mild, moderate, a lot) is important because it correlates fairly well with symptom severity and decisions about treatment. Men who experience a moderate amount to a lot of bother with urinary symptoms are likely to benefit from drugs or surgical interventions. For men with less bother, counseling and lifestyle changes may be a preferable first step. This includes reassuring a man that his symptoms do not put him at increased risk of cancer. In addition, timed voiding, avoidance of caffeine and alcohol, adjustment of diuretic dosing, and reduction in fluid (particularly at night) are effective management strategies for many.27 28 29 A randomized controlled trial showed that treatment failures (such as initiation of medical treatment) in men with uncomplicated lower urinary tract symptoms enrolled in self management training were 48% lower at 12 months than in those on watchful waiting alone.29
Pharmacotherapy (table⇓)
Pharmacotherapies for lower urinary tract symptoms secondary to benign prostatic hyperplasia*
α adrenoceptor antagonists
For men with moderate to a lot of bother from their lower urinary tract symptoms, α adrenoceptor antagonists can improve symptoms and bother. By binding to α1 adrenoceptors located in the prostatic smooth muscle, they inhibit contraction of prostate tissue.34 There are three α1 adrenoceptor subtypes (α1a, α1b, and α1d), but only the α1a variety has been shown to mediate prostatic smooth muscle tonicity.35 Given that α1 adrenoceptors and α2 adrenoceptors are also present in the smooth muscle of the bladder base and proximal urethra,36 37 α adrenoceptor antagonists may decrease outlet resistance caused by urethral smooth muscle too.
About 60% of men treated with an α adrenoceptor antagonist experience a meaningful reduction in urinary symptoms within a month of starting treatment.38 39 This relatively rapid onset of action, which occurs in a high proportion of men, is one reason why α adrenoceptor antagonists are the most commonly prescribed class of drugs for men with lower urinary tract symptoms. Another reason for their popularity is that their effects are independent of prostate size.40 In men who respond to an α adrenoceptor antagonist, the drug often continues to work and be well tolerated for years. However, long term clinical trials show that these drugs do not prevent the need for surgical intervention or the risk of developing acute urinary obstruction.41
Phenoxybenzamine
Phenoxybenzamine, a non-selective long acting antagonist, was the first α adrenoceptor antagonist shown to be efficacious for the treatment of BPH related lower urinary tract symptoms.42 Use was limited by its side effects.
Terazosin and doxazosin
Terazosin and doxazosin were the first long acting α1 adrenoceptor antagonists studied for the treatment of lower urinary tract symptoms. Multicenter trials showed a clinically significant improvement in self reported symptoms in men receiving these drugs compared with placebo.30 43 However, standard preparations of terazosin and doxazosin require slow increases in dose to avoid the sudden, and sometimes severe, fall in blood pressure that can occur when changing from a lying to a standing position after their initial administration. Other common adverse effects include abnormal ejaculation, asthenia, and dizziness.
Tamsulosin
Tamsulosin was the first highly selective α1 adrenoceptor antagonist. Similar to the controlled release gastrointestinal therapeutic system formulation of doxazosin, it does not require titration. Large phase III trials showed that tamsulosin significantly improved urinary symptoms and peak flow rates compared with placebo, and that it was generally well tolerated.44 45 In trials comparing tamsulosin with other α adrenoceptor antagonists, tamsulosin increased peak flow rates and achieved comparable improvements in symptom score to those seen with terazosin.46 However, men taking tamsulosin were significantly less likely to discontinue treatment for all causes than those taking terazosin.
Alfuzosin
Alfuzosin is another second generation selective α1 adrenoceptor antagonist. Similar to tamsulosin and the gastrointestinal therapeutic system formulations of doxazosin, it does not require dose titration. Pooled analysis of three randomized controlled trials showed that alfuzosin significantly reduced symptom scores (mean score changes for alfuzosin and placebo were −6.0 and −4.2, respectively; P<0.001 for the difference) and increased urinary flow rates.40 Alfuzosin seems to be comparable to tamsulosin in terms of efficacy and adverse event profile.
Silodosin
Silodosin is the newest selective α1a adrenoceptor antagonist. It provides lasting symptom relief comparable to that of tamulosin.47 One potential advantage of silodosin over alfuzosin relates to its cardiac tolerability. Data show that it does not routinely prolong the QT interval, which may decrease cardiac arrhythmias in selected populations.48 However, it is associated with a higher risk of retrograde ejaculation,49 50 and it requires dosage adjustment in patients with renal insufficiency.
Adverse effects
One side effect of α adrenoceptor antagonists relates to their impact on pupil dilatation. More than 40% of tamsulosin users undergoing cataract surgery show a flaccid and billowing iris, iris prolapse through the surgical incisions, and progressive intraoperative pupil constriction.51 Although most commonly associated with tamsulosin, the so called intraoperative floppy iris syndrome is also seen with terazosin, doxazosin, and alfuzosin use.52 53 Because this syndrome can result in surgical complications (iris trauma is reported in nearly half54), ophthalmologists should be prepared for possible modifications to their surgical technique in patients taking an α adrenoceptor antagonist, which may increase the complexity and cost of cataract surgery.
5α reductase inhibitors
5α reductase inhibitors are the second most commonly prescribed class of drugs after α adrenoceptor antagonists for the treatment of BPH related lower urinary tract symptoms. Unlike α adrenoceptor antagonists, these drugs do not alter smooth muscle tone. Rather, they shrink the prostate and decrease associated bladder outlet obstruction by blocking the conversion of testosterone to dihydrotestosterone. The rationale behind their use is based on the observation that the development of BPH is an androgen dependent process.55 56 More specifically, surgical castration and the use of gonadotrophin releasing hormone analogues reduce prostate volume.57 58
Finasteride and dutasteride
Finasteride inhibits 5α reductase type 2 and was the first drug in this class to be used for the treatment of BPH. In a trial of 3040 men randomized to receive 5 mg finasteride or placebo for one year, finasteride reduced the risk of acute urinary retention by 57% (95% confidence interval 40% to 69%) and the need for BPH surgery by 55% (41% to 65%).31 However, a one year randomized trial comparing α blockade with terazosin to finasteride and placebo showed that although finasteride reduced prostate volume by 20%, it was not as efficacious as terazosin and no more efficacious than placebo in improving urinary symptoms and flow rates.59
Dutasteride is the newest 5α reductase inhibitor and it inhibits both 5α reductase type 1 and type 2. Similar to finasteride, dutasteride reduces the risk of acute urinary retention and BPH directed surgery compared with placebo (relative risk reduction 57% and 48%, respectively, at two years) in men with moderate to severe lower urinary tract symptoms.60
There are few comparative studies on finasteride and dutasteride. Observational data suggest that the use of dutasteride is associated with greater reductions in urinary symptom scores and faster clinical improvement (within three months) after initiation of therapy compared with finasteride, possibly because of its dual inhibitory effects.61 However, a multicenter randomized double blind trial of once daily dutasteride versus finasteride showed that both drugs, when given for 12 months, had similar efficacy in improving urinary symptoms associated with BPH in men with an enlarged prostate.62
Adverse effects and other effects
Although generally well tolerated, decreased libido and ejaculate volume, as well as gynecomastia, are associated with the use of 5α reductase inhibitors.
In addition to their effects on lower urinary tract symptoms, data from two large placebo controlled randomized studies show that finasteride and dutasteride reduce the risk of prostate cancer by 23-25%.63 64 However, 5α reductase inhibitors also increased the risk of high grade prostate cancer. Although this association may be attributed to histologic artifact as a result of prostate gland shrinkage,65 the US Food and Drug Administration issued a safety announcement in 2011 regarding 5α reductase inhibitors and high risk prostate cancer. These drugs are therefore not indicated for chemoprevention of prostate cancer. Clinicians should discuss this information with men placed on 5α reductase inhibitors even if the treatment is not intended for chemoprevention of prostate cancer.
Combination of an α adrenoceptor antagonist and 5α reductase inhibitor
The Veterans Affairs Cooperative study tested whether combining an α adrenoceptor antagonist with a 5α reductase inhibitor produced any benefit.59 This multicenter study randomized 1229 veterans to receive placebo, terazosin, finasteride, or combination therapy. At 52 weeks of follow-up, the absolute mean change in symptom scores for men on combination therapy (decrease of 6.2 points) was significantly greater than that for men who received finasteride (−3.2) or placebo (−2.6). However, combination therapy offered no advantage over terazosin alone with respect to symptom score improvement (−6.1). The Prospective European Doxazosin and Combination Therapy trial had similar findings.66
Whereas the preceding studies assessed the relatively short term impact of combination therapy on lower urinary tract symptoms, the Medical Therapy of Prostatic Symptoms (MTOPs) trial was designed to examine the long term effect of combination medical therapy on the risk of clinical progression. This was defined by an increase of four points or more in the AUASI score, need for surgical intervention, or development of acute urinary retention.41 This six year multicenter study randomized 3047 men aged 50 years or more with moderate to severe lower urinary tract symptoms (mean AUASI 16.9) to receive placebo, doxazosin, finasteride, or combination therapy.
Over a mean follow-up of 4.5 years, use of combination therapy significantly reduced the risk of overall progression by 66% (54% to 76%) compared with placebo (fig 2⇓). Most of the benefit was in lower rates of symptom progression (risk reduction 64%, 48% to 75%), although combination therapy did reduce the need for surgical intervention (67%, 40% to 82%) and acute urinary retention (81%, 44% to 93%) (fig 3⇓). This risk reduction was also significantly greater than that associated with doxazosin or finasteride alone. A reanalysis of the MTOPs trial suggested that prostate size (as measured by volume >25 mL) predicted benefit from combination therapy.67
Fig 2 Cumulative incidence of progression of benign prostatic hyperplasia in men with moderate to severe symptoms at baseline. Progression was defined by an increase of at least four points in the American Urological Association symptom index score, acute urinary retention, incontinence, renal insufficiency, or recurrent urinary tract infections.
Fig 3 Cumulative incidence of acute urinary retention (A) and invasive treatment (B) for benign prostatic hyperplasia
To further assess the importance of prostate size in response to treatment, the Combination of Avodart and Tamsulosin trial was conceived.68 This study randomized 4844 men with prostate volumes of 30 mL or greater to receive dutasteride, tamsulosin, or combination therapy. At four years of follow-up, the mean reduction in patients’ storage symptom subscores was significantly greater for the combination of dutasteride and tamsulosin than for dutasteride (adjusted mean difference −0.43) and tamsulosin (−0.96) monotherapy (P<0.001). The mean reduction in the voiding subscore was also significantly greater in the combination therapy group than in the dutasteride (−0.51) and tamsulosin (−1.60) monotherapy groups (P<0.001). A recent systematic review evaluated randomized controlled trials that assessed combination drug therapy (α adrenoceptor antagonist and 5α reductase inhibitor) in men with non-neurogenic lower urinary tract symptoms.69 On the basis of findings from five studies, the authors concluded that this combination is beneficial in patients with a prostate volume of 30-40 mL when medical treatment is intended for more than one year.
Antimuscarinic drugs
Storage symptoms can be caused directly by associated bladder outlet obstruction from prostatic enlargement or from secondary effects of the obstruction on the bladder itself.70 In this second situation, treatments that target the prostate exclusively may not relieve urinary urgency and increased daytime frequency. This is the rationale behind using an antimuscarinic agent (alone or combined with an α adrenoceptor antagonist) for men with storage symptoms.
Antimuscarinic drugs work by blocking the muscarinic receptors on the detrusor muscle and urothelium, which are stimulated by acetylcholine during detrusor contraction.
Several studies have examined the efficacy of antimuscarinic drugs, alone and in combination with an α adrenoceptor antagonist, in men with storage symptoms.69 The most definitive data come from a study of 879 men aged 40 years or more who had BPH related lower urinary tract symptoms, with eight or more voids a day and three or more episodes of urgency a day.71 Eighty per cent of patients randomized to receive extended release tolterodine and tamsulosin reported treatment benefit at 12 weeks compared with only 62% of those who received placebo (P<0.001), 71% who received tamsulosin monotherapy (P=0.06 v placebo), and 65% who received tolterodine monotherapy (P=0.48 v placebo).
One of the concerns about the use of antimuscarinic agents in men with lower urinary tract symptoms is that it could exacerbate voiding symptoms. A recent systematic review and meta-analysis assessed these safety concerns.32 Pooled data from seven placebo controlled trials, in which 3629 patient were randomized, showed a slight reduction in maximal urinary flow rate (weighted mean difference −0.59 mL/s, −1.04 to −0.14) and post-void residual urine volumes (11.60 mL, 8.50 to 14.70) with combination therapy compared with α adrenoceptor antagonist monotherapy. However, the increased risk of acute urinary retention was very small (number needed to harm 101). As such, the addition of an antimuscarinic is an option for men who have persistent storage symptoms even though they are taking an α adrenoceptor antagonist, although it is recommended that post-void residual urine is monitored.69
Phosphodiesterase type 5 inhibitors
Tadalafil is the latest drug to be approved for the treatment of BPH related lower urinary tract symptoms. Commonly used as an erectile aid, it targets the phosphodiesterase type 5 (PDE5) enzyme, and 55-70% of men with mild to severe lower urinary tract symptoms report erectile dysfunction.72 73 Although the mechanisms underlying the association are not clear, lower urinary tract symptoms and erectile dysfunction have common links (for example, the nitric oxide-cGMP pathway) that are potential targets for PDE5 inhibitors.74 Moreover, the PDE5 enzyme is highly expressed in the bladder neck, prostatic urethra, and prostate tissue.75
Seven trials have been reported in which 3214 men with concomitant moderate to severe lower urinary tract symptoms and erectile dysfunction were randomized to receive a PDE5 inhibitor versus placebo. Findings from these trials were summarized in a recent meta-analysis.33 Over a median follow-up of 12 weeks, PDE5 inhibitors reduced the severity of lower urinary tract symptoms compared with placebo (mean symptom score change −2.8 points, −3.6 to −2.1; P<0.001), with no differences in urinary flow rates. However, data on long term efficacy are lacking. Not surprisingly, regular use of a PDE5 inhibitor improved patient reported sexual function. Side effects occurred in 16% of men using PDE5 inhibitors and included flushing, headache, and sinusitis. Preliminary data only are available on the combination of a PDE5 inhibitor and an α adrenoceptor antagonist.69
Phytotherapy
A third of men who choose non-surgical management of their lower urinary tract symptoms initially report taking herbal preparations, either alone or combined with prescription drugs.76 Although nearly 30 different phytotherapeutic compounds are marketed for the treatment of symptomatic BPH, extracts from the fruit of the American saw palmetto Serenoa repens are the most commonly used.77
A 1998 systematic review and meta-analysis of generally low quality trials suggested that S repens extracts provided mild improvement in symptoms.78 Rates of adverse effects (such as diarrhea, decreased libido, and ejaculatory disorders) were comparable between the intervention and placebo groups. However, there have been rare reports of hepatic and pancreatic toxicity associated with extract use.79 80
In the interim, more rigorous studies have been conducted. The Saw Palmetto Treatment for Enlarged Prostates trial randomized 225 men aged over 50 years with moderate to severe lower urinary tract symptoms to receive saw palmetto fruit extract (160 mg twice daily) or placebo.81 Over one year of follow-up there was no significant difference in symptom scores or secondary endpoints between the two groups.
More recently, results from another large study showed that increasing doses of saw palmetto fruit extract did not reduce lower urinary tract symptoms or other outcomes related to BPH more than placebo.82 An updated systematic review, which included data from both of these trials,81 82 concluded that S repens does not improve lower urinary tract symptoms or urinary flow rates compared with placebo in men with BPH, even at double and triple the usual dose.83
Surgical options
For men with moderate to severe lower urinary tract symptoms in whom pharmacotherapy has not provided adequate symptom relief, specialist referral for consideration of surgical intervention is appropriate. Urology consultation is also recommended for patients who develop recurrent urinary tract infections, gross hematuria, bladder calculi, or renal insufficiency secondary to BPH, as well as for those who wish to pursue surgery as the primary treatment. Because failure rates after BPH surgery are higher in patients without evidence of associated bladder outlet obstruction, many urologists perform additional testing before surgical intervention.84
Pressure flow studies are regarded as the gold standard for the objective assessment of associated bladder outlet obstruction, defined as a maximum flow rate less than 12 mL/s with detrusor pressure at maximum flow greater than 20 cm H2O.85 However, questions have been raised about the acceptability of these tests owing to their associated morbidity and costs.86 Thus, attempts have been made to diagnose associated bladder outlet obstruction non-invasively. Neither ultrasound measurements of post-void residual urine nor prostate volume show good sensitivity for diagnosing this condition.87 However, measurements of bladder wall thickness and bladder weight show some promise.87 In cases where maximum urinary flow rates are less than 10 mL/s and an adequate volume of urine was voided, uroflowmetry alone is sufficient.38
Transurethral resection of the prostate
If the patient chooses surgery, and there is enough evidence of associated bladder outlet obstruction, the urologist should discuss the risks and benefits of the various interventions. Transurethral resection of the prostate (TURP) has been the standard method of surgical management of BPH for more than half a century. This entails endoscopic removal of the adenoma using a monopolar electrocautery loop. Although highly effective and durable at relieving lower urinary tract symptoms (average improvement in symptom score at 16 months is 10-18 points from baseline), it carries measurable risks.88 Specifically, men undergoing TURP are at risk of dilutional hyponatraemia, which occurs when irrigant solution is absorbed into the bloodstream during surgery. The incidence of this so called TURP syndrome in contemporary case series is between 0.8% and 1.4%.89 Other complications that have been reported in more than 5% of patients include erectile dysfunction, contracture of the bladder neck, need for blood transfusion, urinary tract infection, and hematuria.90 Although bipolar resection abrogates many of these complications,91 newer procedures have been developed (discussed below), some of which do not require a general anesthetic and can be carried out in an outpatient setting with few adverse events.
Minimally invasive surgical therapy
Transurethral needle ablation
During this procedure, low level radiofrequency energy is directly applied to prostate tissue to produce selective necrosis.92 A recent systematic review identified nine studies that compared transurethral needle ablation (TUNA) with TURP.93 Although TUNA significantly improved symptom scores (−12.6 points at one year follow-up, −14.0 to −11.4; P<0.001) and quality of life scores (−2.6 points at one year follow-up, −3.0 to −2.2; P<0.001) over baseline, it was not as effective as TURP with regard to these subjective measures. The difference in means at one year follow-up was 3.7 points (2.1 to 5.3) for studies reporting symptom scores and 0.6 points (0.1 to 1.2) for studies reporting quality of life scores, with both favouring TURP. TURP was also associated with greater improvements in peak urinary flow rates and post-void residual urine. The difference in means at one year follow-up was −5.9 mL/s (−7.7 to −4.1) for studies reporting peak urinary flow rates and 25.0 mL (20.9 to 29.1) for studies reporting post-void residual urine, with both favouring TURP. Furthermore, the efficacy of TUNA declines in the long term, as shown by a significantly higher retreatment rate than for TURP (10% v 1%).
Transurethral microwave thermotherapy
Transurethral microwave thermotherapy (TUMT) heats prostate tissue to 45-60°C.94 A systematic review identified 15 studies that included comparisons of this technique and TURP, sham procedures, and α adrenoceptor antagonist monotherapy.95 Pooled analyses showed that TUMT was an effective alternative to treatment with an α adrenoceptor antagonist for BPH in men with no history of retention or prostate surgery. At six month follow-up, men treated with TUMT had significantly greater symptom relief, as measured by IPSS, than those on terazosin (weighted mean difference −4.20 points, −5.25 to −3.15). However, TURP provided greater improvements in symptom score and flow rate, as well as a reduced need for retreatment compared with TUMT. The weighted mean difference for four studies reporting IPSS at follow-up was −1.00 points (−2.03 to 0.03) and 5.08 mL/s (3.88 to 6.28) for peak urinary flow rate, with both favouring TURP.
Prostatic urethral lift
Several other minimally invasive, parenchymal sparing approaches have been developed.96 97 Prostatic urethral lift is one such approach that has shown promising results. Under cystoscopic guidance, prostatic urethral lift consists of transurethral placement of suture based implants that mechanically hold the lateral prostatic lobes apart.98 A recent review conducted by the UK National Institute for Health and Care Excellence suggests that this approach is safe and efficacious for the treatment of lower urinary tract symptoms.99 However, patient selection is important, and prostatic urethral lift should not be regarded as a substitute for surgery.
Laser prostatectomy
To lessen surgical morbidity, a variety of laser procedures have also been developed. The first was visual laser ablation of the prostate.100 101 Because patients who underwent this procedure often developed long term dysuria and retention, it quickly fell out of favor.
The holmium laser was introduced next.102 103 Its wavelength penetrates less than 500 μm into tissue and is highly absorbed by water. Although the holmium laser can vaporize tissue, it is more commonly used to enucleate the prostate adenoma.
Photoselective vaporization of the prostate has also been described.104 This approach is based on potassium titanyl phosphate laser energy, the wavelength of which is in the visible green spectrum. The newest surgical laser is the thulium laser. With tunable wavelength between 1.75 μm and 2.22 μm, the thulium laser allows for tissue vaporization or cutting.105
The holmium, potassium titanyl phosphate, and thulium laser procedures provide similar improvement in symptoms and quality of life to TURP.106 107 108 These laser procedures are also associated with less blood loss than traditional TURP.106 107 108 This allows for earlier hospital discharge after surgery, shortening the average length of stay by about one day. Their improved hemostatic properties might offer particular advantages for men who are taking anticoagulants and those with cardiac or renal disease, given that the requirement for bladder irrigation during and after surgery is reduced and hemoglobin levels maintained.
A recent analysis of national Medicare data highlights the growing popularity of these newer procedures.109 Between 1999 and 2005, the total number of BPH directed procedures rose by 44%. Minimally invasive surgical therapies (TUNA and TUMT) and laser procedures increased by 529% during the same period. Collectively, they account for 57% of all BPH surgical procedures, whereas traditional TURP accounts for only 39%. Almost all TUMT and 86% of TUNA procedures are performed in the physician’s office. More than three quarters of laser procedures are carried out on an outpatient basis.
Looking ahead
Botulinum neurotoxin type A
Until recently, botulinum neurotoxin type A was considered a possible alternative to surgical intervention for men with medical refractory lower urinary tract symptoms secondary to BPH. This toxin has multiple urological indications, including treatment of neurogenic and idiopathic detrusor overactivity.110 111 When administered intraprostatically, it is thought to induce prostate apoptosis, leading to prostate atrophy and size reduction; inhibit sensory neurons in the prostate and reduce afferent signals to the central nervous system; and relax prostate smooth muscle cells.112 113
Most studies on botulinum neurotoxin type A injection therapy have been non-experimental.114 One small randomized double blind placebo controlled trial suggested that the toxin was superior to saline injection with respect to symptom and urinary flow rate improvement, as well as post-void residual urine and prostate volume reduction.115 Buoyed by these findings, a larger trial was launched by the drug company Allergan.116 However, it found that the toxin was no more efficacious than sham injection. The development of botulinum neurotoxin type A injection therapy for refractory lower urinary tract symptoms has therefore been discontinued.
Drugs that inhibit fibrosis
Fibrosis may be another therapeutic target for the management of lower urinary tract symptoms. Fibrogenesis is recognized as a major cause of morbidity in chronic inflammatory diseases.117 118 Chronic inflammation has been noted in several histological studies of the prostate, and some data suggest that chronic prostatic inflammation may contribute to the development of lower urinary tract symptoms. Specifically, raised collagen content, higher levels of inflammation and fibrocytes, increased tissue stiffness, and reduced levels of elastin and glandularity characterize periurethral prostate tissue in men with moderate to severe lower urinary tract symptoms.119
Thus, for men who do not respond to, are intolerant of, or become refractory to current drug treatments, drugs that inhibit fibrosis may prove useful. Transforming growth factor β1 is a multifunctional cytokine with many regulatory activities, including cell proliferation and migration, inflammation, and fibrosis. Given its central role in fibrosis, antagonists of transforming growth factor β1 are potential candidates. Several large and small molecule drugs that inhibit this growth factor are currently being tested in trials for patients with fibrotic diseases and, perhaps, lower urinary tract symptoms in the future.120
Guidelines
The AUA and the European Association of Urology (EAU) have released BPH guidelines.38 39 In patients who present with complicated lower urinary tract symptoms (suspicious digital rectal examination, hematuria, abnormal PSA, painful urination, recurrent urinary tract infection, palpable bladder, or neurological disease), guidelines recommend consulting a urologist, who will have access to evaluations beyond those recommended as a part of basic management.
For men with uncomplicated lower urinary tract symptoms and little or no bother, education about the condition, reassurance that cancer is not a cause of the symptoms, and periodic monitoring are all that are needed.
In men with bothersome uncomplicated lower urinary tract symptoms, the AUA recommends screening for polyuria (≥3 L urine/24 h) with a frequency volume chart. If polyuria is present, then fluid intake should be reduced (goal 1 L urine/24 h). Predominant nocturnal polyuria (>33% of the 24 hour urine output occurs at night) also warrants fluid restriction and consideration of causes other than BPH (such as obstructive sleep apnea). Drugs for treating BPH (table) and other treatments, such as desmopressin, can also be prescribed.
In men who have bothersome uncomplicated lower urinary tract symptoms without polyuria, clinicians should initially consider modifiable factors, including concomitant drug use (such as diuretics) and behaviors such as physical inactivity, excess alcohol intake, and consumption of irritative foods). Men should be advised to void before sleep or long trips or meetings. If pharmacotherapy is needed, the AUA and EAU recommend monitoring the patient to assess treatment success and adverse effects. The time to treatment assessment depends on the drug prescribed (table). For successfully treated patients, annual follow-up is recommended. Treatment failure and symptom progression warrant referral.
Conclusion
Lower urinary tract symptoms are common in older men. They are often bothersome and can greatly reduce quality of life. Most men can be evaluated and successfully treated by targeted symptom control, with the primary goal of reassurance and improvement in symptoms.
In men with mild to moderate symptoms, lifestyle approaches may be sufficient. For those in whom conservative measures are unsuccessful, an α adrenoceptor antagonist, possibly combined with a 5α reductase inhibitor (especially for men with large prostates) or an antimuscarinic drug, can improve symptoms within one to three months. Furthermore, pharmacotherapy can slow down the long term progression of disease (when an α adrenoceptor antagonist and 5α reductase inhibitor are combined), including acute urinary retention. Additional surgical and minimally invasive procedures provide a larger and often durable response. They are mainly indicated for men with more severe symptoms or those who do not adequately respond to pharmacotherapy. There is no clear evidence that raised post-void residual urine alters the effectiveness of treatment. The use of additional testing, including detailed physical and neurologic examination, PSA, and urodynamic testing, is rarely indicated in primary care. The use of these strategies can provide high value patient care.
Future research questions
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What is the optimal management approach in men with asymptomatic chronic urinary retention as a result of benign prostatic hyperplasia?
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What is the role and impact of the placebo response, especially in men taking herbal treatments with little adverse effect?
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Is the combination of a phosphodiesterase type 5 inhibitor and an α adrenoceptor antagonist efficacious in men with lower urinary tract symptoms?
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Are fibrosis inhibitors useful in the treatment of lower urinary tract symptoms?
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Does treatment for lower urinary tract symptoms affect falls, fracture, and other outcomes in elderly men?
Notes
Cite this as: BMJ 2014;349:g4474
Footnotes
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Contributors: Both authors conceived the idea; contributed intellectual content; acquired and analyzed evidence; and wrote, reviewed, and edited the manuscript.
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Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: Funding from the Agency for Healthcare Research and Quality (1K08HS020927-01A1 to JMH).
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Provenance and peer review: Commissioned; externally peer reviewed.