Optimizing the management of benign prostatic hyperplasia

Abstract

One of the challenges facing primary care physicians and specialists as the population ages is the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). While as many as 18% of men in their 40s report bother from an enlarged prostate, that figure rises dramatically, whereby 50% of men in their 50s and 90% of men in their 90s will complain of bothersome symptoms related to an enlarged prostate. Studies have shown that BPH is a progressive disease, which if left untreated can result in worsening of symptoms, acute urinary retention and renal failure. Until about 20 years ago the only management option available to urologists was surgery. In the early 1990s medical therapy emerged as the predominant treatment for BPH. Therapy may be tailored to target symptoms and progression of disease.

Introduction

One of the challenges facing primary care physicians and specialists as the population ages is the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). While as many as 18% of men in their 40s report bother from an enlarged prostate [Bushman, 2009] that figure rises dramatically, whereby 50% of men in their 50s and 90% of men in their 90s will complain of bothersome symptoms related to an enlarged prostate [Jacobsen et al. 2001].

Studies have shown that BPH is a progressive disease, which if left untreated can result in worsening of symptoms, acute urinary retention and renal failure [Jacobsen et al. 2001; Marks et al. 2006, Barkin, 2011a]. Until about 20 years ago the only management option available to urologists was surgery. In the early 1990s medical therapy emerged as the predominant treatment for BPH [McConnell et al. 1998]. Therapy may be tailored to target symptoms and/or progression of disease [Kaplan, 2006b].

Today, we have better defined the condition and the accepted factors to predict who is at risk for disease progression. Benign prostatic enlargement (BPE) is defined as a prostate volume (PV) >30 cm³ [Djavan et al. 2004]. Markers to assess risk of progression include age over 50 years, serum prostate-specific antigen (PSA) >1.4 ng/ml, PV >30 cm³, and ‘moderately’ severe symptoms as measured by validated questionnaires [moderate International Prostate Symptom Score (IPSS) symptom score >8]. Using these parameters one can identify the patient for whom early introduction of medical therapy may prevent the worsening of symptoms and need for surgery [Barkin, 2011a].

Overactive bladder (OAB) is another clinical entity, which manifests itself in LUTS. There can be significant overlap in the presentation of men with BPH and OAB. Many men will in fact have both conditions. Hyman and colleagues showed that 43% of older men with LUTS had detrusor overactivity, not BPE [Hyman et al. 2001]. OAB should be kept in the differential diagnosis in men presenting wit LUTS, as it is treated with an entirely different class of drugs, anticholinergics (AChs).

Definitions

BPH refers to the microscopic proliferation of prostatic gland smooth muscle and epithelium, most notably in the transition zone. BPH is in fact an asymptomatic histologic diagnosis. The resulting growth of the prostate gland may lead to the clinical or sonographic manifestation of BPE.

LUTS occur when men experience disturbances to their urinary flow, either in the form of storage symptoms (i.e. nocturia, frequency, urgency) or voiding symptoms (i.e. hesitancy, intermittency, weakened stream). Bearing these definitions in mind, the majority of literature on this subject refers to the LUTS complex generically as ‘BPH’. OAB is defined as a syndrome including urinary urgency with or without incontinence, urinary frequency and nocturia.

Pathophysiology

Prostate hyperplasia and resulting enlargement causes its impact through direct bladder outlet obstruction and/or increased smooth muscle tone at the bladder neck and in the prostatic capsule leading to increased resistance. The enlarged prostate results in compression or narrowing of the prostatic urethra affecting urinary flow. OAB is characterized by the inability to hold increasing volumes of urine, with increased sensations of urgency and frequency, often accompanied by uninhibited detrusor contractions.

Background

The physician treating a man with BPH is faced with several dilemmas. How does one quantify LUTS? How does one choose which patient needs which intervention? Many men with clinically enlarged prostates have little in the way of symptoms, whereas many men experience severe bother from their symptoms despite clinically or sonographically small glands.

Barry and colleagues suggested a simple, validated questionnaire to assess both storage and voiding symptoms, which could be used to quantify LUTS and assess response to treatments [Barry et al. 1995]. The IPSS is the most widely used questionnaire, categorizing patients into ‘mild’ symptoms (score 0–7), ‘moderate’ symptoms (score 8–20), and ‘severe’ symptoms (score 21–35). An additional eighth question assesses quality of life (QoL).The question is ‘If you were to maintain the symptoms that you are experiencing today for the rest of your life, how would you feel about it?’ The answers range from delighted (score of 0) to terrible (score of 6). Many refer to this particular measure as the ‘bothersome index’. The American Urological Association Symptom Index (AUA-SI) is a similar questionnaire, using the same questions, domains and scores to assess LUTS/BPH. The sum total of these validated questionnaires allows the clinician to quantify symptoms at baseline, over time and in response to treatment [Kaplan, 2006b].

Evaluation

Patients will often initially present to their clinician with the complaint of LUTS, notably nocturia, frequency, urgency, weakened stream, hesitancy, intermittency, straining, and a sense of incomplete emptying. Occasionally, the first presentation of BPH will be an episode of acute urinary retention (AUR). The clinician must be able to identify LUTS in men who often do not seek medical attention for fear of the treatments, embarrassment by their symptoms or the belief that urinary changes are part of the aging process [Abrams et al. 2009].

The evaluation of BPH should always include a detailed medical history, including assessment of LUTS, severity and bother using a validated questionnaire. A focused physical exam should follow. An abdominal exam will assess for masses, tenderness and a palpable bladder. A brief neurological screen should assess mental capacity, ambulation and stigmata of neurological conditions with symptoms that may resemble BPH. Physical examinations should always include digital rectal examination (DRE), urinalysis, and PSA in men whose life expectancy is more than 10 years and if the diagnosis of cancer can modify the management. A frequency/volume chart may be helpful in men whose predominant symptom is nocturia [McVary et al. 2011]. The DRE aids in the detection of prostate cancer, assessment of PV and assesses neurologic function with anal sphincter tone. DRE alone is insufficient to fully assess PV therefore PSA is used as a surrogate. Studies have shown that a PSA of 1.5 ng/ml corresponds to a volume of approximately 30 cm³ [Barkin, 2011b]. Optional evaluative measures, which may aid in treatment decision making, include uroflometry, postvoid residual ultrasound, and renal ultrasound to rule out hydronephrosis. They are, however, not required prior to the institution of medical therapy.

Watchful waiting

Treatment algorithms have been proposed by the various specialty societies of urology (AUA, Canadian Urological Association, European Association of Urology). They all rely on prostate size, BPH symptoms and degree of bother as the factors steering treatment decision making. According to the AUA, patients with mild degrees of bother (IPSS < 8) and small glands or patients with moderate to severe symptoms (IPSS ≥ 8) who are not bothered by their LUTS may be managed expectantly with watchful waiting (active surveillance) and lifestyle modifications. These measures may include timed voiding or decreased fluid intake. Avoiding certain spicy foods and fluids containing caffeine, stopping smoking, treating constipation, reducing doses of drugs that affect the bladder adversely (i.e. antihistamines) and ‘bladder training’ may all improve LUTS. If significant bothersome symptoms persist despite conservative measures, the initiation of medical management is indicated [McVary et al. 2011].

Medical management

Three main classes of pharmacotherapy exist for the treatment of LUTS secondary to BPH: α-adrenergic antagonists (α-blockers), 5-α reductase inhibitors (5-ARIs) and AChs.

The components of BPH obstruction are divided between ‘fixed’ and ‘dynamic’. The ‘fixed’ portion relates to the growth of prostate tissue that narrows the urethral lumen. The ‘dynamic’ portion is caused by stimulation of α receptors in the smooth muscle at the bladder neck and within the prostate. α-blockers act by decreasing the smooth muscle tone at the bladder neck and inside the prostate. 5-ARIs work by preventing the conversion of testosterone to the more potent dihydrotestosterone, thereby reducing PV [Barkin et al. 2009; Roehrborn et al. 2008]. AChs act by decreasing detrusor overactivity by altering contractility or sensation.

Monotherapy using α-blockers is considered first-line therapy in the treatment of symptomatic BPH. The male prostate and urethra contain α1 receptors with the α1a subtype being the most prevalent. α-Blockers, including doxazosin, alfuzosin, tamsulosin, terazosin and silodosin, are all felt to be similarly efficacious but may have different side-effect profiles. Tamsulosin and silodosin are both α1a-selective adrenergic blockers. Typical side effects, experienced in approximately 5–9% of patients, include postural hypotension, dizziness, rhinitis, asthenia, sexual dysfunction and abnormal ejaculation [Debruyne, 2000; Debruyne et al. 2004]. The major feature of α blockers is that a patient’s symptoms usually resolve very quickly. Improvements in storage and voiding symptoms can improve within 24 h and not longer than 7 days. α-Blocker monotherapy does not prevent the progression of BPH and men on α-blockers can expect a durable response for only up to 4 years.

5-ARIs act by blocking the conversion of testosterone to its metabolite, dihydrotestosterone (DHT). DHT is the active hormone that, when absorbed into the prostate, leads to its cellular and glandular (stromal) growth. After 3–6 months, when DHT absorption into the prostate has been reduced, the prostate shrinks and symptoms of BPH improve [McConnell et al. 1998]. The 5α reductase enzyme has two isoenzymes, type 1 and type 2, which have different concentrations in benign and malignant prostate cells. Finasteride (Proscar, Merck Pharmaceuticals, Quebec, Canada) inhibits only the type 2 receptors whereas dutasteride (Avodart, GlaxoSmithKline, Ontario, Canada) inhibits both the type 1 and type 2 receptors. The additional inhibition results in a greater reduction of DHT by dutasteride compared with finasteride (95% versus 71% reduction) [Clark et al. 2004]. Both finasteride and dutasteride have been shown to reduce the risk of acute urinary retention and the need for prostate surgery [Kaplan, 2006a]. The side effects of 5-ARIs include gynecomastia, decreased libido and erectile dysfunction.

AChs, also known as antimuscarinics, are the first-line pharmacologic treatment of OAB and detrusor overactivity. Their mechanism of action involves competitively blocking cholinergic/muscarinic receptors in the detrusor muscle, preventing their activation by acetylcholine released from presynaptic parasympathetic cholinergic nerves [Andersson, 2011]. In bladder outlet obstruction, demonstrated in both animal and human models, there is reduced detrusor response to intramural nerve stimulation but supersensitivity to acetylcholine [Sibley, 1984; Harrison, 1987]. The supersensitivity may be due to partial detrusor denervation resulting in detrusor overactivity. There exists significant overlap between the LUTS experience by men as a result of bladder outlet obstruction and OAB, particularly frequency, urgency and urgency incontinence. Studies have shown significant improvements in frequency, nocturia, AUA-SI scores, peak urinary flow rate, urgency, and urgency incontinence episodes in men with BPH treated with an ACh as monotherapy or in combination with an α-blocker [Kaplan et al., 2005, 2006; Lee et al., 2004].

Combination therapy

While α-blocker and 5-ARI monotherapy were used as treatment for LUTS/BPH, it was hypothesized that together they could work synergistically to provide early relief from symptoms and long-lasting prevention of progression. The best early long-term study to suggest the benefit of combination therapy was the Medical Therapy of Prostate Symptoms (MTOPS) trial. The trial objective was to determine if therapy with doxazosin (α-blocker), finasteride (5-ARI) or a combination could prevent BPH disease progression, defined as an increase in AUA-SI of more than four points, AUR, incontinence, renal insufficiency or recurrent urinary tract infections. Over a mean duration of 4.5 years, 3047 men were randomized to four arms (doxazosin, finasteride, placebo, combination therapy). The results demonstrated a 67% risk reduction in progression of disease in the combination arm compared with placebo. The combination arm also had a 66% risk reduction in developing AUR or the need for surgery compared with placebo. The monotherapy arms of doxazosin and finasteride both showed reduced risk of clinical progression (39% and 34%) compared with placebo, but the effect was not as robust as the combination arm. When patients were stratified according to PV, there was no benefit of combination therapy compared with monotherapy when prostate glands were <25 cm³. However, moderate sized (25–40 cm³) and larger glands (>40 cm³) did have a significant benefit with combination therapy over monotherapy [McConnell et al. 2003].

The compelling results of the MTOPS trial led researchers to develop the Combination of Avodart and Tamsulosin (CombAT) trial. Dutasteride demonstrated effectiveness in men with BPH compared with placebo and was known to have greater reductions in DHT compared with finasteride due to its dual action on type 1 and type 2 alpha reductase (AR) receptors. Tamsulosin was the most uro-selective α-blocker, which provided maximum therapeutic effect with fewer side effects such as orthostatic hypotension. Hence, a long-term double-blinded randomized non-placebo-controlled trial investigating the effects of dutasteride, tamsulosin and combination therapy in men with LUTS secondary to BPH was initiated. Men in the trial were considered more ‘at risk’ of BPH progression. The average PV in all three arms was 55 ml at baseline and the average PSA was 4.0 ng/ml. A total of 4844 men with moderate to severe LUTS (IPSS ≥ 12) and PV >30 ml were randomized for 4 years. The protocol was designed for 2- and 4-year analysis. The primary endpoint was the change in the IPSS responders’ scores from baseline comparing combination with the active treatment of tamsulosin at 2 years and reduction in risk of AUR or surgery at 4 years, and the improvement in the QoL scores reported by the patients [Barkin et al. 2009; Roehrborn et al. 2008].

For the first time a question was asked concerning ‘Patients’ perception of the study medication’ (PPSM). This was developed to assess whether or not if given the choice and knowing the side effects and benefits, a patient would choose to take that combination of medications and to be compliant in the long term [Barkin, 2011b].

In the first 3 months of the CombAT trial the slopes of the symptom response were identical for tamsulosin and combination therapy. However, at 15 months patients treated with dutasteride monotherapy achieved a better symptom response compared with patients treated with tamsulosin.

This was the first time ever that a combination trial had shown patients with BPH achieving better symptom response with a 5-ARI compared with an α-blocker. However, it should be emphasized that this was a select population, that is, men with PV of at least 30 ml. One should be cautious in extrapolating these results in men with PV <30 ml, which in MTOPS represented almost half of the men in the study. At 4 years, symptom improvement was statistically superior to that of patients in both monotherapy arms. The risk reduction of AUR was 66% with combination therapy compared with the active treatment tamsulosin arm. This result was the same as the risk reduction of AUR in the MTOPS trial except that trial compared combination therapy with placebo.

As previously noted in 5-ARI trials, there was a 50% reduction in serum PSA in the patients treated with a 5-ARI by 6 months of therapy, whereas α-blockers have no effect on serum PSA. This 50% PSA response has now become the expected response, assuming that there is no significant underlying prostate cancer.

The CombAT trial demonstrated that for men over the age of 50 with an enlarged prostate and moderate symptoms, the combination of dutasteride and tamsulosin compared with monotherapy will provide effective and durable long-term benefit [Barkin, 2011a]. This benefit was shown in all outcome measures including symptom response, lack of progression, development of AUR and need for surgery. The results of both MTOPS and CombAT suggest that long-term combination therapy with an α-blocker and 5-ARI is the optimal therapy to prevent progression of BPH symptoms, urinary retention and the need for surgery compared with monotherapy. Healthcare professionals will need to assess and rely on their definitions of what PV constitutes the most appropriate patient for combination therapy.

Symptoms of OAB (urgency, frequency) are managed using ACh medications, which inhibit detrusor overactivity. AChs have been demonstrated to improve bladder capacity, increased volume at first detrusor contraction and maximum cytometric capacity [Abrams et al. 2006]. They did not show increased risk of urinary retention or worse side effects compared with placebo. The most bothersome and common side effects of all AChs typically include dry mouth and constipation.

Many patients will have persistent symptoms of OAB after treatment with α-blockers and 5-ARIs for BPH. In this situation, the addition of an ACh medication as combination therapy is safe and effective. In 2005 Kaplan et al. reported an open-label prospective study evaluating the safety and efficacy of extended-release tolterodine in men whose LUTS had failed to respond to α-blocker therapy. At 6 months, the mean 24 h micturition frequency and nocturia had decreased and improvements were seen in both IPSS and post-void residual volume [Kaplan et al. 2005, 2008]. Another large randomized, double-blind, placebo-controlled trial comparing tolterodine extended release, tamsulosin, combination therapy and placebo in patients who had symptoms of BPH and OAB was completed. Patients in the combination arm had significant reduction in urgency urinary incontinence, urgency without incontinence, total number of 24 h micturitions, micturitions per night, total IPSS, and IPSS QoL score compared with placebo [Kaplan et al. 2008].

It had been reported anecdotally that patients taking certain phosphodiesterase type 5 inhibitors (PDE5) for the treatment of erectile dysfunction also experienced an improvement in irritative voiding symptoms, such as frequency and urgency, but not uroflow rates. Based on these reports, a 12-week and then a 1-year extension study were conducted comparing daily tadalafil 5 mg (Cialis, Eli Lilly, Ontario, Canada) with placebo in the management of BPH/LUTS symptoms when there was no significant obstruction [Donatucci et al. 2011]. Based on the study data, the US Food and Drug Administration (FDA) recently approved daily tadalafil (5 mg) for the treatment of LUTS secondary to BPH with or without simultaneous erectile dysfunction.

Many patients are interested in complementary and alternative medicines for the management of BPH/LUTS. There is no evidence to suggest that dietary supplements, namely saw palmetto plant (Serenoa repens) or stinging nettle (Urtica dioica) have any therapeutic effect on LUTS. The recent double-blind, multicentre, placebo-controlled randomized trial by the CAMUS study group failed to demonstrate reductions in LUTS with increasing doses of saw palmetto compared with placebo. The AUA does not recommend any dietary supplement, combination phytotherapeutic agent or other nonconventional therapy for the management of BPH/LUTS [McVary et al. 2011].

Surgical

There remain several indications to proceed to surgical intervention, forgoing a trial of conservative or medical management. The AUA recommends surgery in patients who report recurrent gross haematuria of prostatic origin, recurrent urinary tract infections, renal insufficiency secondary to BPH, bladder stones, LUTS refractory to other therapies and refractory urinary retention. Open prostatectomy is useful in men with moderate to severe LUTS with significant bother, especially in those with very large glands and coincident bladder stones. Transurethral resection of the prostate, transurethral laser enucleation of the prostate, transurethral incision of the prostate, transurethral vaporization of the prostate are all appropriate and effective treatments for men with moderate to severe LUTS, who have significant bother and enlargement of the prostate. All modalities are considered equivalent [McVary et al. 2011].

Recently, in Canada, Australia and the USA, another approach is under investigation. ‘Urolift’ is essentially multiple transurethrally placed prostate retraction stitches. After insertion of these stitches through the cystoscope, the prostate is literally pulled open from the inside. The sutures are placed distal to the bladder neck and proximal to the sphincter under local anesthetic, as an outpatient. The results have been encouraging and the FDA study remains ongoing [Woo et al. 2011].

Conclusion

The first-line therapy for men with significant LUTS regardless of prostate size remains α-blocker monotherapy. Men with significant symptoms of frequency, urgency, voiding symptoms and a PV >30 ml on transrectal ultrasound or a PSA level >1.5 ng/ml are at high risk of progression of disease. We would recommend combination therapy with an α-blocker and a 5-ARI for at least 9 months. If after taking combination therapy for 3 months there are persistent symptoms of frequency and urgency, we would add an ACh medication to treat symptoms of OAB. After 9 months, the 5-ARI should be exerting its maximal effect, therefore we would attempt to discontinue the α-blocker and monitor the patient clinically [Barkin et al. 2003]. If there are no changes, the ACh medication may be dose reduced or discontinued. If the patient notices a deterioration in voiding symptoms immediately after stopping the α-blocker then it can be resumed. If the patient has a durable improvement in LUTS, he could be maintained on 5-ARI monotherapy. If he still has frequency, urgency or other voiding symptoms as well as erectile dysfunction, then one could consider the addition of a daily PDE5 inhibitor. If medical therapy does not work or cannot be tolerated, then there are many alternative invasive and noninvasive options.

There are many options for the optimal management of symptomatic BPH that can be offered to the patient in an organized and logical manner to achieve the highest chance of success and patient satisfaction.