Benign Prostatic Hyperplasia (BPH)
Conventional BPH treatments typically depend on the severity of the patient’s symptoms. In men with mild or asymptomatic BPH, watchful waiting is appropriate, which includes an annual physical examination and completion of the AUASI (Sarma 2012).
Pharmacological treatment options can be employed for men who have moderate-to-severe (AUASI score ≥ 8) and/or bothersome symptoms after consideration of the risks and benefits (Sarma 2012). Currently, four different classes of medications and/or surgery are used to treat BPH.
α1-adrenergic receptor blockers
- Increased smooth muscle tone in the prostate is responsible, at least in part, for some of the urinary symptoms associated with BPH (McNicholas 2008). Smooth muscle tone is regulated by α1-adrenergic receptors, which respond to levels of certain hormones in the body. One BPH treatment option includes α1-adrenergic receptor blocker medications, since the α1A subtype of these receptors is thought to be the main regulator of smooth muscle tone in the neck of the bladder and prostate (Nickel 2008a). Treatment with α1-adrenergic receptor blockers is generally considered first-line therapy for symptomatic BPH (Elterman 2012), even though some of these drugs were initially developed as high blood pressure treatments (Nickel 2008a).
- There are many different α1-adrenergic receptor blockers, and the four most prescribed – alfuzosin (Uroxatral®), terazosin (Hytrin®, Zyasel®), doxazosin (Cadura®, Carduran®), and tamsulosin (eg Flomax®) – all effectively increase urinary flow rate and relieve BPH symptoms. However, these medications also have side effects, such as low blood pressure and dizziness, although tamsulosin may have a reduced risk of these side effects (Nickel 2008a). Furthermore, these medications do not prevent BPH progression and are usually only effective for up to 4 years (Elterman 2012).
- Medications in the 5-α-reductase inhibitor class block the conversion of testosterone to dihydrotestosterone, helping to shrink the prostate and prevent further growth.
- Finasteride (eg, Proscar®, Propecia®) and dutasteride (Avodart®) are two FDA-approved 5α-reductase inhibitors. Both medications are capable of reducing prostate size by as much as 25% and can reduce AUASI scores by 4–5 points in men with large prostates (Sarma 2012). Combining α1-adrenergic receptor blockers with 5α-reductase inhibitors may increase the benefits for men with BPH (Azzouni 2012).
- Medications in the 5α-reductase inhibitor class are associated with significant sexual side effects, including decreased libido, impotence, reduced ejaculate volume, and problems with ejaculation (Sarma 2012; Azzouni 2012). In addition, some men experience breast enlargement and tenderness. Although sexual side effects associated with 5α-reductase inhibitors tend to decrease over time (Azzouni 2012), some men experience persistent diminished libido, erectile dysfunction, and depression when using these drugs (Traish 2011).
- Some important considerations should be taken into account when choosing between finasteride and dutasteride in the management of BPH. First, there are 2 variants (ie, isoforms) of the 5α-reductase enzyme – type 1 and type 2; both are present in prostate tissue. However, evidence suggests that the type 1 isoform may be more active in malignant prostate tissue (Thomas 2008). This is significant because dutasteride inhibits both type 1 and 2 isoforms, whereas finasteride inhibits only type 2. This means that dutasteride may more effectively control growth of cancerous tissue than finasteride. Since several studies suggest the two drugs confer similar benefits and risks in BPH, dutasteride appears to be a better choice as it might also provide some cancer protection (Fenter 2008; Choi 2010; Nickel 2011; Festuccia 2008; Makridakis 2005).
- Many men with BPH also have an overactive bladder, which can cause symptoms such as urinary urgency and incontinence (Elterman 2012). Antimuscarinic drugs block muscarininc receptors in the detrusor muscle. This muscle contracts and squeezes the bladder to facilitate urination, and remains relaxed otherwise, allowing the bladder to stretch and fill. Activation of muscarininc receptors stimulates contraction of the detrusor muscle. Pharmacologic blockade of these receptors decreases the incidence of overactive-bladder symptoms of BPH (Sarma 2012).
- Many antimuscarinic drugs have been approved to treat symptoms of overactive bladder, including darifenacin (Enablex®), tolterodine (eg, Detrol®), fesoterodine (Toviaz®), trospium chloride (Sanctura®), oxybutynin (Ditropan®), and solifenacin (Vesicare®) (Sarma 2012). Combining antimuscarinic medications with α-adrenergic blockers can improve BPH symptoms, particularly the number of times patients need to urinate during the day and night as well as episodes of urinary urgency (Borawski 2011). However, there is insufficient evidence that these medications are effective when used as a single therapy for individuals with predominantly storage problems (Sarma 2012).
- One concern with these medications is that they can cause increased urinary retention, although studies in men with good emptying (post-voiding residual urine volume less than 250 mL) have not identified any adverse effects associated with urinary retention. However, caution should be used in men with incomplete bladder emptying (Borawski 2011). Common side effects associated with these medications include dry mouth, dry eyes, and constipation (Sarma 2012).
- Men with lower urinary tract symptoms sometimes experience erectile dysfunction, which has led some researchers to speculate that the two symptoms may be linked (Roumeguere 2009). Phosphodiesterase inhibitors are used to treat erectile dysfunction, but may also relieve lower urinary tract symptoms in men with BPH (Sarma 2012).
- These medications may work via several mechanisms. One postulated mechanism is that phosphodiesterase-5 inhibitors block a signaling pathway that causes smooth muscle contraction. They may also increase levels of nitric oxide, a compound that relaxes smooth muscles in the lower urinary tract. They have also been proposed to decrease hyperactivity of the autonomic nervous system affecting the bladder, prostate, and penis (Laydner 2011).
- A comprehensive review found that phosphodiesterase-5 inhibitors alone effectively treat lower urinary tract symptoms and erectile dysfunction, and that treatment with both phosphodiesterase-5 inhibitors and alpha-blockers leads to a small improvement in flow rates in men with BPH. This class of medication may even be effective in patients without erectile dysfunction (Gacci 2012). Tadalafil (Cialis®) is the only medication of this class that has been approved by the Food and Drug Administration (FDA) for treating urinary symptoms. It can cause headaches, flushing, indigestion, back pain, and nasal congestion, and may lead to low blood pressure when combined with α1-adrenergic blockers or organic nitrates (eg, nitroglycerin) (Sarma 2012).
BPH can also be treated surgically. The purpose of surgery is to either remove the prostate or reduce its size, thereby relieving the lower urinary tract symptoms.
Two minimally invasive treatments — transurethral needle ablation of the prostate and transurethral microwave thermotherapy — have been developed to treat BPH, although there is some uncertainty regarding which patients will respond well, and more studies need to be done to evaluate the effectiveness of these treatments. More invasive procedures can be used for patients with moderate-to-severe symptoms of BPH, particularly for patients who have not responded to pharmacologic therapy (McVary 2011).
Transurethral protastectomy (TURP), a procedure in which the prostate is endoscopically removed, is the benchmark surgical therapy for BPH (McVary 2011). Endoscopic procedures involve insertion of fine surgical and viewing devices directly into the patient’s body through small incisions; this type of surgery is less invasive than traditional “open” surgery. However, approximately 14% of men who undergo TURP will become impotent (Roehrborn 1999). This procedure can also cause transurethral prostatectomy syndrome, a serious complication in which fluid used to irrigate the surgical area enters the intravascular space. This can result in cardiopulmonary (heart and lung) complications (eg, high or low blood pressure, slow heart rate, irregular heartbeat, respiratory distress, shock), hematologic and renal (blood and kidney) systems (eg, excess ammonia in the blood, electrolyte disturbance, anemia, acute renal failure), and the central nervous system (eg, nausea/vomiting, confusion/restlessness, blindness, twitches/seizures, lethargy/paralysis, dilated/nonreactive pupils, coma), as well as death (Gravenstein 1997). Other complications include voiding failure, urinary tract infections, and bleeding during or after surgery (Reich 2008).
Men with very large prostates may benefit from an open prostatectomy, in which the entire prostate is removed, but this treatment can result in significant blood loss, incontinence, impotency, pain, and longer hospital stays (McVary 2011).
Transurethral laser therapy is another surgical option that is gaining momentum. This treatment option may reduce the length of stay in the hospital, although more information regarding the safety of this therapy is needed (McVary 2011). The adoption of laser-based operations for BPH has led to more cases of BPH being treated surgically (Schroeck 2012).
Intraprostatic botulinium toxin injections – an emerging BPH therapy
Botulinum toxin is a bacteria-derived neurotoxin that relaxes muscles by preventing certain neurotransmitter (acetylcholine) signals. Since lower urinary tract symptoms are attributable in part to excessive smooth muscle contraction around the bladder and prostate in men, scientists have hypothesized that injecting botulin toxin directly into the prostate may relax those muscles and relive some urinary symptoms (Mangera 2010).
In a preliminary trial, 10 men with lower urinary tract symptoms suggestive of BPH received intra-prostatic injections of botulinum toxin. Significant improvements were noted, including a nearly 50% reduction of urinary symptoms assessed by a standardized assessment, a significant reduction in PSA levels and prostate volume, and a 42% reduction in frequency of nighttime urination. The investigators in this study concluded that “[i]ntraprostatic injection of Botulinum-A may be an effective and safe treatment for symptomatic BPH in selected patients whose medical treatment has faced failure and are poor surgical candidates” (Hamidi Madani 2012). Another similarly designed study on 10 men with BPH demonstrated similar efficacy: “Intraprostatic [purified botulinum neurotoxin] injection induces prostate shrinkage and is effective in men with BPH” (Yokoyama 2012). A slightly larger study (34 men with BPH who failed medical treatment) published in September 2012 reported very similar findings (Arnouk 2012).